Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31](O)=[O:32])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)[OH:43])=[CH:38][C:37]=1[O:50][CH2:51][CH3:52].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:28])([F:27])[F:29])[CH2:23][CH2:22][C:21]([C:31]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([CH:42]([OH:43])[C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=5)=[CH:38][C:37]=4[O:50][CH2:51][CH3:52])=[O:32])=[CH:20][C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C(=O)C(F)(F)F)cc1
Reactant: CCOc1cc(C(O)c2ccccn2)ccc1N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)cc2OCC)CCN3C(=O)C(F)(F)F)cc1
Reaction time: 8 h
Yield: 68.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (500 mg), (4-amino-3-ethoxyphenyl)(2-pyridyl)methanol (320 mg) and 1-hydroxybenzotriazole monohydrate (210 mg) in DMF (15 ml) was added catalytic amount of 4-(N,N-dimethylamino)pyridine, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (263 mg) was added to the mixture and the mixture was stirred overnight under nitrogen atmosphere. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3), and was recrystallized from diisopropyl ether-ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[2-ethoxy-4-[hydroxy(2-pyridyl)methyl]phenyl]-1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxamide (504 mg) as yellow crystals.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=2)[CH:20]=1)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].O>ClCCl>[NH2:14][C:15]1[CH:20]=[C:19]([C:21]#[C:22][C:23]2[CH:24]=[C:25]([CH:26]=[CH:27][CH:28]=2)[C:29]#[N:30])[CH:18]=[N:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(C#Cc2cccc(C#N)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: N#Cc1cccc(C#Cc2cncc(N)c2)c1
Reaction time: 4 h
Yield: 88 %

Procedure:
Add trifluoroacetic acid (1 mL, 13.3 mmol) to a solution of [5-(3-cyanophenylethynyl)-pyridin-3-yl]-carbamic acid tert-butyl ester, prepared as described in EXAMPLE 125), (315 mg, 0.99 mmol) in dichloromethane (5 mL) and stir for 4 h. Add solid potassium carbonate to the reaction mixture until basic (pH=8) and then water to give a biphasic solution. Separate the layers, load the aqueous layer onto an ISOLUTE™ phase separator cartridge and wash the cartridge with dichloromethane (3×15 mL). Concentrate and purify the residue by silica gel chromatography, eluting with 25:75 to 0:100 with dichloromethane:ethyl acetate, to give the title compound (190 mg, 88%).
Reaction SMILES: [Br-].[Li+].[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:29][C:28]2[C@H:23]([CH2:24][CH2:25][C:26](=[O:30])[CH:27]=2)[C@@H:22]2[C@@H:13]1[C@H:14]1[C@@:18]([CH2:20][CH2:21]2)([CH3:19])[C:17](=[O:31])[CH2:16][CH2:15]1)(=[O:5])[CH3:4].O>C(#N)C.[Cu](Br)Br>[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:29][C:28]2[CH:27]=[C:26]([OH:30])[CH:25]=[CH:24][C:23]=2[C@@H:22]2[C@@H:13]1[C@H:14]1[C@@:18]([CH2:20][CH2:21]2)([CH3:19])[C:17](=[O:31])[CH2:16][CH2:15]1)(=[O:5])[CH3:4]
Reactant: CC(=O)OCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Agent: Br[Cu]Br
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Reaction time: 0.17 h
Yield: 73.8 %

Procedure:
17.8 g of lithium bromide and 92.83 g of copper(II) bromide are added to a solution of 82.3 g of 7α-(5-acetoxypentyl)-estr-4-ene-3,17-dione in 936 ml of acetonitrile at a bath temperature of 80° C. After 10 minutes at a bath temperature of 80° C., the reaction solution is cooled, mixed with water, extracted three times with ethyl acetate, the organic phase is washed with water and sodium bicarbonate solution and dried. The residue that is obtained after the concentration by evaporation is chromatographed on silica gel, and 60.4 g of 7α-(5-acetoxypentyl)-3-hydroxy-estra-1,3,5(10)-trien-17-one is obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:27][C:26]4[C:21](=[N:22][C:23](SC)=[N:24][CH:25]=4)[N:20]([CH3:30])[C:19]3=[O:31])[CH:15]=[CH:14][C:13]=2[F:32])=[O:10])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:48][NH2:49]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:27][C:26]4[C:21](=[N:22][C:23]([NH:49][CH3:48])=[N:24][CH:25]=4)[N:20]([CH3:30])[C:19]3=[O:31])[CH:15]=[CH:14][C:13]=2[F:32])=[O:10])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34]
Reactant: CSc1ncc2c(n1)N(C)C(=O)N(c1ccc(F)c(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c1)C2
Reactant: CN
Agent: O=C(OO)c1cccc(Cl)c1
Product: CNc1ncc2c(n1)N(C)C(=O)N(c1ccc(F)c(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c1)C2
Yield: 16 %

Procedure:
Using a procedure analogous to Example A2, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-methyl-7-(methylthio)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea was oxidized with mCPBA to the sulfone and then treated with methylamine to provide 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea (0.045 g, 16% yield). 1H NMR (400 MHz, DMSO-d6: δ 9.55 (s, 1H), 8.77 (s, 1H), 8.12 (d, J=2.5 Hz, 1H)), 8.09 (dd, J=8, 2.5 Hz, 1H), 7.96 (brs, 1H), 7.59 (m, 2H), 7.28 (dd, J=12.9 Hz, 1H), 7.01 (m, 2H), 5.74 (s, 1H), 4.58 (s, 2H), 3.28 (brs, 3H), 2.78 (d, J=5 Hz, 3H); MS (ESI) m/z: 524.0 (M+H+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][OH:14])[CH2:11][S:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC[C@H]1CO)=O)(C)(C)C>>[CH:13]([C@H:12]1[CH2:11][S:10][CH2:9][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1CO
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Product: CC(C)(C)OC(=O)N1CSC[C@@H]1C=O

Procedure:
With the exception that (R)-t-butyl-4-(hydroxymethyl)thiazolidine-3-carboxylate, instead of N-t-butoxycarbonyl-L-prolinol, the same procedure as in Preparation Example 1-1 was repeated to afford the title compound. 9.21 g (44%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].S(=O)(=O)(O)O.C(O)=O.[NH2:13][NH:14][C:15]([NH2:17])=[O:16]>O.C(O)=O.O>[NH2:13][NH:14][C:15]([NH2:17])=[O:16].[N:4]1[C:2](=[O:3])[N:1]=[CH:15][N:14]=1
Reactant: NC(N)=O
Agent: NNC(N)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: O=CO
Product: O=C1N=CN=N1
Temperature: 10 °C
Yield: 43.1 %

Procedure:
Aqueous semicarbazide free base feedstock (523.8 grams) was prepared from 64 percent N2H4 (4.18 moles) and urea (4.17 moles) by the method of Example 1. Ninety-eight percent sulfuric acid (99.8 grams, 0.998 mole) and 90 percent formic acid (510.6 grams, 9.99 moles) were successively added to the aqueous semicarbazide free base. After reflux at 108°-110° C. for four hours, a formic acid/H2O azeotrope was stripped, H2O (160 ml) was added to the concentrate and stripping resumed at 118°-125° C. to give 595 grams of combined distillate. The reaction mixture was cooled to 10° C. and the mother liquor was siphoned (58 grams). Crude 1,2,4-triazol-5-one was recrystallized from H2O (725 ml), the supernatant liquid was siphoned (930 grams), and 200 ml H2O was added for product filtration. Vacuum-drying gave 152.6 grams of 1,2,4-triazol-5-one (1.80 moles, 43.1 percent yield based on N2H4 charged), m.p. 234°-236° C. (Cl-, 0.02 percent).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([S:19][CH3:20])[N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:26]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:11]2[CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([S:19]([CH3:20])=[O:26])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(N)c2c(n1)CCC(c1ccccc1Cl)C2
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nc(N)c2c(n1)CCC(c1ccccc1Cl)C2
Temperature: -10 °C
Reaction time: 18 h

Procedure:
A stirred solution of 1.5 grams (0.005 mole) of 4-amino-2-methylthio-6-(2-chlorophenyl)-5,6,7,8-tetrahydroquinazoline (prepared as in Example 16) in 20 mL of chloroform is cooled to -10° C., and a solution of 1.7 grams (0.005 mole) of 50-60% 3-chloroperoxybenzoic acid in 30 mL of chloroform is added dropwise at a rate to maintain the reaction mixture temperature at -10° C. Upon completion of addition, the reaction mixture is maintained at -10° C. for one hour. After this time the reaction mixture is allowed to warm to ambient temperature, where it stands for about 18 hours. The reaction mixture is then washed with an aqueous 10% solution of potassium carbonate. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel, yielding 4-amino-2-methylsulfinyl-6-(2-chlorophenyl)-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: [CH3:1][S:2]([CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)(=O)=O.[ClH:18]>CO.O1CCOCC1>[ClH:18].[CH3:1][S:2][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(S(C)(=O)=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CSC1CCNCC1

Procedure:
A solution tert-butyl 4-(methylsulfonyl)piperidine-1-carboxylate (100 mg, 0.38 mmol) in methanol (1 mL) and 4 N hydrogen chloride in dioxane (4 mL) was refluxed for 2 min and then concentrated to provide 4-(methylthio)piperidine hydrochloride salt as a colorless solid. MS (EI) for C6H13NO2S: 163 (M+).
Reaction SMILES: [I-].[CH3:2][O:3][CH2:4][CH:5]1[NH+:9]([CH3:10])[C:8]([CH3:12])([CH3:11])[CH2:7][O:6]1.C(=O)([O-])[O-].[K+].[K+].[N:19]([C:21]1[C:30]([OH:31])=[CH:29][CH:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][CH:25]=[N:26]2)=O>C1C=CC=CC=1>[CH3:2][O:3][C:4]1[C:5]2([N:9]([CH3:10])[C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[O:31][C:30]2[CH:29]=[CH:28][C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:21]=2[N:19]=1
Reactant: O=Nc1c(O)ccc2ncccc12
Reactant: COCC1OCC(C)(C)[NH+]1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Product: COC1=Nc2c(ccc3ncccc23)OC12OCC(C)(C)N2C
Temperature: 70 °C
Yield: 4.2 %

Procedure:
Into a dry 250 ml three-necked flask kept under dry nitrogen and fitted with a reflux condenser and internal thermometer was added 2-methoxymethyl-3,4,4-trimethyl-1,3-oxazolidinium iodide (7.13 grams, 25 mmole), powdered potassium carbonate (8.97 grams, 65 mmole) and 125 ml dry benzene. The heterogeneous mixture was heated at 70° C. for 90 minutes before addition of 5-nitroso-6-quinolinol (5.44 grams, 25 mmole). The resulting reaction mixture was heated at 70° C. for 17 hours, cooled and filtered through Celite® diatomaceous earth powder. The solvent was removed in vacuo from the filtrate, and the resulting residue purified by flash chromatography to yield 0.33 grams of 2'-methoxy-3,4,4-trimethylspiro [oxazolidine-2,3'-[3H] pyrido [3,2-f] [1,4] benzoxazine].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][CH:11]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.CO>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][CH:11]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:12]2[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(N[C@H](C)c2cccc(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(N[C@H](C)c2cccc(F)c2)c2cccc(N)c2)cc1

Procedure:
Following a similar procedure to that described in Example (59b), 15.08 g of N-[(R)-1-(3-fluorophenyl)ethyl]-N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]amine [prepared as described in step (a) above], 18.84 g of nickel chloride hexahydrate, 6.0 g of sodium borohydride and 150 ml of methanol were reacted, to obtain 787 mg and 605 mg of isomer A and isomer B of the title compound, respectively, each as a pale yellowish oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)C(Cl)=O)([O-])=O.Cl.[C:14]([O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][NH:21]1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([NH2:1])[CH:5]=1)=[O:25])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: Cl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1c1cccc(N)c1

Procedure:
3-Nitrobenzoyl chloride was reacted with L-proline tert-butyl ester hydrochloride, then hydrogenated to produce (S)-1-(3-amino-phenyl)-pyrrolidin-2-carboxylic acid tert-butyl ester. This was reacted with 5-(2-adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) according to the procedure of Example 20, step d. The tert-butyl ester was deprotected by treating the chloroform solution of the ester with 4.0 M solution of hydrogen chloride in dioxan to afford the title compound as the hydrochloride salt. 1H NMR (300 MHz, d6-DMSO) (mixture of tautomers) 14.10 (1H, br s), 10.95 (1H, br m), 8.00 and 7.79 (1H, 2×m), 7.88 (1H, m), 7.41 (1H, m), 7.26 and 7.11 (1H, 2×), 4.43 (1H, m), 4.12 (1H, m), 3.48 (1H,m), 2.97 (3H, m), 2.28-1.29 (31H, m). Found: C, 64.88; H, 7.78; N, 8.92%; C34H45ClN4O4.1.0 mol H2O requires: C, 65.11; H, 7.55; N, 8.93%.
Reaction SMILES: [H-].[Na+].FC(F)(F)C1C=C(C2C(N)=C(C(OC)=O)SN=2)C=CC=1.CI.[CH3:25][NH:26][C:27]1[C:28]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)=[N:29][S:30][C:31]=1[C:32]([O:34]C)=[O:33]>O1CCCC1>[F:45][C:42]([F:43])([F:44])[C:38]1[CH:37]=[C:36]([C:28]2[C:27]([NH:26][CH3:25])=[C:31]([C:32]([OH:34])=[O:33])[S:30][N:29]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: CNc1c(-c2cccc(C(F)(F)F)c2)nsc1C(=O)OC
Agent: COC(=O)c1snc(-c2cccc(C(F)(F)F)c2)c1N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CNc1c(-c2cccc(C(F)(F)F)c2)nsc1C(=O)O
Temperature: 25 °C

Procedure:
A suspension of 0.5 g. of sodium hydride (washed free of mineral oil) in 15 ml. of tetrahydrofuran was cooled to -20° C. and stirred. To the cold stirred suspension was added in one portion 3.0 g. of methyl 3-(3-trifluoromethylphenyl)-4-amino-5-isothiazolecarboxylate. The reaction mixture was warmed to room temperature, at which time 1.5 ml. of methyl iodide was added in one portion. The reaction mixture was stirred at ambient temperature for two hours, and then was added to 50 ml. of ice water. The aqueous mixture was extracted several times with diethyl ether. The ethereal extracts were combined, washed with water, dried and the solvent was removed by evaporation under reduced pressure to afford 2.0 g. of methyl 4-methylamino-3-(3-trifluoromethylphenyl)-5-isothiazolecarboxylate.
Reaction SMILES: [Si:1]([O:8][CH2:9]/[CH:10]=[CH:11]/[C:12]1[NH:20][C:19]2[C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:17][CH:16]=[N:15][C:14]=2[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:35][CH3:36]>CN(C)C=O.C(OCC)(=O)C>[Si:1]([O:8][CH2:9]/[CH:10]=[CH:11]/[C:12]1[N:20]([CH2:35][CH3:36])[C:19]2[C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:17][CH:16]=[N:15][C:14]=2[CH:13]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC/C=C/c1cc2ncnc(Oc3ccccc3)c2[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(/C=C/CO[Si](C)(C)C(C)(C)C)cc2ncnc(Oc3ccccc3)c21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
6-((1E)-3-{[tert-Butyl(dimethyl)silyl]oxy}-1-propenyl)-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine (100 mg) was dissolved in N,N-dimethylformamide (0.786 mL), cesium carbonate (102.6 mg) was added, and the mixture was stirred at room temperature for 20 min. Iodoethane (0.0231 mL) was added and the mixture was stirred at room temperature for 2 hrs and at 40° C. for 4 hrs. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL) and washed successively with water (30 mL) and saturated brine (30 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→50:50) to give the title compound (79 mg) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[N:6][CH:7]=1.Cl[C:12]1[C:21]([N:22]([CH:24]([CH3:26])[CH3:25])[CH3:23])=[N:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:27]([O:29][CH3:30])=[O:28])[CH:18]=2)[N:13]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:12]2[C:21]([N:22]([CH:24]([CH3:26])[CH3:25])[CH3:23])=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:27]([O:29][CH3:30])=[O:28])[CH:18]=3)[N:13]=2)[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: OB(O)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3cncc(Br)c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of 5-bromopyridin-3-ylboronic acid (288.0 mg, 1.43 mmol) in dioxane (5 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 140.0 mg, 0.48 mmol), K3PO4 (302.0 mg, 1.43 mmol), Pd(PPh3)4 (27.6 mg, 0.02 mmol) and three drops water. The reaction mixture was stirred for 1 h at 90° C. with an inert atmosphere of nitrogen and then concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2-(5-bromopyridin-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (150.0 mg, 72%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[NH:12][N:11]=[N:10]1.[CH3:15]N(C)C=O.[H-].[Na+].CI>O>[CH3:1][C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH3:15])[N:11]=[N:10]1
Reactant: Cc1c(Br)cccc1-n1nn[nH]c1=O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cc1c(Br)cccc1-n1nnn(C)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-(2-methyl-3-bromophenyl)-1,4-dihydrotetrazole-5-one (described in Reference Preparation example 9) 31.40 g and N,N-dimethylformamide 250 ml was added 60% sodium hydride 5.90 g under ice-cooling. The reaction mixture was raised to room temperature and was stirred for one hour. To the reaction mixture was added methyl iodide 8.4 ml under ice-cooling. The resulting mixture was raised to room temperature and was stirred for fourteen hours. To the reaction mixture was added water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with 10% hydrochloric acid, water and saturated saline, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-(2-methyl-3-bromophenyl)-4-methyl-1,4-dihydrotetrazole-5-one 8.47 g.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]3[N:27]=[N:26][NH:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]([CH2:28][OH:29])=[C:7]([Cl:30])[N:6]=1.[OH-].[K+:32]>C(O)(C)C.O.CCCCCCC>[CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]3[N:27]=[N:26][N-:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH2:28][OH:29])=[C:7]([Cl:30])[N:6]=1.[K+:32]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: CCCCCCC
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[n-]n2)cc1
Temperature: 25 °C
Yield: 77.1 %

Procedure:
As already described, to 10.2 g crude losartan of Example 14 (chromatographic purity 98.73%) in 59 ml i-propanol, a solution of 1.4 g potassium hydroxide in 1.5 ml water at a temperature of 38-40° C. to a pH of 10 over half an hour was added. Approximately 19 ml of azeotropic mixture i-propanol/water were removed by distillation, 36 ml n-heptane were added, and reaction mixture was stirred at room temperature until a white solid was formed. The resulting mixture was diluted with 14 ml n-heptane, filtered, washed with 26 ml n-heptane, and dried in vacuo at 50° C. to yield 8.57 g losartan potassium (yield: 77%, chromatographic purity: 99.67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25](O)=[O:26])[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[O:35]1[CH2:36][CH2:37][N:32]([C:25]([C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]4[CH:14]=[C:13]([C:5]5[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=5)[O:21][C:20]=34)[CH:23]=2)=[O:26])[CH2:33][CH2:34]1
Reactant: COc1cc(-c2cc3nccc(-c4cccc(C(=O)O)c4)c3o2)cc(OC)c1OC
Reactant: CN1CCOCC1
Product: COc1cc(-c2cc3nccc(-c4cccc(C(=O)N5CCOCC5)c4)c3o2)cc(OC)c1OC
Yield: 70 %

Procedure:
Starting from 3-[2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridin-7-yl]benzoic acid (0.062 mmol) and 4-methylmorpholin (0.182 mmol) the product is prepared analogously to “A43” and obtained as colorless solid in a yield of 70%. HPLC (method A): Rt 2.59 min (purity 98.1%); LCMS (ESI+) (method E): Rt 1.76 min, M+H+ 475.2 m/z; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.58 (d, J=5.1, 1H), 8.29 (t, J=1.5, 1H), 8.19 (d, J=8.0, 1H), 7.76 (s, 1H), 7.74-7.65 (m, 2H), 7.58 (d, J=7.6, 1H), 7.33 (s, 2H), 3.91 (d, J=11.4, 6H), 3.74 (s, 3H), 3.69-3.37 (m, 8H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH2:30]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][NH:30][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CN(C)CCN
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCCN(C)C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and N,N-dimethylethylenediamine.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)C)(C)(C)C.Cl.O1CCOCC1>ClCCl>[ClH:23].[Cl:23][C:18]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][NH:7][CH3:6])[CH2:12][CH2:13]2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CN(CCN1CCN(c2cccnc2Cl)CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNCCN1CCN(c2cccnc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
Dissolve {2-[4-(2-chloro-pyridin-3-yl)-piperazin-1-yl]-ethyl}-methyl-carbamic acid tert-butyl ester (4.900 g, 13.807 mmol) in dichloromethane (100 mL). Slowly add 4N HCl in dioxane (20.711 mL, 82.845 mmol). Stir at room temperature for 18 hr. Concentrate and wash the resulting solid with diethyl ether to afford the title preparation (7.500 g, 99% yield). MS ES: m/z=255 [M+H]+.