Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[N:17]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])[N:18]=[CH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[CH:10][C:9]=1[CH3:32])[CH3:7])C.[BH4-].[Na+]>C1COCC1.CO>[Cl:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:24]=1[N:17]1[C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([CH:6]([CH3:7])[CH2:5][CH2:4][OH:3])=[C:9]([CH3:32])[CH:10]=2)=[C:20]([CH:21]([CH3:23])[CH3:22])[CH:19]=[N:18]1
Reactant: CCOC(=O)CC(C)c1ccc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1C(C)CCO
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(+/−)-3-{4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-butyric acid ethyl ester (0.581 g, 1.19 mmol) is dissolved in THF (15 mL) and methyl alcohol (3 mL). Sodium borohydride is added portionwise until an excess has been added. After stirring at room temperature for 3 days, the reaction is quenched with water followed by 1N HCl. The resulting mixture is extracted two times with ethyl acetate. The organic layers are combined, washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified via flash chromatography eluting with 5-10% ethyl acetate:toluene to give the title compound. 1H NMR (CDCl3) δ 1.134 (d, 3H), 1.262 (d, 6H), 1.456 (s, 2H), 1.764 (m, 2H), 2.223 (s, 3H), 2.939-3.039 (m, 2H), 3.476-3.539 (m, 2H), 4.747 (s, 2H), 6.516 (d, 1H), 6.559 (dd, 1H), 6.99 (d, 1H), 7.263 (t, 1H), 7.372 (d, 2H), 7.663 (s, 1H)
Reaction SMILES: [C:1]([Mg]Br)([CH3:3])=[CH2:2].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-])=O.[NH4+].[Cl-]>C1COCC1>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:9]=1[NH:14][C:1]([CH3:3])=[CH:2]2
Reactant: COc1ccccc1[N+](=O)[O-]
Reactant: C=C(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc2cc(C)[nH]c12
Reaction time: 1 h

Procedure:
800 ml of a 0.5M solution of isopropenylmagnesium bromide in THF is cooled to −40° C. under a nitrogen atmosphere, a solution of 20.4 g of 2-methoxynitrobenzene in 125 ml of THF is then added dropwise and the mixture is left stirring for 1 hour while allowing the temperature to return to 0° C. The reaction mixture is poured into a saturated NH4Cl solution and extracted with ether, the organic phase is washed with a saturated NaCl solution and dried over MgSO4, and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, elution being carried out with cyclohexane and then with a cyclohexane/EtOAc mixture (90/10; v/v). 2.45 g of the expected compound are obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19]O)[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]1.[CH3:22][C:23]1[N:24]=[N:25][NH:26][N:27]=1.CO>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][N:25]3[N:26]=[N:27][C:23]([CH3:22])=[N:24]3)[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]1
Reactant: Cc1nn[nH]n1
Reactant: Cc1cn(-c2ccc(N3C[C@H](CO)OC3=O)cc2F)nn1
Solvent: CO
Solvent: ClCCl
Product: Cc1cn(-c2ccc(N3C[C@H](Cn4nnc(C)n4)OC3=O)cc2F)nn1
Yield: 44.1 %

Procedure:
This compound was prepared from (5R)-3-[3-Fluoro-4-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one (Intermediate 19) (1.054 g, 3.61 mmol) and 5-methyl-2H-tetrazole (0.608 g, 7.23 mmol), as described for Example 29. Chromatography on silica gel with 5% methanol in dichloromethane gave the crude product (0.72 g) which was purified further by trituration with dichloromethane and diethyl ether to afford the title product (0.571 g). The regioisomeric product (5R)-3-[3-fluoro-4-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-5-[(5-methyl-1H-tetrazol-1-yl)methyl]-1,3-oxazolidin-2-one was also isolated (0.228 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][CH2:11][C:12]1[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH2:11][C:12]2[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CN(c1ncccc1CN)S(C)(=O)=O
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(c1ncccc1CNc1nc(Cl)ncc1Cl)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2,4,5-trichloropyrimidine (1.0 g, 5.45 mmol) is suspended in 20 mL DCM and the reaction mixture is cooled to 0° C. Then a solution of N-(3-aminomethyl-pyridin-2-yl)-N-methyl-methanesulphonamide (1.17 g, 5.45 mmol) and DIPEA (1.95 mL, 10.9 mmol) in 10 mL DCM is added and the mixture is stirred overnight. The reaction mixture is diluted with DCM and washed 3× with 1 N NH4Cl solution. The organic phase is dried on magnesium sulphate and evaporated down in vacuo. The crude product A-2b (HPLC-MS: tRet.=2.00 min; MS (M+H)+=362) is used in successive reactions without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:13])[CH3:12].[CH3:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([CH3:24])[C:22]=1[OH:23])[CH:18]=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:13])[CH:12]=[CH:18][C:17]1[CH:20]=[C:21]([CH3:24])[C:22]([OH:23])=[C:15]([CH3:14])[CH:16]=1
Reactant: COc1ccc(OC)c(C(C)=O)c1
Reactant: Cc1cc(C=O)cc(C)c1O
Product: COc1ccc(OC)c(C(=O)C=Cc2cc(C)c(O)c(C)c2)c1

Procedure:
This compound was synthesized from 2′,5′-dimethoxyacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described earlier.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.P(O)(O)O>C1C=CC=CC=1.O>[CH2:8]([NH:15][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCCCC1
Reactant: NCc1ccccc1
Agent: OP(O)O
Solvent: c1ccccc1
Solvent: O
Product: c1ccc(CNC2CCCCC2)cc1
Reaction time: 0.5 h

Procedure:
The imine from cyclohexanone and benzylamine was prepared in benzene in the normal way. To this imine (37.4 g; 0.2 mole) was added phosphorous acid (16.4 g; 0.2 mole) and the mixture stirred while heating. The reaction mixture became a homogeneous liquid at 70° and at 95°-100° a vigorous reaction took place. After keeping at 110°-130° for 30 minutes the mixture was cooled and diluted with water. Basification with NaOH and extraction with benzene gave after evaporation of the solvent N-benzylcyclohexylamine (80%). Distillation gave pure N-benzylcyclohexylamine bp 120°-125°/3 mm.
Reaction SMILES: C[O:2][C:3](=[O:43])[CH:4]=[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12](S(C1C=CC=CC=1)(=O)=O)[CH:11]=[C:10]2[C:25]1[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:28]=[C:27]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:26]=1[O:39][CH2:40][CH2:41][CH3:42])[CH3:6].[OH-].[Na+]>CO.O1CCOCC1.Cl>[C:35]([C:27]1[C:26]([O:39][CH2:40][CH2:41][CH3:42])=[C:25]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]([CH3:6])=[CH:4][C:3]([OH:43])=[O:2])[CH:8]=3)[NH:12][CH:11]=2)[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:28]=1)([CH3:36])([CH3:37])[CH3:38]
Reactant: CCCOc1c(-c2cn(S(=O)(=O)c3ccccc3)c3ccc(C(C)=CC(=O)OC)cc23)cc(C(C)(C)C)cc1C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCOc1c(-c2c[nH]c3ccc(C(C)=CC(=O)O)cc23)cc(C(C)(C)C)cc1C(C)(C)C
Yield: 127.7 %

Procedure:
3-[1-Benzenesulfonyl-3-(3,5-di-tert-butyl-2-propoxy-phenyl)-1H-indol-5-yl]-but-2-enoic acid methyl ester (171 mg, 0.28 mmol) was dissolved in methanol (1.5 mL)/dioxane (3 mL) and treated with 1N NaOH (2 mL) at 60° C. for 4 h. The reaction was diluted with 1N HCl (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic portions were washed with water (10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to provide 160 mg of a brown solid. The material was purified using radial chromatography (eluent:hexane/ethyl acetate gradient) to provide 73 mg (58%) of a yellow foam. Mp. 105-115° C. 1H NMR (250 MHz, CDCl3): δ 8.31 (bs, 1H), 7.98 (bs, 1H, 8.7), 7.92 (m, 2H) 7.70 (m, 21), 7.47-7.35 (m, 5H), 6.27 (bs, 1H), 3.42 (t, 2H, J=6.4) 2.68 (d, 3H, J=1.0), 1.49 (s, 9H), 1.37 (s, 9H), 1.32 (m, 2H) 0.68 (t, 3H, J=7.4). MS [EI+] 448 (M+E)+, [EI−] 446 (M−H)+. Analytical (C29H37NO3): Calculated C, 77.81; H, 8.33; N, 3.13. Found: C, 77.89; H, 8.68; N, 2.94.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=3)[CH:24]=[C:23]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:36][O:35][C:33](=[O:34])[CH2:32][C:23]1[CH:22]=[C:21]([CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=2)[CH:24]=1
Reactant: COC(=O)Cc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)c2cc(F)ccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
Trifluoroacetic acid (2.9 mL, 38 mmol) was added at 0° C. to a stirred solution of 4-(7-fluoro-3-methoxycarbonylmethyl-naphthalen-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (which may be prepared as described above; 1.05 g, 2.6 mmol) in dry CH2Cl2 (25 mL) under nitrogen. The solution was stirred at room temperature for 16 h and then the solvent was evaporated under reduced pressure. The residue was triturated with diethyl ether (3×5 mL) and dried under vacuum to give (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (0.80 g, 74%) as a white solid. MS cald. for C18H21FNO2 [(M+H)+] 302, obsd. 302.4.
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[C:8]([O:21][CH3:22])[C:9]([CH2:18][CH2:19][CH3:20])=[CH:10][C:11]=2[O:15][CH2:16][CH3:17])[S:4]1(=[O:6])=[O:5].[Na].[C:24]1([N:30]2[C:34]([SH:35])=[N:33][N:32]=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([N:30]2[C:34]([S:35][CH2:2][N:3]3[C:13](=[O:14])[C:12]4[C:7](=[C:8]([O:21][CH3:22])[C:9]([CH2:18][CH2:19][CH3:20])=[CH:10][C:11]=4[O:15][CH2:16][CH3:17])[S:4]3(=[O:6])=[O:5])=[N:33][N:32]=[N:31]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: CCCc1cc(OCC)c2c(c1OC)S(=O)(=O)N(CCl)C2=O
Agent: [Na]
Product: CCCc1cc(OCC)c2c(c1OC)S(=O)(=O)N(CSc1nnnn1-c1ccccc1)C2=O
Yield: 71 %

Procedure:
By the method of part F of Example 45 condensation of 2-chloromethyl-4-ethoxy-6-propyl-7-methoxysaccharin (0.62 g) and 1-phenyltetrazol-5-thiol sodium salt (0.36 g initially and a small amount more after 3.5 hours reaction time, total reaction time 8 hours) and isolation of the oily product by extraction with dichloromethane and purification thereof first by column chromatography on silica gel using dichloromethane as eluant and then by crystallization of the resulting oil (0.62 g., 71% yield) from ethanol gave 2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethoxy-6-propyl-7-methoxysaccharin, mp 110°-111° C.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]2[CH2:10][NH:9][CH2:8]2)=[C:4]([O:13][CH3:14])[CH:3]=1.[C:15]1(=O)[CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[CH2:8]2)=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: COc1cc(Br)ccc1OC1CNC1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc(Br)ccc1OC1CN(C2CCC2)C1
Reaction time: 8 h
Yield: 56.6 %

Procedure:
Dissolve 3-(4-bromo-2-methoxy-phenoxy)-azetidine (1.84 g, 7.13 mmol) in dichloroethane (80 mL). Add cyclobutanone (1.86 mL, 25 mmol), sodium triacetoxyborohydride (3.02 g, 14.3 mmol) and acetic acid (0.82 mL, 14.3 mmol). Stir the mixture overnight, then add saturated sodium bicarbonate and extract three times using dichloromethane. Dry the combined organic portions over sodium sulfate, filter, and concentrate. Purify by silica gel chromatography using a 0-3% gradient of methanol/dichloromethane to give 1.26 g (56%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=3)[C:22]([O:24]CC)=[O:23])=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=3)[C:22]([OH:24])=[O:23])=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)c1cccc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(=O)Nc2cccc(C(=O)O)c2)nnn1Cc1ccc(Cl)c(Cl)c1

Procedure:
A mixture of ethyl 3-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]benzoate (Example 20) (0.06 g, 0.138 mmol) and a 1N NaOH solution (2 mL, 2 mmol) in ethanol (5 mL) was stirred at 40° C. for 4 hours. The solvent was evaporated and the residue was acidified with a 1N HCl solution. The precipitate formed was filtered and dried. The title compound was obtained as a white solid (53 mg, 96%). HRMS calculated for C18H14Cl2N4O5 (M+H)+: 405.0521. found: 405.0520, Rt: 2.23 min. MP: 267.6° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:21](=[CH:22][CH:23]=1)[O:20][C:7]1([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:24].[NH2:25][C:26]1[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:31][N:30]1[C:26]([NH:25][C:2]2[CH:3]=[C:4]3[C:21](=[CH:22][CH:23]=2)[O:20][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][C:5]3=[O:24])=[CH:27][CH:28]=[N:29]1
Reactant: Cn1nccc1N
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Product: Cn1nccc1Nc1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Temperature: 110 °C

Procedure:
tert-Butyl 6-bromo-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (16.3 g), 5-amino-1-methyl-1H-pyrazole (4.00 g), palladium acetate (922 mg), 2-(di-t-butylphosphino)biphenyl (1.23 g) and cesium carbonate (16.1 g) were suspended in 1,4-dioxane (20 mL), and heated under reflux at 110° C. for 5 hours. The reaction liquid was filtered through Celite, the residue on the Celite was washed with chloroform, and the filtrate was concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane/EtOAc) to obtain the intended compound as a yellow amorphous substance.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:21]([O:23][CH3:24])=[O:22]>ClCCl>[C:21](=[O:22])([O:12][C:6]1[CH:7]=[CH:8][C:9]([Br:11])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])[O:23][CH3:24]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)c1cc(Br)ccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Oc1ccc(Br)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-t-butyl-4-bromophenol (380 g, 1.67 mol) in dichloromethane (1000 mL) was added Et3N (202 g, 2 mol) at room temperature. Methyl chloroformate (155 mL) was added dropwise to the above solution at 0° C. After addition, the mixture was stirred at 0° C. for 2 h., quenched with saturated ammonium chloride solution and diluted with water. The organic layer was separated and washed with water and brine, dried over Na2SO4, and concentrated to provide the crude methyl (2-tert-butyl-4-bromophenyl) carbonate (470 g), which was used without further purification.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17](=[O:25])[NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:11]=[N:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1/[CH:34]=[CH:35]/[C:36](O)=[O:37]>>[C:1]([O:7][CH2:8][N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17]([NH:18][CH:19]2[CH2:20][CH2:21][N:22]([C:36](=[O:37])/[CH:35]=[CH:34]/[C:28]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:27]=3[Cl:26])[CH2:23][CH2:24]2)=[O:25])[N:11]=[N:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCn1cc(CCCC(=O)NC2CCNCC2)nn1
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1Cl
Product: CC(C)(C)C(=O)OCn1cc(CCCC(=O)NC2CCN(C(=O)/C=C/c3ccc(Cl)cc3Cl)CC2)nn1

Procedure:
The title compound was prepared from (4-(4-oxo-4-(piperidin-4-ylamino)butyl)-1H-1,2,3-triazol-1-yl)methyl pivalate (Example 37, step 5) (200 mg, 0.516 mmol) and (E)-3-(2,4-dichlorophenyl)acrylic acid (step 1) analogously to Example 38 step 1.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=[C:3]1[CH2:16][C:17]([OH:19])=[O:18].[Br:20]Br>C(O)(=O)C>[Br:20][C:4]1[CH:5]=[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])[N:2]([CH3:1])[C:3]=1[CH2:16][C:17]([OH:19])=[O:18]
Reactant: BrBr
Reactant: Cc1ccc(C(=O)c2ccc(CC(=O)O)n2C)cc1
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)c2cc(Br)c(CC(=O)O)n2C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2.0g. (0.0078 moles) of 1-methyl- 5-(p-toluoyl)pyrrole-2-acetic acid in 40 ml. of glacial acetic acid is added dropwise a solution of 1.2g (0.0078 moles) of bromine in 3 ml. of glacial acetic acid. The mixture is stirred at room temperature for two hours, after which it is poured into 300 ml. of water, and the solid which forms is filtered off. Recrystallization from ether-hexane yields 3-bromo-1-methyl-5-(p-toluoyl) pyrrole-2-acetic acid as a white solid; m.p. 162°-164° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:20])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:23](OC)([CH3:25])[CH3:24].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl>C(Cl)(Cl)Cl.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]2[O:20][C:23]([CH3:25])([CH3:24])[O:18][C:17]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(=O)C(Cc2ccc(OCc3ccccc3)cc2)O1
Yield: 87.7 %

Procedure:
A mixture of 3-(4-benzyloxy-phenyl)-2-hydroxy-propionic acid (2.0 g, 7.34 mmol), 2,2-dimethoxypropane (18.63 g, 179 mmol) and pyridinium p-toluene sulfonate (0.92 g, 3.66 mmol) in CHCl3 (80 mL) was heated to reflux for 40 minutes under N2. The reaction was cooled and worked up extractively with CH2Cl2 and water. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 10:1 hexanes:acetone to afford 2.01 g (88%) 5-(4-benzyloxy-benzyl)-2,2-dimethyl-[1,3]dioxolan-4-one. Rf=0.53 (1:1 hexanes:acetone). 1H NMR (500 MHz, CDCl3) δ 7.43-7.35 (m, 4H), 7.34-7.29 (m, 1H), 7.16 (d, 2H, J=8.80 Hz), 6.91 (d, 2H, J=8.80 Hz), 5.04 (s, 2H), 4.61 (dd, 1H, J=6.36 Hz, J=4.40 Hz), 3.13 (dd, 1H, J=14.67 Hz, J=4.40 Hz), 2.99 (dd, 1H, J=14.67 Hz, J=4.40 Hz), 1.50 (s, 3H), 1.36 (s, 3H); MS (ES+) Calc'd for C19H20O4 (M+NH4) 330. Found m/z 330 (100%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH2:13][C:12](=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.Cl.Cl.[NH2:17][NH2:18].NN.C(O)CO>O>[NH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[C:12]1[NH:18][N:17]=[C:4]([CH2:3][O:2][CH3:1])[CH:13]=1
Reactant: NN
Reactant: COCC1=Nc2ccccc2C(=O)C1
Agent: Cl
Solvent: O
Solvent: OCCO
Product: COCc1cc(-c2ccccc2N)[nH]n1
Yield: 85.5 %

Procedure:
A mixture of 7.5 g (0.04 mol) of 2-methoxymethyl-4-quinolone, 4.2 g (0.04 mol) of hydrazine dihydrochloride, 12.8 ml (0.4 mol) of 95% hydrazine and 30 ml of ethylene glycol is slowly heated to reflux. The resulting solution is refluxed for 5 hours, cooled, diluted with 200 ml of distilled water, and extracted twice with methylene chloride (1×400 ml, 1×200 ml). The combined methylene chloride extracts are washed with 100 ml of distilled water, dried over sodium sulfate, and evaporated to 8.0 g of clear oil. Trituration with 25 ml of hexane gives 6.95 g (86%) of the 5-(2-aminophenyl)-3-methoxymethylpyrazole as a white powder, m.p. 74.0°-78.0° C.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:21])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:5]>>[CH2:4]([O:6][C:7]([C:8]1[NH:2][N:3]=[C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=1)=[O:21])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)COc1ccccc1
Solvent: O
Product: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
Hydrazine hydrate (0.27 mL, 2.76 mmol) was added to a stirred solution of 2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester (0.69 g, 2.76 mmol in EtOH (3 mL)). The mixture was stirred at 80° C. overnight. The solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; DCM in AcOEt 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.66 g, 98% yield) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3](=[O:8])[CH2:4][C:5](=[O:7])[CH3:6].[OH-].[Na+].[Cl-].[C:13]1([N+:19]#[N:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[CH3:1][N:2]([CH3:9])[C:3](=[O:8])[C:4](=[N:20][NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5](=[O:7])[CH3:6]
Reactant: N#[N+]c1ccccc1
Reactant: CC(=O)CC(=O)N(C)C
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C(=NNc1ccccc1)C(=O)N(C)C
Yield: 42.9 %

Procedure:
4.5 g (0.035 mol) of N,N-dimethyl-3-oxobutyramide, a solution of 4.9 g (0.122 mol) of NaOH in 45 ml of water and 0.037 mol of phenyldiazonium chloride were treated as described in preparation 8. The crude reaction mixture was purified by chromatography on silica gel (hexane/Et2O 0%→100%) obtaining 3.5 g of the title compound which was used as such in the subsequent step. M.p.=131°-133° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[CH2:13]([NH:20][C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: NCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc2c(NCc3ccccc3)nc(Cl)nc12
Reaction time: 3 h
Yield: 92.4 %

Procedure:
In 3 ml of DMF was dissolved 300 mg (1.4 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and after 220 mg (2.1 mmol) of benzylamine was added to the resulting solution, the mixture was stirred for 3 hours. Water was added to the reaction mixture, and crystals thus precipitated were filtered to give 375 mg (yield: 94.5%) of the title compound.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NN>>[CH3:4][C:3]1[CH:2]=[C:1]([NH2:7])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: NNc1ccccc1
Agent: NN
Product: Cc1cc(N)n(-c2ccccc2)n1
Yield: 37 %

Procedure:
Synthesized using the procedure for 22 except phenyl hydrazine was used as the hydrazine. Recrystallization of crude from hot EtOH provided the title compound (1.28 g, 37%) as pink crystals. 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.51 (s, 1H), 7.44 (t, J=7.5 Hz, 2H), 7.30 (t, J=7.4 Hz, 1H), 5.43 (s, 1H), 3.77 (s, 2H), 2.22 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 149.37, 145.21, 138.65, 129.38, 126.99, 123.77, 90.68, 13.93.