Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5].[CH2:17](OC(OCC)OCC)C>>[CH3:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:3]2[C:2]=1[N:1]=[CH:17][N:6]([C:7]1[NH:11][N:10]=[N:9][N:8]=1)[C:4]2=[O:5]
Reactant: Cc1cccc(C(=O)Nc2nnn[nH]2)c1N
Reactant: CCOC(OCC)OCC
Product: Cc1cccc2c(=O)n(-c3nnn[nH]3)cnc12

Procedure:
Reaction of 2-amino-3-methyl-N-(1H-tetrazol-5-yl)benzamide with triethoxymethane gave 8-methyl-3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone melting at about 268° C. (dec) after recrystallization from dimethylformamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[O:12][C:13]([CH:16]([O:19][CH3:20])[O:17][CH3:18])=[CH:14][CH:15]=1.[H][H]>[Ni].CO>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH:13]([CH:16]([O:17][CH3:18])[O:19][CH3:20])[O:12]1
Reactant: COC(=O)CCCCCCCc1ccc(C(OC)OC)o1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: COC(=O)CCCCCCCC1CCC(C(OC)OC)O1
Yield: 93.6 %

Procedure:
8-(5-Dimethoxymethyl-2-furyl)-octanoic acid methyl ester (6.03 g, 0.02 mol), methanol (50 ml) and Raney nickel (3.0 g) were shaken under 100 atmospheres of hydrogen for 48 hours at 85°-100° C. After filtration, the methanol was distilled under reduced pressure from a water bath (60° C). Ether (50 ml) was added to the residue, and the turbid colourless solution was filtered. The ethereal solution was evaporated to dryness from a water bath under reduced pressure, at last under 15 mm Hg. The residual clear, colourless oil (6.07 g) was purified by distillation from a potassium acetate-coated flask giving 5.66 g (93%) of 8-(5-dimethoxymethyl-tetrahydro-2-furyl)-octanoic acid methyl ester, b0.1 126°-127° C, nD25 1.4504.
Reaction SMILES: [CH:1]1[CH:6]=[C:5](N2C(=O)C3C(Cl)=C(Cl)C(Cl)=C(Cl)C=3C2=O)[C:4]2[N:22]=[C:23]([CH:26]3[C:31](=[O:32])[C:30]4[C:33](Cl)=[C:34](Cl)[C:35](Cl)=[C:36](Cl)[C:29]=4[C:27]3=[O:28])[CH:24]=[CH:25][C:3]=2[CH:2]=1.S(=O)(=O)(O)O>>[CH:1]1[CH:2]=[C:3]2[CH:25]=[CH:24][C:23]([CH:26]3[C:27](=[O:28])[C:29]4[C:30](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:31]3=[O:32])=[N:22][C:4]2=[CH:5][CH:6]=1
Reactant: O=C1c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)C1c1ccc2cccc(N3C(=O)c4c(Cl)c(Cl)c(Cl)c(Cl)c4C3=O)c2n1
Agent: O=S(=O)(O)O
Product: O=C1c2ccccc2C(=O)C1c1ccc2ccccc2n1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
45 parts of C.I. Pigment Yellow 138 (manufactured by BASF “Paliotol Yellow D0960”) was added gradually to 450 parts of 101% sulfuric acid prepared from fuming sulfuric acid (25% SO3) and sulfuric acid, and the mixture was stirred at 80° C. for 3 hours, allowing a sulfonation reaction to proceed. The reaction solution was poured into 5,000 parts of ice water, and the precipitate was filtered, washed with 2,000 parts of 0.1% hydrochloric acid, and additionally with 2,000 parts of purified water, to give a paste of the sulfonated compound of quinophthalone. The water-wet paste was redispersed in 5,000 parts of water, and the dispersion was adjusted to a pH of 11.5 by addition of an aqueous sodium hydroxide solution. The solution was stirred additionally for one hour while the pH of the solution was adjusted by addition of an aqueous sodium hydroxide solution. The reaction solution changed from an yellow suspension to a red solution. The reaction solution was then heated to 60° C. at pH 11.5 and stirred for 3 hours. The solution was then adjusted to a pH of 1 or less by addition of hydrochloric acid and stirred at 90° C. for 2 hours. Precipitate formed was filtered, washed and dried, to give a quinoline derivative [D].
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:5]([OH:18])[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[CH:10]=1.[O:26]=[C:27]1[N:38]([C@@H:39]([CH3:43])[C:40](O)=[O:41])[CH2:37][CH2:36][C@@:28]21[N:32]([CH2:33][CH2:34][CH3:35])[CH2:31][CH2:30][CH2:29]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>C(Cl)Cl>[CH2:19]([C@H:4]([NH:3][C:40](=[O:41])[C@@H:39]([N:38]1[CH2:37][CH2:36][C@:28]2([N:32]([CH2:33][CH2:34][CH3:35])[CH2:31][CH2:30][CH2:29]2)[C:27]1=[O:26])[CH3:43])[C@H:5]([OH:18])[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:16])[CH3:17])[CH:10]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)c1cccc(CNC[C@@H](O)[C@@H](N)Cc2ccccc2)c1
Reactant: CCCN1CCC[C@@]12CCN([C@@H](C)C(=O)O)C2=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCN1CCC[C@@]12CCN([C@@H](C)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNCc1cccc(C(C)C)c1)C2=O
Yield: 37.2 %

Procedure:
A solution of 100 mg (2R,3S)-3-amino-1-(3-isopropyl-benzylamino)-4-phenyl-butan-2-ol dihydrochloride, 79 mg (S)-2-((S)-6-oxo-1-propyl-1,7-diaza-spiro[4.4]non-7-yl)-propionic acid, 102 mg TBTU and 0.171 mL N-methyl morpholine in 5 mL CH2Cl2 is stirred for 5 h at ambient temperature. The solution is diluted with DCM and subsequently washed with bicarbonate, brine, 0.1N HCl and bicarbonate. After drying with MgSO4 all volatiles are evaporated in vacuo and the product is purified by column chromatography (silica gel, DCM/MeOH 95:5) to give 53 mg (37%) of the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:3]=1.O.[NH2:25][NH2:26].O>O1CCOCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:4]2[N:5]=[C:6]([C:8]3[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=3[F:15])[N:7]=[C:2]([NH:25][NH2:26])[N:3]=2)=[CH:18][CH:19]=1
Reactant: NN
Reactant: Fc1cccc(F)c1-c1nc(Cl)nc(Nc2ccc(Cl)cc2)n1
Solvent: O
Solvent: C1COCCO1
Product: NNc1nc(Nc2ccc(Cl)cc2)nc(-c2c(F)cccc2F)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 165.6 %

Procedure:
General Method 1A Step 3A.1 part a. To a solution of 151 mg (0.4 mmol) of triazine (XXVI) in 4 mL of 1,4-dioxane was quickly added 100 uL (2 mmol) of hydrazine monohydrate. The reaction was stirred at room temperature for 12 hours and 30 mL of water was added and the mixture stirred for an additional 30 minutes. The resultant solid was collected by filtration and washed with several portions of water. The white solid was dried overnight to afford 231 mg of N-(4-chlorophenyl)-4-(2,6-difluorophenyl)-6-hydrazinyl-1,3,5-triazin-2-amine (XXVII). If the hydrazine did not form a solid that could be filtered, then the mixture was extracted three times with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to yield the hydrazine intermediate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:24][O:25][C:26](=[O:46])[C:27]([C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:31]=1[F:45])([CH3:29])[CH3:28].C([O-])([O-])=O.[Cs+].[Cs+]>O.COCCOC.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>[CH3:24][O:25][C:26](=[O:46])[C:27]([C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]([NH:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[N:5]=[C:6]([O:8][CH3:9])[N:7]=2)[CH:33]=[CH:32][C:31]=1[F:45])([CH3:29])[CH3:28]
Reactant: COc1nc(Cl)cc(NCCc2ccc(OC(F)(F)F)cc2)n1
Reactant: COC(=O)C(C)(C)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)C(C)(C)c1cc(-c2cc(NCCc3ccc(OC(F)(F)F)cc3)nc(OC)n2)ccc1F
Yield: 30.2 %

Procedure:
A solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(4-trifluoromethoxyphenyl)-ethyl]amine (1.6 g), 2-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-methyl-propionic acid methyl ester (0.63 g), Cs2CO3 (11.6 g) and tetrakis(triphenylphosphine)palladium (0) (33 mg) in water (8 mL) and DME (32 mL) is heated at 90° C. for 16 hours. The solution is poured into water and extracted with EtOAc (2×200 mL). The combined extract is dried over sodium sulfate, filtered, evaporated in vacuo and chromatographed on silica gel eluting with EtOAc to afford 2-(2-fluoro-5-{2-methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid methyl ester (300 mg). MS: 508 (M+H); 1H NMR (300 MHz, CD3OD) □7.8, (d, 1H, J=0.3 Hz); 7.7 (m, 1H); 7.4 (d, 2H, J=0.4 Hz); 7.2-7.3 (m, 4H); 6.6 (s, 1H); 4.2 (s, 3H); 4 (s, 3H); 3.9 (m, 2H); 3.05 (t, 2H); 1.65 (s, 6H).
Reaction SMILES: [C:1](=[O:29])([O:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([CH2:23][C:24]([OH:26])=[O:25])=[C:16](F)[C:15]=1[F:28])[O:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[NH2:30][C:31]1[C:32]([CH3:37])=[CH:33][CH:34]=[CH:35][CH:36]=1>C(OCC)C>[C:1](=[O:29])([O:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([CH2:23][C:24]([OH:26])=[O:25])=[C:16]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[C:15]=1[F:28])[O:2][C:3]12[CH2:10][CH:9]3[CH2:11][CH:5]([CH2:6][CH:7]([CH2:8]3)[CH2:12]1)[CH2:4]2
Reactant: Cc1ccccc1N
Reactant: O=C(O)Cc1cc([N+](=O)[O-])c(OC(=O)OC23CC4CC(CC(C4)C2)C3)c(F)c1F
Solvent: CCOCC
Product: Cc1ccccc1Nc1c(CC(=O)O)cc([N+](=O)[O-])c(OC(=O)OC23CC4CC(CC(C4)C2)C3)c1F
Temperature: 200 °C
Reaction time: 6 h

Procedure:
The compound 1-adamantyl 4-carboxymethyl-2,3-difluoro-6-nitrophenyl carbonate is dissolved in excess ortho-toluidine. The reaction mixture is stirred at 200° C. for 6 hours. The mixture is allowed to cool and is dissolved in diethyl ether. The organic phase is washed with dilute aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and brine, is dried (MgSO4), and is concentrated in vacuo to afford the desired product. The product is purified by flash chromatography as necessary.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7][OH:8])([O-:3])=[O:2].[F:15][C:16]([F:43])([O:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:31][CH:30]=1)[C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25](O)=[O:26])=[CH:19][CH:18]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[F:15][C:16]([F:43])([O:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:41])([F:40])[F:42])=[CH:31][CH:30]=1)[C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:8][CH2:7][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=2)=[O:26])=[CH:19][CH:18]=1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1
Reactant: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1)OCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
2.33 g (11.8 mmol) of 3,5-dinitrobenzylalcohol, 4.91 g (11.8 mmol) of (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoic acid, 144 mg (1.2 mmol) of 4-dimethylaminopyridine are dissolved in 30 mL of dichloromethane. 2.48 g (13.0 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) are added at 0° C. The solution is stirred for 1 h at 0° C. and allowed to stir at room temperature overnight. After 22 hours at room temperature, the reaction mixture is partitioned between dichloro-methane and water. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Chromatography of the residue on 200 g silica gel using toluene: ethyl acetate 95:5 as eluent and crystallization from ethyl acetate:hexane mixture yields 6.9 g of 3,5-dinitrobenzyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoate as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:15]1([CH:21]([NH2:29])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:29][CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])=[O:12])=[CH:13][CH:14]=1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Reactant: Cc1ccccc1C(N)c1ccccc1
Product: Cc1ccccc1C(NC(=O)CNC(=O)c1ccc(F)cc1)c1ccccc1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-phenyl-C-o-tolyl-methylamine (CA [2936-62-1]).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.Cl[C:19]1[CH:29]=[C:23]2[N:24]([CH3:28])[CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:30])[N:20]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[CH2:16][O:17][C:19]1[CH:29]=[C:23]2[N:24]([CH3:28])[CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:30])[N:20]=1
Reactant: OCc1ccc(Oc2cccc(F)c2)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3cccc(F)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3-fluoro-4-(3-fluorophenoxy)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>>[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:20][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:9]2)=[CH:7][C:2]=1[CH3:1])=[O:26]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: Cc1cc(N2CC[C@H](CN3CCC[C@@H]3C)C2)ccc1N
Product: Cc1cc(N2CC[C@H](CN3CCC[C@@H]3C)C2)ccc1NC(=O)c1cccc(F)c1
Yield: 39 %

Procedure:
The title compound was prepared in a manner substantially the same as example 20 by coupling (2S,3R)-2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenylamine with 3-fluoro-benzoyl chloride in 39% yield.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[C:9]2[N:10]=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[C:8]=2[CH2:7][CH2:6][NH:5]1)#[N:2].CN(C)C=O.C(N(CC)C(C)C)(C)C.[C:47](Cl)(=[O:49])[CH3:48]>>[C:47]([N:5]1[CH2:6][CH2:7][C:8]2[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])=[N:12][C:11]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)=[N:10][C:9]=2[CH:4]1[CH2:3][C:1]#[N:2])(=[O:49])[CH3:48]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3CC#N)cc1
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(C)=O)C3CC#N)cc1
Reaction time: 4 h

Procedure:
1-(4-(8-(Cyanomethyl)-4-((S)-3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea (0.100 g, 0.230 mmol) in dry N,N-Dimethylformamide (1.00 mL, 12.9 mmol) was added N,N-Diisopropylethylamine (0.120 mL, 0.689 mmol) followed by Acetyl chloride (0.0246 mL, 0.346 mmol). The reaction mixture was stirred for 4 hours. The reaction mixture was concentrated and chromatographed through silica gel (12 g, 0-5% MeOH in dichloromethane). LC/MS-m/z+478.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[O:6][C@H:7]([CH2:10]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:8][O:9][C:4]=2[CH:3]=1.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K].O>CN(C=O)C>[Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[O:6][C@@H:7]([CH2:10][N:29]3[C:25](=[O:35])[C:26]4[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:28]3=[O:30])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COc3cc(Cl)c(Cl)cc3O2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C[C@H]1COc2cc(Cl)c(Cl)cc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
Toluene-4-sulfonic acid (2S)-6,7-dichloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester (8.0 g, 20.5 mmol) was combined with potassium phthalimide (6.1 g, 33 mmol) in DMF (75 mL) and heated to reflux for 1 h, cooled to room temperature and poured into vigorously stirring water (0.5 L) and then stirred 30 min. White solid was filtered and the solid was washed several times with water, 2% NaOH, and water again and then let air dry to yield (2S)-2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-isoindole-1,3-dione (6.0 g, 80%) as a white powdery solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH:16]=[CH2:17])[S:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[NH2:14])(=[O:7])=[O:6])[CH:2]=[CH2:3].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[S:27](Cl)(=[O:29])=[O:28])=[C:21]([O:31][CH3:32])[CH:20]=1>>[CH2:15]([N:4]([CH2:1][CH:2]=[CH2:3])[S:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[NH:14][S:27](/[CH:26]=[CH:25]/[C:22]1[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][C:21]=1[O:31][CH3:32])(=[O:28])=[O:29])(=[O:7])=[O:6])[CH:16]=[CH2:17]
Reactant: C=CCN(CC=C)S(=O)(=O)c1cnccc1N
Reactant: COc1cc(Cl)ccc1/C=C/S(=O)(=O)Cl
Product: C=CCN(CC=C)S(=O)(=O)c1cnccc1NS(=O)(=O)/C=C/c1ccc(Cl)cc1OC
Yield: 50 %

Procedure:
The title compound was synthesized as described for Example 204 c) in 50% yield, starting from N,N-diallyl-4-aminopyridine-3-sulfonamide and (E)-2-(4-chloro-2-methoxyphenyl)ethenesulfonyl chloride. Purification by column chromatography, using chloroform/methanol (98:2) as the eluent.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([CH3:22])[CH3:21].[I-].[K+]>C(OCC)(=O)C.[I-].[K+].CN(C)C=O>[CH:20]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6])([CH3:22])[CH3:21]
Reactant: COC(=O)c1ccc(C)c(O)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(OC(C)C)c1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
To a mixture of methyl 3-hydroxy-4-methylbenzoate (5.28 g, 31.8 mmol), potassium carbonate (6.59 g, 47.7 mmol) and N,N-dimethylformamide (50 mL) were added 2-bromopropane (3.58 mL, 38.2 mmol) and potassium iodide (0.53 g, 3.18 mmol) with stirring at room temperature, and the mixture was stirred at 80° C. for 7 hr. 2-Bromopropane (1.79 mL, 19.1 mmol) and potassium iodide (0.27 g, 1.59 mmol) were added to the reaction mixture, and the mixture was further stirred at 80° C. for 15 hr. The reaction mixture was cooled, and diluted with ethyl acetate. The mixture washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=19/1-hexane/ethyl acetate=4/1) to give the title compound (6.3 g, yield 96%) as a colorless oil. MS (ESI+): 209 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([OH:10])=O)=[CH:4][C:3]=1[Cl:21].C(N(CC)CC)C.ClC(OCC)=O.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:3]([Cl:21])=[CH:4][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:10])=[CH:18][C:19]=1[Cl:20]
Reactant: Nc1c(Cl)cc(C(=CC(=O)O)c2ccc(Cl)cc2)cc1Cl
Reactant: C1COCCN1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Nc1c(Cl)cc(C(=CC(=O)N2CCOCC2)c2ccc(Cl)cc2)cc1Cl
Temperature: -10 °C

Procedure:
20 g (0.058 mol) of 4-amino-β-(4-chlorophenyl)-3,5-dichloro-cinnamic acid (mixture of isomers A and B in the ratio 1:1.5) were dissolved in 700 ml of dry chloroform. 5.93 g (0.058 mol) of triethylamine were added while cooling with ice and stirring, and the mixture was cooled to -10° C. and combined with 6.35 g (0.058 mol) of ethyl chloroformate. After the addition had ended, 25.5 g (0.29 mol) of morpholine were added while further stirring and cooling. The resulting mixture was stirred for 4 hours more at room temperature and then extracted three times with water, and the organic phase was dried over sodium sulfate and concentrated to dryness in vacuo. The residue was chromatographed on a silica gel column (silica gel: substance=10:1, eluant: chloroform/ethyl acetate=1:1). The eluates containing substance were combined and evaporated to dryness in vacuo. Colorless crystals were obtained, melting point 140°-144° C., which contained the cis/trans isomer mixture in a proportion of 3:2.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]=[C:33]=[O:34])[CH:27]=1>>[N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH:23][C:33]([NH:32][C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)=[O:34])=[CH:21][CH:20]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: O=C=Nc1cccnc1
Product: O=C(Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1)Nc1cccnc1

Procedure:
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.08 g 0.23 mmoles) and 3-pyridyl isocyanate (30 mg, 0.25 mmoles) the title compound was isolated as a white solid. The product was purified by Silica gel column chromatography by eluting it with 10% MeOH: ethyl acetate. Yield; 60 mg (56%); (M+H)=463.5.
Reaction SMILES: O1C2CCCC([NH2:10])C=2C=C1.[CH3:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][CH2:19][C:20]2=O)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][CH2:19][CH:20]2[NH2:10])=[CH:15][CH:14]=1
Reactant: NC1CCCc2occc21
Reactant: COc1ccc2c(c1)C(=O)CCC2
Product: COc1ccc2c(c1)C(N)CCC2

Procedure:
Following the procedure for the preparation of 4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting 7-methoxy-3,4-dihydronaphthalen-1(2H)-one and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 6.99, 6.75, 3.95, 3.82, 2.74, 2.05, 1.96, 1.71, 1.67, 1.56; 13C NMR (100 MHz, CDCl3) δ 158.28, 142.62, 130.30, 129.19, 113.44, 112.88, 55.73, 50.12, 34.17, 29.12, 20.26.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([CH2:13][CH2:14][CH:15]2[CH:20]=[CH:19][C:18](OC)=[CH:17][C:16]2=C=O)[N:7]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]/[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]/[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[CH:10][CH:9]=[C:8]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:3]([O:2][CH3:1])=[O:25])=[CH:19][CH:20]=2)[N:7]=1
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Reactant: COC(=O)CCc1nc(CCC2C=CC(OC)=CC2=C=O)ccc1O
Product: COC(=O)CCc1nc(CCc2ccc(C(=O)OC)cc2)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 106.1 %

Procedure:
Under the conditions of example 1 D, 280 mg of 3-{6-[2-(4-methoxy-carbonylphenyl)-ethyl]-3-hydroxy-2-pyridyl}-propionic acid methyl ester is reacted with 220 mg of (1E)-6-bromo-1-(4-methoxyphenyl)-1-hexene, worked up, and the crude product is chromatographed on silica gel with hexane/0-10% ethyl acetate. 230 mg of 3-{6-[2-(4-methoxycarbonylphenyl)-ethyl]-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester of melting point 59°-61° C. is obtained.