Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.[CH3:16][N:17]=[C:18]=[S:19]>C(O)C>[CH3:16][NH:17][C:18](=[S:19])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: CN=C=S
Reactant: Nc1ccc(CCc2ccccn2)cc1
Solvent: CCO
Product: CNC(=S)Nc1ccc(CCc2ccccn2)cc1
Yield: 92 %

Procedure:
A solution of 2-[2-(4-aminophenyl)ethyl]pyridine (5.8 g) and methyl isothiocyanate (2.6 g) in ethanol (60 ml) was refluxed for one hour. The reaction mixture was evaporated in vacuo to give a crystalline residue, which was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 2-[2-{4-(3-methylthioureido)phenyl}ethyl]pyridine (7.3 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]([C:16]#[N:17])=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].[N-:20]=[N+:21]=[N-:22].[Na+].O>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]([C:16]1[NH:22][N:21]=[N:20][N:17]=1)=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2[nH]c(=O)c(C#N)cc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc2[nH]c(=O)c(-c3nnn[nH]3)cc2c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
6-tert-Butyl-3-cyano-1,2-dihydroquinolin-2-one (1.74 g, 7.7 mmol) was dissolved in DMF (20 ml), and ammonium chloride (1.65 g, 30.8 mol) and sodium azide (2.00 g, 30.8 mol) were added to the resultant mixture. The mixture was stirred at a bath temperature of 120° C. for 16 hours. Water was added to the reaction mixture. After removal of the precipitates by filtration, the reaction mixture was recrystallized from DMF-methanol. The crystals that precipitated were collected, to thereby obtain the title compound as yellow powder (1.08 g, 4.0 mmol, 52%).
Reaction SMILES: I[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.[O:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:20][N:6]1[C:5]2[CH:21]=[CH:22][C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:3][C:4]=2[C:10]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[N:9][CH2:8][C:7]1=[O:19]
Reactant: OB(O)c1ccccc1Oc1ccccc1
Reactant: CN1C(=O)CN=C(c2cccc(C#N)c2)c2cc(I)ccc21
Product: CN1C(=O)CN=C(c2cccc(C#N)c2)c2cc(-c3ccccc3Oc3ccccc3)ccc21
Yield: 41 %

Procedure:
Prepared from 3-(7-iodo-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 11 using the same conditions used to prepare Example 1 but using 2-phenoxy-phenyl boronic acid instead of benzene boronic acid. The title compound (90 mg) was obtained as a beige solid, in 41% yield.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15]O)[C:11]3[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=3[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:23])=O>ClC(Cl)Cl>[Cl:23][CH2:15][CH2:14][CH2:13][N:12]1[C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=2[N:9]=[C:8]1[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCn1c(Cc2ccccc2)nc2ccccc21
Solvent: ClC(Cl)Cl
Product: ClCCCn1c(Cc2ccccc2)nc2ccccc21
Reaction time: 4 h

Procedure:
To a stirred mixture of 40 parts of 2-(phenylmethyl)-1H-benzimidazole-1-propanol and 225 parts of trichloromethane are added dropwise 30 parts of sulfinyl chloride. Upon completion, stirring is continued for 4 hours at reflux temperature. The reaction mixture is evaporated and the residue is boiled in water. The solution is filtered over hyflo and the filtrate is alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 1-(3-chloropropyl)-2-(phenylmethyl)-1H-benzimidazole; mp. 112° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]([CH3:14])[C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:15])[CH:6]=1)=[O:4].[N+](=[CH2:18])=[N-].O.[OH-].[Li+]>CO.O>[CH3:15][C:7]1[CH:6]=[C:5]([CH:13]=[C:12]([CH3:14])[C:8]=1[C:9]([O:11][CH3:18])=[O:10])[C:3]([OH:2])=[O:4]
Reactant: C=[N+]=[N-]
Reactant: COC(=O)c1cc(C)c(C(=O)O)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1c(C)cc(C(=O)O)cc1C
Reaction time: 8 h

Procedure:
A solution of 4-(methoxycarbonyl)-2,6-dimethylbenzoic acid (2.08 g: 10 mmol) in methanol (25 mL) is treated with ethereal diazomethane until the yellow color persists and the solution is left at room temperature overnight. The solution is concentrated in vacuo to remove the remaining diethyl ether, then tetrahydrofuran (25 mL) is added. The solution is stirred in an ice-water bath as a solution of lithium hydroxide monohydrate (0.462 g, 11 mmol) in water (25 mL) is added. After the cooling bath is removed, the reaction is allowed to proceed at room temperature overnight. The volatiles are removed under reduced pressure on a rotary evaporator (bath temperature <30° C.), then the concentrate is diluted with brine and extracted with dichloromethane to remove residual 2,6-dimethylterephthalic acid dimethyl ester. The aqueous phase is acidified to pH 2 using 3N hydrochloric acid (4 mL), then is extracted with dichloromethane (2×25 mL). The combined organic extracts are washed with brine, then are dried (MgSO4), filtered and evaporated in vacuo to yield 3,5-dimethyl-4-(methoxycarbonyl)benzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].S(O[CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:27][CH2:26]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[CH2:34]([O:33][C:31]([N:28]1[CH2:29][CH2:30][CH:25]([CH2:24][N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=3)[CH:6]=[CH:7]2)[CH2:26][CH2:27]1)=[O:32])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(Cn2ccc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
To 6-fluoroindole (1.35 g, 10.0 mmol) in N,N-dimethylformamide (100 mL) was added a 60% mineral oil dispersion of sodium hydride (0.44 g, 11 mmol). The mixture was stirred at room temperature under nitrogen for 30 min, then 4-tosyloxymethyl-N-carbobenzyloxypiperidine (4.0 g, 10 mmol) added and the mixture heated at 70° C. under nitrogen for 16 hours. The solvent was removed in vacuum and replaced with methylene chloride (350 mL). The solution was washed with 250 mL portions of 2N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and saturated brine and dried over sodium sulfate. Filtration, concentration in vacuum and column chromatography on silica gel with methylene chloride as eluent gave 3.7 g of 4-(6-fluoro-indol-1-ylmethyl)-piperidine-1-carboxylic acid benzyl ester. This material was dissolved in ethyl acetate (100 mL), 10% Pd on carbon (0.50 g) and cyclohexene (3.2 g, 40 mmol) added, and the mixture refluxed under nitrogen for 2 hours. Filtration through celite, followed by concentration in vacuum gave 2.1 g of the title compound as a white solid. 1H-NMR (CDCl3): doublet of doublets 7.5 δ (1 H); doublet 7.0 δ (1 H); doublet of doublets 6.95 δ (1 H); triplet of doublets 6.82 δ (1 H); doublet 6.42 δ (1 H); doublet 3.9 δ (2 H); doublet 3.02 δ (1 H); triplet 2.5 δ (2 H); doublet 1.5 δ (2 H); multiplet 1.2 δ (2 H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl-].[CH3:12][O:13][C:14]1[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=1[CH:16]=[N+:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH3:12][O:13][C:14]1[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=1[CH:16]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:4]1[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])[NH:6][CH:5]=1
Reactant: COc1ccccc1C=[N+]1CCCC1
Reactant: Cc1cccc2[nH]ccc12
Agent: [Cl-]
Product: COc1ccccc1C(c1c[nH]c2cccc(C)c12)N1CCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-methyl-1H-indole and 1-(2-methoxy-benzylidene)-pyrrolidinium chloride, which had been prepared in accordance with example 24.
Reaction SMILES: [C:1]([N:9]1[C@H:13]([C:14](=[O:24])[NH:15][C@H:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][S@@:11](=[O:25])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)Cl>[C:1]([N:9]1[C@H:13]([C:14](=[O:24])[NH:15][C@H:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][S:11](=[O:34])(=[O:25])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@@H](NC(=O)[C@@H]1C[S@@](=O)CN1C(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: C[C@@H](NC(=O)[C@@H]1CS(=O)(=O)CN1C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.3 %

Procedure:
To a solution of 357 mg of (1R,4R)-3-benzoyl-4-[(R)-α-methylbenzylcarbamoyl]-1-oxothiazolidine (prepared as described in Example 25 or 28 ) in 10 ml of methylene chloride were added 203 mg of 85% m-chloroperbenzoic acid, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was then washed, in turn, with 30 ml of a 4% aqueous solution of sodium bicarbonate and with 30 ml of water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to leave an oil, which was then subjected to column chromatography through 80 g of silica gel, eluted with a 97.5:2.5 by volume mixture of methylene chloride and ethanol, to give an oil. This oil was crystallized by the addition of benzene to give 266 mg of the title compound in the form of crystals. The physical properties of these crystals were identical with those of the compound obtained as described in Example 27.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([OH:8])=[N:6][CH:7]=1>O1CCCC1.CO.[C].[Pd]>[NH2:9][C:4]1[C:5]([OH:8])=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cnc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cnc(O)c(N)c1
Reaction time: 24 h
Yield: 100.1 %

Procedure:
At room temperature, to a mixed solvent solution of 5-methyl-3-nitropyridin-2-ol (5.0 g) in tetrahydrofuran (200 ml) and methanol (200 ml) was added 10% palladium carbon (0.5 g), followed by stirring for 24 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and then the filtrate was concentrated under reduced pressure to afford 3-amino-5-methylpyridin-2-ol (4.03 g).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[C:17]([Cl:23])[CH:16]=1>CN(C)C=O.C1C=CC=CC=1>[Cl:23][C:17]1[CH:16]=[C:15]([Cl:14])[CH:20]=[CH:19][C:18]=1[CH2:21][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: COC(=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COC(=O)C(Cc1ccc(Cl)cc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 30 parts of methyl benzeneacetate, 6.8 parts of sodium hydride dispersion 78%, 135 parts of N,N-dimethylformamide and 180 parts of benzene is stirred for 1 hour at room temperature, while nitrogen gas is introduced. Another 90 parts of benzene is added. Then there is added dropwise, during a 30 minutes-period, a solution of 43.4 parts of 1,3-dichloro-4-(chloromethyl)benzene in 45 parts of N,N-dimethylformamide. Upon completion, stirring is continued for 30 minutes at room temperature. The reaction mixture is poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed with water, dried, filtered and evaporated. The residue is distilled, yielding 26.5 parts of methyl 2,4-dichloro-α-phenylbenzenepropanoate; bp. 140°-145° C at 0.05 mm. pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH:12]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:19].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[C:24]([Cl:40])=[CH:23][N:22]=1>>[Cl:40][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])=[N:26][C:21]([NH:19][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH:12]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:11][CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:22][CH:23]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCNC1CCCc2c(ccc(N)c2OC)C1
Product: COCCNC1CCCc2c(ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)c2OC)C1

Procedure:
The title compound was prepared from 1-methoxy-N(6)-(2-methoxyethyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2,6-diamine (60 mg, 0.2 mmol) and 2-(2,5-dichloropyrimidin-4-ylamino)-N,N-dimethylbenzenesulfonamide (79 mg, 0.23 mmol) in an analogous manner to Example 946 to afford an off-white solid (15 mg, 10%). LCMS (m/e) 575 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.42 (s, 1H), 8.54 (d, J=8 Hz, 1H), 8.17 (s, 1H), 8.06 (d, J=8 Hz, 1H), 7.90 (d, J=8 Hz, 1H), 7.65 (m, 1H), 7.51 (s, 1H), 7.30 (m, 1H), 6.88 (d, J=8 Hz, 1H), 3.71 (s, 3H), 3.62 (m, 2H), 3.35 (s, 3H), 3.20-3.05 (m, 4H), 2.76 (s, 6H), 2.62 (m, 1H), 2.27 (m, 1H), 2.00 (m, 2H), 1.51 (m, 1H) 1.28 (m, 2H).
Reaction SMILES: [CH2:1]([OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:16](O)(=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[C:1]([O:30][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCO
Reactant: CCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCC
Temperature: 60 °C
Reaction time: 25 h

Procedure:
329 g of myristyl alcohol and 351 g of myristic acid were heated to 60° C. in a 1 l reservoir vessel and mixed by means of a magnetic stirrer (viscosity of the mixture at 60° C. approx. 6 mPas). The lower region of the reaction vessel was initially charged with 2.7 g of NOVOZYM 435 and the entire reaction vessel was heated to 60° C. The compressed air introduction was regulated to 0.4 l/min and then the peristaltic pump was set to ˜20 ml/min and switched on. The reflux was heated to 60° C. The course of the reaction was monitored for ˜25 h, and a conversion of 99.3% based on the fatty acid was achieved.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[Cl:20])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:21])[N:4]=1.CN(C=O)C.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K]>>[Cl:21][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:12]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[Cl:20])[C:3]([CH2:2][N:31]1[C:27](=[O:37])[C:28]3[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:30]1=[O:32])=[N:4]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Fc1ccc(Cl)c(-c2nc3c(Cl)cccc3nc2CBr)c1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Temperature: 100 °C

Procedure:
To a heterogeneous mixture of 2-(bromomethyl)-5-chloro-3-(2-chloro-5-fluoro-phenyl)quinoxaline (0.1815 g, 0.4702 mmol) in DMF (3.444 mL, 0.4702 mmol) was added potassium phthalimide (0.2177 g, 1.175 mmol) and the heterogeneous mixture was stirred at 100° C. After stirring at 100° C. for 30 min, the mixture was concentrated under reduced pressure and triturated with water (30 mL). The precipitate was collected by filtration. The resulting solid was filtered and washed with 2 N NaOH (30 mL) and then with water (100 mL), and air-dried to give 2-((5-chloro-3-(2-chloro-5-fluorophenyl)quinoxalin-2-yl)methyl)isoindoline-1,3-dione as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (1 H, dd, J=7.6, 1.4 Hz), 7.95-8.01 (1 H, m), 7.82-7.91 (5 H, m), 7.65-7.75 (2 H, m), 7.43-7.52 (1 H, m), 4.99 (2 H, br. s.); LC-MS (ESI) m/z 452.0 [M+H]+. The crude product was carried on crude without purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[NH2:11][CH:12]([CH3:15])[CH2:13][OH:14].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:11][CH:12]([CH3:15])[CH2:13][OH:14])[C:5]#[N:6]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: CC(N)CO
Solvent: CS(C)=O
Solvent: O
Product: CC(CO)Nc1ccc(C#N)cc1Cl
Reaction time: 2 h

Procedure:
4.00 g (25.7 mmol) 3-chloro-4-fluoro-benzonitrile are heated to 60° C. in 20 ml DMSO with 8.00 g (106.5 mmol) 2-amino-1-propanol with stirring for 2 hours. Then the reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9](=[O:15])[CH2:8][C:7]2([CH3:17])[CH3:16])(=[O:3])[CH3:2].[CH2:18](O)[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:14][N:10]1[C:11]2[C:6](=[CH:5][C:4]([C:1]3([CH3:2])[O:20][CH2:19][CH2:18][O:3]3)=[CH:13][CH:12]=2)[C:7]([CH3:17])([CH3:16])[CH2:8][C:9]1=[O:15]
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CC(=O)N2C
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CN1C(=O)CC(C)(C)c2cc(C3(C)OCCO3)ccc21
Yield: 94.1 %

Procedure:
5.0 g of 6-acetyl-3,4-dihydro-1,4,4-trimethyl-2(1H)-quinolinone were dissolved in 200 ml of benzene and, after the addition of 2.1 g of ethylene glycol and a few crystals of p-toluenesulphonic acid, the mixture was boiled under a water separator for 5 hours. After cooling, the mixture was diluted with ethyl acetate, washed with dilute sodium hydrogen carbonate solution, dried and evaporated. There were obtained 5.6 g of 3,4-dihydro-1,4,4-trimethyl-6-(2-methyl-1,3-dioxolan-2-yl)-2(1H)-quinolinone in the form of a colourless oil which solidified upon standing in a refrigerator; melting point 81°-83° C. This compound was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[C:11]2=[O:18].O1CCCC1>C(N(CC)CC)C>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:12](=[O:17])[C:11]2=[O:18]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1C(=O)C(=O)c2cc(Cl)ccc21

Procedure:
Ethoxycarbonyl chloride (10.5 ml) is added dropwise to a mixture of 5-chloroisatin (18.16 g), tetrahydrofuran (180 ml) and triethylamine (15.3 ml) with stirring, and the mixture is stirred at room temperature for 5 minutes. The mixture is concentrated under reduced pressure to remove solvent, and water is added to the residue. Crystalline precipitates are collected by filtration, washed with isopropanol and isopropyl ether and then dried, whereby 5-chloro-1-ethoxycarbonylisatin (23.3 g) is obtained.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].Cl.Cl.[CH3:7][O:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:30][CH2:29][C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C@H:24]4[CH2:28][CH2:27][NH:26][CH2:25]4)[C:17]=3[CH2:16]2)=[CH:11][C:10]=1[C:31]([F:34])([F:33])[F:32].C(N(CC)CC)C>C(Cl)Cl>[CH3:7][O:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:30][CH2:29][C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C@H:24]4[CH2:28][CH2:27][N:26]([C:1]([Cl:4])=[O:2])[CH2:25]4)[C:17]=3[CH2:16]2)=[CH:11][C:10]=1[C:31]([F:34])([F:32])[F:33]
Reactant: O=C(Cl)Cl
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)Cl)C4)c3C2)cc1C(F)(F)F
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To CH2Cl2 (5 mL) in a round bottomed flask was added phosgene (20% solution in toluene, 0.20 mL, 0.379 mmol) and the resulting solution cooled to 5° C. under argon. A solution of 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (prepared using step 1, example 91 from intermediate 13) (50.0 mg, 0.126 mmol) and triethylamine (0.053 mL, 0.380 mmol) in CH2Cl2 (1.0 mL) was added and the mixture allowed to warm to room temperature with stirring under argon over 1 h. Evaporated to dryness by bubbling a stream of argon into the mixture to give a brown gum. Dissolved in CH2Cl2 (3 mL) to give (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl chloride as a solution in CH2Cl2. LCMS: 458.4 [M+1]+, Rt(7)=1.38 min. This solution was used without further purification. 1.5 mL of this solution was added to a solution of piperidin-4-ol (6.4 mg, 0.063 mmol) and triethylamine (0.053 mL, 0.380 mmol) in CH2Cl2 and the mixture stirred at room temperature under argon for 1 h. N,N-dimethylformamide (0.5 mL) was added and stirring continued for 2 h. Diluted with CH2Cl2 (2 mL) and washed with sat. NaHCO3(aq) (2 mL). The organic layer was filtered through a phase separation tube and evaporated in vacuo. Purification by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions by elution through an Isolute® SCX-2 cartridge, eluting with methanol, then with 2M ammonia in methanol. Basic fractions were concentrated in vacuo to give (4-hydroxy-piperidin-1-yl)-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone as a pale yellow powder (22 mg, 64% yield). 1H NMR (400 MHz, MeOH-d4, 298K) δ ppm 1.35-1.57 (m, 2H) 1.80-1.94 (m, 2H) 2.20-2.31 (m, 2H) 2.94-3.09 (m, 4H) 3.45-3.87 (m, 10H) 3.98 (s, 3H) 4.17 (s, 2H) 5.70-5.76 (m, 1H) 7.78 (d, 1H) 8.13 (d, 1H) 8.58 (s, 1H) LCMS: [M+H]+=523.2, Rt(1)=1.58 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.[CH3:21][CH:22]1[CH2:26][C:25](=[O:27])[O:24][C:23]1=[O:28].C1(C)C=CC=CC=1>O>[F:20][C:19]1[CH:18]=[CH:17][C:4]([CH2:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[NH:8][N:7]=2)=[CH:3][C:2]=1[NH:1][C:25](=[O:27])[CH2:26][CH:22]([CH3:21])[C:23]([OH:28])=[O:24]
Reactant: CC1CC(=O)OC1=O
Reactant: Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: O
Solvent: Cc1ccccc1
Product: CC(CC(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)C(=O)O

Procedure:
A stirred mixture of 4-(3-amino-4-fluorobenzyl)-2H-phthalazin-1-one (2.02 g, 7.5 mmol; prepared in a manner similar to that described in Example 23), 3-methyldihydrofuran-2,5-dione (0.856 g, 7.5 mmol) and toluene (100 ml) was heated under reflux for 2.5 hours (for the first 30 minutes of this period, traces of water in the mixture were removed by azeotropic distillation). The resulting solid was collected by filtration from the hot mixture, washed with toluene (20 ml) and dried in vacuo to give N-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-2-methylsuccinamic acid (1.91 g) as an off-white solid, m.pt. 140–144° C.; 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 0.95 (d, 3H) (CH3), 2.2–2.6 (m, 3H) (—CH2CHMe-), 4.1 (s, 2H) (ArCH2—), 6.9–7.2 (m, 2H) (2×ArH), 7.6–7.9 (m, 4H) (4×ArH), 8.1 (d, 1H) (ArH), 9.55 (s, 1H) (chain CONH), 12.0 (br s, 1H) (CO2H), 12.5 (s, 1H) (ring CONH); m/z (M+H)+ 384, 100% purity.