Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[N:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8](OC)=[C:9](OC)[CH:10]=2)[C:5]1=[O:18].ClCCN1N=CC2C(=CC=CC=2)C1=O.C1(N2CCNCC2)C=CC=CC=1.[F:45][C:46]1[CH:59]=[CH:58][C:49]([C:50]([CH:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)=[O:51])=[CH:48][CH:47]=1>C(O)C.C(OCC)C>[ClH:1].[F:45][C:46]1[CH:47]=[CH:48][C:49]([C:50]([CH:52]2[CH2:57][CH2:56][N:55]([CH2:2][CH2:3][N:4]3[N:13]=[CH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]3=[O:18])[CH2:54][CH2:53]2)=[O:51])=[CH:58][CH:59]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: COc1cc2cnn(CCCl)c(=O)c2cc1OC
Agent: O=c1c2ccccc2cnn1CCCl
Agent: c1ccc(N2CCNCC2)cc1
Solvent: CCO
Solvent: CCOCC
Product: Cl
Product: O=C(c1ccc(F)cc1)C1CCN(CCn2ncc3ccccc3c2=O)CC1

Procedure:
Working as described in Example 3 but replacing 2-[2chloroethyl]-6,7-dimethoxy-1(2H)-phthalazinone with an equivalent amount of 2-(2-chloroethyl)-1(2H)-phthalazinone and replacing N-phenyl piperazine with an equivalent amount of 4-(4-fluorobenzoyl)-piperidine, 2-{2-[4-(4-fluorobenzoyl)-piperidin-1-yl]-ethyl}-1(2H)-phthalazinone hydrochloride is obtained (m.p. 230°-250° C., from ethyl alcohol/ethyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:40]#[C:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:40]#[C:41][C:42]3[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: Clc1ccc(C#CBr)cc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: CN1CCc2c(n(C#Cc3ccc(Cl)cc3)c3ccc(Cl)cc23)CC1
Temperature: 80 °C
Yield: 10 %

Procedure:
A mixture of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (235 mg, 1 mmol), CuSO4.5H2O (50 mg, 0.2 mmol), 1,10-Phenanthroline (72 mg, 0.4 mmol), K3PO4 (425 mg, 2 mmol) and 1-(bromoethynyl)-4-chlorobenzene (237 mg, 1.1 mmol) in toluene (10 mL) was flushed with nitrogen heated 80° C. for 16 h. The reaction was monitored by LCMS. The reaction mixture was filtered through Celite, washed with DCM. The organic layer was concentrated and purified by column chromatography (silica gel, 60-80% ethyl acetate in hexane) to get 37 mg of product. 1H NMR (CDCl3, HCl salt) δ (ppm): 7.50 (s, 1H) 7.49-7.40 (m, 3H), 7.38-7.32(m, 2H), 7.25-7.20 (d, 1H), 3.22-3.18 (m, 2H), 3.0-2.90 (m, 6H), 2.60 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:21]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])[CH:18]=2)[CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:21]1([C:19]([C:17]2[CH:18]=[C:14]([CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)[S:15][CH:16]=2)=[O:20])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(C(=O)N3CCCCCC3)cs2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1csc(C2CCCNC2)c1)N1CCCCCC1
Reaction time: 1 h
Yield: 105.8 %

Procedure:
3-[4-(Azepane-1-carbonyl)-thiophen-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.066 g) was dissolved in TFA/DCM (1:1, 5 mL) and stirred for 1 hour. The solvent was then evaporated and the residue dissolved in DCM and purified using a SCX-2 column. After washing with methanol and acetonitrile, the desired compound was washed from the column with ammonia (2 M in MeOH). Evaporation gave the title compound as a clear colourless oil (0.052 g). LCMS m/z 293.14 [M+H]+ RT=5.27min (Analytical Method 2). 1H NMR δ (ppm)(CHCl3-d): 7.3 (s, 1H), 6.9 (s, 1H), 3.8 (m, 2H), 3.5 (m, 2H), 3.3 (d, 1H), 3.1 (d, 1H), 2.9 (m, 1H), 2.7-2.6 (m, 3H), 2.1 (m, 1H), 1.8-1.5 (m, 11H).
Reaction SMILES: [NH4+].[OH:2][C:3]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)([C:11]([O-:13])=[O:12])[CH2:4][C:5](=[N:9]O)[C:6]([O-:8])=[O:7].[NH4+].[H][H]>O.[Ni]>[OH:2][C@@:3]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)([C:11]([OH:13])=[O:12])[CH2:4][C@@H:5]([NH2:9])[C:6]([OH:8])=[O:7].[OH:2][C@:3]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)([C:11]([OH:13])=[O:12])[CH2:4][C@@H:5]([NH2:9])[C:6]([OH:8])=[O:7]
Reactant: O=C([O-])C(CC(O)(Cc1c[nH]c2ccccc12)C(=O)[O-])=NO
Reactant: [H][H]
Agent: [Ni]
Agent: [NH4+]
Solvent: O
Product: N[C@H](C[C@@](O)(Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O
Product: N[C@H](C[C@](O)(Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O

Procedure:
1.0 g (2.94 mmol) of 4-hydroxy-4-(3-indolylmethyl)-2-hydroxyiminoglutarate ammonium salt was dissolved in 10 ml of water, to which 1 ml of a Raney-nickel catalyst (manufactured by Kawaken Fine Chemicals Co., Ltd.; developed nickel catalyst NDHT-90) was added with a syringe, and the mixture stirred at a hydrogen pressure of 20 atmospheres for 10 hours. The catalyst was filtered off, and the resulting solution was concentrated to obtain the residue. The residue was analyzed by NMR. It was shown that 0.29 g (0.89 mmol; yield, 30%) of (2S,4S)/(2R,4R)-4-hydroxy-4-(3-indolylmethyl)-2-aminoglutaric acid (monatin) and 0.29 g (0.89 mmol; yield, 30%) of (2S,4R)/(2R,4S)-4-hydroxy-4-(3-indolylmethyl)-2-aminoglutaric acid were generated.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[Cl:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[Cl:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][CH2:2][C:3]1[C:4]([NH:16][CH:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[C:5]2[CH:13]=[N:12][N:11]([CH2:14][CH3:15])[C:6]2=[N:7][C:8]=1[CH2:9][CH3:10])=[O:29]
Reactant: O=C(O)c1cccc(CCl)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
To a solution of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-amine (0.303 g, 1.0 mmol) in CH2Cl2 (10 mL) was added 3-(chloromethyl)benzoic acid (0.188 g, 1.1 mmol), EDC (0.288 g, 1.5 mmol), HOBt (0.0135 g, 0.1 mmol), and Et3N (0.141 mL, 1.0 mmol). This mixture was stirred at room temperature for 1 h, then washed with H2O (1 mL) and purified by CombiFlash chromatograph to afford the title compound 0.285 g (63%). LC-MS m/z 456 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([OH:7])=O.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@@H:19]1[CH2:24][N:25]1C(=O)C2C(=CC=CC=2)C1=O.F[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1>>[F:1][C:2]1[C:3]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)=[C:4]([C:5]([N:20]2[CH2:21][CH2:22][CH2:23][C@@H:18]([CH3:17])[C@H:19]2[CH2:24][NH:25][C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=2)=[O:7])[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: O=C(O)c1cc(F)cc(F)c1-n1nccn1
Product: C[C@@H]1CCCN(C(=O)c2cc(F)cc(F)c2-n2nccn2)[C@@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared from 3,5-difluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione, and 2-fluoro-5-(trifluoromethyl)pyridine using the methods described herein. ESI-MS (m/z): 481 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=3)=[O:28])[CH:23]=[CH:22][C:20]=2[N:21]=1.O1CCOCC1>CN(C)C=O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27]([NH:26][C:24]2[CH:23]=[CH:22][C:20]3[N:21]=[C:17]([NH:16][C:2]4[C:11]5[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=5)[N:5]=[CH:4][N:3]=4)[S:18][C:19]=3[CH:25]=2)=[O:28])=[CH:31][C:32]=1[C:37]([F:39])([F:38])[F:40]
Reactant: Nc1nc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2s1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)Nc5ccc(Cl)c(C(F)(F)F)c5)cc4s3)c2cc1OC

Procedure:
1-(4-Chloro-3-trifluoromethylphenyl)-3-[2-(6,7-dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl]urea was prepared from 4-chloro-6,7-dimethoxyquinazoline (Fluorochem, 29 mg, 0.13 mmol) and 1-(2-aminobenzothiazol-6-yl)-3-(4-chloro-3-trifluoromethylphenyl)urea (Intermediate 3, 50 mg, 0.13 mmol) according to GP 1. Dimethylformamide was used as a solvent instead of dioxane. After removal of the solvent in vacuo, the residue was subjected to silica gel chromatography applying a dichloromethane-methanol gradient. The crude product was dissolved in dimethylformamide (2 mL) and water was added (2 mL). After storage at 4° C. overnight, the resulting precipitate was filtered off, washed with water and dried to obtain a yellow solid (27 mg, 48 μmol, 37%). LC/ESI-MS: m/z=575 [M(35Cl)+H]+; m/z=573 [M(35Cl)−H]=; Rt=4.14 min.
Reaction SMILES: [N:1]1([C:7]2[N:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:15]=[C:11]3[N:10]=[C:9]([NH:22][NH2:23])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:24]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O)([CH3:26])[CH3:25]>C(O)C>[CH:24]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=[N:23][NH:22][C:9]1[CH:8]=[C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:12]2[N:13]=[C:14]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)[CH:15]=[C:11]2[N:10]=1)([CH3:26])[CH3:25]
Reactant: CC(C)c1cccc(C=O)c1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccncc3)cc2n1
Solvent: CCO
Product: CC(C)c1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccncc4)cc3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
There was dissolved, in ethanol (2 mL), (7-morpholin-4-yl-2-pyridin-4-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (30.1 mg, 0.0967 mM), then 3-isopropyl-benzaldehyde (14.3 mg, 0.0967 mM) was added to the solution and the mixture was stirred at room temperature overnight. The solvent was distilled off from this reaction liquid, the resulting residue was purified by the reversed phase HPLC and then subjected to a desalting treatment to thus give the title compound (11.3 mg, yield: 26%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=[O:14])[CH2:11][CH:10]([OH:16])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].CC([O-])(C)C.[K+].Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1.CO.C(Cl)Cl>CS(C)=O>[C:2]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:16][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)[CH2:11][CH:12]1[C:13]([OH:15])=[O:14])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: Clc1nccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CC(O)C[C@H]1C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(Oc2nccc3ccccc23)CC1C(=O)O
Temperature: 25 °C
Yield: 96 %

Procedure:
A suspension of Boc-L-4-hydroxyproline (N-Boc(2S,4R)-hydroxyproline) (3.85 g 16.6 millimole (“mmol”) (CHEM-IMPEX International) in DMSO (60 mL) was cooled in an ice bath for ˜3 minutes, and then t-BuOK (4.66 g, 41.5 mmol) was added. Stirring and cooling in the ice bath was continued for a few minutes until a solid mass formed. At this time the reaction mixture was allowed to warm to rt over 1.5 h to give a clear colorless solution. 1-Chloroisoquinoline (3.0 g, 18.3 mmol) was added in two portions 10 min apart. The reaction was stirred for 24 h at rt. The dark reaction mixture was partitioned between ether (200 mL) and water (600 mL). The aqueous phase was acidified to pH 4 using 4N HCl. The resulting milky yellow solution was extracted with ether (4×200 mL). The combined ether extracts were dried (MgSO4), filtered, and concentrated in vacuo to give a golden oil. Flash chromatography (2–4% MeOH/CH2Cl2) gave 5.69 g (96%) of 4-(isoquinolin-1-yloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester as an off-white solid: LC-MS (Method A, retention time: 3.06 min), MS m/z 359 (M++1).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:16]=1[CH:17]=O)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH3:36][NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.N1[C:49]2C=CC=C[C:48]=2N=N1>C(O)C>[CH2:38]([N:37]([CH3:36])[CH:17]([C:16]1[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[CH:22][C:15]=1[CH2:14][N:7]([CH2:6][C:5]1[CH:4]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1)[CH2:48][CH3:49])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CNCc1ccccc1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C=O)n1
Reactant: c1ccc2[nH]nnc2c1
Solvent: CCO
Product: CCC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.3 %

Procedure:
To a solution of 2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzaldehyde (200.0 mg, 0.391 mmoles) in ethanol (3.0 mL) was added N-methyl benzylamine (61 μL, 0.469 mmol) and benzotriazole (56 mg, 0.469 mmoles) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated to remove ethanol and the residue was taken up in toluene (6.0 mL), cooled to 0° C. and ethyl magnesium chloride (0.78 mL, 1.564 mmoles of a 2M solution in ether) was added. The reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous NH4Cl. Ether was added and the mixture was stirred for 5 minutes, To the mixture was added 1N NaOH to achieve pH of 10. The aqueous layer was extracted with ether and the combined organic layer was dried over sodium sulfate and concentrated to give a yellow oil. The crude product was purified using silica gel chromatography on the ISCO Combiflash system (Teledyne ISCO, Lincoln, Nebr., USA) with a gradient of 1-3% methanol in dichloromethane to yield the title compound (242.7 mg, 96% yield) as light yellow oil. MS (ES+) Calc: 608.5, Found: 609.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].CO[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1OC)[C:22](=O)[NH:21][C:20](=O)/[C:19]/2=[CH:30]/OC.Cl.OC1C=C([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])CN.Cl.CON>>[O:43]1[CH:42]=[CH:41][C:40]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH:22]=[N:21][CH2:20]/[C:19]/3=[CH:30]\[NH:6][CH2:5][C:4]2[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:2]([OH:1])[CH:3]=2)=[CH:44]1
Reactant: CO/C=C1/C(=O)NC(=O)c2cc(OC)c(OC)cc21
Reactant: COc1cc(CN)cc(O)c1OC
Reactant: COc1ccc(CN)cc1O
Agent: CON
Agent: Cl
Product: COc1cc(CN/C=C2\CN=Cc3ccc(-c4ccoc4)cc32)cc(O)c1OC

Procedure:
Using the procedure described for the preparation of example 46, 120 mg of brown solid (50%) yield is obtained from 150 mg (0.57 mmol) of (4E)-6-(3-furyl)methoxymethylene-isoquinoline-1,3(2H,4H-dione, (prepared similarly to 4-methoxymethylene-6-thiophin-3-yl-isoquinolin-(4H)-1,3-dione) and 3-hydroxy-4,5-dimethoxybenzylamine (115 mg, 0.57 mmol), (prepared similarly to (4E)-6,7-dimethoxy-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione and 3-hydroxy-4-methoxy-benzylamine hydrogen chloride, except methoxy amine hydrogen chloride is used instead of hydroxylamine hydrogen chloride); mp 263-264° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc(CC(=O)O)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A stirred suspension of 3-hydroxyphenylacetic acid (10.2 g, 67 mmol) in acetic anhydride (100 mL, 1.06 mol) under anhydrous conditions was treated with pyridine (0.5 mL). In the mildly exothermic reaction, the solids dissolved within several minutes and the mixture was maintained at 40° C. for 5 h. The reaction was concentrated in vacuo to about half volume, then water (30 g) in the form of ice chips was added at such a rate that the temperature remained <45° C. When the exotherm had subsided, a second portion of water (200 mL) was added slowly and the mixture was stirred for another 30 min. The precipitated solid was filtered, washed with water and dried to constant weight in vacuo over P2O5 to give 3-acetoxyphenylacetic acid (11.7 g, 90%) which was used without further purification. In an inert atmosphere, a solution of the above 3-acetoxyphenylacetic acid (1.942 g, 10 mmol), diphenylphosphoryl azide (2.8 g, 10.17 mmol) and diisopropylethylamine (1.92 mL, 11 mmol) in benzene (25 mL) was stirred at room temperature for 1 h, then the reaction temperature was slowly raised to 70° C. Evolution of gas began to be evident as the reaction temperature reached approximately 55° C. and became much more vigorous as the reaction temperature approached 70° C. Within 30 minutes at that temperature gas evolution had stopped and the reaction solution containing 3-acetoxybenzylisocyanate was cooled to 40° C. Another portion of DIPEA (3.84 mL, 22 mmol) was added, followed by 4-amino-2-chlorobenzoic acid methyl ester hydrochloride salt (2.95 g, 13.3 mmol) and the brownish purple solution was stirred and heated at reflux under argon overnight. The reaction mixture was cooled, diluted with benzene (50 mL) and washed in turn with 1N HCl (50 mL) and dilute brine. The aqueous layers were re-extracted with benzene, and the combined extracts were dried (MgSO4), evaporated, and purified by HPLC (silica gel; 40% ethyl acetate/hexane). Evaporation of the appropriate fractions provided 3.24 g of the solid urea which was then crystallized from dichloromethane-ethyl acetate to give 4-[[[[(3-acetoxy)phenyl]methyl]amino]carbonyl]amino-2-chlorobenzoic acid, methyl ester (2.71 g, 72%) as a colorless solid, mp 113-114° C.
Reaction SMILES: [CH:1]([NH:4][S:5](Cl)(=[O:7])=[O:6])([CH3:3])[CH3:2].[C:9]([NH:13][C:14](=[NH:19])[O:15][CH:16]([CH3:18])[CH3:17])([O:11][CH3:12])=[O:10].C(N(CC)CC)C>O1CCCC1>[C:9]([NH:13][C:14](=[N:19][S:5](=[O:7])(=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])[O:15][CH:16]([CH3:17])[CH3:18])([O:11][CH3:12])=[O:10]
Reactant: COC(=O)NC(=N)OC(C)C
Reactant: CC(C)NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)NC(=NS(=O)(=O)NC(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
95 parts of isopropylaminosulfonyl chloride were stirred into a mixture of 96 parts of N-carbomethoxy-O-isopropyl-isourea and 73 parts of triethylamine in 700 parts of tetrahydrofuran at 10°-15° C., in the course of 25 minutes. After having been stirred for one hour at 25° C., the reaction mixture was extracted once with water and once with 0.5 N hydrochloric acid, dried and evaporated down under reduced pressure. 130 parts of N-carbomethoxy-N'-isopropylsulfamyl-O-isopropylisourea, of melting point 62°-64° C., were obtained. 33.7 parts of this product were cyclized with 17.6 parts of 50 percent strength by weight sodium hydroxide solution in 30 parts of water for 5 minutes at 55°-60° C. After extraction with ether, acidification, filtering, washing the residue with water and drying, 22 parts of 6-isopropyl-3-isopropoxy-6H-1,2,4,6-thiatriazin-5-one-1,1-dioxide, of melting point 164°-167° C., were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][C:8]=1[C:9]([O:11]C(C)(C)C)=[O:10])=[O:5]>C(Cl)Cl.FC(F)(F)C(O)=O>[OH:1][C:2]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[N:34][CH:33]=[N:32][CH:31]=2)=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][C:8]=1[C:9]([OH:11])=[O:10])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2cncnc2)ccc1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(-c2cncnc2)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
A solution mixture of the obtained tert-butyl 2-(2-hydroxy-5-(pyrimidin-5-yl)benzamido)-4-phenylbenzoate (0.73 g) in methylene chloride (25 mL) and trifluoroacetic acid (10 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and water was added to the obtained residue. After adjusting the pH to 6.5 with a saturated aqueous solution of sodium bicarbonate, the solid substance was collected by filtration to obtain 0.49 g of 2-(2-hydroxy-5-(pyrimidin-5-yl)benzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][C:5]=1[OH:13])[CH3:2].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:16]=1.CC(C)([O-])C.[K+].O>CS(C)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][C:5]=1[O:13][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:16]=1)[CH3:2]
Reactant: CC(=O)Nc1cc(Cl)ccn1
Reactant: CCOc1cc2[nH]ccc2cc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1cc2[nH]ccc2cc1Oc1ccnc(NC(C)=O)c1
Temperature: 160 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
6-Ethoxy-1H-indol-5-ol described in Production Example 15-4 (7.0 g, 39.5 mmol) was dissolved in dimethylsulfoxide (40 mL) under nitrogen atmosphere, then N-(4-chloropyridin-2-yl)acetamide described in Production Example 1-5 (8.09 g, 47.4 mmol) and potassium tert-butoxide (4.88 g, 43.5 mmol) were added at room temperature, and the mixture was heated and stirred at 160° C. for 4 hours. The reaction liquid was cooled to room temperature and water and ethyl acetate were added for partition. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with water twice and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under vacuum. The residue was dissolved in dichloromethane, and the resultant was purified with silica gel column chromatography (n-heptane:ethyl acetate=3:1-2:1-3:2-1:3-1:4-0:1), and then the target fraction was concentrated under vacuum to obtain the title compound (7.16 g, 58%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([SH:7])[S:5][CH:6]=1.[H-].[Na+].[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21]2[C:24]([CH2:29]Cl)=[C:25]([Cl:28])[CH:26]=[CH:27][C:20]=2[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CN(C=O)C>[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21]2[C:24]([CH2:29][S:7][C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)=[C:25]([Cl:28])[CH:26]=[CH:27][C:20]=2[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Reactant: Cc1csc(S)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1csc(SCc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
To a solution of 4-methylthiazole-2-thiol (0.32 g, 2.5 mmol) in anhydrous DMF (8.4 mL) add sodium hydride (0.10 g, 2.6 mmol, 60% dispersion in mineral oil) in portions at room temperature. After stirring at room temperature for 10 min, add a solution of 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.74 g, 2.2 mmol) in anhydrous DMF (5.6 mL). Heat the reaction mixture at 45° C. for 2 h under nitrogen atmosphere, cool to room temperature and stir overnight. Quench the reaction mixture with 10% aqueous NaHCO3 (14 mL) and extract the mixture three times with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (40 g) eluting with hexane/EtOAc (1:0 to 85:15 gradient over 30 min; 35 mL/min) to obtain 3-tert-butoxycarbonyl-7-chloro-6-(4-methyl-thiazol-2-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.753 g, 79%) as a white foam.