Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7]([C:9]1(Cl)[CH2:15][CH:14]2[N:11]([C:12](=[O:16])[CH2:13]2)[CH:10]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:8])(=[O:3])[CH3:2].N12CCCCC1C=NCCC2>C(OCC)(=O)C>[C:1]([NH:4][CH2:5][CH2:6][S:7]([C:9]1[CH2:15][CH:14]2[N:11]([C:12](=[O:16])[CH2:13]2)[C:10]=1[C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCS(=O)C1(Cl)CC2CC(=O)N2C1C(=O)OCc1ccccc1
Agent: C1=NCCCN2CCCCC12
Solvent: CCOC(C)=O
Product: CC(=O)NCCS(=O)C1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.8 %

Procedure:
A solution of benzyl 3-(2-acetamidoethylsulphinyl)-3-chloro-7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (62) (0.010 g) in ethyl acetate (1 ml) was treated with 1,5-diazabicyclo[5.4.0]undec-5-ene (0.0037 g) under an argon atmosphere. It was stirred at room temperature for 15 minutes and then washed with brine and dried over sodium sulphate. The solution was concentrated to give benzyl 3-(2-acetamidoethylsulphinyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (63) (0.007 g) as a colourless gum; νmax (CHCl3) 3400, 2980, 2920, 1795, 1920, 1670, 1600 and 1515 cm-1 ; λmax (ethanol) 305 nm; τ (CDCl3) 2.5-2.8 (5H, m, phenyl), 4.76 (2H, s, benzyl CH2), 5.6-5.9 (1H, m, C5-H), 6.3-7.3 (8H, m, C4-H2, C6-H2, NCH2CH2S) and 8.14 (3H, s, COCH3).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])[N:4]=[C:3]1[C:22]([O:24]CC)=[O:23].[OH-].[Na+].Cl>C(O)C.O1CCCC1>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:21])[F:20])=[CH:13][CH:12]=2)=[O:9])[N:4]=[C:3]1[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)c1nc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)cn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)nc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
835 mg (2.13 mmol) of ethyl 1-methyl-4-[({[4-(trifluoromethoxy)phenyl]amino}carbonyl)amino]-1H-imidazole-2-carboxylate are suspended in 5 ml of ethanol and 12 ml of tetrahydrofuran. With ice cooling, 2 ml (25 mmol) of a 50% aqueous sodium hydroxide solution are added. The reaction mixture is stirred at room temperature overnight and then, with ice cooling, acidified with 1N hydrochloric acid. The solution is extracted with dichloromethane. The organic phase is concentrated in vacuo. The residue is purified by preparative HPLC.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]3[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]3)[CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[CH:16]=[C:17]([NH:21][CH:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)[N:18]=[CH:19][N:20]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(Oc2ccc(Nc3cc(NC4CCCNC4)ncn3)cc2)cc1
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a stirred solution of tert-butyl 3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)piperidine-1-carboxylate (110 mg, 0.238 mmol) in dry CH2Cl2 (1.0 mL) at 0° C. was added CF3COOH (0.5 mL, 5 vol) and the reaction mixture was kept at this temperature for 30 min. It was allowed to come to rt and to stir at this temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was quenched with water (2 mL), was basified with NaHCO3 solution, and was extracted with ethyl acetate (2×8 mL). The combined ethyl acetate extract was washed with water (2 mL), brine (2 mL), dried over Na2SO4 and concentrated under reduced pressure to give N4-(4-phenoxyphenyl)-N6-(piperidin-3-yl)pyrimidine-4,6-diamine (0.07 g, 81%) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH:12][C:13](=[NH:22])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:5]=1.[O-]Cl.[Na+]>CO>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:22]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[NH:12][C:6]=2[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)=[O:23]
Reactant: COC(=O)c1ccc(OC)c(NC(=N)c2ccc(F)cc2F)c1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Product: COC(=O)c1ccc(OC)c2[nH]c(-c3ccc(F)cc3F)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 37.1 %

Procedure:
3-[(2,4-difluoro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester (9.5 g, 29.66 mmol) obtained in step 1 was dissolved in 50% methanol and 5% NaOCl (53 ml, 35.71 mmol) was added dropwise thereto at room temperature. After 5 min, Na2l CO3 (6.29 g, 59.34 mmol) was added dropwise thereto and refluxed for 5 min. The resulting solution was cooled to room temperature, extracted with ethyl acetate, and the extract was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (3.50 g, 11.0 mmol) in a yield of 37%.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH:15]2[NH:20][C:19]3[CH:21]=[CH:22][N:23]=[C:24]([C:25]([F:28])([F:27])[F:26])[C:18]=3[C:17](=[O:29])[N:16]2[CH:30]([CH3:40])[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>C(O)C>[F:39][C:34]1[CH:33]=[C:32]([CH2:31][CH:30]([N:16]2[C:17](=[O:29])[C:18]3[C:24]([C:25]([F:26])([F:27])[F:28])=[N:23][CH:22]=[CH:21][C:19]=3[NH:20][CH:15]2[C:10]2[C:9]([OH:8])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH3:40])[CH:37]=[CH:36][C:35]=1[F:38]
Reactant: CC(Cc1ccc(F)c(F)c1)N1C(=O)c2c(ccnc2C(F)(F)F)NC1c1ncccc1OCc1ccccc1
Solvent: CCO
Product: CC(Cc1ccc(F)c(F)c1)N1C(=O)c2c(ccnc2C(F)(F)F)NC1c1ncccc1O
Reaction time: 2 h

Procedure:
2-(3-(benzyloxy)pyridin-2-yl)-3-(1-(3,4-difluorophenyl)propan-2-yl)-5-(trifluoromethyl)-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one (12.1 grams, 21.8 mmol) prepared by the same reactions conditions described above was dissolved in 300 mL of ethanol and added to a parr bottle that contained 10% Pd(C). The mixture was subjected to hydrogenation condition (45 psi) for two hours. At this time, the reaction mixture was filtered through Celite and washed with ethanol. The fitrate was concentrated in vacuo and purified by silica gel chromatography to afford a pale yellow foam of 3-(1-(3,4-difluorophenyl)propan-2-yl)-2-(3-hydroxypyridin-2-yl)-5-(trifluoromethyl)-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[Li]CCCC.[Cl:12][C:13]1[N:18]=[C:17]([Cl:19])[CH:16]=[CH:15][N:14]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1.CCOCC>[Cl:12][C:13]1[N:18]=[C:17]([Cl:19])[CH:16]=[C:15]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[Cl:1])[N:14]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Clc1ccsc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Clc1cc(-c2sccc2Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-chlorothiophene (384 mg, 3.0 mmol) in THF (6 mL) at −78° C. was added n-BuLi (1.6 M, 2 mL) and the resulting mixture stirred for 45 minutes. The resulting product was added to a solution of 2,4-dichloropyrimidine (430 mg, 2.9 mmol) in ether (10 mL) at −30° C. and the resulting mixture stirred for 30 minutes, then warmed up to 0° C. and stirred for another 30 minutes. DDQ (700 mg, 3 mmol) was added and the resulting mixture was stirred overnight, then filtered through Celite®. The filtrate was concentrated and the residue was purified by silica gel column (EtOAc/hexanes, 1:5) to yield a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:28][C:27]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])=[CH:26][C:25](=O)[O:24]1>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:20][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:36]=[CH:35][CH:34]=[C:31]([C:32]#[N:33])[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 80.8 %

Procedure:
Prepared from (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G9) (250 mg, 0.88 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (243 mg, 1.06 mmol) according to the general procedure K. Obtained as a white solid (324 mg).
Reaction SMILES: [C:1]([O:13]CC)(=O)[CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[OH:7][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][C:1]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:13])[CH:11]=[CH:10][C:8]=1[OH:9]
Reactant: CCOC(=O)CCc1ccc(O)c(O)c1
Reactant: C1COCCN1
Product: O=C(CCc1ccc(O)c(O)c1)N1CCOCC1
Temperature: 150 °C
Reaction time: 2 h
Yield: 103.2 %

Procedure:
' 3 g of ethyl dihydrocaffeate was mixed with 3 g of morpholine, and the mixture was then heated with stirring at 150° C. for 2 hours. After cooling, the reaction solution was concentrated, and the resultant residue was then purified through a silica gel column chromatography. Elution was then carried out with a mixture of chloroform:methanol=20:1, thereby obtaining 3.7 g of N-[3-(3,4-dihydroxyphenyl)propionyl]morpholine having a melting point of from 211° to 213° C.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH:15]12[CH2:21][CH:18]([CH2:19][CH2:20]1)[CH2:17][CH:16]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29]([C:31]1[C:32]([CH:37]([F:39])[F:38])=[N:33][N:34]([CH3:36])[CH:35]=1)=O.O.C1CCCCC1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH:15]12[CH2:21][CH:18]([CH2:19][CH2:20]1)[CH2:17][CH:16]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29]([C:31]1[C:32]([CH:37]([F:39])[F:38])=[N:33][N:34]([CH3:36])[CH:35]=1)=[S:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cn1cc(C(=O)Nc2ccccc2C2CC3CCC2C3)c(C(F)F)n1
Solvent: C1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(C(=S)Nc2ccccc2C2CC3CCC2C3)c(C(F)F)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
0.3 g (1.4 mmol) of phosphorus pentasulphide is added to a solution consisting of 0.48 g (1.4 mmol) of N-(2-bicyclo[2.2.1]hept-2-ylphenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide in 20 ml of toluene, and the reaction mixture is stirred at 70° C. for 2 hours. For work-up, the reaction mixture is poured into water and extracted once with 20 ml of toluene and twice with in each case 20 ml of ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. Column chromatography (gradient cyclohexane/ethyl acetate) gives 0.32 g (0.89 mmol, 63% of theory) of N-(2-bicyclo[2.2.1]hept-2-ylphenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-thiocarboxamide [logP (pH 2.3)=3.66].
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47](O)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.ON1C2C=CC=CC=2N=N1.[CH3:61][NH:62][CH3:63]>C1COCC1>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([N:62]([CH3:63])[CH3:61])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: CNC
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)N(C)C)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (60 mg, 0.09 mmol) in THF (2 mL) was added polystyrene-carbodiimide (156 mg, 0.18 mmol), 1-hydroxybenzotriazole hydrate (18 mg, 0.13 mmol) and dimethylamine (0.09 mL, 0.13 mmol). The reaction mixture was stirred at room temperature under nitrogen for 4 h. The reaction was filtered through a micro filter and concentrated. The crude material was purified by preparative TLC (9:1, methylene chloride/methanol) to afford (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-N,N,3-trimethyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide as a mixture of diastereomers (8.0 mg, 13%) and as a red solid: 1H NMR (500 MHz, CDCl3) δ 14.18 (s, 1H), 8.16 (s, 1H), 6.85 (d, J=9.0 Hz, 0.8H), 6.57 (s, 1H), 6.28-6.24 (m, 0.2H), 6.20 (s, 0.2H), 5.87 (s, 0.8H), 5.14-5.08 (m, 1H), 5.00-4.94 (m, 1H), 4.71-4.66 (m, 1H), 4.62-4.56 (m, 1H), 3.79 (s, 3H), 3.75-3.68 (m. 2H), 3.61 (s, 3H), 3.59-3.52 (m, 3H), 3.41 (s, 3H), 3.38-3.28 (m, 2H), 3.13 (t, J=9.0 Hz, 1H), 2.92 (s, 6H), 2.14 (s, 3H), 3.14 (d, J=6.0 Hz, 3H); MS (ESI−) m/z 709 (M−H); HPLC 95.6% (AUC), tR 11.51 min.
Reaction SMILES: [CH:1]([N:4]1[C@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@@H:7]2[N:6]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[C:5]1=[O:26])([CH3:3])[CH3:2].Cl>CO>[CH:1]([N:4]1[C@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@@H:7]2[N:6]([CH:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[C:5]1=[O:26])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)N(C2CCN(C(=O)OC(C)(C)C)CC2)[C@H]2CCCC[C@@H]21
Agent: Cl
Solvent: CO
Product: CC(C)N1C(=O)N(C2CCNCC2)[C@H]2CCCC[C@@H]21
Temperature: 25 °C

Procedure:
Tert-butyl 4-[(3aS,7aS)-3-isopropyl-2-oxooctahydro-1H-benzimidazol-1-yl]piperidine-1-carboxylate was dissolved in methanol (20 mL) and 4 M HCl (7 mL) was then added. The mixture was stirred at room temperature and then concentrated in vacuo to provide the title compound. MS (M+1): 266.34
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH2:9]([N:11]([CH2:33][CH3:34])[C:12]([NH:14][C@H:15]1[CH2:29][C@H:28]2[C@@H:18]([CH2:19][C:20]3[C:30]4[C:23](=[CH:24][CH:25]=[CH:26][C:27]2=4)[NH:22][C:21]=3[CH3:31])[N:17]([CH3:32])[CH2:16]1)=[O:13])[CH3:10].C(O)(=O)C(C(C(O)=O)O)O.N>ClCCl.O>[C:5]([C:25]1[CH:24]=[C:23]2[C:30]3[C:20]([CH2:19][C@@H:18]4[C@@H:28]([C:27]=3[CH:26]=1)[CH2:29][C@H:15]([NH:14][C:12](=[O:13])[N:11]([CH2:33][CH3:34])[CH2:9][CH3:10])[CH2:16][N:17]4[CH3:32])=[C:21]([CH3:31])[NH:22]2)(=[O:7])[CH3:6]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]2N(C)C1
Reactant: CC(=O)Cl
Agent: N
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [Al+3]
Solvent: O
Solvent: ClCCl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(C(C)=O)cc4[nH]c(C)c(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.4 g of anhydrous aluminum chloride and 1.3 ml of acetyl chloride are dissolved in 70 ml of dichloromethane and stirred for 15 minutes at room temperature. 708 mg of 1,1-diethyl-3-(2,6-dimethyl-8alpha-ergolinyl)-urea (2 mmol) dissolved in 30 ml of dichloromethane is added to it, and stirred for 30 minutes at room temperature. Ice is added and after 15 minutes of stirring, a solution of 2.8 g of tartaric acid in 80 ml of water is added. After another 15 minutes, it is made alkaline with conc. ammonia, the organic phase is separated and the water phase is extracted. All organic phases are dried with sodium sulfate and concentrated by evaporation, the residue is chromatographed on silica gel with dichloromethane/methanol, yield 454 mg.
Reaction SMILES: Cl.[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15](=[NH:17])[NH2:16])=[N:7]1.C([N:24](CC)CC)C.O.NN>C(O)C>[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15](=[NH:16])[NH:17][NH2:24])=[N:7]1
Reactant: CCN(CC)CC
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: N=C(NN)c1nn(Cc2ccccc2F)c2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50.000 g (163.535 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide hydrochloride were dissolved in 700 ml of ethanol, and 66.192 g (654.141 mmol) of triethylamine and 10.233 g (163.535 mmol) of hydrazine hydrate (80% strength solution in water) were added at 0° C. The mixture was stirred at RT overnight and then concentrated on a rotary evaporator. The residue was taken up in ethyl acetate and the solution was washed three times with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was stirred with diethyl ether, filtered off with suction and dried under high vacuum. 46.49 g (46% of theory, 68% pure) of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:26][N:25]=[CH:24][N:23]=2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[CH2:34][C:35]([OH:37])=[O:36]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:26][N:25]=[CH:24][N:23]=2)[NH:12][C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[CH2:34][C:35]([OH:37])=[O:36])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)CC1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncns2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2CC(=O)O)NC(c2ncns2)=NC1c1ccc(F)cc1Br
Yield: 33.3 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1,2,4-thiadiazol-5-yl)-1,4-dihydropyrimidine-5-carboxylate (0.77 g, 1.53 mmol) was reacted with 2-(morpholin-3-yl)acetic acid hydrochloride (0.28 g, 1.53 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.29 g, 33%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C([N:6]1[CH2:11][CH2:10][N:9]([CH:12]2[C:18]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=3[S:16][C:15]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:14]=3[CH2:13]2)[CH2:8][CH2:7]1)(OCC)=O.C(O)CO.[OH-].[K+]>O>[F:23][C:20]1[CH:21]=[CH:22][C:17]2[S:16][C:15]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:14]=3[CH2:13][CH:12]([N:9]3[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]3)[C:18]=2[CH:19]=1
Reactant: CCOC(=O)N1CCN(C2Cc3cc(C)ccc3Sc3ccc(F)cc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1ccc2c(c1)CC(N1CCNCC1)c1cc(F)ccc1S2

Procedure:
24.5 G. of 1-carbethoxy-4-[8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl]-piperazine, 350 ml. of ethyleneglycol, 19 g. of potassium hydroxide and 15 ml. of water are heated at 160° C. for 1 hour. The mixture is poured into water and extracted with chloroform. The organic phase is washed with water, dried over magnesium sulfate, evaporated under reduced pressure, and there is obtained 1-[8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl]-piperazine as a light-brown oil.
Reaction SMILES: COP([CH:7]([N:13]([CH2:19][CH:20](OC)OC)C(OCC)=O)[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)(=O)OC.[NH4+].[OH-]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[S:9]1[C:8]2=[CH:7][N:13]=[CH:19][CH:20]=[C:12]2[CH:11]=[CH:10]1
Reactant: CCOC(=O)N(CC(OC)OC)C(c1cccs1)P(=O)(OC)OC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: c1cc2ccsc2cn1
Temperature: 40 °C

Procedure:
The material from Step ii (23.5 g, 61.6 mmol), was dissolved in 100 mL CH2Cl2. The three neck flask was fitted with a reflux condenser and internal thermometer under N2 atmosphere. The flask was evacuated and purged with nitrogen. Titanium (IV) chloride (40 mL, 369 mmol) was added to the reaction slowly. The reaction temperature was maintained at around 40° C. After about 15 mL were added, the reaction was placed in an ice bath to control the temperature. The reaction was allowed to gradually warm to room temperature before heating to 40° C. overnight. The reaction was heated to 40° C. for 18 hours, then cooled to room temperature. The reaction contents were poured, in portions, into a large beaker containing 200 g of ice and 200 mL NH4OH with lots of fuming observed. The reaction was stirred vigorously for a few minutes. The reaction was filtered and the solid was rinsed with CHCl3 (3×100 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:9][N:10]2[CH3:15].[C:25](O)(=O)[CH:26]=C>>[CH2:25]([O:19][C:18](=[O:20])/[CH:17]=[CH:16]/[C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][C:4]2[CH:21]=[CH:22][C:23]([F:24])=[C:2]([Cl:1])[CH:3]=2)[N:10]([CH3:15])[CH:9]=1)[CH3:26]
Reactant: Cn1cc(/C=C/C(=O)O)c2c(Oc3ccc(F)c(Cl)c3)cccc21
Reactant: C=CC(=O)O
Product: CCOC(=O)/C=C/c1cn(C)c2cccc(Oc3ccc(F)c(Cl)c3)c12

Procedure:
Synthesis of (E)-3-[4-(3-Chloro-4-fluoro-phenoxy)-1-methyl-1H-indol-3-yl]-acrylic acid, A38. Following the general procedure P-8, K-59G was hydrolyzed to acrylic acid A38. 1H NMR (DMSO-d6) 3.85 (s, 3H), 6.24 (d, J=16 Hz, 1H), 6.66 (d, J=8 Hz, 1H), 7.00 (m, 1H), 7.20 (dd, J=8 and 8 Hz, 1H), 7.25 (m, 1H), 7.35 (d, J=8 Hz, 1H), 7.43 (dd, J=9 and 9 Hz, 1H), 7.88 (d, J=16 Hz, 1H), 8.07 (s, 1H), 11.8 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([Cl:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>>[Cl:10][C:4]1[CH:3]=[C:2]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[F:11])[CH:8]=[C:7]([Cl:9])[C:5]=1[NH2:6]
Reactant: OB(O)c1ccccc1F
Reactant: Nc1c(Cl)cc(Br)cc1Cl
Product: Nc1c(Cl)cc(-c2ccccc2F)cc1Cl
Yield: 75.4 %

Procedure:
The title compound (0.367 g) was prepared from 4-Bromo-2,6-dichloro aniline (0.5 g, 1.9 mmol) and 2-fluorophenylboronic acid (0.363 g, 2.6 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.50 (t, J 6.3, 1H), 7.43 (s, 2H), 7.39-7.31 (m, 1H), 7.29-7.21 (m, 2H), 5.73 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:42][CH3:43])=[C:6]([C@@:8]2([F:41])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21][O:22][C:23](=[O:39])[CH2:24][CH2:25][O:26][P:27]([O:34]C(C)(C)C)([O:29]C(C)(C)C)=[O:28])[C:9]2=[O:40])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:42][CH3:43])=[C:6]([C@@:8]2([F:41])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21][O:22][C:23](=[O:39])[CH2:24][CH2:25][O:26][P:27]([OH:34])([OH:29])=[O:28])[C:9]2=[O:40])[CH:7]=1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(COC(=O)CCOP(=O)(OC(C)(C)C)OC(C)(C)C)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(COC(=O)CCOP(=O)(O)O)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.7 %

Procedure:
To a 25 mL flask containing (S)-3-(di-tert-butoxy-phosphoryloxy)-propionic acid 3-(5-chloro-2-methoxy-phenyl)-3-fluoro-2-oxo-6-trifluoromethyl-2,3-dihydro-indol-1-ylmethyl ester ((S)-XVII, n=1) (0.144 g, 0.22 mmol) was added 2 mL anhydrous dichloromethane, and trifluoroacetic acid (0.075 g, 0.66 mmol). The reaction was allowed to stir at room temperature for 4 hours. The dichloromethane was evaporated in vacuo, and the crude foam was purified by reverse phase chromatography (C18 2:1CH3CN:H2O) producing the title compound (0.070 g, 59%) as a white powder. 1H NMR (CDCl3 400 MHz): δ=7.70 (s, 1H), 7.36 (s, 1H), 7.32-7.27 (m, 3H), 7.20 (d, 1H, J=6 Hz), 6.73 (d, 1H, J=8 Hz), 5.91 (d, 1H, J=11.2 Hz), 5.73 (d, 1H, J=11.2 Hz), 4.27 (m, 2H), 3.44 (s, 3H), 2.75 (m, 2H); 31P NMR (CDCl3 162 MHz) δ=1.15; 19F NMR (CDCl3 376 MHz) δ=−63.2, −159.4; LRMS [M−H]−539.89, [M+NH4]+564.1.