Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]2[C:9](=[O:19])[NH:10][C:11](=[O:18])[N:12]([CH2:14][CH2:15][CH:16]=O)[CH:13]=2)=[C:5]([CH3:7])[N:6]=1.[F:20][C:21]([F:35])([F:34])[C:22]1[CH:27]=[CH:26][C:25]([C@:28]23[CH2:33][C@H:32]2[CH2:31][NH:30][CH2:29]3)=[CH:24][CH:23]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+].[Cl:56]C(Cl)C>>[ClH:56].[CH3:1][C:2]1[O:3][C:4]([C:8]2[C:9](=[O:19])[NH:10][C:11](=[O:18])[N:12]([CH2:14][CH2:15][CH2:16][N:30]3[CH2:31][C@H:32]4[C@:28]([C:25]5[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:35])[F:34])=[CH:27][CH:26]=5)([CH2:33]4)[CH2:29]3)[CH:13]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: CC(Cl)Cl
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: Cc1nc(C)c(-c2cn(CCC=O)c(=O)[nH]c2=O)o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1nc(C)c(-c2cn(CCCN3C[C@@H]4C[C@]4(c4ccc(C(F)(F)F)cc4)C3)c(=O)[nH]c2=O)o1
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-[5-(2,4-Dimethyl-oxazol-5-yl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionaldehyde (Prep64, 74 mg, 0.28 mmol) in dichloroethane (2 mL), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 57.4 mg, 0.25 mmol), AcOH (18.5 mg, 0.28 mmol) and NaBH(AcO)3 (65 mg, 0.31 mmol) were added portionwise at 0° C. The mixture was stirred at 0° C. for further 30 minutes. A 1N solution of NaOH was added and the mixture extracted with EtOAc. The organic phase was treated with PS isocyanate resin, filtered and evaporated under vacuum. The crude was purified by flash chromatography (DCM/MeOH/NH4OH 95:5:05) to give the title compound as free base. The free base was dissolved in dissolved in dioxane and treated with 4N HCl in dioxane (1 eq), to give the title compound as a white powder. (38 mg, 24%)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[CH2:7][C:6]1=[O:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:26]2[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][N:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[NH:9][C:8](=[O:16])[CH2:7][C:6]3=[O:17])[CH2:30][CH2:31]2)=[CH:23][CH:24]=1
Reactant: O=C1CC(=O)N(CCCBr)c2ccccc2N1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CC(=O)N(CCCN2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)c2ccccc2N1
Temperature: 100 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Twenty five milliliters of dimethylformamide is added to 2.3 g of the compound of Example 209, 2.6 g of 1-[(4-chlorophenyl)phenylmethyl]piperazine and 2.2g of potassium carbonate and the resulting mixture is stirred at 100° C. for 4 hours. To the mixture, 0.35 g of 1-[(4-chlorophenyl)phenylmethyl]piperazine is added and the resulting mixture is stirred at 100° C. for 2.5 hours. The precipitate is removed by filtration and the filtrate is condensed, followed by purification by silica gel column chromatography (ethyl acetate:methanol=9:1-8:1) to obtain 3.7 g of (210).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:44][CH2:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:21]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36](=[O:43])[CH2:37][C:38]5[S:39][CH:40]=[CH:41][CH:42]=5)[CH:30]=4)=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)[CH:17]=[CH:16][N:15]=2)[CH:8]=1)=O.O[Li].O>C1COCC1.O.CCOC(C)=O>[CH3:49][S:46]([CH2:45][CH2:44][NH:5][CH2:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:21]([C:29]4[CH:30]=[C:31]([NH:35][C:36](=[O:43])[CH2:37][C:38]5[S:39][CH:40]=[CH:41][CH:42]=5)[CH:32]=[CH:33][CH:34]=4)=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:47])=[O:48]
Reactant: CS(=O)(=O)CCN(Cc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1)C(=O)C(F)(F)F
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)CCNCc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1
Temperature: 50 °C
Yield: 62 %

Procedure:
To a solution of 2,2,2-trifluoro-N-[2-(methylsulfonyl)ethyl]-N-[(3-{[4-(2-{3-[(2-thienylacetyl)amino]phenyl}pyrazolo[1,5-a]pyridin-3-yl)-2-pyrimidinyl]amino}phenyl)methyl]acetamide (79 mg, 0.11 mmol) in THF (3 mL) was added LiOH hydrate (10 mg, 0.21 mmol) in water (0.5 mL). The solution was heated to 50° C. for 2 h, and then diluted with EtOAc, washed with 1N Na2CO3, dried over Na2SO4, and concentrated to generate the title compound in 62% yield. 1H NMR (400 MHz, d6-DMSO) δ 10.36 (s, 1H), 9.55 (s, 1H), 8.84 (d, J=6.8 Hz, 1H), 8.52 (d, J=8.9 Hz, 1H), 8.24 (d, J=5.4 Hz, 1H), 7.90 (s, 1H), 7.74-7.76 (m, 2H), 7.59 (d, J=8.1 Hz, 1H), 7.38-7.50 (m, 2H), 7.28 (d, J=7.7 Hz, 1H), 7.20 (t, J=7.8 Hz, 1H), 7.13 (t, J=6.8 Hz, 1H), 6.92-6.98 (m, 3H), 6.44-6.51 (m, 2H), 3.88 (s, 2H), 3.66 (s, 2H), 3.23 (t, J=6.3 Hz, 2H), 3.01 (s, 3H), 2.91 (t, J=6.1 Hz). ES-LC/MS m/z=638 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)=[O:34]>CO>[CH3:42][O:41][C:38]1[CH:39]=[CH:40][C:35]([C:33](=[O:34])[CH2:32][N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([N:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5])=[CH:36][CH:37]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1ccc(OC)cc1
Yield: 81.9 %

Procedure:
Using the procedure described in example 5, treatment of L-proline-L-isoleucine benzylamide (208 mg, 0.65 mmol), with sodium carbonate (104 mg, 0.98 mmol), and 2-bromo-4'- methoxyacetophenone (195 mg, 0.85 mmol, 1.3 eq) in MeOH (10 mL), provided 248 mg (81%) of L-isoleucine, N-[1-(2-(4-methoxyphenyl)-2-oxoethyl)-L-prolyl] benzylamide as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][NH:23]3)[N:12]=2)=[C:7]([F:27])[CH:6]=1.[C:33]([CH2:35][C:36](O)=[O:37])#[N:34]>C(Cl)Cl.O>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:36](=[O:37])[CH2:35][C:33]#[N:34])[N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])=[CH:6][C:7]=3[F:27])[C:19]=12
Reactant: N#CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1F)nn2C[C@@H]1CCCN1
Solvent: ClCCl
Solvent: O
Product: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Yield: 69.1 %

Procedure:
A solution of 3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1-((S)-pyrrolidin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.4 g Crude, 3.65 mmol, 1.00 equiv), 2-cyanoacetic acid (0.47 g, 5.48 mmol, 1.50 equiv), HAW (2.08 g, 5.48 mmol, 1.50 equiv), TEA (2.54 ml, 18.25 mmol, 5.00 equiv) in DCM (40 mL) was stirred overnight at room temperature. The resulting mixture was diluted with water, and extracted with DCM. The DCM layers were combined and washed with brine, dried over Na2SO4 and concentrated. The residue was submitted to flash chromatography (SiO2, PE:EtOAc=2:1 to 1:1) to give 1.28 g (69%) of 3-((S)-2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[NH2:6])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH3:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([CH3:36])[CH:35]=1)[C:30](Cl)=[O:31].CCCCCC.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[NH:6][C:30](=[O:31])[C:29]1[CH:33]=[C:34]([CH3:36])[CH:35]=[C:27]([CH3:26])[CH:28]=1)[CH3:2]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(-c2ccno2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@H](Cc1ccc(-c2ccno2)cc1)NC(=O)c1cc(C)cc(C)c1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
Crude 3-[4-(5-isoxazolyl)-phenyl]-alanine ethyl ester (660 mg) is dissolved in chloroform (6.6 ml), stirred vigorously with 2N aqueous sodium carbonate (1,4 ml), and after cooling to 10° C., 3,5-dimethylbenzoylchloride (0.7 ml) is added. Stirring is continued for 1 hour at 10° C. and for 2 hours at ambient temperature. Then extraction with dichloromethane/water, washing with 10% aqueous citric acid, and with brine, followed by evaporation gives the crude product. Flash chromatography on silica gel, hexane/ethyl acetate (4:1), gives pure N-(3,5-dimethylbenzoyl)-3-[4-(5-isoxazolyl)-phenyl]-alanine ethyl ester. NMR (CDCl3, 400 MHz) δ [ppm] 8.28 (d, 1.8 Hz, 1H), 7.72 (d, 8.2 Hz, 2H), 7.33 (s, 2H), 7.26 (d, 8.2 Hz, 2H), 7.15 (s, 1H), 6.65 (d, 7.3 Hz, 1H), 6.50 (d, 1.8 Hz, 1H), 5.09 (m, 1H), 4.24 (q, 7.1 Hz, 2H), 3.32 (m, 2H), 2.34 (s, 6H), 1.29 (t, 7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([OH:14])[C:11]([OH:15])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([OH:9])=[O:8].[N+:16]([O-])([OH:18])=[O:17]>C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([OH:14])[C:11]([OH:15])=[C:10]([N+:16]([O-:18])=[O:17])[C:4]=2[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1sc2cc(O)c(O)cc2c1Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(O)c1sc2c([N+](=O)[O-])c(O)c(O)cc2c1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Chloro-5,6-dihydroxy-benzo[b]thiophene-2-carboxylic acid was dissolved in ethyl acetate and a solution of nitric acid in dichloromethane (2M, 0.38 ml) was gradually added at 20° C. The solution was stirred 10 min at room temperature and then it was poured into ice-cold water and extracted with ethyl acetate. The organic extracts were combined, dried and evaporated to dryness. The residue was recrystallized from acetic acid.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[Br:5][C:6]([Br:10])([CH3:9])[CH2:7][OH:8].N1C=CC=CC=1>C(Cl)Cl>[Br:5][C:6]([Br:10])([CH3:9])[CH2:7][O:8][C:1]([Cl:4])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CC(Br)(Br)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Br)(Br)COC(=O)Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
16 ml (0.22 mol) of liquid phosgene are condensed into 33 g (0.15 mol) of 2,2-dibromopropanol in 150 ml of CH2Cl2, at -20° C, and 12 ml (0.15 mol) of pyridine in 15 ml of CH2Cl2 are then added slowly dropwise at -20° C to -5° C and the mixture is stirred for a further 2 hours at 20° C. The solution is washed, at 0° C, with water, 5% strength sulphuric acid and H2O and dried (Na2SO4) and the solvent is stripped off (46.1 g of crude product). Vacuum distillation gives 36.3 g (86%) of 2,2-dibromopropoxycarbonyl chloride as a colorless liquid. Boiling point12 = 81°-86° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[CH:17]=4)[O:13][N:12]=3)[CH:9]=2)[N:4]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:37](I)[CH3:38].CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:37][CH3:38])=[C:18]([Cl:23])[CH:17]=4)[O:13][N:12]=3)[CH:9]=2)[N:4]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:3]=1
Reactant: CCI
Reactant: CCOC(=O)CCn1cc(Cl)c2cc(-c3noc(-c4ccc(O)c(Cl)c4)n3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCn1cc(Cl)c2cc(-c3noc(-c4ccc(OCC)c(Cl)c4)n3)ccc21
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To ethyl 3-{3-chloro-5-[5-(3-chloro-4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl}propanoate (D108) (180 mg, 0.40 mmol) and K2CO3 (138 mg, 1.0 mmol) in dry DMF (3 ml) was added ethyl iodide (78 mg, 0.50 mmol) and the mixture heated at 80° C. with stirring for 30 minutes. Cooled mixture and added EtOAc (50 ml). Washed with water (3×40 ml) and dried over MgSO4. Evaporated off the solvent and crystallised from ethanol to yield the title compound as 110 mg of white solid. δH (400 MHz, d6-DMSO) 1.10 (3H, t), 1.42 (3H, t), 2.90 (2H, t), 4.02 (2H, q), 4.27 (2H, q), 4.49 (2H, t), 7.40 (1H, d), 7.74 (1H, s), 7.80 (1H, d), 7.95 (1H, dd), 8.16 (1H, dd), 8.21-8.22 (2H, m). MS (ES) C23H2135Cl2N3O4 requires 473; found 474 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[C:6]=2[C:5](=[O:17])[NH:4][C:3]1=[O:18].[OH-].[Na+].[CH2:21](Br)[CH3:22]>CO.O>[CH2:21]([N:4]1[C:5](=[O:17])[C:6]2[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:18])[CH3:22]
Reactant: C=CCCCCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCCCCn1cnc2c1c(=O)n(CC)c(=O)n2C
Reaction time: 40 h

Procedure:
20 g of 3-methyl-7-(hex-5-enyl)-xanthine (see Example 22) are added to a solution of approximately 3.3 g of NaOH in 70 ml of methanol/water (1:1) and 9 g of ethyl bromide are added thereto. The mixture is kept at 40° C. under a nitrogen atmosphere for 40 hours. The solvent is then removed under reduced pressure, the residue dissolved in diethyl ether and the pH of the solution is adjusted with aqueous sodium hydroxide solution to a pH-value of 13.5 to remove unreacted 3-methyl-7-(hex-5-enyl)-xanthine. 1-Ethyl-3-methyl-7-(hex-5-enyl)-xanthine recovered from the ether phase is subsequently subjected to column chromatography using silica gel with methylene chloride/acetone (8:2) as eluent followed by distillation under reduced pressure and is obtained as a colourless oil. Yield: 11.2 g (81.3% of theory relative to reacted starting material) of the title compound, nD20 =1.5415.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24].CCOCC>C(#N)C>[Br-:20].[C:23]([CH2:22][CH2:21][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([OH:25])=[O:24]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)CCBr
Solvent: CCOCC
Solvent: CC#N
Product: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Reaction time: 8 h
Yield: 68.5 %

Procedure:
Reflux a solution of triphenylphosphine (91.3 g, 348 mmol, 1.05 equivalents) and 3-bromopropionic acid (50.7 g, 331 mmol) in acetonitrile (250 ml) for three hours, allow to sit at room temperature overnight. Add ether (400 ml) and cool in the freezer for two hours. Filter solids, rinse with ether, and dry solids under high vacuum to obtain the title compound (94.1 g, 68%). NMR (400 MHz, CDCl3): δ 3.15 (m, 2H), 3.73 (m, 2H), 7.69-7.83 (m, 15H).
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[CH:7]=[N:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.O>CS(C)=O>[C:1]([CH2:5][C:6]1[CH:7]=[N:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)#[N:2]
Reactant: [C-]#N
Reactant: ClCc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 1 h
Yield: 97.8 %

Procedure:
Under nitrogen atmosphere, sodium cyanide (540 mg) was added to a solution of 4-chloromethyl-1-tritylpyrazole (3.58 g) in dimethylsulfoxide (30 ml) at 50° C. After stirring for 1 hour, the mixture was poured into water. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, to afford 4-cyanomethyl-1-tritylpyrazole (3.41 g).
Reaction SMILES: C[C:2]1[CH:7]=[C:6]([N:8](CC)CC)[CH:5]=[CH:4][C:3]=1[N:13]=[C:14]1[CH:23]=[CH:22][C:21](=[O:24])[C:20]2N=CC=C[C:15]1=2>O.C(O)C>[CH:23]1[C:14](=[N:13][C:3]2[CH:2]=[CH:7][C:6]([NH2:8])=[CH:5][CH:4]=2)[CH:15]=[CH:20][C:21](=[O:24])[CH:22]=1
Reactant: CCN(CC)c1ccc(N=C2C=CC(=O)c3ncccc32)c(C)c1
Solvent: CCO
Solvent: O
Product: Nc1ccc(N=C2C=CC(=O)C=C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Then, a solution prepared by dissolving 285.3 mg of Ni(ClO4)2.6H2O in 50 ml of water, was added under a nitrogen atmosphere to a solution prepared by dissolving 100 mg of 5-(2'-methyl-4'-diethylaminophenylimino)quinoline-8-one obtained above in 50 ml of 99% ethanol, and the mixture was stirred at room temperature for about 30 minutes. Formed precipitates were subjected to suction filtration, washed with water and dried to obtain a metal-containing indoaniline compound having the formula: ##STR9##
Reaction SMILES: [H-].[Na+].[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([OH:10])[CH2:6][CH2:5]1.[CH3:11][C@H:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([CH3:18])[N:13]1[C:19]1[N:23]2[CH:24]=[C:25](F)[CH:26]=[CH:27][C:22]2=[N:21][N:20]=1>CN(C=O)C>[CH3:11][C@H:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([CH3:18])[N:13]1[C:19]1[N:23]2[CH:24]=[C:25]([O:10][CH:7]3[CH2:8][CH2:9][CH:4]([NH2:3])[CH2:5][CH2:6]3)[CH:26]=[CH:27][C:22]2=[N:21][N:20]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(F)cn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(OC3CCC(N)CC3)cn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
Sodium hydride (60% in mineral oil, 0.24 g, 6.00 mmol) was added to a stirred solution of trans-4-amino cyclohexanol (0.24 g, 2.08 mmol) in anhydrous DMF (8 mL) at RT under an argon atmosphere. The reaction mixture was stirred at RT for 30 min, then Intermediate 3c (0.50 g, 2.01 mmol) in anhydrous DMF (7 mL) was added and stirred at 60° C. for 4 h. After cooling, the reaction mixture was quenched by careful addition of a saturated aqueous solution of NH4Cl and water (1:1) and extracted with DCM (3×50 mL). The combined organic layers were washed with water followed by brine, dried and concentrated in vacuo. The resultant residue was purified by FCC using 0-10% [2M NH3 in MeOH] in DCM to afford the title compound (0.61 g, 88%) as a brown oil. LCMS (Method 3): Rt 2.19 min, m/z 344 [MH+].
Reaction SMILES: [S:1]1(=[O:13])(=[O:12])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][NH:15][CH3:16]>>[CH3:14][N:15]([CH3:16])[C:10]1[CH:9]=[CH:8][C:7]2[S:1](=[O:12])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]=2[CH:11]=1
Reactant: O=S1(=O)CCCCc2ccccc21
Reactant: CNC
Product: CN(C)c1ccc2c(c1)CCCCS2(=O)=O
Temperature: 110 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of 13.00 g (28.98 mmol) of enantiomerically-enriched tetrahydrobenzothiepine-1,1-dioxide ((4R,5R)-XXV) in 73 mL of dimethylamine (2.0 M in THF, 146 mmol) in a Parr Reactor was added ca. 20 mL of neat dimethylamine. The mixture was sealed and stirred at 110° C. overnight, and cooled to ambient temperature. The excess dimethylamine was evaporated. The crude oil was dissolved in 200 mL of ethyl acetate and washed with 100 mL of water, dried over MgSO4 and concentrated in vacuo. Purification on a silica gel column (Waters Prep 500) using 20% ethyl acetate/hexane gave 12.43 g (90.5%) of the enantiomerically-enriched 7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide ((4R,5R)-XXVI) as a colorless solid: 1H NMR (CDCl3) d 0.87-0.93 (m, 6H), 1.10-1.68 (m, 12H), 2.17-2.25 (m, 1H), 2.81 (s, 6H), 2.99 (d, J=15.3 Hz, 1H), 3.15 (d, J=15.3 Hz, 1H), 3.84 (s, 3H), 4.11 (d, J=7.5 Hz, 1H), 5.49 (s, 1H), 5.99 (d, J=2.4 Hz, 1H), 6.51 (dd, J=8.7 Hz, 2.4 Hz, 1H), 6.94 (d, J=8.7 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.90 (d, J=8.7 Hz, 1H). The product was determined to have 78% e.e. by chiral HPLC on a Chiralpak AD column using 5% ethanol/hexane as the eluent. Recrystallization of this solid from ethyl acetate/hexane gave 1.70 g of the racemic product. The remaining solution was concentrated and recrystallized to give 9.8 g of colorless solid. Enantiomeric excess of this solid was determined by chiral HPLC on a Chiralpak AD column using 5% ethanol/hexane as the eluent. It showed to have 96% e.e with the first eluting peak as the major product.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:31]([S:34][CH2:35][C:36](ON1C(=O)CCC1=O)=[O:37])(=[O:33])[CH3:32]>>[C:31](=[O:33])([S:34][CH2:35][C:36]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]2=[C:10]([C:11]2[CH:25]=[CH:24][C:14]([C:15](=[O:16])[NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:13][CH:12]=2)[N:9]=1)=[O:37])[CH3:32]
Reactant: CC(=O)SCC(=O)ON1C(=O)CCC1=O
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Product: CC(=O)SCC(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 31.8 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 1, from the compound described in intermediate 2b and 2,5-dioxopyrrolidin-1-yl 2-(acetylthio)acetate, to afford the title compound (12.3 mg, 31.8%). Data: UPLC (C) R: 1.51 min; m/z 516.3 (M+H)+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:25]=[C:24]([S:26][Si](C(C)C)(C(C)C)C(C)C)[CH:23]=[CH:22][C:21]=1[NH:37][C:38](=[O:46])[C@:39]([OH:45])([CH3:44])[C:40]([F:43])([F:42])[F:41].Cl[CH2:48][C:49]([N:51]([CH3:53])[CH3:52])=[O:50].C(OCC)(=O)C>C1COCC1>[Cl:19][C:20]1[CH:25]=[C:24]([S:26][CH2:48][C:49](=[O:50])[N:51]([CH3:53])[CH3:52])[CH:23]=[CH:22][C:21]=1[NH:37][C:38](=[O:46])[C@:39]([OH:45])([CH3:44])[C:40]([F:41])([F:42])[F:43]
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)[Si](Sc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C(=O)CSc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Tetrabutylammonium fluoride (1.1 ml of a 1M solution in THF) was added to (R)-N-(2-chloro-4-(triisopropylsilylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 28) (0.50 g) in anhydrous THF (5 ml) at −70° C. After 15 minutes 2-chlorodimethylacetamide (0.17 ml) was added and the mixture was allowed to warm up then was stirred at ambient temperature for 45 minutes. Ethyl acetate (80 ml) was added and the mixture was washed with brine (100 ml) then dried and volatile material was removed by evaporation. The residue was purified on a silica gel Mega Bond Elut column eluting with 10-50% ethyl acetate/hexane to give the title compound (0.30 g) as a solid. NMR (CDCl3) 1.72 (s, 3H), 2.97 (s, 3H), 3.08 (s, 3H), 3.71 (s, 2H), 4.76 (s, 1H), 7.32-7.36 (m, 1H), 7.53 (d, 1H), 8.32 (d, 1H), 9.05 (s, 1H); MS (ESP−): 383.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][C:4](OC)=[O:5].O.[NH2:11][NH2:12]>CCO>[CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][C:4]([NH:11][NH2:12])=[O:5]
Reactant: NN
Reactant: COC(=O)CC(C)(C)C
Solvent: O
Solvent: CCO
Product: CC(C)(C)CC(=O)NN
Temperature: 80 °C
Yield: 18 %

Procedure:
To a mixture of methyl 3,3-dimethylbutanoate (500 mg, 3.84 mmol) in EtOH (12 ml) was added hydrazine monohydrate (1.87 ml, 38.4 mmol). The mixture was heated to 80° C. under reflux for overnight. The reaction was cooled back down to room temperature and concentrated to dryness affording a crude residue. The residue was dried under high vacuum to afford the title compound as crystalline solid (90 mg, 18% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.69-9.12 (s, 1H) 4.13 (br. s, 2H) 1.89 (s, 2H) 0.94 (s, 9H).