Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][CH2:13][OH:14])[N:9]=[C:10](I)[C:3]=12.[CH3:15][O:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[NH:32][C:33]([C:35]1[N:36]([CH3:44])[C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][CH2:13][OH:14])[N:9]=[C:10]([C:21]3[CH:20]=[CH:19][C:18]([NH:32][C:33]([C:35]4[N:36]([CH3:44])[C:37]5[C:42]([CH:43]=4)=[CH:41][CH:40]=[CH:39][CH:38]=5)=[O:34])=[C:17]([O:16][CH3:15])[CH:22]=3)[C:3]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: Nc1ncnc2c1c(I)nn2CCO
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn(CCO)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 85 °C
Yield: 84 %

Procedure:
A mixture of 2-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-ethanol (Intermediate 3) (0.364 g, 1.19 mol), N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (0.485 g, 1.19 mmol), palladium tetrakis(triphenylphosphine) (0.138 g, 0.119 mmol), and sodium carbonate (0.303 g, 2.86 mmol) in DME (12 mL) and water (12 mL) was heated at 85° C. for 4 h then cooled to ambient temperature. The DME was removed in vacuo and the resulting precipitate was collected by filtration and rinsed with water (50 mL) and ether (50 mL) to afford N2-{4-[4-amino-1-(2-hydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide as a tan solid (0.459 g, 1.00 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.44 (1H, s), 8.26 (1H, s), 8.12 (1H, d, J=8.0 Hz), 7.70 (1H, d, J=8.0 Hz), 7.59 (1H, d, J=8.4 Hz), 7.29-7.41 (6H, m), 7.15 (1H, t, J=7.4 Hz), 4.90 (1H, t, J=5.8 Hz), 4.41 (2H, t, J=5.8 Hz), 4.04 (3H, s), 3.96 (3H, s), and 3.86 (2H, q, J=5.9 Hz); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile-0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.52 min.
Reaction SMILES: [CH:1]([C:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])[C:9](=[O:10])[N:8]([CH3:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[S:5]1)([CH3:3])[CH3:2].[OH-].[Na+].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>O>[CH:1]([C:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:25][CH:27]2[CH2:28][O:29]2)[C:9](=[O:10])[N:8]([CH3:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[S:5]1)([CH3:3])[CH3:2]
Reactant: ClCC1CO1
Reactant: CC(C)C1(c2ccccc2O)Sc2ccccc2N(C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C1(c2ccccc2OCC2CO2)Sc2ccccc2N(C)C1=O

Procedure:
4.7 g (15.0 mmol) of 3,4-dihydro-2-isopropyl-4-methyl-2-(2-hydroxyphenyl)-2H-1,4-benzothiazin-3-one are stirred for 24 hours at 85° C. with 0.6 g of NaOH, 2 ml of H2O and 50 ml of epichlorohydrin. After dilution with water, the mixture is extracted with methylene chloride, and the extract is dried with sodium sulfate and concentrated. This gives 5.3 g of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:3]=1[C:4]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[N:13]1[C:2]2[C:3](=[CH:22][C:23]([F:27])=[C:24]([F:26])[CH:25]=2)[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12]1
Reactant: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)c1cc(F)c(F)cc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2cc(F)c(F)cc2c1=O
Reaction time: 2 h
Yield: 92 %

Procedure:
8.0 g of ethyl 2-(2-chloro-4,5-difluorobenzoyl)-3-(2,4-difluorophenylamino)acrylate was dissolved in 80 ml of acetonitrile under heating to 75˜80° C. 11.84 g (2.8 eq.) of K3PO4 was added in portions to the reaction mixture, which was then stirred at the same temperature for 2 hours. The reaction mixture was filtered under a reduced pressure and washed with 40 ml of dichloromethane. The filtrate was concentrated under a reduced pressure. The resulting residue was dissolved in 88 ml of dichloromethane and then washed with water. The organic layer was concentrated under a reduced pressure to give 6.69 g of ethyl 1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (Yield: 92%).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1)[NH2:2].[C:22]([O:26][C:27]([N:29]1[CH2:33][C@H:32]([CH2:34][CH3:35])[C@H:31]([C:36](O)=[O:37])[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:34]([C@H:32]1[C@@H:31]([C:36]([NH:2][NH:1][C:3]2[N:4]=[C:5]3[CH:11]=[CH:10][N:9]([S:12]([C:15]4[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=4)(=[O:13])=[O:14])[C:6]3=[N:7][CH:8]=2)=[O:37])[CH2:30][N:29]([C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:28])[CH2:33]1)[CH3:35]
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (5.00 g, 16.48 mmol, Example 1, Step D) and (cis)-1-(tert-butoxycarbonyl)-4-ethylpyrrolidine-3-carboxylic acid (4.01 g, 16.48 mmol) in DCM (70 mL) were added TEA (5.75 mL, 41.2 mmol) and HATU (6.90 g, 18.15 mmol, Novabiochem). The resulting suspension was stirred at about 25° C. for about 2 h. The reaction mixture was transferred to a separatory funnel and washed with saturated aqueous NaHCO3 (4×30 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concd in vacuo to give a brown foam. The crude material was purified via flash chromatography on silica gel by dry loading the compound onto the column and eluting with 50-100% EtOAc in DCM/petroleum ether (1:1) to afford (cis)-tert-butyl 3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)pyrrolidine-1-carboxylate with EtOAc as an excipient (9.41 g, 100%) as a tan foam: LC/MS (Table 1, Method a) Rt=2.45 min; MS m/z: 529 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]1=[O:18].[CH3:19][C:20]1[C:28]2[CH2:27][O:26][C:25](=[O:29])[C:24]=2[CH:23]=[CH:22][C:21]=1[C@@H:30]1[CH2:32][O:31]1>C(O)C>[OH:31][C@H:30]([C:21]1[CH:22]=[CH:23][C:24]2[C:25](=[O:29])[O:26][CH2:27][C:28]=2[C:20]=1[CH3:19])[CH2:32][N:15]1[CH2:16][CH2:17][C:10]2([C:9](=[O:18])[N:8]([C:3]3[CH2:4][O:5][C:6](=[O:7])[C:2]=3[CH3:1])[CH2:12][CH2:11]2)[CH2:13][CH2:14]1
Reactant: CC1=C(N2CCC3(CCNCC3)C2=O)COC1=O
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Product: CC1=C(N2CCC3(CCN(C[C@H](O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O

Procedure:
A solution of 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-17, 6.00 g, 24.0 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (1-4B, 5.93 g, 31.2 mmol) in ethanol (20 mL) in a sealed tube was heated at 95° C. overnight. After concentration, the residue was purified on silica gel column using methanol/dichloromethane, then precipitated from methanol to give the title compound. LC/MS, (M+1)+: 440.93. 1HNMR (500 MHz, CDCl3), δ7.845-7.809 (m, 2H), 5.290-5.278 (m, 4H), 5.139-5.112 (m, 1H), 4.072-4.044 (t, J=7.1 Hz, 2H), 3.190-3.167 (m, 1H), 2.876-2.859 (m, 1H), 2.636-2.604 (m, 2H), 2.468-2.421 (m, 1H), 2.311 (s, 3H), 2.350-2.328 (m, 1H), 2.193-2.165 (t, J=7.1 Hz, 2H), 2.101-2.039 (m, 5H), 1.668-1.618 (m, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[CH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.Cl>O1CCCC1>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: ClCc1cccc2ccccc12
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cccc2ccccc12)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.4 %

Procedure:
To a suspension of sodium hydride (8 g of 60% dispersion in mineral oil, 200 mmols) in tetrahydrofuran (200 mL) was added diethyl malonate (30.5 mL, 200 mmols) dropwise over 15 minutes; gas evolution was observed. When the addition was complete, the mixture was stirred for 10 minutes at 25° C. A solution of 1-chloromethyl naphthalene (35.5 g, 200 mmols) in tetrahydrofuran (20 mL) was added dropwise over 15 minutes, after which the mixture was heated at reflux under argon for 18 hours. Excess 1N hydrochloric acid was then added and the mixture was extracted with ether. The extract was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was transferred to a flask fitted with a vacuum distillation head. Unreacted diethyl malonate (bp 45°-55° C./0.2 torr) and 1-chloromethyl naphthalene (bp 120°-130° C.) were distilled off and the residue was recooled to 25° C. The distillation residue (43.5 g) was crystallized from petroleum ether at -30° C. to give the title A compound as a low melting (mp about 30° C.) solid (27.3 g, 46%).
Reaction SMILES: [C:1]1([C:7](=[N:14][CH2:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:17])[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.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:39]1([S:45]([N:48]2[C:56]3[C:51](=[C:52]([CH2:60]Br)[CH:53]=[C:54]([Cl:59])[C:55]=3[O:57][CH3:58])[CH:50]=[N:49]2)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[NH4+].[Cl-]>C1COCC1>[C:39]1([S:45]([N:48]2[C:56]3[C:51](=[C:52]([CH2:60][CH:15]([N:14]=[C:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:17])[CH:53]=[C:54]([Cl:59])[C:55]=3[O:57][CH3:58])[CH:50]=[N:49]2)(=[O:47])=[O:46])[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(CN=C(c1ccccc1)c1ccccc1)NCCCCc1ccccc1
Reactant: COc1c(Cl)cc(CBr)c2cnn(S(=O)(=O)c3ccccc3)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1c(Cl)cc(CC(N=C(c2ccccc2)c2ccccc2)C(=O)NCCCCc2ccccc2)c2cnn(S(=O)(=O)c3ccccc3)c12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
2-(Diphenylmethylenamino)-N-(4-phenyl-butyl)-acetamide (7) (0.57 g, 1.5 mmol) is dissolved in dry THF (5 mL) and cooled to −78° C. A solution of KHMDS (0.5 M in PhMe, 3.0 mL, 1.5 mmol) is added slowly to the imide. The solution is warmed to 0° C. and then cooled to −78° C. A solution of 1-benzenesulfonyl-4-bromomethyl-6-chloro-7-methoxy-1H-indazole (0.57 g, 1.4 mmol) in dry THF (4 mL) is added slowly at −78° C. and the solution is allowed to stir 15 min. The reactio is then poured into a solution of aqueous NH4Cl and extracted with EtOAc. The organic phase is washed with water, brine, dried over MgSO4 and concentrated. The crude reaction is purified by column chromatography (silica, 10–20% EtOAc/PhMe) to provide 3-(1-benzenesulfonyl-6-chloro-7-methoxy-1H-indazol-4-yl)-2-(diphenylmethylenamino)-N-(4-phenyl-butyl)-propionamide.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7]([NH2:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.F[B-](F)(F)F.[CH2:16]([O+](CC)CC)[CH3:17]>ClCCl>[CH3:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[NH:9])[O:8][CH2:16][CH3:17]
Reactant: Cc1ccccc1C(N)=O
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=N)c1ccccc1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 133 %

Procedure:
To a solution of o-toluamide (13.5 g, 0.100 mol) in dichloromethane (150 mL) was added a solution (1.0 M, 106 mL, 0.106 mol) of triethyloxonium tetrafluoroborate in dichloromethane. The resulting mixture was stirred at room temperature for 14 h. Two-thirds of dichloromethane was evaporated under reduced pressure. After addition of ether (400 mL) to the concentrate, the mixture was stirred for 3 h under ice-cooling. Precipitates were collected by filtration, washed with ether, and dried in vacuo to give 21.7 g (86%) of ethyl 2-methylbenzimidate hydrotetrafluoroborate as a colorless solid.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[C:13]([N:15]=[CH:16][N:17]([CH3:19])[CH3:18])[CH:12]=[CH:11][C:10]=1[C:20]([O:22][CH3:23])=[O:21])(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[CH3:18][N:17]([CH3:19])[CH:16]=[N:15][C:13]1[CH:12]=[CH:11][C:10]([C:20]([O:22][CH3:23])=[O:21])=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=1
Reactant: COC(=O)c1ccc(N=CN(C)C)cc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(N=CN(C)C)cc1S(N)(=O)=O
Temperature: 25 °C

Procedure:
A mixture of 2.13 g of N-tert-butyl-2-methoxycarbonyl-5-(2-dimethylamino-1-azaethenyl)benzenesulfonamide and 20 ml of trifluoroacetic acid is stirred at room temperature until the reaction has ended. The volatile components are then distilled off under reduced pressure. The residue is washed with diisopropyl ether and then with NaHCO3 solution. This affords 1.77 g of the desired compound.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:5]=1[C:6](O)=[O:7])#[N:2].C[N:15](C)C=O.C(Cl)(=O)C(Cl)=O>O1CCCC1>[C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:5]=1[C:6]([NH2:15])=[O:7])#[N:2]
Reactant: Cc1ccc(CC#N)c(C(=O)O)c1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: Cc1ccc(CC#N)c(C(N)=O)c1

Procedure:
2-Cyanomethyl-5-methylbenzoic acid (16.3 g) and dimethylformamide (0.1 mL) were suspended in tetrahydrofuran (160 mL), and oxalyl dichloride (12.2 mL) was added dropwise under ice-cooling. After cease of foaming, the solvent was evaporated. The obtained residue was dissolved in tetrahydrofuran, and the solution was added dropwise to 28% aqueous ammonia solution under ice-cooling. After the completion of the reaction, the solvent was evaporated, and the precipitated crystals were collected by filtration to give 2-cyanomethyl-5-methylbenzamide (10.9 g).
Reaction SMILES: [OH:1][CH:2]=[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]1=[CH:22][OH:23]>C(O)CCC>[CH2:2]([O:1][CH:2]=[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]1=[CH:22][O:23][CH2:15][CH2:10][CH2:11][CH3:12])[CH2:3][CH2:4][CH3:5]
Reactant: OC=c1cccc(N(c2ccccc2)c2ccccc2)c1=CO
Solvent: CCCCO
Product: CCCCOC=c1cccc(N(c2ccccc2)c2ccccc2)c1=COCCCC

Procedure:
A mixture of di(hydroxymethylene)-triphenylamine (0.25 g), butanol (1 g) and an ion exchange resin AMBERYST® 15 (0.05 g) was shaken at room temperature (about 23° C.) until the reaction was completed as indicated by thin layer chromatography (TLC). The mixture was filtered to remove the AMBERLYST 15 catalyst. Removal of the solvent under reduced pressure yielded charge transport compound (1). The structure was confirmed by 1H NMR spectrum.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:6]=2[N:7]=1.S1C2C=CC(N)=CC=2N=C1>>[CH3:1][N:2]([CH3:15])[C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)c1nc2cc([N+](=O)[O-])ccc2s1
Agent: Nc1ccc2scnc2c1
Product: CN(C)c1nc2cc(N)ccc2s1

Procedure:
N2,N2-Dimethylbenzo[d]thiazole-2,5-diamine was prepared from N,N-dimethyl-5-nitrobenzo[d]thiazol-2-amine similar to that described in the preparation of Benzo[d]thiazol-5-amine.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=O.[CH3:19][O:20][C:21](=[O:32])[CH2:22][CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl[Si](C)(C)C>CN(C=O)C>[C:25]1([C:24]2[N:1]=[C:2]3[S:6][C:5]4[CH2:7][CH2:8][CH2:9][C:4]=4[C:3]3=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[C:23]=2[CH2:22][C:21]([O:20][CH3:19])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccc(C(=O)c2c(N)sc3c2CCC3)cc1
Reactant: COC(=O)CCC(=O)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(-c2ccccc2)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Yield: 47.9 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-p-tolylmethanone (0.257 g; 1 mmol), methyl-3-benzoylpropionate (0.211 g; 1.1 mmol), chlorotrimethylsilane (0.526 mL; 4 mmol) in DMF (4 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane furnished 0.198 g (48%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][CH2:2][CH:3](O)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C(Cl)=NC(Cl)=NC=1[Cl:12]>>[Cl:12][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:2][CH3:1]
Reactant: CCCCCC(O)CC
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: CCCCCC(Cl)CC

Procedure:
Using a procedure analogous to that of Example 1, 81 g (0.522 mol) of 3-octanol is reacted with 62.1 g (0.337 mol) of cyanuric chloride over a period of 9 hours at a reaction temperature of 70° C. The liquid reaction phase after extraction with sodium hydroxide has the following composition:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([C:24]([O:26]C)=[O:25])=[CH:22][N:21]=[C:20]3[NH:28][CH:29]=[CH:30][C:19]=23)[CH2:14][CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[Li+].[OH-]>O.CO.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1)[C:10]([N:12]1[CH2:13][CH2:14][N:15]([C:18]2[C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=[C:20]3[NH:28][CH:29]=[CH:30][C:19]=23)[CH2:16][CH2:17]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cnc2[nH]ccc2c1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(C(=O)O)cnc3[nH]ccc23)CC1
Temperature: 65 °C
Yield: 24.4 %

Procedure:
(R)-Methyl 4-(4-(2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoyl)piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.210 g, 0.3874 mmol, see Example 2) was placed in 2:1 THF:MeOH (6 mL). 3M LiOH (aq., 1.29 mL, 3.87 mmol) was then added, and the reaction was heated to 65° C. for 2 hours. The reaction was then diluted with water and extracted with DCM. The combined organic fractions were dried, filtered, and concentrated to give a crude residue. The residue was purified by column:chromatography (20:1 DCM:MeOH) to give (R)-4-(4-(2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoyl)piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (0.050 g, 24.4% yield).
Reaction SMILES: [Li+].[OH-:2].OO.[CH2:5]([N:12]1[CH2:16][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[C:19]([F:27])[CH:18]=2)[C@H:14]([C:28](N2[C@H](C3C=CC=CC=3)COC2=O)=[O:29])[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S([O-])([O-])=O.[Na+].[Na+].OS([O-])(=O)=O.[K+]>C1COCC1>[CH2:5]([N:12]1[CH2:16][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[C:19]([F:27])[CH:18]=2)[C@H:14]([C:28]([OH:29])=[O:2])[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1OC[C@@H](c2ccccc2)N1C(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(C(F)(F)F)c(F)c1
Reactant: [OH-]
Agent: O=S(=O)([O-])O
Agent: O=S([O-])[O-]
Agent: OO
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(C(F)(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
To a 1M LiOH solution (8.20 mL, 8.20 mmol) cooled to 0° C. was added 30% hydrogen peroxide (1.06 mL, 10.2 mmol). The mixture was stirred for 10 min at 0° C. and then added to solution of 340 (2.10 g, 4.10 mmol) in THF (15 mL) cooled to 0° C. over 15 min. The mixture was stirred for 4 h at 0° C. then 2M sodium sulfite (10 mL) was added and the mixture stirred for 30 min. The pH was adjusted to ca. 5-6 with 2M KHSO4 and the mixture was thrice extracted with 50 mL portions of 3:1 CHCl3/IPA. The combined organic extracts were combined, washed with brine, dried (MgSO4), filtered and evaporated. The crude product was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (5 to 10% MeOH) to afford 1.28 g (85.0%) of (3S,4R)-1-benzyl-4-(3-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-3-carboxylic acid (342) as white solid: MS m/z (APCI-neg) M−1=366.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([O:22][CH2:23][CH2:24]Cl)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH:26][C:27]1[C:32]([CH2:33][CH2:34][CH3:35])=[C:31]([SH:36])[CH:30]=[CH:29][C:28]=1[C:37](=[O:39])[CH3:38].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([O:22][CH2:23][CH2:24][S:36][C:31]2[CH:30]=[CH:29][C:28]([C:37](=[O:39])[CH3:38])=[C:27]([OH:26])[C:32]=2[CH2:33][CH2:34][CH3:35])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(S)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCCCl)ccc(C(C)=O)c1OCCCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(SCCOc2ccc(C(C)=O)c(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Reaction time: 19 h
Yield: 82.8 %

Procedure:
A mixture of ethyl 4-[6-acetyl-3-(2-chloroethoxy)-2-propylphenoxy]butyrate (0.60 g), (2-hydroxy-4-mercapto-3-propylphenyl)ethanone (0.51 g), potassium iodide (0.1 g) and potassium carbonate (0.65 g) in acetone (40 ml) was heated and refluxed with stirring for 19 hours. After cooled, inorganic materials were separated by filtration and the filtrate was concentrated. The resultant residue was separated and purified through silica gel column chromatography (eluting with benzene:ethyl acetate=15:1, then 9:1) to give the title compound (0.73 g, 82.8%) as brown oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:14])=[N+:11]([O-:13])[CH:12]=1.[OH-].[Na+]>CCOC(C)=O>[CH3:5][O:6][C:7]1[C:8]([N+:1]([O-:4])=[O:2])=[CH:9][C:10]([CH3:14])=[N+:11]([O-:13])[CH:12]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C)[n+]([O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To fuming nitric acid (20 mL, Spectrochem, India) was added (5-methoxy-2-methylpyridine 1-oxide (14 g, 0.100 mol) in one lot and the reaction was stirred at rt for 2 h. Reaction progress was monitored by TLC (50% EtOAc in pet ether.). After completion of the reaction, the reaction mixture was poured in to ice water (100 mL) and neutralized with 40% NaOH solution (PH˜7-7.5) to get a yellow precipitate. The precipitate was stirred for 5-10 min, then filtered and dried to give the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.51 (s, 1H), 8.21 (s, 1H), 3.95 (s, 3H), 2.31 (s, 3H). MS (ESI, positive ion) m/z: 184.8 (M+H).
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][O:7][C:8](=[O:19])[C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[Br:18]>CO.Cl>[CH3:6][O:7][C:8](=[O:19])[C:9]1[C:10]([Br:18])=[CH:11][CH:12]=[C:13]([NH2:15])[CH:14]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(N)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tin (II) chloride dihydrate (22.56 g, 100 mmol) was added to a stirred solution of methyl-2-bromo-5-nitrobenzoate (9 g, 34.61 mmol) in methanol (250 mL) and conc. HCl (25 mL). The solution was stirred at RT for 8 h and then treated with satd. aq. KHCO3 solution (600 mL). Additional solid KHCO3 (50 g) was added. The mixture was extracted with EtOAc (200 mL, 5×). The EtOAc extracts were combined, dried (MgSO4), filtered and concentrated. The residue was diluted with EtOAc (250 mL) and washed with brine (50 mL, 2×), dried (MgSO4), filtered and concentrated to obtain the title compound of this step (7.45 g, 94%) as a brown oil.