Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2.[Br:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[O:22][C:23]([CH2:26]Cl)=[N:24][N:25]=2)[CH:20]=1>>[Br:14][C:15]1[CH:20]=[C:19]([C:21]2[O:22][C:23]([CH2:26][N:6]3[C:7]4[C:3](=[C:2]([Cl:1])[C:10]([C:11]#[N:12])=[CH:9][CH:8]=4)[CH:4]=[C:5]3[CH3:13])=[N:24][N:25]=2)[CH:18]=[N:17][CH:16]=1
Reactant: Cc1cc2c(Cl)c(C#N)ccc2[nH]1
Reactant: ClCc1nnc(-c2cncc(Br)c2)o1
Product: Cc1cc2c(Cl)c(C#N)ccc2n1Cc1nnc(-c2cncc(Br)c2)o1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-methyl-1H-indole-5-carbonitrile and 3-bromo-5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyridine: 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.94 (s, 1H), 8.48 (s, 1H), 7.96 (s, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 5.96 (s, 2H), 2.47 (s, 3H); MS (ES) m/z 429 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([NH2:20])[C:10]=2[C:11]2[CH:16]=[C:15](S(C)=O)[N:14]=[CH:13][N:12]=2)[CH:7]=1.[NH:21]1[CH2:29][CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22]1>CN1C(=O)CCC1>[NH2:20][C:9]1[C:10]([C:11]2[N:12]=[CH:13][N:14]=[C:15]([N:21]3[CH2:29][CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22]3)[CH:16]=2)=[C:5]2[N:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]2[N:8]=1
Reactant: NC(=O)C1CCCNC1
Reactant: Cc1cnc2c(-c3cc(S(C)=O)ncn3)c(N)nn2c1
Solvent: CN1CCCC1=O
Product: Cc1cnc2c(-c3cc(N4CCCC(C(N)=O)C4)ncn3)c(N)nn2c1
Temperature: 200 °C

Procedure:
6-methyl-3-(6-(methylsulfinyl)pyrimidin-4-yl)pyrazolo[1,5-a]pyrimidin-2-amine (60 mg, 0.21 mmol) was dissolved in NMP with nipecotamide (100 mg, 0.78 mmol)and heated to 200° C. in a microwave for 20 min. The reaction mixture was purified by RP HPLC (C18, CH3CN/H2O 0.1% TFA) and the pure fractions were poured into ethyl acetate/0.5 N NaOH. The organic phase was dried over sodium sulfate and concentrated to a yellow solid which was dissolved in 1N HCl in MeOH and concentrated to the HCl salt as a yellow solid, 20 mg, 0.052 mmol, 26%. LC/MS MH+353.4
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[NH:14][N:13]=[C:12]([CH3:15])[N:11]=2)[CH:3]=1.[C:16]([OH:19])(=[O:18])[CH3:17]>>[C:16]([OH:19])(=[O:18])[CH3:17].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([C:10]2[NH:14][N:13]=[C:12]([CH3:15])[N:11]=2)[CH:3]=1
Reactant: Cc1n[nH]c(-c2cc(F)ccc2C#N)n1
Solvent: CC(=O)O
Product: Cc1n[nH]c(-c2cc(F)ccc2CN)n1
Yield: 73 %

Procedure:
4-Fluoro-2-(3-methyl-1H-1,2,4-triazol-5-yl)benzonitrile (0.803 g, 4.1 mmol) was hydrogenated as described in the procedure for intermediate 151 to give 0.796 g (73% yield) the title acetic acid salt as a white solid. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.41 (3H, s, CH3), 3.97 (2H, s, CH2), 7.24 (1H, m, aromatic), 7.55 (1H, dd, J=6.1 Hz and J=8.1 Hz, aromatic), 7.66 (1H, dd, J=2.8 Hz and J=10.3 Hz, aromatic). HRMS (ESI+) calculated for C10H12FN4 [M+H+]: 207.1046; found: 207.1049.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[CH2:15]([C:17]1[O:21][C:20]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:19]=2[CH:18]=1)[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>CO>[CH2:15]([C:17]1[O:21][C:20]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:19]=2[C:18]=1[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:4]=1)[CH3:16]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: CCc1cc2cc(C)ccc2o1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Product: CCc1oc2ccc(C)cc2c1C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
is obtained as described in Example 1 from 10 g 4-chloro-3-sulfamoylbenzoyl chloride and 6.2 g 2-ethyl-5-methylbenzo[b]furan in the presence of 11.4 g aluminum chloride. Colorless crystals, m.p. 147°-150° C. (from methanol).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22][CH2:23][C:24]2[O:28][CH:27]=[C:26]([C:29]3[CH:57]=[CH:56][C:32]4[N:33]([C:37]([C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:34](=[O:36])[O:35][C:31]=4[CH:30]=3)[CH:25]=2)[CH2:18][CH2:17]1.[F:58][C:59]1[CH:66]=[CH:65][C:62]([CH:63]=O)=[CH:61][CH:60]=1.C(O)(=O)C>ClCCCl.C(Cl)(Cl)Cl>[F:58][C:59]1[CH:66]=[CH:65][C:62]([CH2:63][N:22]([CH2:23][C:24]2[O:28][CH:27]=[C:26]([C:29]3[CH:57]=[CH:56][C:32]4[N:33]([C:37]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)[C:50]5[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=5)[C:34](=[O:36])[O:35][C:31]=4[CH:30]=3)[CH:25]=2)[CH:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)=[CH:61][CH:60]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CN1CCC(NCc2cc(-c3ccc4c(c3)oc(=O)n4C(c3ccccc3)(c3ccccc3)c3ccccc3)co2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CN1CCC(N(Cc2ccc(F)cc2)Cc2cc(-c3ccc4c(c3)oc(=O)n4C(c3ccccc3)(c3ccccc3)c3ccccc3)co2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.5 %

Procedure:
Sodium triacetoxyborohydride (71 mg, 0.33 mmol) was added to a solution of 6-{5-[(1-methyl-piperidin-4-ylamino)-methyl]-furan-3-yl}-3-trityl-3H-benzooxazol-2-one (95 mg, 0.17 mmol) and 4-fluorobenzaldehyde (21 mg, 0.2 mmol) and acetic acid (20 mg, 0.33 mmol) in 1.5 mL of 1,2-dichloroethane. The mixture was stirred at ambient temperature for 20 h, and then it was diluted with chloroform and washed with saturated sodium carbonate solution. The aqueous phase was extracted with chloroform, and the combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and concentrated to leave the crude product. Chromatography (elution with dichloromethane/methanol) gave 64 mg of product.
Reaction SMILES: CN(C)C=[N:4][C:5]1[S:6][C:7]([N+:13]([O-:15])=[O:14])=[C:8]([Cl:12])[C:9]=1[C:10]#[N:11].Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([N+:13]([O-:15])=[O:14])=[C:8]([Cl:12])[C:9]=1[C:10]#[N:11]
Reactant: CN(C)C=Nc1sc([N+](=O)[O-])c(Cl)c1C#N
Agent: Cl
Solvent: CCO
Product: N#Cc1c(N)sc([N+](=O)[O-])c1Cl
Yield: 79 %

Procedure:
A mixture of 5.2 parts of N,N-dimethyl-N'-(4-chloro-3-cyano-5-nitrothien-2-yl)-formamidine, 50 parts of ethanol and 5 parts of concentrated hydrochloric acid is heated at the boil for 3 hours and then poured onto ice water. The precipitate is filtered off under suction, washed with water and dried. 3.2 parts (79% of theory) of 2-amino-4-chloro-3-cyano-5-nitrothiophene are obtained. Decomposition temperature: 227° C. (from o-dichlorobenzene).
Reaction SMILES: O1CCCCC1[N:7]1[C:11](=[O:12])[CH:10]=[C:9]([CH2:13][N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:17][CH:16]([NH:31][C:32]([C:34]3[NH:35][C:36]4[C:41]([CH:42]=3)=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[C:15]2=[O:43])[O:8]1.Cl.O1CCCC1>CO>[OH:12][C:11]1[CH:10]=[C:9]([CH2:13][N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:17][CH:16]([NH:31][C:32]([C:34]3[NH:35][C:36]4[C:41]([CH:42]=3)=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[C:15]2=[O:43])[O:8][N:7]=1
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2N(Cc2cc(=O)n(C3CCCCO3)o2)C1=O)c1cc2ccccc2[nH]1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2N(Cc2cc(O)no2)C1=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Yield: 82 %

Procedure:
To a suspension of (3RS)-1,3-dihydro-1-[[2-(2-tetrahydropyranyl)-3-oxo-2,3-dihydroisoxazol-5-yl ] methyl]-3-(2-indolylcarbonylamino)-5-phenyl-1,4-benzodiazepine-2-one (212.9 mg) in methanol (4 ml) was added 2N hydrochloric acid under stirring at room temperature. Tetrahydrofuran (1 ml) was added thereto in order to gain a clear solution, which was stirred at the same temperature for 30 minutes. The reaction mixture was evaporated to dryness to afford yellow powder, which was washed with ether by stirring overnight, collected by filtration and dried to give (3RS)-1,3-dihydro-1-[(3-hydroxyisoxazol-5-yl)methyl]-3-(2-indolylcarbonylamino)-5-phenyl-1,4-benzodiazepine-2-one (149.1 mg) as yellow powder.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:24])([CH3:23])[O:6][CH:7]1[CH2:11][CH:10](O)[C:9](=[CH2:13])[CH:8]1[CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:44][C:45]1[N:53]=[C:52]2[C:48]([NH:49][CH:50]=[N:51]2)=[C:47]([Cl:54])[N:46]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(Cl)Cl>[Cl:54][C:47]1[N:46]=[C:45]([NH2:44])[N:53]=[C:52]2[C:48]=1[N:49]=[CH:50][N:51]2[CH:10]1[CH2:11][CH:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:8]([CH2:7][O:6][Si:5]([C:2]([CH3:4])([CH3:1])[CH3:3])([CH3:24])[CH3:23])[C:9]1=[CH2:13]
Reactant: C=C1C(O)CC(O[Si](C)(C)C(C)(C)C)C1CO[Si](C)(C)C(C)(C)C
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C1C(CO[Si](C)(C)C(C)(C)C)C(O[Si](C)(C)C(C)(C)C)CC1n1cnc2c(Cl)nc(N)nc21
Temperature: -20 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a suspension of 56 (120 mg, 0.32 mmol), triphenylphosphine (84.5 mg, 0.64 mmol), and 2-amino-6-chloropurine (108 mg, 0.64 mmol) in THF (10 mL) was added diethyl azodicarboxylate (111 mg, 0.64 mmol) at −20° C. The reaction mixture was stirred at −20° C. for 1 hour. It was poured into DCM (50 mL), washed with 0.5 N sodium hydroxide (3×10 mL), dried over sodium sulfate, and concentrated in vacuo. Purification via silica gel chromatography gave the title compound (0.11 g, 63%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][C:13](=[O:15])[O:12][C:11](=[O:16])[CH2:10]1.[NH3:19].CO>>[C:11]([CH2:10][CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:18])([F:17])[F:1])[CH2:14][C:13]([OH:12])=[O:15])(=[O:16])[NH2:19]
Reactant: O=C1CC(c2ccccc2C(F)(F)F)CC(=O)O1
Reactant: N
Solvent: CO
Product: NC(=O)CC(CC(=O)O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Saturated ammonia/methanol (10 mL) was added to 4-(2-trifluoromethylphenyl)dihydropyrane-2,6-dione (636 mg), and the mixture was stirred at room temperature for 15 hours. Concentration under reduced pressure gave a crude product (716 mg) which was used for the next reaction without purification.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.[CH3:31][O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:9]([CH3:8])[C:37](=[O:38])[C:36]4[CH:40]=[CH:41][C:33]([O:32][CH3:31])=[CH:34][CH:35]=4)[CH:12]=3)=[CH:22][CH:21]=2)[S:28]1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)N(C)Cc2cccc(-c3ccc(CC4SC(=O)NC4=O)cc3)c2)cc1

Procedure:
In a manner similar to that of Example 37(e), by reacting 500 mg (1.1 mmol) of 5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione trifluoroacetate with 170 μl (1.25 mmol) of 4-methoxybenzoyl chloride, and after purification, 300 mg (50%) of N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)-biphenyl-3-ylmethyl]-4-methoxy-N-methylbenzamide are obtained in the form of a white solid with a melting point of 170° C.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si](C(C)(C)C)(C)C)[CH:12]=[CH:11][C:10]=1[C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][OH:30])[CH2:25][CH2:24]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:30][CH2:29][C@H:26]1[CH2:25][CH2:24][C@H:23]([C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[OH:8])[CH2:28][CH2:27]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](CO)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
cis/trans-[4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]methanol (24 mg) was dissolved in THF (5 ml), and tetrabutylammonium fluoride (0.12 ml, 1.0M in THF) was added. The resulting solution was stirred at room temperature for 15 hr and then partitioned between ethyl acetate (20 ml) and water (2 ml). The aqueous phase was extracted with ethyl acetate (3×20 ml) and the combined organic phases were washed with brine (20 ml), dried over anhydrous magnesium sulphate, and concentrated in vacuo. Purification via flash column chromatography (SiO2 eluting with ethyl acetate:petroleum ether, 1:1 v/v) furnished the desired compound (7 mg, 59%) as a white solid. δH(CD3OD): 0.95-1.06 (0.5H, m), 1.24-1.38 (0.5H, m), 1.43-1.60 (4H, m), 1.69-1.83 (4H, m), 2.62-2.77 (1H, m), 3.30 (1H, d), 3.56 (1H, d), 6.11-6.17 (2H, m), 6.76-7.01 (1H, m); m/z (ES−) 281 (M−1+60)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:19]([C:21]1[CH:22]=[C:23]([CH:28]=[C:29]([O:31][C:32]2[CH:33]=[N:34][CH:35]=[N:36][CH:37]=2)[CH:30]=1)[C:24](OC)=[O:25])#[N:20]>C1COCC1>[C:19]([C:21]1[CH:22]=[C:23]([CH:28]=[C:29]([O:31][C:32]2[CH:37]=[N:36][CH:35]=[N:34][CH:33]=2)[CH:30]=1)[C:24]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1)=[O:25])#[N:20]
Reactant: Nc1ccc(F)cn1
Reactant: COC(=O)c1cc(C#N)cc(Oc2cncnc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1cc(Oc2cncnc2)cc(C(=O)Nc2ccc(F)cn2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 6.7 %

Procedure:
5-fluoropyridin-2-amine (4.2 mg, 0.037 mmol, 1.2 eq) was dissolved in THF (0.20 mL), and potassium bis(trimethylsilyl)amide (13 mg, 0.066 mmol, 2.1 eq) was added. The reaction was stirred at rt for 5 minutes. Compound 9 (8.0 mg, 0.031 mmol, 1.0 eq) was dissolved in THF (0.20 mL) and added to the reaction mixture. The reaction was stirred at rt for 30 minutes, dried on air concentrator, and purified by reverse-phase preparatory HPLC to afford 0.7 mg (10%) of the title compound as a mono-TFA salt: 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.78 (s, 2H), 8.41 (d, J=3.0, 1H), 8.27 (t, J=1.3 Hz, 1H), 8.19 (dd, J=9.2, 4.1 Hz, 1H), 8.03-8.00 (m, 2H), 7.81 (td, J=8.7, 3.0 Hz, 1H); ES-MS [M+1]+:336.1.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16][NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([C:31]#[N:32])[CH:29]=5)[NH:24][CH:23]=4)[O:12][C:8]3=2)[N:3]=1.C=O.[C:35]([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:35][N:17]([CH2:16][CH:13]1[O:12][C:8]2=[C:9]3[C:4](=[CH:5][CH:6]=[C:7]2[O:15][CH2:14]1)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]3)[CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]#[N:32])[CH:29]=2)[NH:24][CH:23]=1
Reactant: [BH3-]C#N
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](CNCCCCc1c[nH]c2ccc(C#N)cc12)O3
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc2c3c(ccc2n1)OCC(CN(C)CCCCc1c[nH]c2ccc(C#N)cc12)O3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2S)-3-{4-[(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amino]-butyl}-1H-indole-5-carbonitrile (0.13 g, 0.30 mmol) and formaldehyde (37 wt. % in water, 0.24 g, 3.0 mmol) in methanol (20 mL) was added sodium cyanoborohydride (0.35 g, 0.54 mmol) and acetic acid (0.035 mL, 0.6 mmol) at room temperature. The mixture was stirred at room temperature under nitrogen for 4 hours, then quenched with 1N NaOH (5 mL). The mixture was extracted with methylene chloride (3×50 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. The crude oil was column chromatographed on silica gel (5% methanol-ethyl acetate). The product-containing fractions were concentrated in vacuum to give 0.11 g of the (S)-enantiomer of the title compound as a brown oil. The dihydrochloride salt was prepared in ethyl acetate as a yellow solid (decomposed at 155° C.).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:19]1([NH:25][OH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C1C=CC=CC=1.O1CCCCC1.C1COCC1.O.CCOC(C)=O.CN(C)C=O>[OH:26][N:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ONc1ccccc1
Reactant: O=C(O)CCCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOCC1
Product: O=C(CCCc1ccccc1)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a stirring solution of 3-phenylpropylcarboxylic acid (500 mg, 3.1 mmol) in 10 ml of dry benzene under argon was added oxalyl chloride (0.30 ml, 1.1 eq.). To this solution was added dimethylformamide dropwise in 10 minute intervals, until no gas was evolved and the solution turned slightly cloudy (2 drops). The mixture was stirred for 1 hour then reduced on the rotovap without heating. The crude product was diluted with 5 ml of tetrahydropyran and added dropwise to a 0° C. solution of N-phenylhydroxylamine (666 mg, 2 eq.) in 20 ml of THF:H2O (1:1) with triethylamine (0.85 ml, 2.0 eq.). The solution was stirred for 1 hour at 0° C. then allowed to warm to room temperature and stir overnight. The reaction mixture was diluted with EtOAc and the organic layer was washed with H2O, 1N HCl (2X), and brine, then dried over anhydrous MgSO4. Concentration in vacuo gave a white solid which was recrystallized from hot hexane/EtOAc, to give title product (451 mg, 58%) as a flat golden crystalline solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([OH:22])=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC12CCC(C(=O)O)(CC1)CC2)OCc1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: O=C(NC12CCC(C(=O)OC3CCCCO3)(CC1)CC2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Benzyloxycarbonylaminobicyclo[2,2,2]octane-1-carboxylic acid (1.00 g) was suspended in dichloromethane (10 mL). To this suspension, 3,4-dihydro-2H-pyran (1.20 mL) and then p-toluenesulfonic acid monohydrate (6.3 mg) were added and the mixture was stirred at room temperature for 30 minutes. Subsequently, the reaction mixture was sequentially washed with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=4:1) to give 2-tetrahydropyranyl 4-benzyloxycarbonylaminobicyclo[2,2,2]octane-1-carboxylate (1.18 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:17]=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:20](Cl)(=[O:22])[CH3:21]>C(#N)C>[C:2]1([CH3:1])[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[C:10]3[CH:17]=[CH:16][N:15]([C:20](=[O:22])[CH3:21])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:3]=1
Reactant: Cc1cccc(Nc2ncnc3[nH]ccc23)c1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)n1ccc2c(Nc3cccc(C)c3)ncnc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 23.2 %

Procedure:
To (3-methyl-phenyl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (0.75 g, 3.4 mmol) dissolved in hot acetonitrile (30 ml) was added sodium hydride (0.16 g, 4.0 mmol, 60% dispersion in mineral oil). After stirring at ambient temperature for 0.75 hours, acetyl chloride (0.48 ml, 6.7 mmol) was added and stirring continued for 48 hours. The reaction mixture was concentrated in vacuo, triturated in hot ethyl acetate, and filtered. The filtrate was concentrated in vacuo to give an orange solid residue. The solid was purified by flash chromatography on silica gel (13 g,40 mm mesh) using 1:3 ethyl acetate/hexanes to afford 1-(4-m-tolylamino-pyrrolo[2,3-d]pyrimidin-7-yl)-ethanone as a yellow solid (0.21 g). TS-MS: 309 (MH+); anal. RP18-HPLC RT: min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]1.CN1CCOCC1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:22]>C(Cl)Cl>[C:21](=[O:22])([O:23][C:24]1[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=1)[O:12][CH2:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:6][CH2:7]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COCCN1CCC(CO)CC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COCCN1CCC(COC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of (1-(2-methoxyethyl)piperidin-4-yl)methanol (3.65 g, 21.1 mmol) and NMM (2.5 mL, 22.8 mmol) in DCM (100 mL) at 0° C. was added p-nitrophenyl chloroformate. The reaction mixture was stirred at room temperature overnight and then washed sequentially with sat aq NaHCO3 solution (5×100 mL), dried (MgSO4) and concentrated in vacuo. The resulting orange oil was recrystallised from EtOAc and heptane to give (1-(2-methoxyethyl)piperidin-4-yl)methyl 4-nitrophenyl carbonate (3.65 g, 51%) as an orange solid.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl>C(O)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][CH:13]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=2)[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cn2)CC1
Reaction time: 1 h
Yield: 52 %

Procedure:
A 2 M sodium hydroxide solution (20 mL) was added to a solution of methyl 6-(1-(tert-butoxycarbonyl)piperidin-4-yl)nicotinate described in Production Example 28-2 (1.07 g, 3.32 mmol) in ethanol (5 mL), and the mixture was stirred for 1 hour. 2 M hydrochloric acid was added to the reaction liquid at 0° C. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum to obtain the title compound (534 mg, 52%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[C:13]([O:18][CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:25]([O:27]C)=[O:26].CO.[OH-].[Na+].Cl>C(Cl)Cl>[CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[C:13]([O:18][CH:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:25]([OH:27])=[O:26]
Reactant: COC(=O)c1sc2ncnc(Nc3cccnc3OC3CCOCC3)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Methyl 5-methyl-4-(2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-ylamino)thieno[2,3-d]pyrimidine-6-carboxylate (0.921 g, 2.30 mmol) was added into a solution of MeOH (8 mL) and 2M aqueous sodium hydroxide (2.0 mL). The reaction was stirred at 60° C. for two hours. The mixture was cooled to ambient temperature and acidified with concentrated hydrochloric acid. On addition of DCM a precipitate formed which was collected and washed with water. The product was purified by reverse phase preparative HPLC to yield off-white solid which was used in the next step without further purification.