Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3][N:2]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>N.CO.[Ni]>[CH2:1]1[C@H:13]2[C@H:5]([NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=32)[CH2:4][CH2:3][N:2]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)N1CCc2[nH]c3ccccc3c2C1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCOC(=O)N1CC[C@H]2Nc3ccccc3[C@H]2C1
Temperature: 0 °C
Yield: 69.1 %

Procedure:
A mixture of ethyl 1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (49.2 g), prepared as described in J. Med. Chem. 23:635-643 (1980), in NH3 /CH3OH (400 ml) was hydrogenated with Raney nickel (5 g) as a catalyst. The mixture was cooled and the catalyst was filtered off. The filtrate was evaporated. The residue was dissolved in anhydrous diethyl ether (600 ml) and HCl(g) was allowed to bubble through the solution for 30 minutes. The resulting precipitate was filtered off, dissolved in water (200 ml) and extracted with diethyl ether (100 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was solidified in DIPE (150 ml), cooled to 0° C., filtered off and dried, yielding 34.3 g (70%) of (±)-ethyl cis-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate (intermediate 1).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6](C3CCNCC3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C.BrCCCN1C2C=CC=CC=2N=N1>O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: BrCCCn1nnc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2ccc(Cl)cc2[nH]1
Reaction time: 8 h

Procedure:
A mixture of 5 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 3.7 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed with water-separator. Then there are added 4.8 parts of 1-(3-bromopropyl)-1H-benzotriazole and stirring is continued overnight at reflux temperature. The reaction mixture is cooled, water is added and the undissolved product is filtered off and set aside. The organic phase is separated from the filtrate, dried, filtered and evaporated. The residue is combined with the undissolved product (see above) and purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 2 parts (25%) of 1-{1-[3-H-benzotriazol-1-yl)propyl]-4-piperidinyl}-5-chloro-1,3-dihydro-2H-benzimidazol-2-one; mp. 203.4° C.
Reaction SMILES: [Br:1]Br.[NH:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([O:14][CH3:15])=[O:13])[N:5]=[CH:4]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(#N)C>[Br:1][C:4]1[NH:3][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([O:14][CH3:15])=[O:13])[N:5]=1
Reactant: BrBr
Reactant: COC(=O)c1nc[nH]c1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)c1nc(Br)[nH]c1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At ambient temperature 9.50 g (59.45 mmol) bromine were added dropwise to a solution of 9.90 g (53.76 mmol) dimethyl imidazole-4,5-dicarboxylate in 300 ml dichloromethane and 80 ml acetonitrile. 7.46 g (54.00 mmol) potassium carbonate was added, and the reaction mixture was stirred for 2 hours at ambient temperature. Then the dichloromethane was eliminated using the rotary evaporator and the residue was combined with a saturated solution of sodium chloride and sodium thiosulphate. It was extracted ten times with ethyl acetate, the organic extracts were dried over sodium sulphate and then the solvent was eliminated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.[N:40]1([C:47](=O)[CH2:48]Cl)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[N:40]1([CH2:47][CH2:48][O:39][C:38]2[CH:37]=[CH:36][C:4]([CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]3[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=3[C@@H:16]3[CH2:17][CH2:18][C:23]4[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:24]=4[CH2:25]3)=[CH:3][C:2]=2[F:1])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: O=C(CCl)N1CCCCCC1
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCCCCC3)c(F)c2)C(C)C)c1
Yield: 25 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 1-azepan-1-yl-2-chloroethanone (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (5.0 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@H:19]2[C@@H:10]([N:11]([CH2:26][C:27](O)=[O:28])[C:12](=[O:25])[C:13]3[C:14]([C:21]([F:24])([F:23])[F:22])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[OH:28][CH2:27][CH2:26][N:11]1[C@H:10]2[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:20][C@@H:19]2[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:21]([F:23])([F:22])[F:24])[C:13]=2[C:12]1=[O:25]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3C(=O)N(CC(=O)O)[C@H]2C1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3C(=O)N(CCO)[C@H]2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 2-((3aR,9bS)-2-(tert-butoxycarbonyl)-5-oxo-6-(trifluoromethyl)-1,2,3,3a-tetrahydro-5H-pyrrolo[3,4-c]isoquinolin-4(9bH)-yl)acetic acid from Example 19, Part A (70 mg, 0.17 mmol) in 4 mL of THF at 0° C. was added triethylamine (0.028 mL, 0.20 mmol) and ethyl chloroformate (0.019 mL, 0.20 mmol). The reaction was allowed to stir for 30 min at 0° C. and then there was added sodium borohydride (19 mg, 0.51 mmol) in a minimal amount of water. The resulting mixture was stirred for 1 h at 0° C. and then was quenched with 10 mL of 1N HCl. The mixture was extracted with ethyl acetate and the organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford 60 mg (88%) of the title compound which was sufficiently pure to be used without purification. LRMS (ESI): 401.21 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:23]2[O:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:26][N:27]=2)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.[CH2:34]1[C@@H:38]2[CH2:39][CH2:40][CH:41]([OH:42])[C@@H:37]2[CH2:36][NH:35]1.C(N(CC)CC)C>CN(C=O)C>[OH:42][CH:41]1[C@@H:37]2[CH2:36][N:35]([C:2]3[N:3]=[C:4]([C:23]4[O:24][C:25]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)=[N:26][N:27]=4)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[N:6][CH:7]=3)[CH2:34][C@@H:38]2[CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1nnc(-c2ccccc2)o1
Reactant: OC1CC[C@H]2CNC[C@@H]12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(N2C[C@@H]3CCC(O)[C@@H]3C2)nc1-c1nnc(-c2ccccc2)o1
Yield: 83.7 %

Procedure:
A solution of tert-butyl N-[5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (115 mg, 0.22 mmol), (3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-4-ol (73 mg, 0.57 mmol) and triethyl amine (34 mg, 46 μL, 0.33 mmol) in DMF was heated to 90° C. for 90 minutes. The solvent was removed under reduced pressure and the crude material was purified by silica gel column chromatography using 5-60% EtOAc in DCM to yield tert-butyl N-[5-[(3aR,6aS)-6-hydroxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (104 mg, 83%). LC/MS m/z 465.5 [M+H-Boc]+.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][C:7]1[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([N:17]([CH3:29])[CH2:18][C:19]2[N:20]([CH3:28])[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[CH:9][CH:8]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([N:17]([CH3:29])[CH2:18][C:19]2[N:20]([CH3:28])[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N)nc1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(/C=C/C(=O)N(C)Cc2cc3ccccc3n2C)cn1
Reaction time: 144 h
Yield: 24.3 %

Procedure:
Ethyl isocyanate (0.13 mL, 1.68 mmole) was added to a solution of (E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (0.27 g, 0.84 mmole) and triethylamine (0.29 mL, 2.1 mmole) in DMF (30 mL) at RT. The reaction was stirred for 6 days, then was concentrated in vacuo, and the residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. Flash chromatography on silica gel (ethyl acetate) gave the tide compound (80 mg, 24%) as a light yellow solid: MS (ES) m/e 392 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.N1C=CC=CC=1.[Cl:20][C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:20][C:21]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1)=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)Cl)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 248.9 %

Procedure:
A flask was charged with (R)-tert-butyl pyrrolidin-3-ylcarbamate (1.0 g, 5.4 mmol, Lancaster) in DCM (15 mL) to give a colorless solution. Pyridine (0.89 mL, 10.8 mmol) was added and the solution was cooled to about 0° C., followed by the addition of triphosgene (0.64 g, 2.1 mmol). The mixture was stirred for about 1 h while slowly warming to ambient temperature. To the reaction solution was added DCM (50 mL) and the solution was washed with water (20 mL) and HCl (1N, 10 mL). The organic portion was separated, dried over anhydrous MgSO4, filtered, and concentrated to dryness under reduced pressure to give (R)-tert-butyl 1-(chlorocarbonyl)pyrrolidin-3-ylcarbamate (1.3 g, 98%) as a yellow oil: 1H NMR (DMSO-d6) δ 7.28 (s, 1 H), 4.03 (m, 1 H), 3.73-3.20 (m, 4 H), 2.05 (m, 1 H), 1.81 (m, 1 H), 1.39 (s, 9 H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](Cl)=[O:6].Cl.[CH3:11][O:12][NH:13][CH3:14].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([N:13]([O:12][CH3:11])[CH3:14])=[O:6]
Reactant: CNOC
Reactant: O=C(Cl)CCC(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)CCC(F)(F)F
Temperature: 0 °C
Yield: 270.9 %

Procedure:
4,4,4-Trifluorobutyric acid chloride (6.4 g from above) in CH2Cl2 (80 ml) was treated with O,N-dimethylhydroxylamine hydrochloride (60.0 mmol, 5.85 g). The mixture was cooled to 0° C., then treated with pyridine (160.0 mmol, 12.9 ml), then allowed to warm to room temperature overnight. The mixture was diluted with CH2Cl2 (200 ml), then washed with brine(2×50 ml). Solvent was removed from the volatile product by simple distillation at atmospheric pressure to provide 20 g of 4,4,4-trifluoro-N-methoxy-N-methyl butyramide, which may be used without further purification. 1H NMR (CDCl3) δ3.70 (3H, s), 3.19 (3H, s), 2.78-2.65 (2H, m), 2.57-2.40 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([O:12][CH2:13][CH3:14])=[C:10](Cl)[N:9]=[C:8]([Cl:16])[N:7]=1)=[O:5])[CH3:2].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:11]([O:12][CH2:13][CH3:14])=[C:10]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:9]=[C:8]([Cl:16])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Cl)nc(Cl)c1OCC
Reactant: C1COCCN1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(Cl)nc(N2CCOCC2)c1OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
2,6-dichloro-5-ethoxy-pyrimidine-4-carboxylic acid ethyl ester (2 g, 1 eq.) was stirred in toluene (80 ml) and a solution of morpholine (0.73 ml, 1.1 eq.) in toluene (20 ml) was added dropwise in about 10 minutes at −10˜0° C., after stirring the resulting solution for 3 h at r.t. Water was added and extracted with EA. The combined organic layers were washed with brine, dried and evaporated in vacuo. Purification by flash chromatography gave a product (1.79 g, 75%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.N1C=CC=CC=1.S(Cl)([Cl:23])(=O)=O>ClCCCl>[Cl:23][C:13]1[C:9]([C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[C:6]([Br:8])[CH:5]=2)=[N:10][NH:11][CH:12]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Brc1cc(Br)cc(-c2cc[nH]n2)c1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Clc1c[nH]nc1-c1cc(Br)cc(Br)c1
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
4 g (0.0132 mol) of 3-(3,5-dibromophenyl)pyrazole and 1 g of pyridine (0.0132 mol) are dissolved, at room temperature and with stirring, in 50 ml of 1,2-dichloroethane. 2 g (0.0145 mol) of sulphuryl chloride in 10 ml of 1,2-dichloroethane are then added dropwise at 50° C. and stirring is then continued for 30 min days at this temperature. After cooling, the precipitate is filtered and recrystallised from 200 ml of 1,2-dichloroethane. 2.9 g (yield: 66%; melting point: 188° C.) of 4-chloro-3-(3,5-dibromophenyl)pyrazole are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](Cl)=[N:10]2.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[N+](=C)=[N-]>C1COCC1.CCOCC.C1(C)C=CC=CC=1.C(O)(=O)C.O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([O:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:10]2
Reactant: COC(=O)Cc1cccc2nc(Cl)ccc12
Reactant: OCc1ccccc1
Agent: C=[N+]=[N-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)Cc1cccc2nc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-Chloroquinolin-5-yl)-acetic acid methyl ester (0.198 g, 1.01 mmol), whose synthesis was previously described, and benzyl alcohol (0.722 g, 6.67 mmol) were dissolved in anhydrous THF, and NaH (60% in oil, 0.244 g, 6.10 mmol) was added. The reaction was stirred at room temperature overnight. The solution was poured into ethyl acetate and water and the layers were separated. The organic layer was washed twice with water, then washed with brine, dried over magnesium sulfate, filtered and rotovapped to give the excess starting benzyl alcohol. The basic aqueous layer was acidified with 5% citric acid solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and rotovapped. The crude product was dissolved in ether and treated with freshly prepared diazomethane (14 mmol) in ether. The diazomethane solution was treated with acetic acid (1 mL). The solvent was stripped off, toluene was added and stripped off. Traces of toluene were removed by azeotroping with acetonitrile. (2-Benzyloxy-quinolin-5-yl)-acetic acid methy ester was used without further purification. MS m/z 308 (M+1).
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][C:7]1=O)=[O:5])C.FC(F)(F)C([O-])=O.[CH2:28]([N+:30]([CH2:34][CH3:35])=[C:31]([NH2:33])[NH2:32])[CH3:29].[O-]CC.[Na+]>CCO.O>[C:16]([O:15][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C:6]2[C:4]([OH:5])=[N:32][C:31]([N:30]([CH2:34][CH3:35])[CH2:28][CH3:29])=[N:33][C:7]=2[CH2:8]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)CC1=O
Reactant: CC[N+](CC)=C(N)N
Agent: CC[O-]
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCN(CC)c1nc(O)c2c(n1)CN(C(=O)OC(C)(C)C)CCC2
Temperature: 25 °C
Yield: 0 %

Procedure:
To a solution of 3-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.67 g, 2.3 mmol) in EtOH (10 mL) was added diethyl guanidinium trifluoroacetate (0.54 g, 2.3 mmol) and sodium ethoxide (21 wt % in EtOH, 2.3 mL). The reaction was heated at reflux for 16 h then cooled to room temperature (rt). The reaction mixture was diluted with H2O and extracted with CH2Cl2 (2×). The combined organic extracts were dried and concentrated. The resulting material was triturated with hexanes/Et2O (9:1) to give the title compound (0.334 mg, 43%) as a light brown solid. MS (ESI): mass calcd. for C17H28N4O3, 336.4; m/z found, 337.4 [M+H]+. 1H NMR (CDCl3): 4.34-4.25 (m, 2H), 3.62-3.46 (m, 6H), 2.66-2.58 (m, 2H), 1.88-1.77 (m, 2H), 1.50-1.36 (m, 9H), 1.21-1.14 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:7][CH2:6][CH:5]([C:8]2[S:24][C:11]3[N:12]=[C:13]([CH3:23])[N:14]=[C:15]([CH2:16][NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.CN(C=O)C.Br[CH2:32][CH2:33][CH2:34][OH:35].C([O-])([O-])=O.[Na+].[Na+]>O>[CH:18]1([N:17]([CH2:16][C:15]2[C:10]3[CH:9]=[C:8]([CH:5]4[CH2:6][CH2:7][C:2]([CH3:25])([CH3:1])[CH2:3][CH2:4]4)[S:24][C:11]=3[N:12]=[C:13]([CH3:23])[N:14]=2)[CH2:32][CH2:33][CH2:34][OH:35])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: OCCCBr
Reactant: Cc1nc(CNC2CCCC2)c2cc(C3CCC(C)(C)CC3)sc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(CN(CCCO)C2CCCC2)c2cc(C3CCC(C)(C)CC3)sc2n1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a mixture of N-{[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}cyclopentaneamine (128 mg) and DMF (3 mL) were added 3-bromopropan-1-ol (100 μL) and Na2CO3 (110 mg), followed by stirring at 100° C. for 15 hours. The reaction mixture was cooled to room temperature and then water was added thereto, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by basic silica gel column (hexane/EtOAc) to obtain 3-(cyclopentyl{[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}amino)propan-1-ol (88 mg).
Reaction SMILES: [F:1][C:2]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[C:21]([N:25]5[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]5)[CH:22]=[CH:23][CH:24]=4)[CH:17]=3)[NH:12][CH:11]=2)[CH:7]=[N:6]1.Cl.CCOCC>CO.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]5)[CH:20]=4)[CH:17]=3)[NH:12][CH:11]=2)[CH:7]=[N:6]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3cnc4[nH]cc(-c5cnn(Cc6cc(F)ccc6F)c5)c4c3)c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Fc1ccc(F)c(Cn2cc(-c3c[nH]c4ncc(-c5cccc(N6CCNCC6)c5)cc34)cn2)c1
Reaction time: 4 h
Yield: 9.7 %

Procedure:
To a stirred solution of tert-butyl 4-(3-(3-(1-(2,5-difluorobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (Example-31) (200 mg, 0.351 mmol) in methanol (5 ml) added saturated HCl in methanol at 0° C. This gradually brought to RT and stirred for four hours. Reaction mass was cooled and added ether to get solids. Solvents decanted and solids washed by ethyl acetate and dried. This residue was made free base using saturated sodium carbonate. This afforded 16.0 mg (9.75% yield) of titled compound after purification by preparative TLC (SiO2 using 3% methanol in chloroform as eluent). 1H NMR (CD3OD, 300 MHz): δ 8.557-8.550 (d, 1H), 8.192-8.184 (d, 1H), 7.866 (s, 1H), 7.762 (s, 1H), 7.446-7.360 (m, 2H), 7.160-7.10 (m, 2H), 7.05-6.85 (m, 3H), 5.420 (s, 2H), 3.276-3.242 (m, 4H), 3.119-3.086 (m, 4H). MS: m/z=470.9 (M+1); HPLC: 97.41% in method A.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:15][CH2:16][CH3:17])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]([C@@H:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])[C:26](O)=[O:27])=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>N1C=CC=CC=1.CN(C=O)C.C(OCC)(=O)C>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([CH:9]([CH2:15][CH2:16][CH3:17])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[C@H:25]([C:22]1[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][CH:23]=1)[C@@H:29]([CH3:34])[C:30]([F:31])([F:32])[F:33]
Reactant: CCCC(CC(=O)OC)c1ccc(Cl)c(N)c1
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCC(CC(=O)OC)c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
1.45 g (5.67 mmol) of (+/−)-methyl 3-(3-amino-4-chlorophenyl)hexanoate and 1.81 g (6.80 mmol) of (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in 5.0 ml of pyridine and 10.0 ml of DMF, and 2.80 g (7.37 mmol) of HATU were added at RT. The reaction mixture was stirred at RT overnight and then diluted with ethyl acetate. The mixture was washed with 1 N hydrochloric acid and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase initially cyclohexane, then cyclohexane/ethyl acetate 50:1). In two fractions, in total 2.02 g of the target product were obtained (70.6% of theory).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH:10]=[CH:9][C@H:8]([O:11]CC2C=CC=CC=2)[C@@H:7]([O:19]CC2C=CC=CC=2)[C@@H:6]1[OH:27])=[N+:2]=[N-:3].B(Cl)(Cl)Cl>C(Cl)Cl>[N:1]([CH2:4][C@@H:5]1[C@@H:6]([OH:27])[C@H:7]([OH:19])[C@@H:8]([OH:11])[CH:9]=[CH:10]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC[C@H]1C=C[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1O
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@H]1C=C[C@H](O)[C@@H](O)[C@@H]1O
Temperature: -78 °C
Reaction time: 4 h

Procedure:
Azide 11 (103 mg, 0.28 mmol) was dissolved in CH2Cl2 (5 mL) and cooled to −78° C. before BCl3 (5 mL, 1M in CH2Cl2) was added. After 4 h stirring at −78° C., the reaction was quenched by the addition of MeOH. The temperature was raised to room temperature and the solution was concentrated in vacuo. Trace of BCl3 were removed by coevaporating with MeOH. The resulting crude triol 17 was used as such in the click reaction.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:15]=[C:14]([C:16]#[N:17])[O:13][N:12]=2)[CH2:7][CH2:6]1.Cl.[NH+]1C=CC=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+].Cl>CN1C(=O)CCC1.O>[Br:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:15]=[C:14]([C:16]3[NH:32][N:31]=[N:30][N:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(N2CCC(Oc3cc(F)ccc3Br)CC2)no1
Agent: Cl
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1ccc(Br)c(OC2CCN(c3cc(-c4nnn[nH]4)on3)CC2)c1
Temperature: 130 °C

Procedure:
A mixture of 3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]isoxazole-5-carbonitrile (1.4 g, 3.82 mmol), pyridinium hydrochloride (0.9 g, 7.79 mmol) and sodium azide (1.3 g, 20.00 mmol) in NMP (12 mL) was stirred and heated at 130° C. bath for 2 h. After cooling, the mixture was diluted with water and acidified with 1N HCl (some precipitate appeared). The whole mixture was then extracted with EtOAc. The EtOAc extract was washed with water (3×), dried (Na2SO4) and concentrated. The residue was triturated with diethyl ether to give the title compound as a light brown powder.