Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[N:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>N1C=CC=CC=1>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:36]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:37])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: NCCCCn1c(CCCOc2ccccc2)nc2c(N)nc3ccccc3c21
Solvent: c1ccncc1
Product: Nc1nc2ccccc2c2c1nc(CCCOc1ccccc1)n2CCCCNC(=O)N1CCOCC1
Yield: 31.1 %

Procedure:
Using the general method of Example 143 except that pyridine was used in place of chloroform, 1-(4-aminobutyl)-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.25 g, 3.2 mmol) was reacted with 4-morpholinecarbonyl chloride (0.41 mL, 3.5 mmol) to provide 0.50 g of N-{4-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}morpholine-4-carboxamide as a light brown solid, m.p. 71.5–72.1° C. Analysis: Calculated for C28H34N6O3.0.5 H2O: % C, 65.73; % H, 6.90; % N, 16.43; Found: % C, 65.43; % H, 6.90; % N, 16.29.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[Se:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1>>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:8])[C:10]2[Se:9][C:13]([CH:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[OH:8])=[CH:12][CH:11]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccncc1
Reactant: c1cc[se]c1
Product: OC(c1ccncc1)c1ccc(C(O)c2ccncc2)[se]1

Procedure:
2,5-bis(4-pyridylhydroxymethyl)selenophene was prepared by a reaction of 9.04 mL (0.09 mol) 4-pyrdinecarboxaldehyde with 3.5 mL (0.04 mol) selenophene by a procedure similar to that described above. The 2,5-bis(4-pyridylhydroxymethyl)selenophene was obtained in 20% yield. 1H NMR (DMSO-d6) δ 8.48 (d, J=3.4 Hz, 4H), 7.36 (d, J=3.4 Hz, 2H), 7 6.87 (s, 2H), 6.93 (s, 2H), 6.44 (brs, 2H), 5.82 (s, 2H); HRMS (FAB) (M+) calcd. for C16H15O2N2Se: 347.0299; found, 347.0301.
Reaction SMILES: [CH:1]1[O:2][CH:3]=[C:4]2[C:9]([CH2:10][C:11]([N:13]([CH:15]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=3)[CH2:16][CH:17]3[CH2:21][CH2:20][CH:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:18]3)[CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][C:5]=12.C(=O)([O-])[O-].[K+].[K+].[C:43]([O:47][C:48](=[O:51])[CH2:49]Br)([CH3:46])([CH3:45])[CH3:44].O>CN(C)C=O>[C:43]([O:47][C:48](=[O:51])[CH2:49][O:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([CH:15]([N:13]([C:11](=[O:12])[CH2:10][C:9]2[C:4]3[CH:5]=[CH:1][O:2][C:3]=3[CH:6]=[CH:7][CH:8]=2)[CH3:14])[CH2:16][CH:17]2[CH2:21][CH2:20][CH:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:18]2)[CH:31]=1)([CH3:46])([CH3:45])[CH3:44]
Reactant: CN(C(=O)Cc1cccc2cocc12)C(CC1CCC(O[Si](C)(C)C(C)(C)C)C1)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)Cc1cccc2occc12)C(CC1CCC(O[Si](C)(C)C(C)(C)C)C1)c1cccc(OCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of Example 35 1.63 g, 3.2 mmol) in dimethylformamide (22 mL) was added potassium carbonate (1.37 g, 9.9 mmol) and, under argon, t-butylbromoacetate (0.47 mL, 3.2 mmol). After stirring at room temperature for 23 hours, the reaction was poured into water (160 mL), extracted with dichloromethane (160 mL), dried (MgSO4), and the solvent removed in vacuo. Purification by column chromatography (dichloromethane:methanol 39:1 followed by ethyl acetate:heptane 4:1) gave the product as a clear oil, 1.4 mmol, 45%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[S:7][C:8]([C:10]([NH2:12])=O)=[CH:9][C:5]=2[CH:4]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[S:7][C:8]([C:10]#[N:12])=[CH:9][C:5]=2[CH:4]=1
Reactant: COc1cc2cc(C(N)=O)sc2cc1OC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2cc(C#N)sc2cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
5,6-Dimethoxy-benzo[b]thiophene-2-carboxamide (65 g) was suspended in pyridine (325 ml). The solution was cooled to 0° C. and treated dropwise with trifluoro acetic anhydride (185 ml) whilst maintaining the internal reaction temperature below 10° C. The mixture was then stirred at room temperature for 30 min. then cooled and treated dropwise with water (170 ml) whilst maintaining the internal temperature below 30° C. The reaction mixture was diluted with more water (800 ml), stirred and the brown solid was filtered and dried under vacuum over calcium chloride at 60° C. Recrystallisation from acetone/ether afforded 5,6-dimethoxy-benzo[b]thiophene-2-carbonitrile as a white solid (47 g), m.p. 125° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([NH2:8])[CH:7]=1.[C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:10](=[N:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:9])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cc(Br)ccc1F
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Fc1ccc(Br)cc1N=C(c1ccccc1)c1ccccc1
Yield: 42.2 %

Procedure:
While a solution of 2.43 g 5-bromo-2-fluorophenylamine (compound in Production Example 335), 2.6 g benzophenone and 122 mg 4-toluenesulfonic acid in 50 ml toluene was azeotropically dehydrated, the mixture was heated for 6 hours under reflux. The reaction mixture was diluted with ethyl acetate and washed with brine, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1.91 g of the title compound (colorless oil).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[OH:14][C:15]1[C:16]([CH3:30])=[C:17]([CH3:29])[C:18]2[O:22][CH:21]([CH2:23][CH2:24][CH2:25][I:26])[S:20][C:19]=2[C:27]=1[CH3:28].O>C1C=CC=CC=1>[Si:1]([O:14][C:15]1[C:16]([CH3:30])=[C:17]([CH3:29])[C:18]2[O:22][CH:21]([CH2:23][CH2:24][CH2:25][I:26])[S:20][C:19]=2[C:27]=1[CH3:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(C)c2c(c(C)c1O)SC(CCCI)O2
Agent: c1c[nH]cn1
Solvent: O
Solvent: c1ccccc1
Product: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)SC(CCCI)O2
Temperature: 50 °C

Procedure:
5.2 g of t-butyldimethylsilyl chloride and 4.6 g of imidazole were dissolved in 80 ml of benzene, and then the reaction mixture was heated for 1 hour at 50° C., after which a solution of 6.3 g of 5-hydroxy-2-(3-iodopropyl)-4,6,7-trimethyl-1,3-benzoxathiole (prepared as described in Examples 74 and 75) in 10 ml of benzene was added and the reaction mixture was allowed to react for 8 hours at 40°-45° C. The reaction product was cooled, poured into water, and then extracted with benzene. The extract was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography and the title compound was obtained from the fraction eluted with a 9:1 by volume mixture of cyclohexane and benzene.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][Cl:21])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].Cl>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[C:13]([C:14]([CH3:16])=[O:15])[C:12]([O:18][CH2:19][CH2:20][Cl:21])=[O:17])([O-:3])=[O:2]
Reactant: CC(=O)CC(=O)OCCCl
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCCl
Reaction time: 48 h

Procedure:
10 Grams of 3-nitrobenzaldehyde and 11 g of 2-chloroethyl acetoacetate were dissolved in 100 ml of toluene, then under an ice-cooled condition, hydrogen chloride gas was introduced into the solution for 2 hours. The reaction mixture was allowed to stand at room temperature for 2 days, and was concentrated. The residue obtained was extracted with chloroform, then the chloroform layer was washed with a saturated sodium chloride aqueous solution and with a saturated sodium hydrogen carbonate aqueous solution and dried with anhydrous magnesium sulfate. Chloroform was removed by distillation and the residue was recrystallized from isopropanol to yield 10 g of 2-chloroethyl 2-(3-nitrobenzyliden)acetoacetate in the form of colorless needle-like crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)[CH2:8][CH2:7]1.[ClH:22].[CH2:23]([OH:25])[CH3:24]>N1C=CC=CC=1>[ClH:22].[F:21][C:19]1[CH:18]=[CH:17][C:16]2[C:12]([CH:9]3[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]4[C:23](=[O:25])[C@H:24]5[C@H:16]([CH2:12][CH2:9][CH2:8][CH2:7]5)[C:15]4=[O:14])[CH2:7][CH2:8]3)=[N:13][O:14][C:15]=2[CH:20]=1
Reactant: CCO
Reactant: NCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: Cl
Solvent: c1ccncc1
Product: O=C1[C@H]2CCCC[C@H]2C(=O)N1CCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 1-(4aminobutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.7 g, 16.1 mmol) and cis-1,2-cyclohexanedicarboxy]ic anhydride (3.23 g, 21 mmol) in pyridine (45 ml) was heated at reflux for 8 hours. At the end of the reaction, pyridine was removed to dryness. The crude product was purified on a silica gel column. The material thus obtained weighed 3.18 g (45%) as a clear oil. This oil was dissolved in ethanol (15 ml), then was treated with HCl in ethanol (45 ml). Crystallization took place upon cooling. The crystals were collected, 3.2 g, m.p.=229°-231 ° C.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Br:12][C:13]1[CH:14]=[N:15][C:16]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:29])[CH:26]=3)[C:21]([S:36][CH3:37])=[CH:20]2)=[N:17][CH:18]=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Br:12][C:13]1[CH:18]=[N:17][C:16]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[O:29])[CH:26]=3)[C:21]([S:36]([CH3:37])=[O:6])=[CH:20]2)=[N:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of m-chloroperoxybenzoic acid (77%, 2.10 g, 9.42 mmol) in dichloromethane (20 mL) was added at 0° C. to (1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indol-6-yl)(morpholino)methanone (0.18 g, 0.25 mmol) in dry dichloromethane (300 mL). The mixture was stirred at room temperature for 4 h and then poured onto saturated sodium sulfite solution (20 mL). The organic layer was separated after stirring for 15 min and washed with saturated sodium hydrogen carbonate solution and brine. The organic phase was then dried over sodium sulphate and concentrated. The residue was purified by flash column chromatography [methanol/dichloromethane=1:40]. White solid. Yield: 3.2 g.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[C:12]4C=CN(S(C5C=CC(C)=CC=5)(=O)=O)[C:13]=4[N:14]=[C:15](Cl)[N:16]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.NC1C=CC([N:38]2[CH2:43][CH2:42][CH:41]([C:44]([N:46]([CH3:48])[CH3:47])=[O:45])[CH2:40][CH2:39]2)=CC=1.C[Si](Cl)(C)C.[OH-].[K+].[CH2:56](O)[CH2:57][CH2:58][CH3:59]>CO.O>[NH:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[CH:9]=[CH:4][C:5]([C:41]4([C:44]([N:46]([CH3:47])[CH3:48])=[O:45])[CH2:40][CH2:39][NH:38][CH2:43][CH2:42]4)=[C:13]([NH:14][C:15]4[N:16]=[CH:59][C:58]5[CH:57]=[CH:56][NH:3][C:2]=5[N:1]=4)[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CN(C)C(=O)C1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5nc[nH]c5c4)nc(Cl)nc32)cc1
Reactant: CCCCO
Agent: C[Si](C)(C)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)C(=O)C1(c2ccc(Nc3ccc4nc[nH]c4c3)cc2Nc2ncc3cc[nH]c3n2)CCNCC1
Temperature: 115 °C

Procedure:
To a mixture of N-(1H-benzo[d]imidazol-6-yl)-2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.1 g, 0.24 mmol) in n-butyl alcohol (1 mL) was added 1-(4-aminophenyl)-N,N-dimethylpiperidine-4-carboxamide (0.11 g, 0.44 mmol) and TMSCl (0.014 mL, 0.11 mmol). After heating at 115° C. for 15 h, the mixture was diluted with MeOH (1 mL), and a solution of KOH (0.1 g) in H2O (0.5 mL) was added. After heating at 60° C. for 2 h, the mixture was purified by preparative HPLC to give 1-(4-(4-(1H-benzo[d]imidazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylaminophenyl)-N,N-dimethylpiperidine-4-carboxamide (0.02 g, MS (MH 496.3) (Compound 18-1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9][CH2:10][CH3:11])=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([CH2:10][CH3:11])=[O:20])=[CH:4][N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1cnc(Cl)c(Cl)c1
Solvent: ClCCl
Product: CCS(=O)c1cnc(Cl)c(Cl)c1
Yield: 42 %

Procedure:
4 g (0.02 mol) of 2,3-dichloro-5-ethylthiopyridine were reacted with 3.47 g (0.02 mol) of m-chloroperbenzoic acid in 30 ml of methylene chloride by a method similar to Example 1, Precursor β. After the crude product had been purified by means of flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate=2:1), 1.9 g of product of value were obtained in the form of white crystals. Yield: 42%. m.p.: 78-79° C.; 1H-NMR (d6 dimethyl sulfoxide): δ [ppm]=1.1 (t; CH3); 3.0 and 3.2 (2×m, CH2); 8.35 and 8.6 (2×s, pyr H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.CN([C:12]([O:16][N:17]1N=NC2C=CC=C[C:18]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNOC.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:12][O:16][N:17]([CH3:18])[C:6]([CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[O:8]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)C1CCOC1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CCOC1
Reaction time: 1 h
Yield: 161.8 %

Procedure:
Tetrahydro-3-furoic acid (412 μL, 4.31 mmol) was dissolved in DMF (18 mL) and HBTU (1.96 g, 5.17 mmol) was added. The reaction mixture was stirred for 1 h and N,O-dimethylhydroxylamine hydrochloride (504 mg, 5.17 mmol) and DIPEA (2.25 mL, 12.9 mmol) were added. The reaction mixture was stirred overnight and concentrated in vacuo. The residue was diluted with DCM (40 mL) and washed with sat aq NH4Cl (20 mL) and sat aq Na2CO3 (20 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography to give the crude title compound as a yellow gum (1.11 g). LCMS (ES+): 160.1 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=1)[CH2:3][NH2:4].[C:14]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](=O)[CH3:28])=[CH:22][CH:21]=1)([O:16][CH3:17])=[O:15].C([BH3-])#N.[Na+]>CO>[C:14]([CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH:27]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=2)[CH3:28])=[CH:24][CH:25]=1)([O:16][CH3:17])=[O:15]
Reactant: NCC(O)c1csc(C(F)(F)F)n1
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1

Procedure:
Prepared by analogy to Example 13 by reaction of 2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with 1-(4-carbomethoxymethoxyphenyl)propan-2-one and sodium cyanoborohydride in methanol=(reaction time: 5 hours) followed by purification on a silica gel column using methylene chloride/methanol 20:1. This results in an approximately 50:50 diastereomer mixture of the base. This is recrystallised from a mixture of ether/ethyl acetate=65:10, and twice more from ethyl acetate. This results in diastereomer A in 98-99% purity.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[O:5][C@@H:6]1[CH2:11][N:10]([C:12]([O:14][CH3:15])=[O:13])[C@H:9]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[O:17])[C@@H:8]([C:30]([O:32]C)=O)[CH2:7]1.[OH:37][NH2:38].Cl.C[O-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[O:5][C@@H:6]1[CH2:11][N:10]([C:12]([O:14][CH3:15])=[O:13])[C@H:9]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:20][CH2:19]2)=[O:17])[C@@H:8]([C:30]([NH:38][OH:37])=[O:32])[CH2:7]1
Reactant: NO
Reactant: COC(=O)[C@H]1C[C@H](Oc2cccc(F)c2)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)N1C[C@@H](Oc2cccc(F)c2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
To a solution of dimethyl (2S,3S,5S)-5-(3-fluorophenoxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (27 mg, 0.000054 mol) in methanol (0.2189 mL, 0.005405 mol) was added 1.640 M of N-hydroxyamine in Methanol (0.659 mL) made from the corresponding HCl salt and sodium methoxide. After stirred at rt for 1 h, the mixture was acidified with 1N HCl. The resultant mixture was applied directly on RP-HPLC to afford the product as a TFA salt (18 mg 54.5%). MS (ESI): (M+H)+=501.2.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[SH:31][CH2:32][CH:33]([OH:36])[CH2:34][OH:35]>>[OH:36][CH:33]([CH2:34][OH:35])[CH2:32][S:31][C:19]1[CH:20]=[CH:21][C:9]2[C:8](=[O:30])[C:7]3[C:6]4[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[NH:13][C:12]=3[C:11]([CH3:16])([CH3:17])[C:10]=2[CH:18]=1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: OCC(O)CS
Product: CC1(C)c2cc(SCC(O)CO)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B2-17, the title compound was prepared from Compound B1 and 3-mercaptopropane-1,2-diol.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([S:12]([CH2:15][CH2:16][OH:17])(=[O:14])=[O:13])=[CH:11][C:5]=2[N:4]=1.Cl.Cl.[CH:22]([N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)([CH3:24])[CH3:23].C([O-])(O)=[O:33].[Na+]>C1COCC1.O.ClCCl>[CH:22]([N:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:2]([C:3]2[NH:7][C:6]3[CH:8]=[CH:9][C:10]([S:12]([CH2:15][CH2:16][OH:17])(=[O:14])=[O:13])=[CH:11][C:5]=3[N:4]=2)=[O:33])[CH2:27][CH2:26]1)([CH3:24])[CH3:23]
Reactant: O=C([O-])O
Reactant: O=S(=O)(CCO)c1ccc2[nH]c(C(Cl)(Cl)Cl)nc2c1
Reactant: CC(C)N1CCC(N)CC1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(C)N1CCC(NC(=O)c2nc3cc(S(=O)(=O)CCO)ccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
360 mg (1.05 mmol) 2-(2-Trichloromethyl-1H-benzoimidazole-5-sulfonyl)-ethanol were added to a mixture of 225.4 mg (1.05 equiv.) 1-isopropyl-piperidine-4-ylamine-dihydrochloride and 880 mg (10 equiv.) NaHCO3 in 6 mL THF and 3 mL H2O and stirred vigorously for 2 h at room temperature. The reaction mixture was diluted with dichloromethane and washed with a saturated NaHCO3-solution and brine. The organic layer was dried over MgSO4 and concentrated. The obtained product was pure enough for further reactions.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH3:24][C:25]([CH3:30])([CH3:29])[CH2:26][CH2:27][NH2:28]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:28][CH2:27][CH2:26][C:25]([CH3:30])([CH3:29])[CH3:24])=[O:3])([CH2:5][CH2:6]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: CC(C)(C)CCN
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CC(C)(C)CCNC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-[4-carboxybicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 3,3-dimethylbutylamine (45.8 μL) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(3,3-dimethylbutyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (24.6 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:18]([CH2:19][C:20]([O:22]CC)=[O:21])[C:17](=[O:25])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[N:11]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Li+:33].[OH-].Cl>C1COCC1.O>[C:29]([O:28][C:26]([N:11]1[CH2:10][C@@H:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[N:18]([CH2:19][C:20]([O-:22])=[O:21])[C:17](=[O:25])[C:12]21[CH2:13][CH2:14][CH2:15][CH2:16]2)=[O:27])([CH3:32])([CH3:30])[CH3:31].[Li+:33]
Reactant: CCOC(=O)CN1C(=O)C2(CCCC2)N(C(=O)OC(C)(C)C)C[C@H]1c1cc(F)cc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)[O-])C(=O)C12CCCC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl (8R)-8-(3,5-difluorophenyl)-9-(2-ethoxy-2-oxoethyl)-10-oxo-6,9-diazaspiro[4.5]decane-6-carboxylate from Step C (50 mg, 0.11 mmol) in THF (0.75 mL) and H2O (0.25 mL) was added 1 N aqueous LiOH (0.12 mL, 0.12 mmol) and the resulting mixture was stirred at ambient temperature for 6 h. The mixture was adjusted to pH 7 by addition of 1 N HCl and concentrated to dryness in vacuo to give the title compound. MS: m/z=369 (M−C4H7).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH2:19][C:20]4([CH3:24])[CH2:23][O:22][CH2:21]4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:25]=1.[CH3:26][C:27]1[O:31][N:30]=[C:29]([C@:32]([OH:36])([C:34]#[CH:35])[CH3:33])[CH:28]=1>>[OH:36][C@:32]([C:29]1[CH:28]=[C:27]([CH3:26])[O:31][N:30]=1)([CH3:33])[C:34]#[C:35][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:19][C:20]4([CH3:24])[CH2:23][O:22][CH2:21]4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:25]=1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: CC1(Cc2c(C(N)=O)nc3n2C2CC(C2)c2ccc(Br)cc2-3)COC1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(CC4(C)COC4)n2C2CC3C2)no1

Procedure:
Similar to as described in General Procedure E, 10-bromo-3-((3-methyloxetan-3-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with (R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol to give the titled compound.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]1>CCCCO>[Br:1][C:2]1[C:3]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:25]2)=[C:4]2[C:10]([NH:11][C:12](=[O:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: COc1ccc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)cc1F
Solvent: CCCCO
Product: COc1ccc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)cc1F
Temperature: 155 °C
Reaction time: 16 h
Yield: 27.2 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-fluoro-4-methoxybenzamide (300 mg, 0.785 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (472 mg, 2.36 mmol) in n-BuOH (3 mL) was stirred at 155° C. for 16 hours in a sealed tube. The reaction was then cooled to room temperature and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Gilson) to provide (R)-tert-butyl 1-(5-bromo-3-(3-fluoro-4-methoxybenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (120 mg, 27% yield).