Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:14][NH:13][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[N:20][CH:19]=[C:18](Cl)[N:17]=1.CCN(C(C)C)C(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:12][N:13]([C:18]3[CH:19]=[N:20][CH:21]=[C:16]([Cl:15])[N:17]=3)[CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC2(CNC2)C1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC2(C1)CN(c1cncc(Cl)n1)C2

Procedure:
In analogy to the procedure described for the preparation of intermediate A-20, 2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester was reacted with 2,6-dichloropyrazine in presence of Hunig's base to give the title compound as a white solid.
Reaction SMILES: C[O-].[Na+].[NH:4]([CH2:11][CH2:12][C:13]#[N:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O[CH:16]([C:22]1[CH:31]=[C:30]([O:32][CH3:33])[C:25]([NH:26][C:27](=[O:29])[CH3:28])=[C:24]([O:34][CH3:35])[CH:23]=1)CS(C)(=O)=O>CS(C)=O>[NH:4]([CH:11]=[C:12]([C:13]#[N:14])[CH2:16][C:22]1[CH:31]=[C:30]([O:32][CH3:33])[C:25]([NH:26][C:27](=[O:29])[CH3:28])=[C:24]([O:34][CH3:35])[CH:23]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#CCCNc1ccccc1
Reactant: COc1cc(C(O)CS(C)(=O)=O)cc(OC)c1NC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(CC(C#N)=CNc2ccccc2)cc(OC)c1NC(C)=O

Procedure:
A mixture of 3.78 g. of sodium methylate, 5.1 g. of β-anilino-propionitrile and 9.8 g. of 4'-[(1-hydroxy-2-(methylsulfonyl)-ethyl)]-2',6'-dimethoxy-acetanilide in 40 ml. of dimethylsulfoxide was stirred at 50° C. for 4 hours with the exclusion of moisture. The mixture was poured into 400 ml. of water and the resulting emulsion was extracted with three 500 ml. portions of ethyl acetate. The ethyl acetate extracts were washed with two 200 ml. portions of water, combined, dried over magnesium sulfate and evaporated under vacuum. Recrystallization of the residue from ethyl acetate gave 4'-(3-anilino-2-cyano-allyl)-2',6'-dimethoxyacetanilide having a melting point of 165°-167° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Br[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: BrC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC2CCCCC2)c(Br)c1
Temperature: 90 °C
Yield: 38.4 %

Procedure:
3-Bromo-4-hydroxy-benzaldehyde (24.8 mmol, 5.0 g), bromo-cyclohexane (37.3 mmol, 6.08 g) and K2CO3 (37.3 mmol, 5.15 g) were suspended in DMF (15 mL) and stirred over night at 90° C. The mixture was cooled to room temperature, and bromo-cyclohexane (36.8 mmol, 6.0 g) and K2CO3 (36.2 mmol, 5.0 g) were added stirred at 90° C. for another 24 h. The mixture was cooled and filtered. The filtrate was extracted with ethyl acetate. The organic layer was washed with 1.0 N NaOH (200 mL), water, and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to provide 3-bromo-4-cyclohexyloxy-benzaldehyde (2.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH:19]C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][NH2:19])[CH2:16][CH2:17]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CCC(CN2CCC(CNC(=O)OC(C)(C)C)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1CCC(CN2CCC(CN)CC2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-[4-(tert-butoxycarbonylamino-methyl)piperidin-1-ylmethyl]-piperidine-1-carboxylic acid methyl ester (4.4 g, 10.8 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (20 mL). After stirring for 20 min at room temperature, the solution was evaporated in vacuo, yielding the bis-trifluoroacetate salt of the title compound as a pale yellow oil, which was used without further treatment. (m/z): [M+H]+ calcd for C14H27N3O2 270.22. found 270.5. 1H-NMR (CD3OD) δ (ppm) 4.0 (br d, 2H), 3.6 (m, 5H), 2.9-2.7 (m, 6H), 2.1-1.9 (m, 2H), 1.7-1.5 (m, 6H), 1.2-1.0 (m, 4H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11][CH2:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15](O)=[O:16])[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl.CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11][CH2:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([Cl:25])=[O:16])[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccccc1CSc1cccc2cccnc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1CSc1cccc2cccnc12
Temperature: 25 °C

Procedure:
A solution of 1.0 eq. of 2-(quinolin-8-ylsulfanylmethyl)benzoic acid in CH2Cl2 was cooled to 0° C. To this was added 1.1 eq. of oxalyl chloride followed by one drop of DMF. The mixture was warmed to room temperature and stirred for a time sufficient for reaction completion. The mixture was concentrated to give 42 which was used directly.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][NH:27][CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:31]1([CH2:36][CH2:37][C:38](O)=[O:39])[CH2:35][CH2:34][CH2:33][CH2:32]1.CCN(CC)CC>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27]([C:38](=[O:39])[CH2:37][CH2:36][N:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCN1CCCC1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(C(=O)CCN1CCCC1)CC2
Temperature: 25 °C

Procedure:
To a solution of 4-benzyloxy-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (100 mg, 0.26 mmol) in DMF (3 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU) (148 mg, 0.389 mmol), 3-(pyrrolidin-1-yl)propanoic acid hydrochloride (56 mg, 0.31 mmol), and Et3N (73 μL, 0.52 mmol). The reaction mixture was stirred at room temperature under Ar until the reaction was complete. The reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered and concentrated. Purification by flash column chromatography (silica gel, 5% CH3OH in CH2Cl2) gave 4-(benzyloxy)-1-(5-methyl-2-(3-(pyrrolidin-1-yl)propanoyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridine-2(1H)-one as a yellow foam. The free base was converted to the HCl salt to give the title compound (75 mg, 86%) as a yellow solid: mp 110-115° C.; 1H NMR (500 MHz, CD3OD) δ 7.79-7.76 (m, 1H), 7.61-7.55 (m, 1H), 7.49-7.36 (m, 6H), 7.05-7.02 (m, 1H), 6.55-6.52 (m, 1H), 6.33-6.32 (m, 1H), 5.26 (s, 2H), 4.06 (t, J=5.5 Hz, 1H), 3.94 (t, J=5.5 Hz, 1H), 3.70-3.69 (m, 5H), 3.54-3.50 (m, 2H), 3.18-2.89 (m, 8H), 2.18-2.04 (m, 4H); ESI MS m/z 511 [M+H]+; HPLC (Method B) 97.7% (AUC), tR=13.6 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.[CH3:26][O:27][N:28]1[C:33]([CH3:35])([CH3:34])[CH2:32][C:31](=[O:36])[CH2:30][C:29]1([CH3:38])[CH3:37]>>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][C:18]([C:4]2[CH:3]=[C:2]([C:31]3([OH:36])[CH2:32][C:33]([CH3:34])([CH3:35])[N:28]([O:27][CH3:26])[C:29]([CH3:38])([CH3:37])[CH2:30]3)[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[CH:19][CH2:20]1
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: CON1C(C)(C)CC(=O)CC1(C)C
Product: CON1C(C)(C)CC(O)(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)c2)CC1(C)C

Procedure:
The title compound was prepared as described in Example 1 step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g) and 1-methoxy-2,2,6,6-tetramethyl-piperidin-4-one (WO 9854174). 1H-NMR (CD3OD; 400 MHz): δ 8.21 (d, 1H, J=8.4 Hz), 8.01 (s, 1H), 7.45 (dd, 1H, J=8.4, 2.0 Hz), 7.37 (d, 1H, J=2.0 Hz), 5.75 (br s, 1H), 4.08 (s, 3H), 2.35 (m, 4H), 2.09 (m, 4H), 1.72 (s, 6H), 1.61 (m, 2H), 1.50 (s, 6H), 1.10 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C29H39N5O3, 506.3 (M+H). found 506.3.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].C1(=O)O[CH2:14][CH2:13][O:12]1.O.O.[F-].[K+]>CN(C)C=O>[CH3:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:14][CH2:13][OH:12])=[CH:6][CH:5]=1)=[CH2:3]
Reactant: O=C1OCCO1
Reactant: C=C(C)c1ccc(O)cc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)c1ccc(OCCO)cc1
Temperature: 150 °C
Yield: 69 %

Procedure:
A mixture of 20 g p-isopropenylphenol, 1.1 equivalents ethylene carbonate, 0.02 equivalent potassium fluoride dihydrate, and 200 ml N,N-dimethylformamide (DMF) was heated at about 150° C. for about 1.5 hours. After removal of DMF under reduced pressure, the crude product was distilled. 2-(4-(1-Methylethenyl)phenoxy)ethanol, bp 143° C./7 torr, was obtained as a white solid in 69% yield.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][NH:37][C:38]([NH2:40])=[S:39])[CH2:31][CH2:30]2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[CH2:28][CH:29]2[CH2:30][CH2:31][N:32]([CH2:35][CH2:36][NH:37][C:38]3[S:39][CH:2]=[C:3]([C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:40]=3)[CH2:33][CH2:34]2)=[CH:16][CH:17]=1
Reactant: NC(=S)NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1ccc(Cn2c(CC3CCN(CCNc4nc(-c5ccccc5)cs4)CC3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
A mixture of 3.3 parts of 2-bromo-1-phenylethanone, 7 parts of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]thiourea, 4parts of potassium carbonate and 90 parts of tetrahydrofuran was stirred for 2 hours at room temperature. The reaction mixture was filtered over Hyflo and the filtrate was evaporated. The reaction mixture was poured into water. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.8 parts (33.3%) of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-N-(4-phenyl-2-thiazolyl)-1-piperidineethanamine; mp. 122.2° C. (454).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]=[O:3].[NH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CN(C=O)C>[C:23]([O:22][C:20]([NH:19][CH2:18][CH2:17][CH2:16][NH:15][C:2](=[O:3])[NH:1][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOC(=O)c1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(NC(=O)NCCCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.00 g (8.12 mmol) of ethyl 3-isocyanatobenzoate (78%) are dissolved in 10 ml of DMF..A solution of 1.42 g (8.12 mmol) of 1-amino-3-tert-butyloxycarbonylaminopropane in 20 ml of DMF is slowly added dropwise at 2°-8°C. After stirring at room temperature for 2 h, the solvent is removed in vacuo, and the residue is treated with ethyl acetate and the mixture is washed with water. After drying (MgSO4), solid is filtered off and the solvent is removed in vacuo. The residue is chromatographed on silica gel.
Reaction SMILES: C(CN)O.C(=O)([O-])[O-].[K+].[K+].[F:11][C:12]1[C:20]([F:21])=[C:19]2[C:15]([C:16]([NH:30]C(=O)CCC)=[N:17][N:18]2[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:14][C:13]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C=O>[F:11][C:12]1[C:20]([F:21])=[C:19]2[C:15]([C:16]([NH2:30])=[N:17][N:18]2[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:14][C:13]=1[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2c(F)c(F)c(-c3ccccc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: NCCO
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(N)c2cc(-c3ccccc3)c(F)c(F)c21
Yield: 23.7 %

Procedure:
1.1 cm3 of ethanolamine and then 1.50 g of potassium carbonate are added to 1.6 g of N-[6,7-difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]-butanamide described above, in 50 cm3 of dimethylformamide, and the mixture is refluxed for one week. The reaction medium is concentrated to dryness under reduced pressure and taken up in 150 cm3 of ethyl acetate and 75 cm3 of water. The organic phase is separated out after settling of the phases and washed successively with twice 75 cm3 of water and 50 cm3 of brine. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa; 50° C.). The crude oil obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40–60 μm; diameter 4 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 45° C.), 0.32 g of 6,7-difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazole-3-amine is obtained.
Reaction SMILES: FC(F)(F)S(O[C@H:7]1[CH2:12][C@@H:11]([CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])[O:10][C@@:9]([O:33][CH3:34])([C@@H:18]2[CH2:22][S:21][C:20](=[O:23])[N:19]2[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:8]1)(=O)=O.[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:37]([C@@H:7]1[CH2:12][C@@H:11]([CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])[O:10][C@:9]([C@@H:18]2[CH2:22][S:21][C:20](=[O:23])[N:19]2[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)([O:33][CH3:34])[CH2:8]1)=[N+:38]=[N-:39]
Reactant: C=CCCC[C@@H]1C[C@H](OS(=O)(=O)C(F)(F)F)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCCC[C@@H]1C[C@@H](N=[N+]=[N-])C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Temperature: 25 °C
Reaction time: 22 h
Yield: 82 %

Procedure:
A solution of the title compound from Example 22 (1.19 mmol, used directly from the previous reaction) in DMF (12 mL) was treated with sodium azide (400 mg, 6.15 mmol), and the mixture was stirred at room temperature for 22 h. The reaction mixture was diluted with ethyl acetate, washed with satd aq NaHCO3, ice cold 5% aq citric acid, and brine, and the organic phase was dried and concentrated. Chromatography of the residue on silica gel eluting with dichloromethane/ethyl acetate gave the title compound (432 mg, 82%) as an oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C@@H:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)C.[BH4-].[Na+]>CO>[F:27][C:23]1[CH:22]=[C:21]([C@H:7]([O:6][CH2:5][CH2:4][OH:3])[C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:9]2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)CO[C@@H](c1cccc(F)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCO)c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 41 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-ethoxy-2-oxoethoxy)(3-fluorophenyl)methyl)piperidine-1-carboxylate (29.88 g, 75.9 mmol) in MeOH (300 mL) was added NaBH4 (23 g, 605.2 mmol) in portions while the temperature was lower than 40° C. After addition, the mixture was stirred at rt for 2-3 hr. The solvent was removed in vacuo to give a residue which was partitioned between water and ethyl acetate. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on silica gel chromatography to afford (R)-tert-butyl 3-((R)-(3-fluorophenyl)(2-hydroxyethoxy)methyl)piperidine-1-carboxylate (11 g, 41%).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(=[O:44])=[O:43])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:30]=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:37][CH:38]=2)(=[O:28])=[O:27])=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)(=[O:43])=[O:44])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 92 %

Procedure:
Methyl 4-{[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]sulfonyl}benzoate (1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) were stirred together overnight. Solvents were removed and the resulting residue was taken up in water. The solution was acidified with 1N HCl and collected resulting precipitate by filtration. Obtained 4-{[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]sulfonyl}benzoic acid (off-white solid) in 92% yield. HRMS calc for [C39H35ClN2O6S2—H] 725.15523 found 725.15437.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[C:13]1[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]1)=[N:7][C:6]=2[NH2:16].[C:17](Cl)(=O)[CH3:18].C(=O)(O)[O-].[Na+]>O.C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([CH:17]=[CH:18][N:16]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH:15]=1
Reactant: CC(=O)Cl
Reactant: Nc1nc2ccccc2c2cc(F)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Fc1ccc2c(c1)c1ccccc1n1ccnc21
Temperature: 25 °C
Yield: 52 %

Procedure:
9-Fluoro-6-Phenanthridinamine (0.8 g, 3.7 mmol), and a 50% solution of acetyl chloride (0.4 g, 5.66 mmol) in water containing sodium bicarbonate (0.6 g, 7.54 mmol) was dissolved in isopropyl alcohol (25 mL). The reaction mixture was refluxed for 17 hours under a nitrogen pad. The reaction mixture was cooled to room temperature and the precipitate vacuum filtered and washed with methylene chloride. The crude product was purified by column chromatography using a 1:1 ratio of ethyl acetate and hexanes as the eluants followed by distillation to give 10-fluoro-imidazo[1,2-f]phenanthridine) (0.46 g, 52% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:12]=[C:11]([N:21](C)[C:22](=O)C)[N:10]=2)=[CH:5][C:4]=1F)#[N:2].O.[NH2:28][NH2:29]>CCO>[CH3:22][NH:21][C:11]1[N:10]=[C:9]([C:6]2[CH:5]=[C:4]3[C:3]([C:1]([NH2:2])=[N:28][NH:29]3)=[CH:8][CH:7]=2)[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:12]=1
Reactant: NN
Reactant: CC(=O)N(C)c1nc(-c2ccc(C#N)c(F)c2)cc(N2CCCCC2)n1
Solvent: O
Solvent: CCO
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCCCC2)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
In a 25 mL sealable tube were combined N-[4-(4-cyano-3-fluorophenyl)-6-(1-piperidinyl)-2-pyrimidinyl]-N-methylacetamide (0.04 g, 0.11 mmol) and hydrazine monohydrate (0.11 mL, 2.21 mmol) in EtOH (10 mL). The tube was sealed, and the reaction mixture was stirred overnight at 95° C. The reaction was cooled to room temperature and concentrated. The resulting oil was dissolved in EtOH (3 mL) followed by the addition of water (6 mL). Since no solid was observed (a yellow oil was formed), the mixture was concentrated to dryness. The resulting oil was diluted with CH3CN (2 mL) and sonicated. The resulting yellow solid was filtered, washed with CH3CN (1 mL) and dried to afford the title compound (18 mg, 48%). LC-MS (ES) m/z=324 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.60 (m, 4H), 1.68 (m, 2H), 2.92 (d, J=4.3 Hz, 3H), 3.84 (bs, 4H), 5.54 (bs, 2H), 6.81 (bs, 1H), 7.21 (bs, 1H), 7.40 (bs, 1H), 7.76 (bs, 1H), 7.85 (d, J=8.3 Hz, 1H), 11.83 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]O>C1COCC1>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1
Reactant: CN(C)CCO
Reactant: Nc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(N)cc1

Procedure:
Following the procedure described in part E of Example 1 (R), (S)-α-[[2-[((1,1-dimethylethyl)dimethylsilyl)oxy]-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-4-methoxybenzeneacetic acid was condensed with 4-[2-(dimethylamino)ethoxy]aniline to generate the title compound. The 4-[2-(dimethylamino)ethoxy]aniline was prepared by treating commercial 4-aminophenol with DEAD, φ3P, and 2-(dimethylamino)ethanol in THF.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[CH:8][CH:9]=[CH:10][N:11]=1)=[O:15]
Reactant: NCCSCc1ncccn1
Reactant: CN=C=O
Product: CNC(=O)NCCSCc1ncccn1

Procedure:
By the procedure of Example 24, 2-[(2-aminoethyl)thiomethyl]pyrimidine is reacted with methyl isocyanate to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:18]=[C:17]3[C:11]([CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH2:16]3)=[N:10]2)=[CH:5][CH:4]=1)#[N:2].Cl.CO>O1CCOCC1>[N:10]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:18]=[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=12
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(C#N)cc3)nc2CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N#Cc1ccc(-n2cc3c(n2)CCNCC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl 2-(4-cyanophenyl)-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 10) (150 mg, 0.443 mmol) was dissolved in 1,4-dioxan (ml) and 4M hydrogen chloride in 1,4-dioxan (3 ml) added. The mixture was stirred at room temperature for 2 hours. Methanol was added and the mixture purified on 10 g SCX column, eluting initially with methanol, than with 2M ammonia in methanol. Evaporation of the basic fractions gave the title compound (D11). MS (ES+) m/e 239 [M+H]+