Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:26][CH2:27][CH3:28])([C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29]>CO>[ClH:29].[CH2:26]([C:11]1([C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH2:27][CH3:28]
Reactant: CCCC1(C(=O)c2ccc3ccccc3n2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: CCCC1(C(=O)c2ccc3ccccc3n2)CCNCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
4-Propyl-4-(quinoline-2-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester (124 mg, 0.32 mmol) was dissolved in a solution of anhydrous 1.0M HCl in MeOH (5 mL). The reaction mixture was stirred at room temperature for 15 hours then concentrated under reduced pressure to afford 82 mg (80%) of (4-propyl-piperidin-4-yl)-quinolin-2-yl-methanone hydrochloride as a yellow solid, MS=283 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:21])([CH3:20])[N:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH2:18]O)[CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:24][CH2:18][C:16]1[CH:17]=[C:12]([N:7]2[C:6]([CH3:21])([CH3:20])[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[C:8]2=[O:11])[CH:13]=[N:14][CH:15]=1
Reactant: CC1(C)c2ccc(F)cc2C(=O)N1c1cncc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1(C)c2ccc(F)cc2C(=O)N1c1cncc(CCl)c1
Temperature: 3.5 °C
Reaction time: 0.5 h
Yield: 104.8 %

Procedure:
To a solution of 6-fluoro-2-(5-hyroxymethyl-pyridin-3-yl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one (52 mg) in DCM (10 mL) was added thionyl chloride (0.14 mL, 1.9 mmol) slowly at 0° C. After the addition, the reaction mixture was stirred at 2-5° C. for 0.5 hour before it was poured into satd. aq. NaHCO3 solution (10 mL) and extracted with DCM (2×15 mL). The combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (58 mg 100%) as light yellowish solid. MS: 322.1 (M+H+).
Reaction SMILES: [NH2:1][NH2:2].[N:3]([C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])[CH3:7])=[C:4]=[S:5]>CCO>[C:9]1([C:6]([NH:3][C:4]([NH:1][NH2:2])=[S:5])([CH3:8])[CH3:7])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NN
Reactant: CC(C)(N=C=S)c1ccccc1
Solvent: CCO
Product: CC(C)(NC(=S)NN)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Anhydrous hydrazine (1.161 mL, 37.0 mmol) (Sigma-Aldrich) was added to a stirring solution of (2-isothiocyanatopropan-2-yl)benzene (6.56 g, 37.0 mmol) in EtOH (150 mL). The reaction was stirred at RT for 2 h to give N-(2-phenylpropan-2-yl)hydrazinecarbothioamide. MS (ESI, pos. ion) m/z: 210.2 (M+1). The material was used without purification.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:3][CH2:2]1.[Cl-].[NH4+]>[Fe]>[S:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccccc1OC1CCSCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: Nc1ccccc1OC1CCSCC1
Yield: 98.3 %

Procedure:
Following a reaction similar to that of Example 1 (2) using 5.0 g of 2-(tetrahydro-4H-thiopyran-4-yloxy)nitrobenzene, iron powder and ammonium chloride, there was obtained 4.3 g of 2-(tetrahydro-4H-thiopyran-4-yloxy)aniline.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[N:23][CH:22]=[C:21]([Cl:25])[C:18]=2[C:19]#[N:20])=[CH:13][CH:12]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>ClCCl.CO>[Cl:25][C:21]1[CH:22]=[N:23][CH:24]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([CH:3]([OH:10])[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:16][CH:15]=2)[C:18]=1[C:19]#[N:20]
Reactant: N#Cc1c(Cl)cncc1-c1ccc(C(=O)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: N#Cc1c(Cl)cncc1-c1ccc(C(O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
Granular sodium borohydride (225 mg, 5.94 mmol) was added to a solution of 3-(4-benzoylphenyl)-5-chloroisonicotinonitrile (473 mg, 1.187 mmol, 80% pure) in dichloromethane (10 mL) and methanol (10 mL). After 30 min at room temperature, the mixture was quenched with saturated ammonium chloride (30 mL). The organic solvents were evaporated in vacuo. The aqueous residue was extracted with ethyl acetate (2×40 mL). The combined extracts were washed with brine (5 mL), dried (MgSO4) and concentrated. Silica gel chromatography, loading with dichloromethane and eluting with 20-60% ethyl acetate in hexanes, gave 3-chloro-5-(4-(hydroxy(phenyl)methyl)phenyl)isonicotinonitrile as white solid (327 mg, 69% yield), which was approximately 80% pure. MS (ES+) m/z: 303 (M−water+H); LC retention time: 3.798 min (analytical HPLC Method A).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21]3[C:22]4=[C:23]5[C:18](=[CH:19][CH:20]=3)[CH:17]=[CH:16][C:15]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[C:14]5[CH:13]=[CH:12][C:11]4=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:31]N1C(=O)CCC1=O>CN(C)C=O>[Br:31][C:17]1[CH:16]=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:14]2[C:23]3=[C:22]4[C:11]([CH:10]=[CH:9][C:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)=[C:21]4[CH:20]=[CH:19][C:18]=13)=[CH:12][CH:13]=2
Reactant: Fc1ccc(-c2ccc3ccc4c(-c5ccc(F)cc5)ccc5ccc2c3c54)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Fc1ccc(-c2ccc3ccc4c(-c5ccc(F)cc5)cc(Br)c5ccc2c3c54)cc1
Temperature: 25 °C
Yield: 44 %

Procedure:
Next, a mixed solution of 1.8 g of 1,6-bis(4-fluorophenyl)pyrene, 835 mg of N-bromosuccinimide and 60 ml of dimethylformamide was stirred under a nitrogen gas flow at 80° C. for 5 hours. After cooling the solution to room temperature, the resultant precipitate was filtered. The solid was washed with 30 ml of methanol and then vacuum-dried to obtain 951 mg of 3-bromo-1,6-bis(4-fluorophenyl)pyrene.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[Cl:16][C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C@H:24]2[CH3:29])[CH:20]=[C:19]([C:30]([S:33]([CH3:35])=[O:34])([CH3:32])[CH3:31])[N:18]=1.[O-2].[Mg+2].[F:38][C:39]([F:44])([F:43])[C:40]([NH2:42])=[O:41]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[Cl:16][C:17]1[N:18]=[C:19]([C:30]([S:33]([CH3:35])(=[O:34])=[N:42][C:40](=[O:41])[C:39]([F:44])([F:43])[F:38])([CH3:32])[CH3:31])[CH:20]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C@H:24]2[CH3:29])[N:22]=1
Reactant: C[C@@H]1COCCN1c1cc(C(C)(C)S(C)=O)nc(Cl)n1
Reactant: NC(=O)C(F)(F)F
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: C[C@@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=NC(=O)C(F)(F)F)nc(Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.6 %

Procedure:
(3R)-4-(2-Chloro-6-(methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (1.75 g, 6.04 mmol) was dissolved in DMF (34.6 ml), to this was added slowly NaH (0.604 g, 15.10 mmol) and the reaction mixture was stirred for 5 minutes at RT. To the mixture was rapidly added methyl iodide (0.944 ml, 15.10 mmol) and the mixture was stirred for 1 hour. The reaction mixture was quenched with saturated NH4Cl solution (50 mL), extracted with DCM (3×50 mL) and the combined organic layers were passed through a phase separating column and then evaporated to afford a yellow gum. Water (50 mL) was added to the gum and the mixture extracted with EtOAc (3×50 mL). The combined organic layers were dried over MgSO4, filtered and then evaporated. The residue was purified by flash chromatography on silica, eluting with a gradient of 0 to 3% MeOH in DCM. Pure fractions were evaporated to afford (3R)-4-(2-chloro-6-(2-(methylsulfinyl)propan-2-yl)pyrimidin-4-yl)-3-methylmorpholine (1.693 g, 88%); 1H NMR (400 MHz, DMSO-d6) 1.19 (3H, d), 1.49 (6H, dd), 2.17 (3H, t), 3.19 (1H, dd), 3.37-3.48 (1H, m), 3.57 (1H, dd), 3.71 (1H, d), 3.92 (1H, d), 4.03 (1H, s), 4.41 (1H, s), 6.70 (1H, s); m/z: (ES+) MH+, 318.09 and 320.04. b) Iodobenzene diacetate (1.716 g, 5.33 mmol) was added to (3R)-4-(2-chloro-6-(2-(methylsulfinyl)propan-2-yl)pyrimidin-4-yl)-3-methylmorpholine (1.693 g, 5.33 mmol), magnesium oxide (0.859 g, 21.31 mmol), 2,2,2-trifluoroacetamide (1.204 g, 10.65 mmol) and rhodium(II) acetate dimer (0.059 g, 0.13 mmol) in DCM (100 mL). The resulting suspension was stirred at RT for 18 hours. The reaction mixture was filtered through Celite and then concentrated in vacuo onto silica (15 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 0 to 10% MeOH in DCM. Pure fractions were evaporated to afford N-[(2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}propan-2-yl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide (0.700 g, 31%); 1H NMR (400 MHz, DMSO-d6) 1.20 (3H, dd), 1.83 (6H, d), 3.20 (1H, dd), 3.41 (1H, dddd), 3.56 (1H, d), 3.59 (3H, d), 3.72 (1H, d), 3.94 (1H, dd), 4.07 (1H, s), 4.45 (1H, s), 6.93 (1H, d); m/z: (ES+) MH+, 429.4 and 431.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[O:26][C:25]3[C:16](=[CH:17][C:18]4[CH2:19][CH:20]([C:36](O)=[O:37])[N:21]([C@H:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:28][CH3:29])[CH2:22][C:23]=4[CH:24]=3)[N:15]([CH3:39])[C:14]2=[O:40])=[CH:9][CH:8]=1.[CH3:45][O:46][C:47](=[O:66])[C@:48]([NH2:65])([CH3:64])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][C:59]([C:62]#[N:63])=[CH:58][CH:57]=2)=[CH:52][CH:51]=1>>[CH3:45][O:46][C:47](=[O:66])[C@:48]([NH:65][C:36]([CH:20]1[CH2:19][C:18]2[CH:17]=[C:16]3[C:25]([O:26][C@@H:13]([C:10]4[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]5[CH:41]=[CH:42][C:43]([Cl:44])=[C:2]([Cl:1])[CH:3]=5)=[CH:12][CH:11]=4)[C:14](=[O:40])[N:15]3[CH3:39])=[CH:24][C:23]=2[CH2:22][N:21]1[C@H:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][CH3:29])=[O:37])([CH3:64])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][C:59]([C:62]#[N:63])=[CH:58][CH:57]=2)=[CH:52][CH:51]=1
Reactant: COC(=O)[C@@](C)(N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2CC1C(=O)O)N(C)C(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2CC1C(=O)N[C@@](C)(Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (31.6 mg) was coupled with (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-2-methyl-propionic acid methyl ester (14.7 mg) following general procedure O to provide (S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-2-methyl-propionic acid methyl ester (LC-MS (m/z): 909). Title compound was prepared from (S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-2-methyl-propionic acid methyl ester (25 mg) following general procedure B. LC-MS (m/z): 893.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:35])[C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.O1CCCC1.[Pd]>[C:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[N:22]1[CH2:21][CH2:20][N:19]([C:17](=[O:18])[C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[O:35])[CH2:24][CH2:23]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)Nc2ccc(OCc3ccccc3)cc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)Nc2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.5 %

Procedure:
A mixture of N-[4-(benzyloxy)phenyl]-2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoacetamide (Example 198, 3.64 g, 7.72 mmol) and palladium (10% on carbon, wetted with ca. 50% water, 300 mg) in ethyl acetate (10 mL) was stirred at room temperature for 24 h under hydrogen. The reaction mixture was diluted with tetrahydrofuran and filtered. The filtrate was concentrated under reduced pressure to give the title compound (2.90 g, 98%) as a white solid.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=[O:9])[CH2:8][CH:4]2[CH2:3][NH:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11].C(N(CC)CC)C>C(#N)C>[C:10]([N:2]1[CH2:3][CH:4]2[CH2:8][C:7](=[O:9])[CH2:6][CH:5]2[CH2:1]1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CC2CNCC2C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)N1CC2CC(=O)CC2C1
Reaction time: 8 h
Yield: 71.8 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (717 mg, 3 mmol) was dissolved in 20 mL of acetonitrile, and acetic anhydride (0.42 mL, 4.5 mmol) and triethylamine (0.98 mL, 9 mmol) were then added to the solution in an ice-water bath. Upon completion of the addition, the reaction mixture was then stirred overnight in an ice-water bath. The solvent was evaporated, and water (50 mL) was then added to the residue. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-acetyl-hexahydro-cyclopenta[c]pyrrol-5-one 5a (0.36 g, yield 72%) as a colorless oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(O)(C(F)(F)F)=O.[Br:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[CH:39]=[C:38]([C:43]1[N:44]=[C:45]([C@@H:48]3[CH2:53][C@@H:52]4[C@@H:50]([CH2:51]4)[NH:49]3)[NH:46][CH:47]=1)[CH:37]=[CH:36]2.[CH3:54][O:55][C:56]([NH:58][C@@H:59]([CH:63]([CH3:65])[CH3:64])[C:60](O)=[O:61])=[O:57].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Br:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[CH:39]=[C:38]([C:43]1[N:44]=[C:45]([C@@H:48]3[CH2:53][C@@H:52]4[C@@H:50]([CH2:51]4)[N:49]3[C:60](=[O:61])[C@@H:59]([NH:58][C:56](=[O:57])[O:55][CH3:54])[CH:63]([CH3:65])[CH3:64])[NH:46][CH:47]=1)[CH:37]=[CH:36]2
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: Brc1ccc2cc(-c3c[nH]c([C@@H]4C[C@H]5C[C@H]5N4)n3)ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc(-c2ccc3cc(Br)ccc3c2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
HATU (411 mg, 1.082 mmol) was added to a solution of a TFA salt of (1R,3S,5R)-3-(4-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (525 mg, 0.902 mmol) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (190 mg, 1.08 mmol) in DMF (10 mL) and DIPEA (0.79 mL, 4.5 mmol) and the reaction was stirred at rt for 4 h. The reaction was diluted with EtOAc (˜80 mL) and washed with sat. aq. NaHCO3, water (30 mL) and brine (30 mL). The organics were then dried (MgSO4), filtered and concentrated to a brown oil (625 mg). This material was purified on a BIOTAGE® Horizon (40 g SiO2, 40-80% EtOAc/hexanes) to yield methyl(S)-1-((1R,3S,5R)-3-(4-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate (412 mg) as a yellow glass. LC-MS retention time 1.843 min; m/z 511.24, 513.12 (1:1) (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1.0 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.N1C=CN=C1.Cl[Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27]>C1COCC1>[C:15]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][O:14][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])=[CH:9][CH:8]=2)[N:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(CO)cc2)n1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1ccc(-n2nc(C(C)(C)C)cc2N)cc1)(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
To a solution of (4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)phenyl)methanol (Ito, K. et al., WO 2010/067131) (8.50 g, 35.0 mmol) and 1H-imidazole (2.71 g, 39.8 mmol) in dry THF (100 mL) under N2 was added chlorotriisopropylsilane (8.16 mL, 38.1 mmol) and the reaction mixture maintained at RT for 5 days. The resulting mixture was evaporated in vacuo and the residue was partitioned between EtOAc (250 mL) and water (100 mL). The organic layer was separated and was washed with (water (100 mL) and brine (80 mL) and then dried and evaporated in vacuo to afford the title compound, Intermediate A12 as a dark red solid (14.6 g, 97%); Rt 3.26 min (Method 2); m/z 402 (M+H)+, (ES+).
Reaction SMILES: C(O[C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][CH3:25])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[BrH:26]>ClCCl.C(O)(=O)C>[C:8]([O:7][C@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][CH3:25])[O:22][C@@H:5]1[Br:26])(=[O:10])[CH3:9]
Reactant: COC[C@H]1O[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC[C@H]1O[C@H](Br)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
A solution of 1,2,3,4-tetra-O-acetyl-6-O-methyl-β-D-mannopyranose (2.8 g) in dry dichloromethane (2 ml) at 0°-5° C. is treated with 30% hydrobromic acid in glacial acetic acid (25 ml) for 2 hours. The reaction mixture is worked-up in the normal manner to give 2,3,4-tri-O-acetyl-6-O-methyl-α-D-mannopyranosyl bromide (2.8 g), which is reacted with thiourea (0.76 g) in dry acetone (5 ml) at reflux temperature for 2 hours. The solution is evaporated in vacuo to a syrup, which is partitioned between ethyl ether (25 ml) and water (25 ml). The aqueous layer is extracted three times with ethyl ether. A solution of cinnamyl bromide (1.44 g) in acetone (30 ml) is added to the aqueous solution containing 2-S-(2,3,4-tri-O-acetyl-6-O-methyl-α-D-mannopyranosyl)-2-thiopseudourea hydrobromide. This is followed by the addition of potassium carbonate (1.26 g) and potassium metabisulfite (1.77 g) and the reaction mixture is stirred vigorously for 2 hours at room temperature. Acetone is evaporated in vacuo and the product is extracted with chloroform and washed twice with water. The solution is dried and evaporated to an oil, which is put on a column of silica gel and eluted with CHCl3 --EtOAc (98:2, v/v). The desired fractions are combined and evaporated in vacuo to give 19 as an oil (1.15 g, 33% overall yield): [α]D27 +147° (C 2.08, chloroform).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:51][C:52]1[CH:57]=[CH:56][N:55]=[CH:54][C:53]=1[O:58][CH:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>CN(C=O)C.O>[CH3:51][C:52]1[CH:57]=[CH:56][N:55]=[CH:54][C:53]=1[O:58][CH:59]1[CH2:64][CH2:63][N:62]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]2[CH:17]=[C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:20][N:19]=2)=[O:22])[CH2:61][CH2:60]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Cc1ccncc1OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccncc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 8 h
Yield: 63.2 %

Procedure:
DIPEA (154 mg, 1.4 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (107 mg, 0.4 mmol) in DMF (2 mL) followed by HOBt (54 mg, 0.4 mmol) and EDCI.HCl (84 mg, 0.44 mmol). After 2 minutes 4-methyl-3-(piperidin-4-yloxy)-pyridine hydrochloride (100 mg, 0.4 mmol) (prepared by method used for the synthesis of Intermediate 15) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, the solid collected. Purification of the solid by washing with 10% MeOH in CHCl3 afforded 106 mg (66% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(4-methyl-pyridin-3-yloxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 420, 98.9%. 1H NMR (300 MHz, DMSO-d6): δ 14.0 (b, 1H), 8.6 (s, 1H), 8.4 (d, 1H), 8.2 (b, 1H), 7.8 (m, 3H), 7.5 (m, 2H), 7.4 (m, 1H), 7.2 (s, 1H), 4.9 (m, 1H), 4.2 (m, 2H), 3.8 (m, 2H), 3.5 (m, 2H), 2.4 (s, 3H), 2.0 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[C:11]2[O:13][CH2:14][O:15][C:10]2=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17].[CH2:19](O)C>>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([NH:6][CH2:5][CH2:4][OH:3])[C:8]([N+:16]([O-:18])=[O:17])=[CH:9][C:10]=1[OH:15])[CH3:19]
Reactant: O=[N+]([O-])c1cc2c(cc1NCCO)OCO2
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: CCOc1cc(NCCO)c([N+](=O)[O-])cc1O
Reaction time: 0.17 h

Procedure:
0.16 mol (10.5 g) of 85% pure potassium hydroxide pellets are dissolved in 80 ml of absolute ethanol on a boiling water bath. 0.08 mol (18.1 g) of 2-(β-hydroxyethyl)amino-4,5-methylenedioxy-1-nitrobenzene is added with stirring in the course of 10 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([C:20]5[CH2:29][CH2:28][NH:27][CH2:26][C:21]=5[N:22]4[CH3:25])=[CH:18][CH:17]=3)[C:12](=[O:30])[CH:11]=2)=[N:6][CH:7]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:35](C)=O.[Na+].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:59].Cl>C(Cl)Cl.CO>[ClH:1].[ClH:59].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([C:20]5[CH2:29][CH2:28][N:27]([CH3:35])[CH2:26][C:21]=5[N:22]4[CH3:25])=[CH:18][CH:17]=3)[C:12](=[O:30])[CH:11]=2)=[N:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cn5)cc4=O)cc31)CCNC2
Agent: C=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Solvent: ClCCl
Product: CN1CCc2c(n(C)c3cc(-n4ccc(OCc5ccc(Cl)cn5)cc4=O)ccc23)C1
Reaction time: 0.75 h
Yield: 86 %

Procedure:
4-((5-Chloropyridin-2-yl)methoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one (80 mg, 0.19 mmol) was dissolved a mixture of MeOH (3 mL) and CH2Cl2 (1 mL) and formaldehyde (9.0 mg, 0.29 mmol, 37% aqueous solution) was added. After stirring for 45 minutes, NaBH(OAc)3 (80 mg, 0.38 mmol) was added and the reaction mixture was stirred for a further 10 minutes. The mixture was diluted with CH2Cl2, washed with saturated Na2CO3 solution and concentrated to provide the free base. Conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound (83 mg, 86%) as an orange solid: mp 202-210° C.; 1H NMR (500 MHz, CD3OD) δ 8.68 (br s, 1H), 8.05 (dd, J=8.0, 2.4 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.51 (d, J=1.6 Hz, 1H), 7.09 (dd, J=8.3, 1.8 Hz, 1H), 6.53 (dd, J=7.6, 1.7 Hz, 1H), 6.28 (d, J=1.6 Hz, 1H), 5.36 (s, 2H), 4.85-4.80 (m, 1H), 4.49 (d, J=15.3 Hz, 1H), 3.89-3.84 (m, 1H), 3.72 (s, 3H), 3.53-3.47 (m, 1H), 3.22-3.19 (m, 2H), 3.16 (s, 3H); ESI MS m/z 435 [M+H]+; HPLC (Method B) 97.8% (AUC), tR=12.2 min.