Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:19]([O:21][CH3:22])=[O:20])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2OS(C(F)(F)F)(=O)=O)[CH2:3]1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:23]([NH:30][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH2:10][C:2]([CH3:1])([C:19]([O:21][CH3:22])=[O:20])[CH2:3]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)C1(C)Cc2cccc(OS(=O)(=O)C(F)(F)F)c2C1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)C1(C)Cc2cccc(NCc3ccccc3)c2C1
Temperature: 25 °C

Procedure:
Under argon, a solution of 1 g (2.96 mmol) of methyl 2-methyl-4-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1H-indene-2-carboxylate, 290 μl (2.66 mmol) of benzylamine, 2.41 g (7.29 mmol) of cesium carbonate, 56 mg (0.12 mmol) of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl and 54 mg (0.059 mmol) of tris(dibenzylideneaceton)dipalladium in 50 ml of dioxane was stirred at a bath temperature of 100° C. overnight. After cooling to room temperature, the reaction mixture was filtered through kieselguhr and the residue was washed repeatedly with dioxane. The combined filtrates were concentrated to dryness under reduced pressure. The crude product obtained was purified by flash chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1→4:1→1:1). This gave 769 mg (2.42 mmol, 93% content, 82% of theory) of a colorless solid.
Reaction SMILES: C([O:5][C:6](=[O:63])[C@H:7]([CH2:59][CH:60]([CH3:62])[CH3:61])[NH:8][CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([C@@H:16]2[O:48][C@H:47]([CH2:49][O:50]C(=O)C3C=CC=CC=3)[C@H:37]([O:38]C(=O)C3C=CC=CC=3)[C@H:27]([O:28]C(=O)C3C=CC=CC=3)[C@H:17]2[O:18]C(=O)C2C=CC=CC=2)[CH2:10]1)(C)(C)C.Cl.Cl.C(OC(=O)[C@H](CC(C)C)N)(C)(C)C.C([BH3-])#N.[Na+]>ClCCl.CO>[C@@H:16]1([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH:9]([NH:8][C@H:7]([C:6]([OH:63])=[O:5])[CH2:59][CH:60]([CH3:61])[CH3:62])[CH2:10]2)[O:48][C@H:47]([CH2:49][OH:50])[C@H:37]([OH:38])[C@H:27]([OH:28])[C@H:17]1[OH:18]
Reactant: CC(C)C[C@H](NC1CCCCC([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)C1)C(=O)OC(C)(C)C
Agent: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Solvent: ClCCl
Product: CC(C)C[C@H](NC1CCCCC([C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)C1)C(=O)O
Reaction time: 48 h
Yield: 78 %

Procedure:
Step B--Synthesis of Nα-(3-(2,3,4,6-Tetra-O-benzoyl-β-D-galactopyranosyl)cyclohept-1-yl)-L-leucine tert-Butyl Ester: To the product from Step A (50 mg, 71 μmol) and L-leucine tert-butyl ester dihydrochloride (80 mg, 354 μmol) in dichloromethane (700 μL) and methanol 700 μL) was added sodium cyanoborohydride (2 mg). After 48 h, the mixture was concentrated and purified by column chromatography (SiO2, toluene/ethyl acetate, 8:1) to give the title compound (48 mg, 78%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11]CC3C=CC=CC=3)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[OH:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4]2
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1C
Solvent: CCO
Product: CCOC(=O)c1cc2cc(O)ccc2n1C
Yield: 80 %

Procedure:
Prepared from ethyl 1-methyl-5-(phenylmethoxy)-1H-indole-2-carboxylate (Monge Vega A, et al., An. Ouim. 72:267) by catalytic hydrogenolysis in ethanol as described in Example 15. Recrystallization from ether gives the product in 80% yield; mp 140°-142° C.
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:19])[C:15](I)=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2[O:20][CH:21]2[CH2:26][CH2:25][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:3][CH:2]=1.[C:38]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[C:38]1([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:43]=[CH:42][C:41]([C:15]2[C:14]([F:19])=[CH:13][C:12]3[N:8]([CH2:7][C:4]4[CH:5]=[CH:6][C:1]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)=[CH:2][CH:3]=4)[C:9]([O:20][CH:21]4[CH2:22][CH2:23][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:26]4)=[N:10][C:11]=3[C:16]=2[F:17])=[CH:40][CH:39]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C1CCC(Oc2nc3c(F)c(I)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)CC1
Temperature: 120 °C

Procedure:
A 250 mL flask was charged with ethyl 4-{[1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-iodo-1H-benzimidazol-2-yl]oxy}cyclohexane carboxylate (2 g, 3.24 mmol), 4-Biphenylboronic acid (0.700 g, 3.53 mmol), Pd(PPh3)4 (0.185 g, 0.160 mmol), DMF (30 mL), and 1 M aqueous K2CO3 (6.5 ml, 6.50 mmol). The reaction was degassed with N2 and then heated at 120° C. for 1 hour. The volatiles were removed in vacuo and the resulting residue was partitioned between EtOAc and H2O. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. Chromatography of the resulting residue over silica eluting with 15% [EtOAc:DCM (1:1)]/hexanes afforded the desired trans product as white solid. LC-MS: calculated for C41H36F2N2O3 642.27, observed m/e: 643.14 (M+H)+ (Rt 3.07/4 min).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[NH2:18].[Cl-].[NH4+].[OH-].[NH4+].C[N:24]([CH:26]=[O:27])C>O.[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH2:18][C:3]1[C:2]([C:26]([NH2:24])=[O:27])=[N:7][CH:6]=[C:5]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:4]=1
Reactant: Nc1cc(-c2ncccc2C(F)(F)F)cnc1Cl
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [C-]#N
Agent: [Cl-]
Solvent: O
Product: NC(=O)c1ncc(-c2ncccc2C(F)(F)F)cc1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Heat a solution of 6′-chloro-3-trifluoromethyl-[2,3′]bipyridinyl-5′-ylamine (25 g, 0.091 mol), zinc cyanide (6.75 g, 0.058 mol), tris[dibenzylidineacetone]di-palladium (pd2(dba)3; 2.63 g, 2.86 mmol), and 1,1′-bis(diphenylphosphino)ferrocene (DPPF; 3.16 g, 5.72 mmol) in DMF (250 mL) and water (2.5 mL), under a nitrogen atmosphere, at 120° C. for 1 hour. Add water (30 mL) and heat the solution at 120° C. for a further 4 hours to complete the hydrolysis. Cool the reaction to 0° C. and add a solution of saturated ammonium chloride (200 ml), water (200 mL) and concentrated ammonium hydroxide (50 mL). After stirring at 0° C. for 1 hour, filter the yellow precipitate, and wash with water (200 mL) and a 1:1 mixture of ether-hexane (200 mL). Air dry the solid, and then dry in a vacuum oven to give (23 g, 90%) of the title compound.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([OH:10])[CH:9]=[C:4]2[CH:3]=[CH:2]1.N1C=CN=C1.[CH:16]([Si:19](Cl)([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17].ClCCl>CN(C)C=O>[CH:16]([Si:19]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[O:10][C:8]1[CH:9]=[C:4]2[CH:3]=[CH:2][NH:1][C:5]2=[N:6][CH:7]=1)([CH3:18])[CH3:17]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Oc1cnc2[nH]ccc2c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1cnc2[nH]ccc2c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
To a solution of 1H-Pyrrolo[2,3-b]pyridin-5-ol (0.5 g, 0.004 mol) and 1H-imidazole (0.98 g, 0.014 mol) in N,N-dimethylformamide (5 mL) was added triisopropylsilyl chloride (1 mL, 0.005 mol). The reaction mixture was stirred at room temperature overnight. Dichloromethane (10 mL) was added and the solution was washed with brine and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a viscous liquid (83, 0.4 g, 40%).
Reaction SMILES: C([N:4]1[C:8]2=[N:9][C:10](Br)=[CH:11][CH:12]=[C:7]2[C:6]([C:14]#[N:15])=[CH:5]1)(=O)C.C(N(CC)CC)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH2:57]([O:59][C:60]1[CH:65]=[CH:64][C:63](B(O)O)=[CH:62][N:61]=1)[CH3:58]>O1CCOCC1>[CH2:57]([O:59][C:60]1[N:61]=[CH:62][C:63]([C:10]2[N:9]=[C:8]3[NH:4][CH:5]=[C:6]([C:14]#[N:15])[C:7]3=[CH:12][CH:11]=2)=[CH:64][CH:65]=1)[CH3:58]
Reactant: CC(=O)n1cc(C#N)c2ccc(Br)nc21
Reactant: CCOc1ccc(B(O)O)cn1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOc1ccc(-c2ccc3c(C#N)c[nH]c3n2)cn1
Temperature: 100 °C
Yield: 66.7 %

Procedure:
In a 100 mL round-bottomed flask, 1-acetyl-6-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (250 mg, 947 μmol, Eq: 1.00), triethylamine (575 mg, 792 μl, 5.68 mmol, Eq: 6) and X-PHOS (181 mg, 379 μmol, Eq: 0.40) were combined with dioxane (25 ml) to give a colorless solution. [1,1′-bis(diphenylphosphino)ferrocene]dichloropaladium(II) (173 mg, 237 μmol, Eq: 0.25) and 2-ethoxy-5-pyridineboronic acid (205 mg, 1.23 mmol, Eq: 1.3) were added and the resultant mixture was degassed for 5 minutes under Nitrogen. The reaction mixture was heated to 100° C. and stirred for O/N h. The reaction mixture was poured into 50 mL H2O and extracted with EtOAc (3×50 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 20% to 30% EtOAc in hexanes) to give 6-(6-ethoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (167 mg, 67%).
Reaction SMILES: [N+:1]([C:4]1[CH:45]=[CH:44][C:7]([CH2:8][O:9][C:10]([O:12][CH:13]([CH:15]2[C:21](=[O:22])[N:20]3[CH:16]2[CH2:17][C:18](S(C2N=CC=CN=2)=O)=[C:19]3[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:46]([NH:49][CH2:50][CH2:51][SH:52])(=[O:48])[CH3:47].O.[OH-].[Na+]>ClCCl.[Cl-].C([N+](C)(C)CCCCCCCCCCCCCCCC)C1C=CC=CC=1>[C:46]([NH:49][CH2:50][CH2:51][S:52][C:18]1[CH2:17][CH:16]2[N:20]([C:21](=[O:22])[CH:15]2[CH:13]([O:12][C:10]([O:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:45][CH:44]=2)=[O:11])[CH3:14])[C:19]=1[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=1)=[O:24])(=[O:48])[CH3:47]
Reactant: CC(OC(=O)OCc1ccc([N+](=O)[O-])cc1)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S(=O)c3ncccn3)CC12
Reactant: CC(=O)NCCS
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(C(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
p-NItrobenzyl (5RS, 6SR)-6-[(1RS)-1-p-nitrobenzyloxycarbonyloxyethyl]-3-(2-pyrimidylsulphinyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (15 mg) in dichloromethane (2 ml) was cooled in an ice-bath and treated with benzyldimethyl-n-hexadecylammonium chloride (1.1 mg), followed by 2-acetamidoethanethiol (3 mg) in dichloromethane (1 ml), followed by water (1 ml), followed by 0.1M aqueous NaOH (0.25 ml). After stirring in the cold for 30 min. the reaction mixture was allowed to warm to room temperature and stirred for 1.5 h. After dilution with CH2Cl2 /H2O and separation, the dichloromethane layer was dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel, eluting with ethyl acetate, followed by ethylacetate/ethanol (95:5) to give the title compound νmax. (CH2Cl2) 3450, 1790, 1750, 1700(sh), 1680, 1525, 1350 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[C:25]3[C:20](=[C:21]([O:26]CC4C=CC=CC=4)[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)[CH:5]=[C:6]([F:16])[C:7]=1[O:8]CC1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[F:16][C:6]1[CH:5]=[C:4]([N:17]2[C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:26])[C:20]=3[CH:19]=[CH:18]2)[CH:3]=[C:2]([F:1])[C:7]=1[OH:8]
Reactant: Fc1cc(-n2ccc3c(OCc4ccccc4)cccc32)cc(F)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1c(F)cc(-n2ccc3c(O)cccc32)cc1F
Yield: 34.5 %

Procedure:
1-{3,5-difluoro-4-[(phenylmethyl)oxy]phenyl}-4-[(phenylmethyl)oxy]-1H-indole (D21) (299 mg, 0.678 mmoL) was dissolved in ethyl acetate (10 mL) and was hydrogenated at room temperature and atmospheric pressure in the presence of 10% palladium on charcoal (50% wet) (150 mg). After 21 hours the mixture was filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Biotage SP4) eluting with a gradient of 0 to 100% Et2O in hexane to give the title compound (E11), (61 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[N:15]=[CH:14][N:13]=3)[CH:9]=[C:8]([C:21](O)=[O:22])[C:5]2=[N:6][CH:7]=1.[F:24][CH2:25][CH2:26][NH2:27].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>>[F:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[N:15]=[CH:14][N:13]=3)[CH:9]=[C:8]([C:21]([NH:27][CH2:26][CH2:25][F:24])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: NCCF
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncc(F)cc32)c1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Product: COc1ncnc(Cn2cc(C(=O)NCCF)c3ncc(F)cc32)c1C
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
See FIG. 20(c). 6-fluoro-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (20 mg, 0.06 mmol) and 2-fluoroethanamine (7.18 mg, 0.11 mmol), TEA (0.026 mL, 0.19 mmol) was added. After 3 min, 1-Propanephosphonic acid cyclic anhydride (50.3 mg, 0.16 mmol) was added. The resulting reaction mixture was stirred at rt for 50 min. LCMS analysis showed formation of required product. Reaction was diluted with DCM and water.DCM layer was extracted and washed with brine and dried over sodium sulphate and concentrated. Purification was done on Waters RP system to get product 6-fluoro-N-(2-fluoroethyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (20.00 mg, 88%). ES+MS m/z: 362. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.24 (s, 3 H ) 3.57-3.70 (q, 1 H ) 3.70-3.80 (q, 1 H ) 3.94 (s, 3 H ) 4.43-4.58 (t, 1 H ) 4.66 (t, J=4.99 Hz, 1 H ) 5.68 (s, 2 H ) 8.03 (dd, J=9.89, 2.54 Hz, 1 H ) 8.29 (s, 6 H ) 8.40 (s, 1 H ) 8.53 (t, J=2.07 Hz, 1 H ) 8.71 (t, J=5.84 Hz, 1 H ).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]2[C:10]=1[C:9](=[N:11]O)[CH2:8][CH2:7]2.[H][H].[ClH:16]>C(O)(=O)C.[Pt]=O.C(O)C>[ClH:16].[NH2:11][CH:9]1[C:10]2[C:6](=[C:5]([CH3:13])[CH:4]=[CH:3][C:2]=2[OH:1])[CH2:7][CH2:8]1
Reactant: [H][H]
Reactant: Cc1ccc(O)c2c1CCC2=NO
Agent: O=[Pt]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(O)c2c1CCC2N

Procedure:
15.0 Grams of 7-hydroxy-4-methyl-1-indanone oxime was dissolved in 200 ml of acetic acid, then 1.0 g of platinum oxide catalyst was added thereto and the mixture was subjected to catalytic reduction under 5 atmospheric pressure of hydrogen gas at a room temperature for 8 hours. The catalyst was removed by filtration, then the filtrate was concentrated to dryness under a reduced pressure. The residue thus obtained was dissolved in 200 ml of ethanol and hydrogen chloride gas was blown into the solution to become saturated. The solvent was removed by evaporation under a reduced pressure, the residue was recrystallized from ethanol to obtain 3.30 g of 1-amino-7-hydroxy-4-methylindane hydrochloride in the form of colorless needle-like crystals. Melting point: 221°-223° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:11][N:12]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[S:13]1(=[O:15])=[O:14].C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[N:5]1[CH:6]=[CH:7][C:2]([C:1]([O:9][CH2:11][N:12]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:13]2(=[O:14])=[O:15])=[O:8])=[CH:3][CH:4]=1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CBr
Reactant: O=C(O)c1ccncc1
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: O=C(OCN1C(=O)c2ccccc2S1(=O)=O)c1ccncc1
Yield: 35.3 %

Procedure:
A mixture of isonicotinic acid (0.98 g, 0.008 mol), 2-bromomethylsaccharin (2.11 g, 0.008 mol), triethylamine (0.81 g, 0.008 mol) and xylene (25 ml) were refluxed for 1 hour. The solvent was removed in vacuo and the residue was partitioned between water and methylene chloride. The organic layer was separated and the solvent removed in vacuo. The solid residue was recrystallized from CH3CN to afford 0.9 g (37%) of 2-saccharinylmethyl pyridine-4-carboxylate as a yellow solid, m.p. 145°-146° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([CH3:17])=[CH:4][N:3]=1.[F:18][C:19]1[C:20]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)=[CH:21][C:22]([O:26][CH3:27])=[C:23]([CH:25]=1)[NH2:24]>>[F:18][C:19]1[C:20]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)=[CH:21][C:22]([O:26][CH3:27])=[C:23]([NH:24][C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][CH:9]=3)[C:5]([CH3:17])=[CH:4][N:3]=2)[CH:25]=1
Reactant: Cc1cnc(Cl)nc1-c1c[nH]c2ccccc12
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(F)cc1N
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(F)cc1Nc1ncc(C)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 1) and 5-Fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 54).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][CH3:20]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10](=[O:11])[N:19]([CH3:20])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CNC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylearbodiimide hydrochloride (2.48 g) was added to a stirred suspension of N-tert-butoxycarbonyl-L-hydroxyproline (2.0 g), 4-(dimethylamino)pyridine (5.28 g) and dimethylamine hydrochloride (1.4 g) in methylene chloride (100 ml) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with citric acid (1.0 M), saturated sodium bicarbonate and saturated brine before drying over magnesium sulfate. The product was then purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10). The fractions containing the expected product were combined and evaporated under vacuum to give (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-(N,N-dimethylcarbamoyl)pyrrolidine as a colourless gum (1.01 g); 1H NMR Spectrum: (DMSO d6) 1.29-1.40 (m, 9H), 1.74-1.83 (m, 1H), 2.04-2.15 (m, 1H), 2.80-2.87 (m, 3H), 3.03 (s, 3H), 3.26 (m, 1H), 3.40 (m, 1H), 4.28 (m, 1H), 4.64 (m, 1H), 4.95 (d, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])=[CH:11][CH:10]=2)[S:3]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:48]([O:52][C:53](=[O:59])[NH:54][CH2:55][CH2:56][CH2:57][NH2:58])([CH3:51])([CH3:50])[CH3:49]>CN(C=O)C>[C:48]([O:52][C:53](=[O:59])[NH:54][CH2:55][CH2:56][CH2:57][NH:58][C:23](=[O:24])[CH2:22][CH2:21][CH2:20][O:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([CH:8]=[C:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[O:7])=[CH:10][CH:11]=1)([CH3:51])([CH3:49])[CH3:50]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C(O)CCCOc1ccc(C=C2SC(=O)NC2=O)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCNC(=O)CCCOc1ccc(C=C2SC(=O)NC2=O)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To a mixture of 4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]butyric acid (example 291, 5.9 g, 16.5 mmol) and 1-hydroxybenzotriazole (3.35 g, 24.8 mmol) in DMF (60 mL) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (4.75 g, 24.8 mmol) and the resulting mixture was stirred at room temperature for 2 hours. N-(3-aminopropylcarbamic acid tert-butyl ester (3.45 g, 19.8 mmol) was added and the resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and ethyl acetate and dichloromethane were added to the residue. The mixture was filtered, washed with water and dried in vacuo to afford 4.98 g (59%) of (3-{4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]butyrylamino}propyl)carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:22][C:23]([C:25]2[N:26](COCC[Si](C)(C)C)[CH:27]=[C:28]([C:30]#[N:31])[N:29]=2)=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:22][C:23]([C:25]2[NH:26][CH:27]=[C:28]([C:30]#[N:31])[N:29]=2)=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CN1C(=O)CC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)CC1=O
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)CC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1=O
Yield: 8.1 %

Procedure:
A solution of 130 mg (0.237 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(1-methyl-2,6-dioxo-piperidin-4-yl)-phenyl]-amide (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with MeOH (200 μL) and TFA (3 mL) at RT for 1.25 h. MeOH (30 mL) was added, the mixture was concentrated to half volume, MeOH (20 mL) was added, and the solvents were removed completely in vacuo at <35° C. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 25-50% EtOAc-hexane and by RP-HPLC (C18) with 10-80% CH3CN in 0.1% TFA/H2O over 30 min afforded 8.0 mg (8%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.19 (d, 1H, J=8.4 Hz), 8.03 (s, 1H), 7.24 (dd, 1H, J=8.4, 2.4 Hz), 7.16 (d, 1H, J=2.4 Hz), 5.87-5.82 (m, 1H), 3.47-3.37 (m, 1H), 3.16 (s, 3H), 2.96-2.91 (m, 4H), 2.33-2.25 (m, 4H), 1.92-1.77 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C23H23N5O3, 418.2 (M+H), found 418.1.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:11]=O)[C:5]=2[CH:4]=[CH:3]1.[CH3:13][NH2:14].[BH4-].[Na+].O>CO>[CH3:13][NH:14][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]2[CH3:1]
Reactant: CN
Reactant: Cn1ccc2c(C=O)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1cccc2c1ccn2C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
1-Methyl-1H-indole-4-carbaldehyde (427 mg, 2.68 mmol) was dissolved in anhydrous methanol (12 mL). Methylamine (1.07 mL of 33% solution in ethanol, 8.59 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to a yellow oil and then dissolved in anhydrous methanol (12 mL). Sodium borohydride (104 mg, 2.74 mmol) was added and the mixture was stirred overnight at room temperature. Water (10 mL) was added and the solution was concentrated. Sodium hydroxide (20 mL, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×30 mL). Combined organic layers were dried over Na2SO4, filtered and concentrated to afford N-methyl(1-methyl-1H-indol-4-yl)methanamine (432 mg, 92%) as a yellow oil: 1H NMR (400 MHz, DMSO-d6) δ 7.29-7.26 (m, 2H), 7.10-7.06 (m, 1H), 7.00-6.98 (m, 1H), 6.51 (d, J=3.2 Hz, 1H), 3.87 (s, 2H), 3.76 (s, 3H), 2.29 (s, 3H).