Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].CC(N(C)C)=O.[CH:13]([NH2:15])=O.BrC1[C:26]2[N:27]=[CH:28][NH:29][C:25]=2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]=1>O>[CH2:1]([N:29]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:13]([NH2:15])[C:26]=2[N:27]=[CH:28]1)[CH:2]([CH3:5])[CH3:3]
Reactant: Brc1nc2ccccc2c2[nH]cnc12
Reactant: CC(C)(C)[O-]
Reactant: NC=O
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
Potassium tert-butoxide (3.69 g, 0.033 mole), 5 mL of dimethylacetamide and 1.31 mL (0.033 mole) of formamide were added in a 50 mL round-bottomed flask, under inert atmosphere followed by stirring for 30 minutes. After addition of 4-bromo-1H-imidazo[4,5-c]quinoline (1 g, 3.3 mmoles), the mixture was heated at 140° C., followed by stirring for 2 hours and then cooled to room temperature. Then 10 mL of water were added and the reaction mixture was filtered followed by washing with abundant water and dried to give 0.75 g of 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine. Yield 75.4%.
Reaction SMILES: [NH2:1][C:2](=[O:37])[C@@H:3]([NH:12][C:13](=[O:36])[C@@H:14]([NH:16][C:17](=[O:35])[C@@H:18]([NH:20][C:21](=[O:34])[CH:22]([NH:26][C:27]1[S:28][C:29]([CH:32]=[O:33])=[CH:30][N:31]=1)[CH:23]([CH3:25])[CH3:24])[CH3:19])[CH3:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[BH4-].[Na+]>CCO.O>[NH2:1][C:2](=[O:37])[C@@H:3]([NH:12][C:13](=[O:36])[C@@H:14]([NH:16][C:17](=[O:35])[C@@H:18]([NH:20][C:21](=[O:34])[CH:22]([NH:26][C:27]1[S:28][C:29]([CH2:32][OH:33])=[CH:30][N:31]=1)[CH:23]([CH3:24])[CH3:25])[CH3:19])[CH3:15])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: CC(C)C(Nc1ncc(C=O)s1)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)C(Nc1ncc(CO)s1)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the material from Example 21 (21.5 mg, 0.033 mmol) in EtOH/H2O (4:1) (2.5 mL) is added sodium borohydride (8.35 mg, 0.221 mmol) in 2 portions, separated by ˜5 min and the resulting off white slurry is allowed to stir at room temp for 1.5 h. The reaction is quenched with MeOH (750 μlit) and evaporated to dryness under a gentle stream of N2 to give the title compound that is used directly in the next step. LC/MS (Condition A): ret. T=1.74 min, (M+H)+ 535.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:12][CH2:11][CH2:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1.[OH2:24]>C(Cl)Cl>[Cl:1][C:2]1[C:3]2[CH2:12][CH2:11][CH2:10][C:4]=2[N:5]=[C:6]([S:8]([CH3:9])(=[O:21])=[O:24])[N:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(Cl)c2c(n1)CCC2
Reactant: O
Solvent: ClCCl
Product: CS(=O)(=O)c1nc(Cl)c2c(n1)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 4-chloro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.208 g, 1.04 mmol) in methylene chloride (4 mL) was added m-CPBA (0.805 g, 4.66 mmol) in portions over a 15 min period at 0° C. and then the mixture was slowly warmed to rt and stirred overnight. After this time, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford the title compound (0.157 g, 75%). MW=232.69. 1H NMR (CDCl3, 300 MHz) δ 3.39-3.28 (m, 5H), 3.11 (t, J=7.6 Hz, 2H), 2.27 (t, J=7.6 Hz, 2H); APCI MS m/z 233 [M+H]+.
Reaction SMILES: [Na].[CH3:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]2[N:10]=[C:11]([CH2:16][C:17]([OH:19])=O)[NH:12][C:13](=[O:15])[CH:14]=2)[CH2:4]1.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][NH:25]2.Cl.CN(C)CCCN=C=NCC>O.CN(C=O)C.N1C=CC=CC=1>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][N:25]2[C:17](=[O:19])[CH2:16][C:11]1[NH:12][C:13](=[O:15])[CH:14]=[C:9]([N:5]2[CH2:6][CH2:7][O:8][CH:3]([CH3:2])[CH2:4]2)[N:10]=1
Reactant: CC1CN(c2cc(=O)[nH]c(CC(=O)O)n2)CCO1
Reactant: Clc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1CN(c2cc(=O)[nH]c(CC(=O)N3CCc4c(Cl)cccc43)n2)CCO1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
0.975 g of the sodium salt of [4-(2-methylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid (example 1b, step 2b), 0.534 g of 4-chloroindoline, 0.57 ml of pyridine and 15 ml of DMF are placed in a round-bottomed flask, and then 0.9 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride is added. The reaction mixture is stirred at ambient temperature for 72 hours. The reaction mixture is poured into 50 ml of water, with stirring, and then the solid formed is filtered off through sintered glass and washed 3 times with approximately 15 ml of water, washed with 10 ml of EtOAc and rinsed with twice approximately 5 ml of diisopropyl ether, and the resulting product is left to air-dry under a hood. 2-[2-(4-Chloro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(2-methylmorpholin-4-yl)-3H-pyrimidin-4-one is isolated (0.98 g) and characterized in the form of an off-white solid (yield 71%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[O:24]=[C:25]1[N:29]=[C:28]([NH:30][CH2:31][C:32]([NH2:34])=[O:33])[CH2:27][S:26]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:27]2/[C:28]([NH:30][CH2:31][C:32]([NH2:34])=[O:33])=[N:29][C:25](=[O:24])[S:26]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: NC(=O)CNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: NC(=O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 32.3 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.5 g) in 2-propanol (15 mL) were added N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)glycinamide (0.65 g) and piperidinium acetate (0.64 g). The reaction mixture was stirred at 80° C. for 3 hr and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) and recrystallized from ethyl acetate/heptane/ethanol/water to give the title compound (0.60 g).
Reaction SMILES: [CH:1]1([C:4]2[C:14]3[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=3[CH:7]=[C:6]3[O:22][CH2:23][CH2:24][N:25]([CH2:26][C@@H:27]([O:40][CH3:41])[CH2:28]OS(C4C=CC(C)=CC=4)(=O)=O)[C:5]=23)[CH2:3][CH2:2]1.[F-:42].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>C1COCC1>[CH:1]1([C:4]2[C:14]3[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=3[CH:7]=[C:6]3[O:22][CH2:23][CH2:24][N:25]([CH2:26][C@@H:27]([O:40][CH3:41])[CH2:28][F:42])[C:5]=23)[CH2:3][CH2:2]1
Reactant: CO[C@@H](COS(=O)(=O)c1ccc(C)cc1)CN1CCOc2cc3c(c(C4CC4)c21)CCN(C(=O)OC(C)(C)C)CC3
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H](CF)CN1CCOc2cc3c(c(C4CC4)c21)CCN(C(=O)OC(C)(C)C)CC3
Temperature: 60 °C
Reaction time: 13 h

Procedure:
To 400 mg of t-butyl 5-cyclopropyl-4-[(2R)-2-methoxy-3-{[(4-methylphenyl)sulfonyl]oxy}propyl]-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate was added 7 ml of a 1 M solution of tetrabutylammonium fluoride in THF, followed by heating and stirring at 60° C. for 13 hours under an argon atmosphere. The reaction mixture was cooled to room temperature and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate twice. The combined organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 257 mg of t-butyl 5-cyclopropyl-4-[(2R)-3-fluoro-2-methoxypropyl]-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate as a white foamed solid.
Reaction SMILES: [F:1][C:2]([F:15])([C:11]([F:14])([F:13])[F:12])[CH2:3][CH2:4][S:5]([CH2:8][C:9]#[N:10])(=[O:7])=[O:6].[F:16][C:17]([S:20][CH2:21][CH2:22]OS(C(F)(F)F)(=O)=O)([F:19])[F:18].C([O-])([O-])=O.[K+].[K+]>COCCOC.O>[F:15][C:2]([F:1])([C:11]([F:12])([F:13])[F:14])[CH2:3][CH2:4][S:5]([CH:8]([CH2:22][CH2:21][S:20][C:17]([F:19])([F:18])[F:16])[C:9]#[N:10])(=[O:6])=[O:7]
Reactant: O=S(=O)(OCCSC(F)(F)F)C(F)(F)F
Reactant: N#CCS(=O)(=O)CCC(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: N#CC(CCSC(F)(F)F)S(=O)(=O)CCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (3,3,4,4,4-Pentafluoro-butane-1-sulfonyl)-acetonitrile (WO2007/060839) (0.50 g, 1.99 mmol), trifluoro-methanesulfonic acid 2-trifluoromethylsulfanyl-ethyl ester (WO 2007/147888) (0.55 g, 1.99 mmol), and K2CO3 (0.82 g, 5.97 mmol) in 1,2-dimethoxyethane (20 mL) was stirred under nitrogen at room temperature overnight. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexanes/EtOAc 19:1) to afford compound II-1 (0.28 g, 37%) as a white solid.
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:9](=[O:10])[O:8][C:6](=[O:7])[CH2:5]1)=[O:2].C(O)=[O:12]>>[CH:1]([NH:3][C@H:4]([C:9]([OH:8])=[O:10])[CH2:5][C:6]([OH:12])=[O:7])=[O:2].[C:6]([O:8][C:9](=[O:10])[CH3:4])(=[O:7])[CH3:5]
Reactant: O=CN[C@H]1CC(=O)OC1=O
Reactant: O=CO
Product: CC(=O)OC(C)=O
Product: O=CN[C@@H](CC(=O)O)C(=O)O

Procedure:
N-formyl-L-aspartic anhydride (hereinafter referred to as FAA) is usually obtained by the reaction of N-formyl-L-aspartic acid with formic acid and acetic anhydride (hereinafter referred to as dehydration reaction). As such a reaction known is a reaction in which acetic acid and formic acid are employed in almost stoichiometric amounts based on aspartic acid (U.S. Pat. No. 4,526,985 and U.S. Pat. No. 4,810,816), which is problematic in that the yield is low as based on the amount of aspartic acid as the starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH2:13]Cl.[Na].CN(C)[CH:18]=[O:19]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH2:13][O:19][C:18]1[CH:9]=[CH:8][C:7]([Cl:12])=[CH:6][CH:5]=1
Reactant: ClCc1c(Cl)ccc2cc(Cl)cnc12
Reactant: CN(C)C=O
Agent: [Na]
Product: Clc1ccc(OCc2c(Cl)ccc3cc(Cl)cnc23)cc1

Procedure:
24.6 parts of 3,7-dichloro-8-chloromethylquinoline (Example 1) and 15 parts of sodium p-chlorophenate in 200 parts of dimethylformamide were stirred at 100° C. for 10 hours. The solvent was distilled off, water was added to the residue and the solid was filtered off with suction, dried and recrystallized from a suitable solvent. 32 parts of 3,7-dichloro-8-p-chlorophenoxymethylquinoline of melting point 110° C. were obtained. The yield corresponds to 95% of theory.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][C@H:14]([CH2:17][CH3:18])[CH2:15][OH:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C@H:14]([CH2:17][CH3:18])[CH2:15][O:16][C:27]3=[O:29])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@H](CO)Nc1nc(-c2ccc(Br)cc2)cs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H]1COC(=O)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 0 °C
Reaction time: 16 h
Yield: 47.9 %

Procedure:
(2R)-2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}butan-1-ol (2.80 g, 8.56 mmol), prepared in the previous step, and triethylamine (10.5 mL, 60 mmol) in dry dichloromethane (75 mL) was cooled to 0° C. under a nitrogen atmosphere. Triphosgene (5.90 g, 20 mmol) in dry dichloromethane (25 mL) was then added drop wise. After 16 h, the mixture was washed with water and dried (anhydrous MgSO4). The crude product was recrystallized from diethyl ether to afford (4R)-3-[4-(4-bromophenyl)-1,3-thiazol-2-yl]-4-ethyl-1,3-oxazolidin-2-one (1.46 g, 4.1 mmol). mp 134-135° C.; [α]D25=−46° (c=0.0107 g/mL, DMSO); MS (ES) m/z 353.0; HPLC purity 100% at 210-370 nm, 10.8 min; 100% at 270 nm, 10.8 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min. Anal. Calcd for C14H13BrN2O2S: C, 47.60; H, 3.71; N, 7.93. Found: C, 47.45; H, 3.43; N, 7.74.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23](O)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.[NH:27]1[CH2:30][CH2:29][CH2:28]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[N:27]1([C:23]([C:17]2([C:14]3[CH:13]=[CH:12][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]4)=[CH:16][CH:15]=3)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:24])[CH2:30][CH2:29][CH2:28]1
Reactant: C1CNC1
Reactant: CC(C)N1CCC(Oc2ccc(C3(C(=O)O)CCOCC3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)N1CCC(Oc2ccc(C3(C(=O)N4CCC4)CCOCC3)cc2)CC1
Yield: 43.3 %

Procedure:
4-{4-[(1-Isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carboxylic acid (200 mg, 0.58 mmol), azetidine hydrochloride (81 mg, 0.87 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (121 mg, 0.63 mmol), 1-hydroxybenzotriazole hydrate (97 mg, 0.63 mmol) and triethylamine (210 μL, 1.51 mmol) were stirred in dichloromethane (8 mL) at room temperature for 18 hours. The reaction was diluted with dichloromethane (60 mL) and washed with aqueous sodium bicarbonate. The aqueous were extracted again with dichloromethane. The organics were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.5, by volume) to provide the title compound (97 mg, 43%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 1.11 (d, 6H), 1.77-1.82 (m, 2H), 1.88-1.95 (m, 2H), 2.01-2.08 (m, 4H), 2.26-2.29 (m, 2H), 2.47-2.52 (m, 2H), 2.76-2.86 (m, 3H), 3.66-3.74 (m, 4H), 3.79-3.82 (m, 2H), 3.92-3.96 (m, 2H), 4.40 (m, 1H), 6.95 (d, 2H), 7.22 (d, 2H). HRMS ESI+ m/z 387.2634 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH:19]([NH:22][CH:23]([CH3:25])[CH3:24])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([N:22]([CH:23]([CH3:25])[CH3:24])[CH:19]([CH3:21])[CH3:20])=[O:7]
Reactant: O=C(O)c1cc(F)cc(C(F)(F)F)c1
Reactant: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)N(C(=O)c1cc(F)cc(C(F)(F)F)c1)C(C)C
Temperature: 85 °C
Yield: 85 %

Procedure:
To a suspension of 15.9 mmol 3-Fluoro-5-(Trifluoromethyl) benzoic acid in 20 ml toluene containing 2 drops of DMF was added 79.7 mmol thionylchloride at 0° C. The mixture was heated at 85° C. for 5 hours. The solvent was carefully removed in vacuo. The colorless liquid was dissolved in 25 ml dichloromethane and cooled to 0° C. 63.8 mmol diisopropylamine was added dropwise. The mixture was allowed to warm to RT. After 1 hour the solvent was removed in vacuo. The residue was taken in ethyl acetate and washed twice with water. The washings were extracted once with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a light yellow solid (85% yield). MS (m/e): 291.9 (M+, 100%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Cl)[CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.ClCCl>CN(C)C=O.O>[C:12]([O:11][C:9]([N:8]([CH2:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:27]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: ClCc1cccc(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1cccc(OCc2ccccc2)c1)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 6 h
Yield: 38.9 %

Procedure:
Next, to a solution of iminodicarboxylic acid di-tert-butyl ester (2.12 g, 8.76 mmol) in N,N-dimethylformamide (13 mL) was added sodium hydride (0.39 g, 9.86 mmol, 60% in oil), the solution was stirred at 60° C. for 6 hours, 1-benzyloxy-3-chloromethyl-benzene (1.0 g, 4.30 mmol) was added, and the solution was further stirred at 60° C. for 4 hours. The reaction solution was allowed to room temperature, then, dichloromethane and water were added for partitioning, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, then, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), and (3-benzyloxybenzyl)iminodicarboxylic acid di-tert-butyl ester (691 mg, 39%) was obtained as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=2)[N:7]=1)=O)C.BrC1C=C[C:23]([NH:26][NH2:27])=NC=1.C(O)(=[O:30])C.O=C(CC(=O)C)C(OCC)=O>C(O)C>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[C:9]([CH3:11])=[CH:10][C:6]([C:4]3[O:3][C:1](=[O:30])[N:26]([CH3:23])[N:27]=3)=[N:7]2)=[N:13][CH:14]=1
Reactant: CC(=O)O
Reactant: NNc1ccc(Br)cn1
Reactant: CCOC(=O)c1cc(C)n(-c2ccc(Br)cn2)n1
Agent: CCOC(=O)C(=O)CC(C)=O
Solvent: CCO
Product: Cc1cc(-c2nn(C)c(=O)o2)nn1-c1ccc(Br)cn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 10 %

Procedure:
Step-1: Ethyl-1-(5-bromopyridin-2-yl)-5-methyl-1H-pyrazole-3-carboxylate: To a stirred solution of 5-bromo-2-hydrazinylpyridine (16.6 g, 89.0 mmol), in ethanol (5 mL) and acetic acid (10 mL) was added ethyl 2,4-dioxopentanoate (14.0 g, 89.0 mmol) drop-wise at 0° C. and the resulting mixture was stirred at 100° C. for 2 h. The reaction mixture was then cooled to room temperature and the solvent was evaporated under vacuum. The residue was diluted with water (50 mL) followed by ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated and the crude product was purified by flash column chromatography (silica gel, ethyl acetate-hexanes system as eluent) to afford 2.60 g (10%) of the title compound as white solid. 1HNMR (400 MHz, CDCl3) δ 8.51-8.50 (m, 1H), 7.96-7.93 (m, 2H), 6.71 (s, 1H), 4.41 (q, J=7.0 Hz, 2H), 2.67 (s, 3H), 1.41 (t, J=7.0 Hz, 3H); ESI-MS (m/z) 310, 312 [(MH)+, Br79,81].
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([CH:8]1[CH2:27][C:11]2[NH:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=[O:7])[CH3:4].[CH3:28]I.O>CN(C)C=O>[CH2:3]([O:5][C:6]([CH:8]1[CH2:27][C:11]2[N:12]([CH3:28])[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=[O:7])[CH3:4]
Reactant: CCOC(=O)C1Cc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1Cc2c(n(C)c3ccc(OCc4ccccc4)cc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.2 %

Procedure:
To a suspension of sodium hydride (60% in oil, 3.0 g, 0.075 mole) in 25 ml of dry dimethylformamide, was added a solution of 1,2,3,4-tetrahydro-7-phenylmethoxycyclopent[b]indole-2-carboxylic acid ethyl ester (23.5 g, 0.07 mole) in 100 ml of dry dimethylformamide. After stirring at ambient temperature for two hours, a solution of methyl iodide (4.7 ml, 0.075 mole) in 20 ml of dimethylformamide was added, and the mixture was stirred at 70° C. for five hours. After cooling, the mixture was poured into 500 ml of water, stirred for five minutes, and then extracted with ethyl acetate (3×). The organic layer was washed successively with water and saturated sodium chloride solution, and dried over anhydrous MgSO4. After filtering, the solvent was evaporated to afford a brown oil (~25 g), which was eluted on a silica gel column with 5% ethyl acetate/dichloromethane via HPLC. The desired fraction was concentrated to a thick brown oil, 20.6 g, which solidified on cooling, m.p. 90°-95° C. A sample of this material was recrystallized from ethanol to give the product as an off-white solid, m.p. 109°-110° C.
Reaction SMILES: [F:1][C@@:2]1([CH2:15][NH:16][C:17]2[N:26]=[C:25]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][O:33][CH3:34])[CH:31]=3)[CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][CH:21]=[N:22]3)[CH2:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C@@:2]1([CH2:15][NH:16][C:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[N:22][C:23]=3[CH:24]=[C:25]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][O:33][CH3:34])[CH:31]=3)[N:26]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: COCn1cc(-c2cc3ncccc3c(NC[C@]3(F)CCCN(C(=O)OC(C)(C)C)C3)n2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCn1cc(-c2cc3ncccc3c(NC[C@]3(F)CCCNC3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
To 1,1-dimethylethyl (3R)-3-fluoro-3-{[(7-{1-[(methyloxy)methyl]-1H-pyrazol-4-yl}-1,6-naphthyridin-5-yl)amino]methyl}-1-piperidinecarboxylate (813 mg, 1.728 mmol) in DCM (10 ml) was added trifluoroacetic acid (2 ml, 26.0 mmol) and stirred at room temperature for 2 h. LCMS showed product as the main peak. The solvent was removed and dissolved in methanol and loaded onto a pre-equilibrated 50 g SCX cartridge. Washed with methanol and eluted with 2M methanolic ammonia. The solvent from the ammonia fractions was removed and the residue dried under high vacuum overnight. The residue was purified on the large scale high pH MDAP (Method D). Appropriate fractions were combined and the solvent removed. The resulting product was dried under high vacuum for 1 h to give the title compound as a yellow solid (349 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([S:14](Cl)(=O)=O)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[Sn].C(Cl)Cl>CO.Cl.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:9]=[CH:10][C:11]([SH:14])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(S(=O)(=O)Cl)cc2)CC1
Agent: Cl
Agent: [Sn]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)C1(c2ccc(S)cc2)CC1
Reaction time: 3 h
Yield: 85.7 %

Procedure:
The above product 36B (1.0 g, 3.64 mmol) was refluxed with tin powder (2.2 g, 18.8 mmol) in MeOH (10 mL) and 4M HCl/dioxane (10 mL). After 3 h, the reaction mixture was poured into ice with CH2Cl2 (100 mL). The phases were separated and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic layers were dried with magnesium sulfate, filtered and evaporated to give the thiol compound 36C as a yellow oil (650 mg, 86%). MS: 207 (M−1)+. Step 4. Preparation of (4′-Trifluoromethyl-biphenyl-4-yl)-methanol (Compound 36D)