Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH3:13][CH:14]([CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22].O>C(OCC)(=O)C>[CH3:13][CH:14]([CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:12][CH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1)=[O:22]
Reactant: COc1cc(CCO)ccc1O
Reactant: CC(C)CCCCCCC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(CCOC(=O)CCCCCCC(C)C)ccc1O
Temperature: 50 °C
Yield: 93.4 %

Procedure:
Homovanillyl alcohol (769 mg, 4.57 mmol), 8-methylnonanoic acid (751 mg, 4.35 mmol) and Novozyme 435 (51 mg) were measured and placed in a flask (25 ml). The mixture was stirred with heating in an oil bath at 50° C. for 16 hr without plugging the flask. After stirring with heating for 2 to 3 hr, attachment of water onto the upper wall of the flask was observed. The reaction mixture was allowed to cool to room temperature, ethyl acetate (25 ml) was added, and Novozyme 435 and the precipitated insoluble material were removed by filtration. Ethyl acetate (50 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml×2), saturated brine (25 ml), 5% aqueous sodium hydrogen carbonate solution (25 ml×2) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was developed by PTLC (preparative thin layer chromatography) (n-hexane:ethyl acetate=3:1), and silica gel containing the object product was stirred with ethyl acetate (100 ml) for 30 min for extraction. The silica gel was filtered off, and the filtrate was concentrated under reduced pressure to give homovanillyl 8-methylnonanoate (1.31 g, yield 93.2%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[Cl:12][S:13](O)(=[O:15])=[O:14].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[S:13]([Cl:12])(=[O:15])=[O:14]
Reactant: Cc1ccc2scc(C)c2c1
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc2sc(S(=O)(=O)Cl)c(C)c2c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 39.7 %

Procedure:
To a solution of 3,5-dimethylbenzothiophene (Intermediate 12) (5.0 g, 33.8 mmol) in CHCl3 (70 mL), chlorosulfonic acid (5.6 mL, 85 mmol) was added dropwise at −5° C. The reaction mixture was stirred at 0° C. for 3 h before it was poured into a mixture of ice and NaHCO3 and stirred vigorously for 5 min. The organic phase was immediately separated, dried with MgSO4 and concentrated yielding 3.5 g (40%) of the title compound.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.C(N(CC)CC)C>CCO>[CH:13]1([NH:16][C:4]2[C:5](=[O:12])[C:6](=[O:11])[C:7]=2[O:8][CH2:9][CH3:10])[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOc1c(NC2CC2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.5 %

Procedure:
To a solution of 3,4-diethoxycyclobut-3-ene-1,2-dione (0.596 g, 3.5 mmol) in EtOH (5 mL) was added cyclopropylamine (0.2 g, 3.5 mmol), followed by triethylamine (0.49 mL, 3.5 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The title compound (0.13 g, 20%) formed as a white precipitate that was collected by filtration and washed with diethyl ether. LCMS (ES+) 182 (M+H)+, RT 1.42 minutes (method 1).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][C@H:19]([C:27]([NH:29][C@H:30]([C:35]([OH:37])=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][C@H:19]([C:27]([NH:29][C@H:30]([C:35]([OH:37])=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O
Yield: 69.2 %

Procedure:
In a fashion analogous to Step B of Example 3A, 1.1 g of Boc-Tyr-DAla-Phe-Met-OH was treated with 10% anisole in TFA and chromatographed on Amberlite XAD-2 to give 0.64 g (60%) of H-Tyr-DAla-Phe-Met-OH, m.p. 248°-249° C., [α]D25.5 =41.06° (c, 1.00 in 50% acetic acid).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17](B(O)O)=[C:12]2[CH:11]=[N:10]1.[F:21][C:22]1([F:33])[CH2:25][N:24]([C:26]2[C:31](I)=[CH:30][N:29]=[CH:28][N:27]=2)[CH2:23]1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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.O>[F:33][C:22]1([F:21])[CH2:23][N:24]([C:26]2[C:31]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]4[N:9]([C:3]5[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=5[F:1])[N:10]=[CH:11][C:12]=34)=[CH:30][N:29]=[CH:28][N:27]=2)[CH2:25]1
Reactant: OB(O)c1ccnc2c1cnn2-c1ccc(F)cc1F
Reactant: FC1(F)CN(c2ncncc2I)C1
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: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: Fc1ccc(-n2ncc3c(-c4cncnc4N4CC(F)(F)C4)ccnc32)c(F)c1
Temperature: 90 °C
Reaction time: 0.42 h

Procedure:
To a solution of Intermediate 63A (35.7 mg, 0.1 mmol) and Intermediate 102A (44.6 mg, 0.150 mmol) in a mixture of DME (1 mL), ethanol (0.5 mL) and water (0.5 mL) was added Na2CO3 (0.042 g, 0.400 mmol). This suspension was degassed with a stream of N2 for 10 minutes and then tetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 mmol) was added followed by degassing for 10 minutes. The tube was then sealed, heated at 90° C. for 14 hours, and cooled to room temperature. The contents of the tube were diluted with MeOH, filtered, rinsed with MeOH, and concentrated to a brown sludge. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of Example 103 was 6.0 mg, and its purity was approximately 100%. LC/MS (condition C): ret time=1.52 min, MS (ES): m/z=401.01 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH3:29][C:30]1([CH3:47])[CH2:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][C:32]([CH3:46])([CH3:45])[NH:31]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:34]4[CH2:33][C:32]([CH3:46])([CH3:45])[NH:31][C:30]([CH3:47])([CH3:29])[CH:35]=4)[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)N1
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: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a stirred solution of 6-bromo-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (0.5 g, 1.12 mmol), was added 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (0.36 g, 1.35 mmol) and Pd(PPh3)4 (0.066 g, 0.057 mmol) in 1,4-dioxane (10 mL) and the flask purged with argon for 10 min 2M Na2CO3 solution (0.43 g, 4.06 mmol) was then added and the flask again purged with argon for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion, water was added and extraction carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole-4-carboxamide (0.53 g, 77.6%). LCMS: 502.55 (M+1)+; HPLC: 99.25% (@ 254 nm) (Rt;5.528); 1H NMR (DMSO-d6, 400 MHz) δ 11.52 (bs, 1H), 8.54 (t, 1H), 8.26 (s, 1H), 7.75 (s, 1H), 7.62 (s, 1H), 6.26 (s, 1H), 5.88 (s, 1H), 5.29-5.24 (m, 1H), 4.37 (d, 2H, J=5.2 Hz), 2.32 (m, 2H), 2.23 (s, 3H), 2.12 (s, 3H), 1.99-1.93 (m, 4H), 1.92-1.88 (m, 2H), 1.72-1.69 (m, 2H), 1.23 (s, 6H), 1.17 (s, 6H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:16][CH2:17][CH3:18])=[C:12]([CH:15]=1)[CH:13]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCOCC>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:16][CH2:17][CH3:18])=[C:12]([CH:15]=1)[CH:13]=[CH2:1]
Reactant: CCOc1ccc(Br)cc1C=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=Cc1cc(Br)ccc1OCC
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
Methyltriphenylphosphonium bromide (1.09 g, 3.05 mmol) was added to a solution of potassium t-butoxide (0.5 g, 2.29 mmol) in THF (8 mL). The resulting reaction mixture turned bright yellow and was stirred for 40 min after which, it was cooled to −78° C. 5-bromo-2-ethoxybenzaldehyde was dissolved in THF (2 mL) and added to the reaction which was stirred for 2 h. The reaction was warmed to rt, diluted with ether and filtered through celite. The filtrate was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography eluting with 15% EtOAc/hexanes yielded 320 mg of the desired product: 1H NMR (500 MHZ, CDCl3) δ 7.58 (d, J=2.5 Hz, 1H), 7.31 (dd, J=6.4, 2.4 Hz, 1H), 6.96-7.04 (m, 1H), 6.74 (d, J=8.7 Hz, 1H), 5.77 (d, 1H), 5.32 (d, 1H), 4.03-4.07 (m, 2H), 1.45 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH:8](OCC)OCC)[N:5]=[CH:4][C:3]=1[C:15]#[N:16]>Cl>[C:15]([C:3]1[CH:4]=[N:5][N:6]2[CH:7]=[CH:8][NH:1][C:2]=12)#[N:16]
Reactant: CCOC(Cn1ncc(C#N)c1N)OCC
Agent: Cl
Product: N#Cc1cnn2cc[nH]c12
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
A solution of 5-amino-4-cyano-1-(2,2-diethoxyethyl)-pyrazole (23 g) in 1N hydrochloric acid (205 ml) was heated at 60-70° C. The mixture was stirred for 0.5 hour at the same condition. The reaction mixture was cooled under ice-water and the resultant solid was collected by filtration, washed with ice-water and dried over phosphorus pentoxide in vacuo to the crude product. The product was crystallized from ethanol (400 ml) to give 7-cyano-1H-imidazo[1,2-b]pyrazole (12.4 g).
Reaction SMILES: [Br:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[CH3:13].[Cl:14][C:15]1[CH:16]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1.CC(C)([O-])C.[Na+]>C1COCC1>[Br:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[CH:16]=3)(=[O:23])=[O:22])=[C:4]2[C:3]=1[CH3:13]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: Cc1cc(N)c2c(C)c(Br)sc2n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(Br)sc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.8 %

Procedure:
To a solution of 2-bromo-3,6-dimethylthieno[2,3-b]pyridin-4-amine (Description 62) (1.351 g, 5.25 mmol) in THF (10 mL) was added 3-chlorobenzenesulfonyl chloride (1.11 mL, 7.88 mmol), sodium tert-butoxide (1.262 g, 13.13 mmol) and the mixture stirred at RT for 16 h. The mixture was then evaporated to dryness and the resulting material taken-up in water (10 mL) and extracted with ethyl acetate (20 mL×3). The organics were then combined, dried (phase separation cartridge) and concentrated. Purification on silica, eluting with a gradient of 0-20% ethyl acetate in cyclohexane, followed by MDAP (acidic conditions), afforded the title compound (380 mg). LCMS (A) m/z: 431/433 [M+1]+, Rt 1.22 min (acidic).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1>C(O)CCC>[ClH:1].[CH3:19][C:15]1[CH:14]=[C:13]([NH:12][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[S:8]([NH2:11])(=[O:10])=[O:9])[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cccc(N)c1
Reactant: NS(=O)(=O)c1cnccc1Cl
Solvent: CCCCO
Product: Cc1cccc(Nc2ccncc2S(N)(=O)=O)c1
Product: Cl
Temperature: 25 °C
Yield: 98 %

Procedure:
A 2-L, three-necked flask equipped with mechanical stirrer, thermometer and condenser was charged with 4-chloro-3-pyridinesulfonamide I (300.0 g, 1.56 mol), m-toluidine (200.3 g, 1.87 mol) and 1200 mL n-butanol. The reaction mixture was heated for 2-4 hours and then cooled to room temperature. The solid was filtered and washed with n-butanol. After drying, 4-[(3-methylphenyl)amino]-3-pyridinesulfonamide hydrochloride (457.1 g, 98%) was obtained as pale-yellow solid having a purity of 99.96% by HPLC.
Reaction SMILES: [S:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C([Li])CCC.[CH2:15]([Sn:19]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])Cl)[CH2:16][CH2:17][CH3:18].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:25]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:21][CH2:22][CH2:23][CH3:24])[C:2]1[S:1][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1cc2ccsc2cn1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc2ccncc2s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To a cold (−78° C.) solution of thieno[2,3-c]pyridine (524 mg, 3.88 mmol) in anhydrous THF (50 mL) was added n-butyllithium (2.66 mL, 4.26 mmol) dropwise. The mixture was stirred for 60 minutes at −78° C. A solution of tributylchlorostannane (1.254 mL, 4.65 mmol) in anhydrous THF (10 mL) was added, and the reaction mixture was stirred for 30 minutes at −78° C. The solution was allowed to warm to room temperature over a period of 2 to 3 hours. Saturated aqueous sodium bicarbonate was added. The aqueous phase was extracted with diethyl ether (3×200 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. The crude product was purified by silica gel column chromatography, eluting with a gradient of 10-50% EtOAc and hexane over a period of 60 minutes. The desired fractions were collected to give the title compound as a clear oil (1.1 g, 67%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.86 (t, J=7.32 Hz, 9H), 1.08-1.38 (m, 12H), 1.45-1.71 (m, 6H), 7.59 (s, 1H), 7.76-7.93 (m, 1H), 8.41 (s, 1H), 9.23 (s, 1H).
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:34]([O:38][C:39]([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=2[F:54])=[N:44][C:43]=1[C:55]([OH:57])=O)=[O:40])([CH3:37])([CH3:36])[CH3:35].[NH2:58][C:59]1[CH:60]=[N:61][N:62]([CH2:78][C:79]2[CH:84]=[CH:83][C:82]([O:85][CH3:86])=[CH:81][CH:80]=2)[C:63]=1[N:64]1[CH2:69][CH2:68][N:67]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:66][C@@H:65]1[CH3:77].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:34]([O:38][C:39]([NH:41][C:42]1[S:46][C:45]([C:47]2[C:48]([F:54])=[CH:49][CH:50]=[CH:51][C:52]=2[F:53])=[N:44][C:43]=1[C:55]([NH:58][C:59]1[CH:60]=[N:61][N:62]([CH2:78][C:79]2[CH:84]=[CH:83][C:82]([O:85][CH3:86])=[CH:81][CH:80]=2)[C:63]=1[N:64]1[CH2:69][CH2:68][N:67]([C:70]([O:72][C:73]([CH3:75])([CH3:76])[CH3:74])=[O:71])[CH2:66][C@@H:65]1[CH3:77])=[O:57])=[O:40])([CH3:36])([CH3:37])[CH3:35]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: COc1ccc(Cn2ncc(N)c2N2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Cn2ncc(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)c2N2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 45.1 %

Procedure:
A solution of PyBOP (328 mg, 0.63 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (176 mg, 0.50 mmol) in DCM (5 mL) was stirred at room temperature for 30 min. A solution of Intermediate 33 (S)-tert-butyl 4-(4-amino-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-3-methylpiperazine-1-carboxylate (181 mg, 0.45 mmol) and DIPEA (0.13 mL, 0.72 mmol) in DCM (5 mL) was added and the mixture stirred at room temperature for 65 hr. The mixture was diluted with DCM (40 mL) and washed with water (15 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave (S)-tert-butyl 4-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-3-methylpiperazine-1-carboxylate as a yellow solid (150 mg). This solid was re-dissolved in DCM (10 mL) and TFA (2 mL) was added before being heated at 65° C. for 2.5 hr. The mixture was concentrated under reduced pressure before being re-dissolved in 7 N ammonia in MeOH (20 mL) and heated in a sealed pressure vessel behind a blast shield at 55° C. for 16 hr. The mixture was concentrated under reduced pressure, re-dissolved in MeOH and passed through an SCX column, washing with DCM and MeOH and eluting with 3-10% 7 N ammonia in MeOH/DCM to give 174 as an off-white solid (60 mg, 32% over two steps). 1H NMR (400 MHz, d4-MeOD) δ 8.03 (s, 1H), 7.51-7.41 (m, 1H), 7.16 (t, J=8.9 Hz, 2H), 3.20-3.14 (m, 1H), 3.08-2.98 (m, 5H), 2.64 (dd, J=12.7, 9.4 Hz, 1H), 0.93 (d, J=6.2 Hz, 3H). LCMS (ES+) m/z 420 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:19]2[C:5](=[CH:6][C:7]3[NH:11][C:10]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=4)=[N:9][C:8]=3[CH:18]=2)[NH:4][C:3]1=[O:20].N1C=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29]>O>[OH2:20].[OH2:20].[CH3:1][C:2]1([CH3:21])[C:19]2[C:5](=[CH:6][C:7]3[NH:11][C:10]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=4)=[N:9][C:8]=3[CH:18]=2)[NH:4][C:3]1=[S:29]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC1(C)C(=O)Nc2cc3[nH]c(-c4ccncc4)nc3cc21
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)C(=S)Nc2cc3[nH]c(-c4ccncc4)nc3cc21

Procedure:
A solution of 2.0 g (7.2 mmol) 7,7-dimethyl-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one in 35 ml. pyridine is heated for about 5 hours to 100° C. with 4 g. phosphorus pentasulphide (P4S10). Subsequently, the reaction mixture is decomposed with water, rendered alkaline and the desired product is extracted and purified on silica gel (elution agent: methylene chloride/ammonia-saturated methanol 20:1 v/v). Yield: 1.7 g. (72% of theory); m.p. 205°-220° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:18][CH:17]([N:19]2[CH:23]=[C:22]([C:24]3[C:25]([O:39][C:40]4[CH:45]=[CH:44][C:43](F)=C(Cl)C=4)=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]([C:34]([O:36][CH3:37])=[O:35])[C@@H:29]([CH3:38])[CH2:28][CH2:27]4)[CH:21]=[N:20]2)[CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:18][CH:17]([N:19]2[CH:23]=[C:22]([C:24]3[C:25]([O:39][CH:40]4[CH2:43][CH2:44][CH2:45]4)=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]([C:34]([O:36][CH3:37])=[O:35])[C@@H:29]([CH3:38])[CH2:28][CH2:27]4)[CH:21]=[N:20]2)[CH2:16]1
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CN(C(=O)OC(C)(C)C)C4)c3)c(Oc3ccc(F)c(Cl)c3)c2CC[C@@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1c2ccc(-c3cnn(C4CNC4)c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.5 %

Procedure:
Trifluoroacetic acid (1.0 mL, 6.49 mmol) was added to a solution of (S)-methyl 6-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-(3-chloro-4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.132 g, 0.265 mmol) in dichloromethane (1.0 mL) and the reaction mixture stirred at rt for 2 h. The reaction mixture was concentrated and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to afford methyl (S)-6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.115 g, 88%) as an off-white solid. MS (ESI, pos. ion) m/z 396 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH:28]=[O:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[BH4-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][OH:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC=O)cn(C)c34)no2)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCO)cn(C)c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]acetaldehyde (D88) (500 mg) in THF (15 mL) and ethanol (15 mL) was added sodium borohydride (185 mg) in portion during 5 mins. The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was washed with water, 2 M hydrochloric acid and saturated brine, dried over sodium sulphate and evaporated to give the crude product as an off-white gum, which was purified by ISCO (10% ethyl acetate in hexanes) to afford 2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethanol (D126) (450 mg). MS (ES): C22H22ClN3O3 requires 411; found 412.1 (M+H+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.P(Br)(Br)([Br:23])=O.O>CC1C=CC=CC=1>[CH2:1]([O:8][CH2:9][C@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][Br:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: CC(C)[C@H](CO)COCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[C@H](CBr)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.2 %

Procedure:
Dissolve (R)-2-(benzyloxy-methyl)-3-methyl butanol (15.6 g, 75 mmol) and N,N-dimethyl formamide (0.6 g, 8.25 mmol) in methyl benzene (351 ml), add phosphorus oxybromide (25.8 g, 90 mmol) in droplets slowly, and control the temperature below 60° C. in that process; then, let them to react at 80° C. for 2 hours; cool down to room temperature, add water (702 ml), stir for 20 minutes, and separate the layers; extract the aqueous layer with petroleum ether for three cycles, combine the organic layers and wash twice with saturated sodium bicarbonate and saturated sodium chloride respectively; dry the organic layer with anhydrous sodium sulfate, filter, and condense the filtrate so as to obtain 17.5 g of oily matter; treat the oil matter by reduced pressure distillation to obtain 16.1 g of colorless transparent liquid; the yield is 79.2%, and the chiral purity is ≧99.9%.