Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][S:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][C@@H:14]23)[CH:19]=1>>[C:3]1([C@H:2]([NH:9][C:11]2[CH:12]=[C:13]3[C:17]4=[C:18]([CH2:20][S:21][CH2:22][CH2:23][N:16]4[C@H:15]4[CH2:24][CH2:25][NH:26][CH2:27][C@@H:14]34)[CH:19]=2)[CH3:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCSC3
Reactant: C[C@@H](N)c1ccccc1
Product: C[C@@H](Nc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2)c1ccccc1

Procedure:
Using (R)-(−)-α-methylbenzylamine and following the procedures described in EXAMPLE 168, tert-butyl (7bR,11aS)-6-bromo-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 7, Part A was converted into the title compound of EXAMPLE 170. 1H NMR(CDCl3) δ: 7.40-7.20 (m, 5H), 6.17 (d, 1H, J=2.2 Hz), 6.10 (d, 1H, J=2.2 Hz), 4.35 (q, 1H, J=6.6 Hz), 3.56 (ABq, 2H, JAB=15.7 Hz), 3.50-3.42 (m, 1H), 3.29-3.21 (m, 2H), 3.15-2.80 (m, 5H), 2.58-2.48 (m, 1H), 2.00-1.85 (m, 2H), 1.45 (d, 3H, J=6.6 Hz). LRMS (ES)+: 366.4 (M+H)+.
Reaction SMILES: C([Li])CCC.CCCCCC.CO[C:14]([C:16]1[CH:17]=[N:18][N:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=12)=[O:15].Cl.[C:26](#[N:28])[CH3:27]>C1(C)C=CC=CC=1>[O:15]=[C:14]([C:16]1[CH:17]=[N:18][N:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=12)[CH2:27][C:26]#[N:28]
Reactant: CC#N
Reactant: COC(=O)c1cnn2ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: N#CCC(=O)c1cnn2ccccc12
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of dry acetonitrile in toluene (0.66 mL, 13 mmol, 5 eq) cooled down to −78° C. under nitrogen, a solution of n-butyllithium in n-hexane (5.2 mL, 13 mmol, 5 eq) was added dropwise. The mixture was left stirring at −78° C. for 20 minutes and then a solution of pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (0.46 g, 2.6 mmol, 1 eq, prepared according to the reported procedure (Anderson et al. Journal of Heterocyclic Chemistry 1981, 18, 1149-1152) in toluene was added and the reaction allowed to reach room temperature. Upon reaction completion, after about 20 minutes, the mixture was cooled down to 0° C. and HCl 2N was added to pH 2. The organic phase was recovered, dried over Na2SO4 and concentrated under reduced pressure, affording the title product which was used without further purification in the following step.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[N:9]1([C:16]2[N:21]=[C:20]([NH2:22])[N:19]3[N:23]=[C:24]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[C:18]3[N:17]=2)[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CCN(CC)CC>CC#N>[O:27]1[CH:28]=[CH:29][CH:30]=[C:26]1[C:24]1[CH:25]=[C:18]2[N:17]=[C:16]([N:9]3[CH2:15][CH2:14][CH2:13][N:12]([CH2:2][C:3]4[CH:7]=[C:6]([CH3:8])[O:5][N:4]=4)[CH2:11][CH2:10]3)[N:21]=[C:20]([NH2:22])[N:19]2[N:23]=1
Reactant: Cc1cc(CCl)no1
Reactant: Nc1nc(N2CCCNCC2)nc2cc(-c3ccco3)nn12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(CN2CCCN(c3nc(N)n4nc(-c5ccco5)cc4n3)CC2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Chloromethyl-5-methyl-isoxazole (1.5 eq.) was directly added to a solution of 2-[1,4]diazepan-1-yl-7-furan-2-yl-pyrazolo[1,5-a][1,3,5]triazin-4-ylamine (0.14 mmol) and Et3N (0.3 mmol) in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temp for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 7.90 (br s, 2 H), 7.80 (d, J=1.0 Hz, 1H), 7.05 (d, J=3.6 Hz, 1H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 6.30 (s, 1H), 3.65 (m, 2H), 3.20-2.75 (m, 10 H), 2.35 (s, 3H) ppm. MS: m/z: 395 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[C:6]([CH:19]=1)[C:7]([C:9](=[CH:15][N:16]([CH3:18])C)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].[CH3:21][N:22]1[CH2:27][CH2:26][CH:25](CN)[CH2:24][CH2:23]1>C1COCC1>[Br:1][C:2]1[CH:19]=[C:6]2[C:5](=[N:4][CH:3]=1)[N:16]([CH2:18][CH:25]1[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]1)[CH:15]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7]2=[O:8]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Br)cnc1F
Reactant: CN1CCC(CN)CC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(CC2CCN(C)CC2)c2ncc(Br)cc2c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
To a solution of ethyl 2-(5-bromo-2-fluoronicotinoyl)-3-(dimethylamino)acrylate (Intermediate 3, 784 mg, 2.27 mmol) dissolved in THF (12 mL) was added (1-methylpiperidin-4-yl)methanamine (291 mg, 2.27 mmol). The reaction mixture was stirred at 60° C. for 2 h, then cooled to room temperature, concentrated under reduced pressure, and the resulting residue was resuspended in DMF (12 mL). Potassium carbonate was added (942 mg, 6.81 mmol, 3 equiv.) to the suspension, and the reaction was stirred at 70° C. for 18 h. The reaction mixture was cooled to room temperature then quenched with 1 N HCl. The reaction mixture was partitioned between water (15 mL) and dichloromethane (15 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2×15 mL), and the combined organic layers were concentrated to provide ethyl 6-bromo-1-((1-methylpiperidin-4-yl)methyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (945 mg, >99%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[C:5](/[NH2:19])=[CH:6]/[C:7](=[O:18])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[F:17])[CH3:2]>O1CCOCC1>[CH2:1]([O:3][C:4]([C:5]1[NH:19][CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[F:17])[CH2:8][C:7](=[O:18])[CH:6]=1)=[O:20])[CH3:2]
Reactant: CCOC(=O)/C(N)=C/C(=O)/C=C/c1ccc(Cl)cc1F
Solvent: C1COCCO1
Product: CCOC(=O)C1=CC(=O)CC(c2ccc(Cl)cc2F)N1

Procedure:
Using the procedure of Example 5, (2Z,5E)-2-amino-6-(4-chloro-2-fluoro-phenyl)-4-oxo-hexa-2,5-dienoic acid ethyl ester (7; 88 g, 0.296 mol) in 1,4-dioxane (880 mL) in a 2 liter Parr reactor gave, following purification by silica gel chromatography eluting with 40% EtOAc/hexanes, 6-(4-chloro-2-fluorophenyl)-4-oxo-1,4,5,6-tetrahydropyridine-2-carboxylic acid ethyl ester (11; 43 g, 49%, 96% pure by HPLC) as a tan solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([O:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](O)=[O:39])=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:38]([C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28]([F:27])=[CH:29][CH:30]=2)=[O:39])[CH2:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([O:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(CC(N)C(O)c2ccc(F)cc2)cc(OC(F)(F)C(F)F)c1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: Cc1cc(CC(NC(=O)c2ccc(F)c3ccccc23)C(O)c2ccc(F)cc2)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(5-methyl-3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-propanol (197 mg, 0.53 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (100 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (151 mg, 0.79 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (234 mg, 81%).
Reaction SMILES: [CH3:1][N:2]1CCCC1=O.[CH3:8][O:9][C:10]1[CH:25]=[CH:24][C:13]2[S:14][C:15]3[CH:22]=[CH:21][CH:20]=[C:19](Cl)[C:16]=3[CH2:17][CH2:18][C:12]=2[CH:11]=1.[Cu](C#N)C#N.O.N>S([O-])([O-])(=O)=O.[Cu+2].C1C=CC=CC=1.O>[CH3:8][O:9][C:10]1[CH:25]=[CH:24][C:13]2[S:14][C:15]3[CH:22]=[CH:21][CH:20]=[C:19]([C:1]#[N:2])[C:16]=3[CH2:17][CH2:18][C:12]=2[CH:11]=1
Reactant: COc1ccc2c(c1)CCc1c(Cl)cccc1S2
Reactant: CN1CCCC1=O
Agent: N#C[Cu]C#N
Agent: [Cu+2]
Agent: N
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc2c(c1)CCc1c(C#N)cccc1S2
Reaction time: 15 h
Yield: 50 %

Procedure:
To 100 ml of N-methylpyrrolidone was added 10.8g of 2-methoxy-9-chloro-10,11-dihydrodibenzo[b,f]thiepin, 10.7g of copper cyanide and 0.4g of anhydrous copper sulfate and the resulting mixture was stirred at 190°-195° C for 15 hours. After cooling, to the mixture was added 28% ammonia water, 200 ml of water and 200 ml of benzene and the resulting mixture was shaked and filtered with celite. The filtrate was extracted with benzene. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and freed of the solvent to obtain 9.0g of light brown cyrstals. This product was chromatographed over silica gel and eluted with benzene, there was obtained 5.4g (50%) of 2-methoxy-9-cyano-10,11-dihydrodibenzo[ b,f]thiepin as colorless prismatic crystals having a melting point of 129°-130° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][S:16]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[C:20]=2[OH:27])(=[O:18])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:35]([CH3:37])[CH3:36]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:15][S:16]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[C:20]=2[O:27][CH:35]([CH3:37])[CH3:36])(=[O:18])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)Br
Reactant: CCOC(=O)C1(NS(=O)(=O)c2cc(Cl)cc(Cl)c2O)Cc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NS(=O)(=O)c2cc(Cl)cc(Cl)c2OC(C)C)Cc2ccccc2C1
Yield: 99.1 %

Procedure:
To a suspension of 2-(3,5-dichloro-2-hydroxy-benzenesulfonylamino)-indan-2-carboxylic acid ethyl ester (30) (226 mg, 0.53 mmol), anhydrous Cs2CO3 (300 mg, 0.92 mmol), and KI (15 mg, 0.09 mmol) in DMF (15 mL) is added 2-bromopropane (432, 4.60 mmol). The resulting reaction suspension is filled with argon and run in a microwave reaction: 110° C., 2.5 h. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (30 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 10%-60% EtOAc in heptane) to give a pure product (31) as a white semi-solid (248 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:29]([S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:25]=2[F:36])[C:20]([Cl:37])=[CH:19][N:18]=1>>[Cl:37][C:20]1[C:21]([NH:23][C:24]2[C:29]([S:30]([CH:33]([CH3:34])[CH3:35])(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:25]=2[F:36])=[N:22][C:17]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:18][CH:19]=1
Reactant: CC(C)S(=O)(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Product: CC(C)S(=O)(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl

Procedure:
Title compound was prepared from 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 1221d. Title compound isolated as an off-white solid (69 mg, 48%). LCMS 534.14 (M+H), HPLC purity 95%, 1H-NMR (CDCl3, 400 MHz) δ 10.96 (s, 1H), 9.11 (s, 1H), 8.06 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.66-7.62 (m, 1H), 7.54-7.49 (m, 2H), 7.26 (d, 2H), 6.69 (d, J=8.2 Hz, 1H), 4.08-4.00 (m, 1H), 2.35 (dd, J=6.9 Hz, 2H), 2.05 (dd, J=7.3 Hz, 2H), 1.30 (s, 6H), 1.26 (d, J=6.8 Hz, 6H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2scnc2c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4scnc4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using benzo[d]thiazole-5-carboxylic acid (Apollo) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.64-7.73 (m, 1H), 8.35 (s, 1H), 8.36 (s, 1H), 8.48 (dt, J=8.1, 2.0, 1.7 Hz, 1H), 8.83 (dd, J=4.7, 1.7 Hz, 1H), 9.17 (t, J=1.2 Hz, 1H), 9.29 (dd, J=2.2, 0.8 Hz, 1H), 9.66 (s, 1H) ppm; MS (DCI/NH3) m/z 281 (M+H)+.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[C:13]([OH:15])=[O:14])=[O:8])(=O)C.[OH-].[Na+].Cl>CO>[SH:4][CH2:5][CH:6]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[C:13]([OH:15])=[O:14])=[O:8]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cc(C)cc(C(=O)O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(NC(=O)C(CS)Cc2ccccc2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
3-[(2-Acetylthiomethyl-3-phenylpropionyl)amino]-5-methylbenzoic acid (compound of Example 1) (1.7 g) is dissolved in methanol (9 ml), and thereto is added 1 N aqueous sodium hydroxide solution (9 ml) under nitrogen, and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is adjusted to pH 1 by adding dropwise conc. hydrochloric acid, and the residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected and concentrated into dryness under reduced pressure to give the title compound (0.9 g).
Reaction SMILES: [CH3:1][OH:2].Cl[C:4]1[N:5]=[C:6]2[S:16][C:15]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][N:7]2[C:8](=[O:13])[C:9]=1[N+:10]([O-:12])=[O:11].N1C=CC=CC=1>O>[CH2:18]([S:17][C:15]1[S:16][C:6]2=[N:5][C:4]([O:2][CH3:1])=[C:9]([N+:10]([O-:12])=[O:11])[C:8](=[O:13])[N:7]2[N:14]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CO
Reactant: CCCCCCSc1nn2c(=O)c([N+](=O)[O-])c(Cl)nc2s1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCSc1nn2c(=O)c([N+](=O)[O-])c(OC)nc2s1
Yield: 63 %

Procedure:
To 50 ml of methanol, 3.0 g of 7-chloro-2-hexylthio-6-nitro-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one and 1.0 g of pyridine were added, and the mixture was stirred under refluxing for 30 minutes. Water was added to the reaction mixture and the organic layer was extracted with ethyl acetate The ethyl acetate solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography using an ethyl acetate/hexane mixture as an eluent. Thus 1.9 g of brown transparent viscous liquid of 2-hexylthio-7-methoxy-6-nitro-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 63%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[N:8]1[CH:18]([CH3:20])[S:19][C:7]1=[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]2=[O:26].C(=O)(O)[O-].[K+].Br[CH2:33][C:34]1[O:35][C:36](=[O:40])[O:37][C:38]=1[CH3:39]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:33][C:34]3[O:35][C:36](=[O:40])[O:37][C:38]=3[CH3:39])[CH2:14][CH2:13]1)[N:8]1[CH:18]([CH3:20])[S:19][C:7]1=[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]2=[O:26]
Reactant: Cc1oc(=O)oc1CBr
Reactant: CCOC(=O)c1c2n(c3cc(N4CCNCC4)c(F)cc3c1=O)C(C)S2
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2n(c3cc(N4CCN(Cc5oc(=O)oc5C)CC4)c(F)cc3c1=O)C(C)S2
Reaction time: 3 h
Yield: 66 %

Procedure:
Ethyl 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate (3.88 g) and 1.23 g of potassium bicarbonate were suspended in 20 ml of N,N-dimethylformamide, 2.38 g of 4-bromomethyl-5-methyl-1,3-dioxolen-2-one was dropped thereinto with ice cooling, and the mixture was stirred for 3 hours. After the reaction, the solvent was evaporated in vacuo therefrom at 50° C. and the residue was extracted with chloroform containing a few amount of methanol. The extract was washed with water, dried, the solvent was evaporated therefrom and the residue was purified by a column chromatography (chloroform-methanol/silica gel) to give 3.32 g of desired product. M.p. 241°-243° C. (decompn.)
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[CH2:13][CH:12]3[CH:10]([CH2:11]3)[CH:9]2[C:14]([NH:16][C@H:17]([C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)[CH3:18])=[O:15])=[CH:5][CH:4]=1.O[Li].O>O1CCOCC1.O>[F:31][C:2]([F:1])([F:32])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH:12]3[CH:10]([CH2:11]3)[CH:9]2[C:14]([NH:16][C@H:17]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=2)[CH3:18])=[O:15])=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)C2C3CC3CN2Cc2ccc(C(F)(F)F)cc2)cc1
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](NC(=O)C1C2CC2CN1Cc1ccc(C(F)(F)F)cc1)c1ccc(C(=O)O)cc1
Temperature: 150 °C
Yield: 36.5 %

Procedure:
To a mixture of methyl 4-((1S)-1-(3-(4-(trifluoromethyl)benzyl)-3-azabicyclo[3.1.0]hexane-2-carboxamido)ethyl)benzoate (D153) (84 mg, 0.19 mmol) in a 1:1 mixture dioxane/water, LiOH H2O (12 mg, 0.28 mmol) was added and the reaction heated at 150° C. under microwave irradiation for 5 min. Dioxane was evaporated off and the aqueous phase was acidified with CH3CO2H. The precipitate (58 mg) was filtered off and submitted for chiral HPLC separation (Preparative chromatographic conditions: Column: DAICEL AD-H; Mobile phase: n-heptane/EtOH/TFA 60%/40%/0.2% v/v; DAD: 235 nm). Solvent evaporation of second eluted peak from chiral column, afforded the title compound (E37) (30 mg)
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[S:10][C:11]([C:14]([OH:16])=O)=[CH:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:18][C:19]1([F:25])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[F:18][C:19]1([F:25])[CH2:24][CH2:23][N:22]([C:14]([C:11]2[S:10][C:9]([C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:13][CH:12]=2)=[O:16])[CH2:21][CH2:20]1
Reactant: FC1(F)CCNCC1
Reactant: O=C(O)c1cnc(C#Cc2ccccc2)s1
Agent: Cl
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: O=C(c1cnc(C#Cc2ccccc2)s1)N1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 92.8 %

Procedure:
In a small culture tube, 2-phenylethynyl-thiazole-5-carboxylic acid (28 mg, 0.12 mmol) [Intermediate 1], 4,4-difluoropiperidine hydrochloride (23 mg, 0.14 mmol) (Oakwood Products, Inc. (West Columbia, S.C., USA) and dichloromethane (1.5 mL) were added. To the mixture, PyBOP® (76 mg, 0.14 mmol) was added, followed by N,N-diisopropylethylamine (63 μL, 0.36 mmol), and the reaction was stirred at room temperature for about 17 hours. Afterwards, the crude reaction mixture was directly purified by Preparative TLC, eluting with 40% EtOAc in hexanes to give 37 mg (92%) of the titled compound, (4,4-difluoro-piperidin-1-yl)-(2-phenylethynyl-thiazol-5-yl)-methanone, as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.66-7.59 (m, 2H), 7.49-7.37 (m, 3H), 3.92-3.82 (m, 4H), 2.18-2.01 (m, 4H). LC/MS (Method 3), RT=1.43 min. Calculated [M+H]+=333; Observed [M+H]+=333.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[CH2:35]([N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[NH:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)[CH2:36][CH:37]=[CH2:38]>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:52]2[CH2:53][CH2:54][CH:49]([NH:48][C:40]3[N:39]([CH2:35][CH2:36][CH:37]=[CH2:38])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:50][CH2:51]2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)=[O:6]
Reactant: C=CCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Agent: I
Product: C=CCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 99.1 using 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and (1-(but-3-en-1-yl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid salt to give the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16](O)=[O:17])[CH2:12][CH2:11]1)[CH2:8][CH3:9].C(OCC)(=O)C.N>C1COCC1>[CH2:7]([C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][OH:17])[CH2:12][CH2:11]1)[CH2:8][CH3:9]
Reactant: CCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](CO)CC1
Reaction time: 2 h

Procedure:
Lithium aluminum hydride (33.4 g) was suspended in THF (500 ml). trans-4-Propylcyclohexylcarboxylic acid (s30) (50.0 g) was added dropwise to the suspension in the temperature range of −20° C. to −10° C., and the mixture was stirred at the same temperature range for 2 hours. After the completion of reaction had been confirmed by means of GC analysis, ethyl acetate and a saturated aqueous solution of ammonia were added successively to the reaction mixture under ice-cooling, and the deposits were removed by filtration through Celite. The filtrate was extracted with ethyl acetate. The combined organic layers were washed successively with water and brine, and then dried over anhydrous magnesium sulfate. The products were purified by recrystallization from heptane to give trans-4-propyl cyclohexylmethanol (s31) (45.0 g). The yield based on the compound (s30) was 98.1%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][NH:6][CH:7]1[CH2:12][CH2:11][S:10][CH2:9][CH2:8]1.[CH3:17][N:18]1[CH:22]=[C:21]([C:23](O)=[O:24])[N:20]=[CH:19]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(N(CC)CC)C.CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][N:6]([CH:7]1[CH2:8][CH2:9][S:10][CH2:11][CH2:12]1)[C:23]([C:21]1[N:20]=[CH:19][N:18]([CH3:17])[CH:22]=1)=[O:24]
Reactant: Cn1cnc(C(=O)O)c1
Reactant: Fc1ccc(CNC2CCSCC2)cc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cnc(C(=O)N(Cc2ccc(F)c(Br)c2)C2CCSCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
A mixture of N-(3-bromo-4-fluorobenzyl)tetrahydro-2H-thiopyran-4-amine (1.72 g), 1-methyl-1H-imidazole-4-carboxylic acid (0.71 g), EDC.HCl (1.63 g), HOBt (0.87 g), dimethylformamide (30 mL) and triethylamine (1.8 mL) was stirred overnight at room temperature. The solvent was distilled off under reduced pressure and after extraction with ethyl acetate, the extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was concentrated. The residue was purified by column chromatography (NH silica gel cartridge; ethyl acetate) to give the titled compound (1.55 g).