Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH3:9].CCN(CC)CC.[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([C:26]3([C:29](Cl)=[O:30])[CH2:28][CH2:27]3)=[CH:25][C:20]=2[O:19][CH2:18]1>ClCCl>[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([C:26]3([C:29]([NH:8][C:6]4[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([Cl:1])[N:7]=4)=[O:30])[CH2:27][CH2:28]3)=[CH:25][C:20]=2[O:19][CH2:18]1
Reactant: Cc1ccc(N)nc1Cl
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
To a solution of 6-chloro-5-methylpyridin-2-amine (71 mg, 0.50 mmol) and Et3N (140 μL, 1.0 mmol) in dichloromethane (2 mL) was added a solution of 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (110 mg, 0.50 mmol) in dichloromethane (2 mL). The resulting reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was then washed with 1N aqueous HCl (1×5 mL) and saturated aqueous NaHCO3 (1×5 mL). The organic layer was dried over sodium sulfate and evaporated to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-chloro-5-methylpyridin-2-yl)cyclopropanecarboxamide (120 mg, 71% over 2 steps). 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.94-7.91 (m, 1H), 7.79-7.77 (m, 1H), 7.09 (m, 1H), 7.00-6.88 (m, 2H), 6.06 (s, 2H), 2.25 (s, 3H), 1.47-1.44 (m, 2H), 1.13-1.10 (m, 2H) ESI-MS m/z calc. 330.1. found 331.5 (M+1)+. Retention time 1.99 minutes.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[C:13]=1[C:20]([O:22][CH3:23])=[O:21].[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>ClCCl>[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][C:28]([CH:25]2[CH2:27][CH2:26]2)=[O:29])[C:13]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1cccc(CN)c1C(=O)OC
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(CNC(=O)C2CC2)c1C(=O)OC
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 103 %

Procedure:
Triethylamine (1.87 g, 18 mmol) was added dropwise to a stirred suspension of methyl-3-(aminomethyl)-2-(methoxycarbonyl)benzoate hydrochloride (2.0 g, 7 mmol) in dichloromethane (40 ml). The mixture was cooled in an ice bath to 4° C. Cyclopropylcarbonyl chloride (0.99 g, 9 mmol) was added slowly at 4–8° C. After addition, the mixture was stirred in ice bath for 30 min and then warmed to room temperature for 2 hours. The mixture was washed with water (2×30 ml), brine (30 ml) and dried. Solvent was removed in vacuo and the product was purified by flash chromatography (dichloromethane/ethyl acetate 9 to 1) to give 2.1 g (93%) of the product as a white solid: 1H NMR (CDCl3) (7.87 (d, J=7.8 Hz, 1H), 7.63 (d, J=7.7 Hz, 1H), 7.46 (t, J=7.77 Hz, 1H), 6.31 (m, 1H), 4.43 (d, J=6.0 Hz, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 1.36–1.29 (m, 1H), 0.99–0.93 (m, 2H), 0.76–0.69 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:25])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH:19]([CH3:24])[CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:32][CH2:33][C:34](Cl)=[O:35]>ClCCl>[C:1]1([C:7]2[NH:8][C:9](=[O:25])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:34](=[O:35])[CH2:33][Cl:32])[CH:19]([CH3:24])[CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)CCl
Reactant: CC1Cc2cc(S(=O)(=O)n3cc(-c4ccccc4)[nH]c3=O)ccc2N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1Cc2cc(S(=O)(=O)n3cc(-c4ccccc4)[nH]c3=O)ccc2N1C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
4-Phenyl-1-(2-methylindoline-5-sulfonyl)-2-imidazolone (300 mg, 0.85 mmol) prepared in Preparation 3 was dissolved in 10 ml of dichloromethane. Pyridine (75 μl, 0.93 mmol) and chloroacetylchloride (74 μl, 0.93 mmol) were added thereto one after another, and then the reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. After stirring, the reaction mixture was diluted with 50 ml of dichloromethane, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=10/1, v/v) to afford 342 mg of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][O:29][C:28]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:27]1=2.O1CCOCC1>CO.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].Cl[Pd]Cl>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([C:33]3[CH:34]=[CH:35][C:27]4[N:26]([CH3:25])[CH2:31][CH2:30][O:29][C:28]=4[CH:32]=3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: CN1CCOc2cc(B(O)O)ccc21
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc4c(c3)OCCN4C)n2n1
Temperature: 110 °C
Yield: 58.9 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 60 mg, 0.174 mmol), 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ylboronic acid (62 mg, 0.226 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 13.6 mmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.58 mL of 1,4-dioxane and 0.29 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (50-50% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (46.9 mg, 59%). 1H NMR (DMSO-d6) δ: 10.99 (s, 1H), 7.95 (d, J=8.6 Hz, 2H), 7.89 (s, 1H), 7.57-7.62 (m, 2H), 7.54 (d, J=8.3 Hz, 2H), 6.81 (d, J=8.8 Hz, 1H), 6.25 (s, 1H), 4.20-4.24 (m, 2H), 3.32-3.35 (m, 2H), 2.91 (s, 3H), 2.35 (s, 3H), 1.39 (s, 6H); ESI-MS: m/z 458.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([C:25]([C:27]2[CH:36]=[C:35]([CH3:37])[C:30]3[NH:31][C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)=[O:26])[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][C:22]1[N:23]=[C:18]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH:19]=[C:20]([C:25]([C:27]2[CH:36]=[C:35]([CH3:37])[C:30]3[NH:31][C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)=[O:26])[N:21]=1
Reactant: Cc1nc(Cl)cc(C(=O)c2cc(C)c3[nH]c(=O)oc3c2)n1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)c2cc(C)c3[nH]c(=O)oc3c2)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1

Procedure:
65 mg (0.30 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 91 mg (0.30 mmol) 6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and 0.11 mL (0.60 mmol) DIPEA were stirred overnight in 3 mL DMF at RT. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent evaporated down. The residue was neutralised with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: Clc1cccc(CBr)c1
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
To a mixture of 4-(4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.7 g, 2.364 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-3-chlorobenzene (0.583 g, 2.84 mmol) and potassium carbonate (0.980 g, 7.09 mmol). The resulting reaction mixture was stirred at 90° C. for 4 h. It was cooled to room temperature and poured into water (100 mL). The aqueous mixture was extracted with DCM (100 mL×2). The combined organic phases were washed with Brine (100 mL) and concentrated. The crude material was purified on silica column (20˜70% EtOAc in Hexane) to give the product as solid (0.65 g, 65%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.57 (s, 3H) 2.90-3.16 (m, 4H) 3.69-3.95 (m, 4H) 5.25 (s, 2H) 6.60 (d, J=2.02 Hz, 1H) 6.88 (d, J=7.07 Hz, 1H) 7.07 (s, 1H) 7.16 (d, J=2.02 Hz, 1H) 7.20-7.37 (m, 2H); MS (ES+) m/e 420.0 [M+H]+.
Reaction SMILES: Br[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:5]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:4][CH:3]=1.[CH3:24][O:25][CH2:26][C@H:27]([CH3:45])[O:28][C:29]1[CH:30]=[C:31]([OH:44])[CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[OH:44][C:31]1[CH:32]=[C:33]([C:2]2[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:5]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[CH:4][CH:3]=2)[CH:34]=[C:29]([O:28][C@@H:27]([CH3:45])[CH2:26][O:25][CH3:24])[CH:30]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)n1c(Br)ccc1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C(=O)OCc3ccccc3)n2C(=O)OC(C)(C)C)c1
Temperature: 55 °C
Reaction time: 3 h
Yield: 75.1 %

Procedure:
2-Benzyl 1-t-butyl 5-bromo-1H-pyrrole-1,2-dicarboxylate (8.75 g, 23.0 mmol) synthesized in Example (780 and 3-[(1S)-2-methoxy-1-methylethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (7.11 g, 23.1 mmol) synthesized in Example (78d) were dissolved in a mixed solvent of 1,4-dioxane (92 mL) and water (23 mL), and [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (570 mg, 0.698 mmol) and potassium carbonate (7.95 g, 57.5 mmol) were added, followed by stirring at 55° C. for 3 hours under nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (200 mL) was added, and extraction was carried out with ethyl acetate (200 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=15%-35%) to afford the desired compound (8.32 g, yield 75%) as a brown oil.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:2]1=[O:3].[OH-].[K+].[CH3:14]I>CS(C)=O.C(Cl)(Cl)Cl>[CH3:14][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:2]1=[O:3]
Reactant: CI
Reactant: O=C1CCc2ccccc2N1
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: CN1C(=O)CCc2ccccc21
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A solution of 3,4-dihydrocarbostyril (20 g) in DMSO (100 ml) is added to a suspension of KOH (31.4 g) in DMSO (50 ml). Methyl iodide (39.7 g) in DMSO (25 ml) is added to the reaction mixture and the mixture is stirred under an atmosphere of N2 at RT. After 2 hours a second portion of methyl iodide (20 g) is added and after 3 hours a third portion of methyl iodide (20 g) is added and stirring continued for 4.5 hours. The reaction mixture is diluted with chloroform (200 ml), quenched with sat'd aq. NH4Cl, separated, extracted with chloroform, washed with H2O and dried. The organic extracts are filtered and concentrated in vacuo affording the desired product as an oil.
Reaction SMILES: Cl.[CH:2]1([CH2:5][N:6]([C@H:15]2[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]2)[C:7]([C@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[O:8])[CH2:4][CH2:3]1.[Cl:22][C:23]1[C:24]([CH3:33])=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.C(N(CC)CC)C>C(#N)C>[Cl:22][C:23]1[C:24]([CH3:33])=[C:25]([S:29]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([C:7]([N:6]([CH2:5][CH:2]3[CH2:3][CH2:4]3)[C@H:15]3[CH2:16][CH2:17][C@H:18]([OH:21])[CH2:19][CH2:20]3)=[O:8])[CH2:10]2)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: O=C([C@H]1CCCNC1)N(CC1CC1)[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(Cl)cccc1S(=O)(=O)N1CCC[C@H](C(=O)N(CC2CC2)[C@H]2CC[C@H](O)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (3S)—N-(cyclopropylmethyl)-N-(trans-4-hydroxycyclohexyl)piperidine-3-carboxamide hydrochloride (10 mg, 0.03 mmol), 3-chloro-2-methylbenzenesulfonyl chloride (7.1 mg, 0.03 mmol), triethylamine (11 μL, 0.08 mmol) in acetonitrile (0.2 mL) was stirred at r.t. for 1 hour, then purified with flash column. 5.1 mg (yield: 34%) final product was obtained. LCMS: m/z 468.9 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([CH:9]=[O:10])[C:7]([OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][CH2:14]OC>>[Cl:13][CH2:14][C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[CH:9]=[O:10]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: COCCl
Product: O=Cc1cc([N+](=O)[O-])c(CCl)cc1O

Procedure:
5-nitrosalicylaldehyde was obtained upon reaction of salicylaldehyde with nitric acid according to the method described by G. Miller in Chem. Ber., 20, 1928 (1888). This 5-nitrosalicylaldehyde was made to react with chloromethyl-methyl ether according to D. Taylor and B. Davis, J. Org. Chem., 28, 1713 (1963) to form 4-chloromethyl-5-nitro-salicylaldehyde, which was converted into the 4-hydroxymethyl derivative by refluxing the chloromethyl derivative for 3 hours in water. The 4-hydroxymethyl-5-nitro-salicylaldehyde had a melting point of 135°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.O>[CH2:18]([O:10][C:9]1[C:2]([F:1])=[CH:3][C:4]([CH:5]=[O:6])=[CH:7][C:8]=1[F:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cc(F)c(O)c(F)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(F)c(OCc2ccccc2)c(F)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of 3,5-difluoro-4-hydroxybenzaldehyde (6) (8.26 g, 52.2 mmol), and potassium carbonate (14.4 g, 104.4 mmol) in dimethylformamide (100 mL) was added benzyl chloride (7.2 mL, 62.7 mmol) and stirred overnight at 50° C. The reaction was diluted with water and extracted with ethyl acetate (3×75 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-100% EtOAc in hexanes) to afford 4-(benzyloxy)-3,5-difluorobenzaldehyde (7).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[C:22]([O:24]C)=[O:23])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:27]1[S:28][C:29]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:30]=2[N:31]=1.[OH-].[Na+]>C(O)CCC>[Cl:36][C:34]1[CH:33]=[CH:32][C:30]2[N:31]=[C:27]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]5[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]5[C:22]([OH:24])=[O:23])=[O:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)[S:28][C:29]=2[CH:35]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: COC(=O)[C@@H]1CCCC[C@@H]1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: O=C(O)[C@@H]1CCCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(Cl)cc4s3)cc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
To a solution of cis-methyl 2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclohexanecarboxylate (200 mg, 0.59 mmol) in n-butanol (8 mL) was added 2,6-dichloro-1,3-benzothiazole (241 mg, 1.19 mmol), and the resulting reaction mixture was heated at 90° C. overnight. The mixture was evaporated to dryness and the residue was combined with MeOH. Then 1 N NaOH (6.0 mL, 6.0 mmol) was added to the suspension, and the reaction mixture was stirred at 50° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in water. Concentrated aqueous HCl was added to adjust the acidity to pH 1, and the precipitate was collected by filtration, washed with water and MeOH, and dried in a vacuum oven to give trans-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclohexanecarboxylic acid (45 mg, 15%). LC-MS m/z 491.1 (, ret. time 3.90 min; 1H NMR (400 MHz, DMSO-d6) δ 1.13 (m, 1H), 1.28-1.51 (m, 3H), 1.78 (m, 1H), 1.93 (m, 1H), 2.09 (m, 1H), 2.68 (m, 1H), 3.63 (m, 1H), 7.35 (m, 1H), 7.60 (m, 1H), 7.80 (m, 4H), 7.90 (d, 1H), 7.96 (m, 1H), 8.05 (d, 2H), 10.75 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]2([NH:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15](/[CH:18]=[CH:19]/[C:20](O)=[O:21])[CH:16]=[CH:17][C:9]=3[O:8]2)[CH2:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:37][O:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][O:40]1>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]2([NH:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15](/[CH:18]=[CH:19]/[C:20]([NH:37][O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][O:40]4)=[O:21])[CH:16]=[CH:17][C:9]=3[O:8]2)[CH2:3]1
Reactant: NOC1CCCCO1
Reactant: CN1CCCC2(C1)NC(=O)c1cc(/C=C/C(=O)O)ccc1O2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1CCCC2(C1)NC(=O)c1cc(/C=C/C(=O)NOC3CCCCO3)ccc1O2
Yield: 88.6 %

Procedure:
A suspension of (±)-(E)-3-{1′-methyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid (208 mg, 0.61 mmol) in DCM (7 ml) was treated with TEA (0.14 ml, 1.0 mmol) and then with EDC (196 mg, 1.03 mmol), HOBt (140 mg, 1.03 mmol) and NH2OTHP (97 mg, 0.82 mmol) following the procedure described in Example 30, Step B, giving (±)-(E)-3-{1′-methyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (217 mg) as a light yellow solid.
Reaction SMILES: C([Li])CCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Cl:12][C:13]1[C:18]([CH2:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][CH:16]=[CH:15][N:14]=1.ICCCCCCI>O.C(COC)OC>[Cl:12][C:13]1[C:18]([C:19]2([S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: CCCCCC
Reactant: O=S(=O)(Cc1cccnc1Cl)c1ccc(Cl)cc1
Agent: ICCCCCCI
Agent: [Li]CCCC
Solvent: O
Solvent: COCCOC
Product: O=S(=O)(c1ccc(Cl)cc1)C1(c2cccnc2Cl)CCCCCC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 32 %

Procedure:
At −78° C., butyl lithium (a 1.57M hexane solution; 0.62 ml, 0.966 mmol) was added dropwise to a dimethoxyethane (5 ml) solution of the 2-chloro-3-(4-chlorophenylsulfonylmethyl)pyridine (146 mg, 0.483 mmol) obtained in Example 98. At −78° C., the resulting mixture was stirred for 20 minutes, followed by the addition of 1,6-diiodohexane (0.095 ml, 0.580 mmol). The temperature of the reaction mixture was gradually raised to room temperature, at which stirring was performed for 4 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the 15% ethyl acetate/hexane eluate was concentrated under reduced pressure. The residue thus obtained was purified by high performance liquid chromatography (using a mixed solvent of water/acetonitrile/formic acid) to yield the title compound (60 mg, 32%) as a white solid. The resulting solid was washed with hexane-ether and then collected by filtration, whereby the title compound was obtained as a white powder.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4](O)=[O:5].S(Cl)([Cl:17])=O>CN(C=O)C.C1C=CC=CC=1>[CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4]([Cl:17])=[O:5]
Reactant: Cc1ccc(C(C)(C)CC(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: Cc1ccc(C(C)(C)CC(=O)Cl)cc1
Temperature: 25 °C
Yield: 107.4 %

Procedure:
A solution containing 3-methyl-3-(4-methylphenyl)butyric acid (8.5 g, 44.2 mmol) and anhydrous DMF (5 drops) in anhydrous benzene (110 mL) was refluxed under nitrogen as thionyl chloride (8.1 mL, 110 mmol)was added dropwise under nitrogen. The solution was refluxed an additional 15 h after complete addition of thionyl chloride. The dark brownish reaction mixture was allowed to cool to room temperature and concentrated under vacuum. TLC analysis of the crude material showed complete disappearance of the starting material. Presence of DMF was evident from the proton NMR. The crude material, 3-methyl-3-(4-methylphenyl)butyric acid chloride (305) (about 10 g), thus obtained was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[C:44](=[O:46])=[O:45]>C1COCC1>[Br:15][C:13]1[CH:14]=[C:9]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]([F:16])=[C:11]([CH:12]=1)[C:44]([OH:46])=[O:45]
Reactant: Fc1ccc(Br)cc1N(Cc1ccccc1)Cc1ccccc1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)cc(N(Cc2ccccc2)Cc2ccccc2)c1F
Reaction time: 0.75 h
Yield: 40 %

Procedure:
Add dropwise a solution of dibenzyl-(5-bromo-2-fluorophenyl)-amine (4.00 g, 10.8 mmol) in THF (12 mL) to a solution of lithium diisopropylamide, freshly prepared by adding n-butyllithium (1.6 M in hexanes, 7.09 mL, 11.3 mmol) to diisopropylamine (1.74 mL, 12.4 mmol) in THF (25 mL) at −78° C. Stir the resulting yellow solution at −78 C for 45 min. Pour into a dry ice slurry containing about 100 g in dry THF (40 mL). Stir the solution until it reaches room temperature. Concentrate the solution and dissolve the residue in 10% aqueous potassium hydroxide solution (40 mL) and extract with diethyl ether (70 mL). Acidify the aqueous layer to about pH=3 with concentrated HCl. Extract the aqueous layer with diethyl ether (2×200 mL). Combine the organic layers and wash with water (150 mL), dry (magnesium sulfate) and concentrate to give the title compound as a solid (1.81 g, 40%).