Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=2[O:21][CH3:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:23]I>>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=2[O:21][CH3:22])[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CI
Reactant: COc1cccc(Nc2nc(Cl)nc3ccccc23)c1OC
Product: COc1cccc(N(C)c2nc(Cl)nc3ccccc23)c1OC

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl)-amine and methyl iodide by a procedure similar to Example 7 (71% yield). 1H NMR (CDCl3): 7.74 (d, J=8.4 Hz, 1H), 7.53-7.59 (m, 1H), 7.12 (t, J=8.4 Hz, 1H), 6.94-7.01 (m, 3H), 6.87 (dd, J=8.1 and 1.5 Hz, 1H), 3.89 (s, 3H), 3.56 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18]OC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.CN([Si](C)(C)C)C(=O)C(F)(F)F.[I:43][Si](C)(C)C>C(Cl)Cl>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18][I:43])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C[Si](C)(C)I
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: ClCCl
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CI)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7β-[(Z)-2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (240 mg) was suspended in methylene chloride (4 ml), followed by an addition of N-methyl-N-(trimethylsilyl)trifluoroacetamide (330 μl). The resulting mixture was stirred at room temperature for 30 minutes. After ice-cooling, iodotrimethylsilane (200 μl) was added and the resulting mixture was stirred for 15 minutes. The reaction mixture was then concentrated under reduced pressure to obtain the silylated derivative of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-iodomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)=[CH:11][CH:12]=2)[C:7]([CH3:27])([CH3:26])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH:28](=O)[CH2:29][CH:30]([CH3:32])[CH3:31].C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.C(#N)C>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:14]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)=[CH:11][CH:12]=2)[C:7]([CH3:27])([CH3:26])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)CC=O
Reactant: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C)(C)CCN3C(C)C)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)c1ccc(N(CCC(C)C)c2ccc3c(c2)C(C)(C)CCN3C(C)C)cc1
Yield: 45.8 %

Procedure:
Ethyl 4-[(1-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)amino]benzoate (Compound 8, 37 mg, 0.10 mmol) was dissolved in a 10% acetic acid in acetonitrile solution (1.5 mL). The solution was treated with isovaleraldehyde (0.08 mL, 0.74 mmol) and then sodium cyanoborohydride (13 mg, 0.20 mmol) and the reaction mixture was stirred at room temperature for 5 hours. 1M aqueous NaOH was added until pH=6 and the solution was extracted with ether (2×), washed with brine, and dried (Na2SO4). The filtered solution was concentrated under reduced pressure and the residue purified by silica gel chromatography (5% ethyl acetate in hexanes) to give the title compound (20 mg, 45%) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[CH2:14][CH2:15][CH3:16].O1CCCC1.C([Li])CCC.C([O:30][B:31](OC(C)C)[O:32]C(C)C)(C)C>CCCCCC>[CH2:9]([C:8]([C:5]1[CH:6]=[CH:7][C:2]([B:31]([OH:32])[OH:30])=[C:3]([CH2:14][CH2:15][CH3:16])[CH:4]=1)([OH:13])[CH2:11][CH3:12])[CH3:10]
Reactant: CCCc1cc(C(O)(CC)CC)ccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCc1cc(C(O)(CC)CC)ccc1B(O)O
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
In a three-necked flask, introduce under nitrogen 5 g of 3-(4-bromo-3-propylphenyl)pentan-3-ol (17.5 mmol) and 50 cm3 of tetrahydrofuran. Cool the mixture to −70° C. and add dropwise 17.5 cm3 (43.7 mmol) of a 2.5M solution of n-butyllithium in hexane, over 30 minutes. Leave the reaction mixture for approximately 2 h with stirring at −70° C. and then add dropwise 10 cm3 of triisopropylborate (43.7 mmol), over 20 minutes. Leave the reaction mixture with stirring for 4 h, allowing the temperature to increase to −40° C. Hydrolyse the mixture with saturated NH4Cl solution and extract twice with ethyl acetate. Wash the combined organic phases with saturated sodium chloride solution and evaporate the solvents under vacuum. This gives 5.4 g of a colorless oil, which is chromatographed on silica gel (heptane/ethyl acetate=3/1). This gives 1.92 g of 4-(1-ethyl-1-hydroxypropyl)-2-propylphenylboronic acid in the form of a highly viscous oil. (Yield=44%)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:22])[NH:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.[NH:23]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCCl.S(Cl)(Cl)=O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:22])[NH:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(NC(=O)NC(Cc2ccccc2)C(=O)O)c1
Reactant: CC(C)(C)OC(=O)CNc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: Cc1cccc(NC(=O)NC(Cc2ccccc2)C(=O)N(CC(=O)OC(C)(C)C)c2ccccc2)c1
Yield: 41.2 %

Procedure:
Working as in Example 15, but starting with (RS)-2-[3-(3-methylphenyl)ureido]-3-phenylpropanoic acid (4.8 g) and tert-butyl anilinoacetate (3.3 g) in anhydrous 1,2-dichloroethane (300 cc) and thionyl chloride (1.16 cc), and recrystallizing successively in diethyl ether and then in isopropanol, tert-butyl (RS)-N-{2-[3-(3-methylphenyl)ureido]-3-phenylpropionyl}-N-phenylglycinate (3.2 g), m.p. 198° C., is obtained.
Reaction SMILES: [C:1]1([C:7]2([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][N:25]=[C:26]=[O:27]>C1C=CC=CC=1>[CH3:24][NH:25][C:26]([N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[CH2:12][CH2:11]1)=[O:27]
Reactant: FC(F)(F)c1cccc(OC2(c3ccccc3)CCNCC2)c1
Reactant: CN=C=O
Solvent: c1ccccc1
Product: CNC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78 %

Procedure:
To a solution of 2.22 g of 4-phenyl-4-(3-trifluoromethylphenoxy)piperidine in 50 ml of benzene was added 0.40 g of methyl isocyanate. The reaction mixture was stirred at room temperature for 2.5 hours. Evaporation of the volatile afforded an oil which was purified by means of high pressure liquid chromatography (silica gel; elution with 50% ethyl acetate/dichloromethane) to yield 2.04 g (77%) of 1-(N-methylamino)carbonyl-4-phenyl-4-(3-trifluoromethylphenoxy)piperidine, m.p. 124°-127° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1([CH2:14][OH:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17]N(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1([CH2:14][O:15][CH3:17])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(CO)CCOCC1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COCC1(NC(=O)OC(C)(C)C)CCOCC1
Reaction time: 5 h

Procedure:
To a solution of tert-butyl[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]carbamate (0.89 g, 3.8 mmol) in methylene chloride (19.2 mL) was added sequentially powdered MS 4 Å, N,N,N′,N′-tetramethyl-1,8-naphthalenediamine (2.0 g, 9.6 mmol), and trimethyloxonium tetrafluoroborate (1.1 g, 7.7 mmol) at RT. The mixture was stirred for 5 h., filtered through a pad of Celite, and washed with EtOAc. The filtrate was washed with aqueous CuSO4, water, brine, dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography on silica gel with EtOAc in hexanes (0-30%) to afford the desired product. LCMS: (M+Na)=268.0
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:41]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:41])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccc4)ccc3n2C)cc1
Yield: 34 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-octyl chloroformate. Yield: 34% of theory, C37H46N6O5 (654.8) Rf value: 0.15 (silica gel; dichloromethane/ethanol=19:1) ##EQU102##
Reaction SMILES: [CH2:1]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([O:25][CH2:26][C:27]#[N:28])[CH:19]=[CH:18]2)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:29][C:30](OC(C)=O)=[O:31].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>>[C:30]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[C:7]1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([O:25][CH2:26][C:27]#[N:28])[CH:19]=[CH:18]2)(=[O:31])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCc1c(-c2ccc3cc(OCC#N)ccc3c2)[nH]c2ccccc12
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: CCCCCc1c(-c2ccc3cc(OCC#N)ccc3c2)n(C(C)=O)c2ccccc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 49.1 %

Procedure:
To a stirred solution of {[6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile (0.300 g, 0.814 mmol) in Ac2O (3 mL, 3.18 mmol) at rt was added a catalytic amount of CSA (0.019 g, 0.0814 mmol). The reaction was heated to 70° C. for 18 h, and by TLC the reaction was about one half complete. Another 19 mg of CSA added and kept at 70° C. for an additional 24 h. After this time, the reaction mixture was quenched with 1 N HCl (˜2 mL). The resulting solution was extracted with EtOAc (100 mL). The organic layer was washed with 1 N HCl (10 mL), sat. aq. NaHCO3 (10 mL), and brine (10 mL) and then dried (MgSO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (10 to 20% EtOAc:petroleum ether gradient) to afford the product (0.164 g, 49%) as a solid; 1H NMR (DMSO-6) δ 0.73 (t, J=7.2 Hz, 3H), 1.03-1.23 (m, 4H), 1.47-1.61 (m, 2H), 1.92 (s, 3H), 3.24-3.42 (m, 2H), 5.34 (s, 2H), 7.27-7.43 (m, 3H), 7.52-7.70 (m, 3H), 7.94-8.08 (m, 3H), 8.33 (d, J=8.8 Hz, 1H); mass spectrum [(+) ESI], m/z 411 (M+H)+, 433 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.[BH4-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: O=Cc1ccccc1Cl
Reactant: COc1ccc(CCN)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(CCNCc2ccccc2Cl)cc1OC

Procedure:
2-(3,4-Dimethoxyphenyl)-ethylamine (80.3 g, 0.443 mol) and o-chlorobenzaldehyde (62 g, 0.443 mol) are boiled (1 hour) in toluene (500 ml) using a water separator. The reaction mixture is evaporated, the oily residue is taken up in methanol (500 ml) and combined, under vigorous stirring and intensive cooling, with a solution of sodium borohydride (16.9 g, 0.443 mol) in water (50 ml). After it has all been added, the resulting mixture is stirred (1 hour) at ambient temperature, concentrated in vacuo and the residue is distilled in vacuo. Yield: 108.8 g. Bp16.9 Pa : 188°-190° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][C:8]2[C:6]3[N:7]=[C:2]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(Sc2ncnc3c(N4CCOCC4)nc(Cl)nc23)cc1
Reactant: C1CNCCN1
Product: COc1ccc(Sc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(4-methoxyphenyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 196°-199° C.) and piperazine.
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:10][OH:11].CCN(CC)CC>C(Cl)Cl>[CH:1]1([CH:7]=[N:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CCCCC1
Reactant: NO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ON=CC1CCCCC1
Reaction time: 8 h

Procedure:
To a solution of cyclohexanecarbaldehyde (4 ml, 33.02 mmol) in CH2Cl2 (100 ml) at room temperature was added hydroxylamine hydrochloride (2.76 g, 39.62 mmol) followed by Et3N (5.52 ml, 39.62 mmol) and the reaction was stirred overnight. The resulting mixture was partitioned between CH2Cl2 and H2O and the layers were separated. The organic layer was dried over Na2SO4, concentrated in vacuo and used directly for the next step. 1H NMR (CDCl3) δ 1.0-2.0 (m, 10H), 3.0 (m, 1H), 6.6 (d, 0.5H), 7.4 (d, 0.5H), 8.2 (bs, 1H).
Reaction SMILES: Br[CH:2]1[CH2:17][CH2:16][C:5]2=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:7][C:8]([S:9][CH3:10])=[C:4]2[C:3]1=O.[C:19]([NH2:27])(=[S:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)C>O>[CH3:10][S:9][C:8]1[S:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[C:4]=1[C:3]1[N:27]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:26][C:2]=1[CH2:17][CH2:16]2
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(Br)C2=O
Reactant: NC(=S)c1ccccc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1sc(SC)c2c1CCc1sc(-c3ccccc3)nc1-2
Yield: 33.9 %

Procedure:
A mixture of ethyl 5-bromo-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (6.99 g), thiobenzamide (5.49 g) and ethanol (150 ml) was refluxed under heating for 3 hours, after which it was poured over water (500 ml) and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with chloroform-hexane (1:1, v/v) to yield ethyl 4,5-dihydro-8-methylthio-2-phenylthieno[3,4-e]benzothiazole-6-carboxylate (2.63 g, 33.9%), which was then recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 153-154° C.
Reaction SMILES: [NH2:1][C:2]1[C:13]([CH3:14])=[CH:12][C:11]([Br:15])=[CH:10][C:3]=1[C:4]([NH:6][CH:7]([CH3:9])[CH3:8])=[O:5].[C:16](Cl)(Cl)=[O:17].C1(C)C=CC=CC=1>O1CCOCC1>[Br:15][C:11]1[CH:10]=[C:3]2[C:2](=[C:13]([CH3:14])[CH:12]=1)[NH:1][C:16](=[O:17])[N:6]([CH:7]([CH3:9])[CH3:8])[C:4]2=[O:5]
Reactant: Cc1cc(Br)cc(C(=O)NC(C)C)c1N
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Br)cc2c(=O)n(C(C)C)c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the anthranilamide of Step F, (1.11 g, 4.1 mmol) in dioxane (20 mL) was added a 2.0 M solution of phosgene in toluene (2.3 mL, 4.6 mmol). The reaction was stirred at room temperature for 1 hour then heated to reflux for 4 hours and cooled to room temperature. The white solids were filtered and dried to afford the title compound (0.89 g).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[CH2:11]([S:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Sc1nc2ccccc2[nH]1
Solvent: CCO
Product: c1ccc(CSc2nc3ccccc3[nH]2)cc1
Yield: 77.6 %

Procedure:
15 g of 2-mercaptobenzimidazole and 16.5 g of benzylbromide were dissolved in 50 ml of ethanol and the mixture was refluxed with a water bath for 5 hours. After cooling, the formed crystals were collected and recrystallized from ethanol to obtain 18 g of compound (7).
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[C:4]([C:13]#[N:14])[C:5](=[O:12])[N:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1.P(Cl)(Cl)([Cl:18])=O.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[C:3]([Cl:18])=[C:4]([C:13]#[N:14])[C:5](=[O:12])[N:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)Cn1cc(Br)c(O)c(C#N)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)Cn1cc(Br)c(Cl)c(C#N)c1=O
Temperature: 120 °C

Procedure:
A mixture of 5-bromo-4-hydroxy-1-isobutyl-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step B (6.6 g) and phosphorus oxychloride (0.126 mL) was heated at 120° C. for 24 hr, and cooled to room temperature. The reaction mixture was poured into water, and the pH was adjusted to 10 with potassium carbonate. The reaction mixture was extracted with ethyl acetate. The extract was washed with washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the title compound (4.60 g).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=3)[CH:16]=1)[CH2:11]2.[CH2:29]([CH:31]1[CH2:39][C:38]2[C:33](=[CH:34][C:35]([F:40])=[CH:36][CH:37]=2)[NH:32]1)[CH3:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:29]([CH:31]1[CH2:39][C:38]2[C:33](=[CH:34][C:35]([F:40])=[CH:36][CH:37]=2)[N:32]1[C:26]([C:22]1[CH:21]=[C:20]([NH:19][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[CH2:11][C:3]2([C:4]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[NH:10][C:2]2=[O:1])[CH2:18]3)[CH:25]=[CH:24][N:23]=1)=[O:27])[CH3:30]
Reactant: CCC1Cc2ccc(F)cc2N1
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC1Cc2ccc(F)cc2N1C(=O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ccn1

Procedure:
186 mg (0.50 mmol) 4-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)picolinic acid, 220 mg (0.60 mmol) 2-ethyl-6-fluoro-2,3-dihydro-1H-indole, 0.26 mL (1.5 mmol) DIPEA and 0.18 g (0.55 mmol) TBTU in 5.0 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and the organic solvent was evaporated down. The aqueous residue was made alkaline with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[CH:1]1([O:7][CH2:8][CH2:9][CH:10]=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCOC1CCCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCCOC1CCCCC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 75.5 %

Procedure:
The obtained 3-cyclohexyloxypropan-1-ol (11.5 g, 72.9 mmol) was dissolved in dichloromethane (240 ml), and then molecular sieve 4 Å (58 g) and pyridinium chlorochromate (23.8 g, 0.11 mol) were added thereto in the ice bath followed by stirring under a nitrogen atmosphere for 1 hour and 40 minutes. The reaction solution was diluted with ether, and then the solution was filtered through Celite. The Celite was washed with diethyl ether, and this filtrate was added to the previous filtrate. The total filtrate was evaporated in vacuo, and the residue was purified roughly by chromatography on a silica gel column (elution solvent; n-hexane:ethyl acetate=20:1-10:1) to give a crude 3-cyclohexyloxypropionaldehyde (8.6 g).
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[CH3:7][C:8]1[CH:18]=[CH:17][C:11](OCC(O)=O)=[CH:10][CH:9]=1>CN(C)C=O.ClCCl>[CH3:7][C:8]1[CH:18]=[CH:17][C:11]([O:3][CH2:2][C:1]([Cl:6])=[O:5])=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(OCC(=O)O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(OCC(=O)Cl)cc1
Reaction time: 1.5 h

Procedure:
Oxalyl chloride (8.83 ml) and N,N-dimethylformamide (3 drops) were added at room temperature to a solution of 4-methylphenoxyacetic acid (6.73 g) in dichloromethane (70 ml), and the reaction mixture was stirred for 1.5 hours. The reaction solution was concentrated under reduced pressure, then the resulting acidic gas was removed as the toluene azeotrope, and the product was dried under reduced pressure to give 4-methylphenoxyacetyl chloride. A 1.61N solution of n-butyl lithium in hexane (25.2 ml) was added dropwise at −78° C. to a solution of (S)-4-benzyl-2-oxazolidinone (7.08 g) in tetrahydrofuran (70-ml), and after the completion of the dropwise addition, the reaction mixture was stirred at −78° C. for 30 minutes. To this resulting solution was added at −78° C. a solution of 4-methylphenoxyacetyl chloride obtained above in tetrahydrofuran (70 ml) followed by stirring at 0° C. for 1 hour. The resulting reaction mixture was partitioned between ethyl acetate and water, and the ethyl acetate layer was washed successively with a 1N aqueous solution of hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column (eluant; hexane/ethyl acetate =3/1˜1/1) to afford the target compound (9.00 g) as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:30])[C:17]([OH:29])([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=3)[C:18]([F:21])([F:20])[F:19])=[C:12]([Cl:31])[CH:11]=2)=[N:6][CH:5]=1.[Li+].[OH-].CO>C1COCC1>[Cl:31][C:12]1[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:32])=[O:2])=[CH:5][N:6]=2)[CH:15]=[CH:14][C:13]=1[CH:16]([CH3:30])[C:17]([OH:29])([C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=1)[C:18]([F:20])([F:19])[F:21]
Reactant: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccnc(C)c3)C(F)(F)F)c(Cl)c2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(O)(C(C)c2ccc(-c3ccc(C(=O)O)cn3)cc2Cl)C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To 6-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(2-methyl-pyridin-4-yl)-propyl]-phenyl}-nicotinic acid methyl ester (22 mg) aqueous 1N LiOH (5 ml), MeOH (2.5 ml) and THF (5 ml) were added. The resulting solution was stirred for 2 h at room temperature. Volatile solvents were removed in vacuo. The residual aqueous solution was diluted with water (10 ml) and washed with DCM (10 ml), then acidified to pH 6 with 1 N aqueous HCl and extracted with EtOAc. The combined EtOAc layers were dried over Na2SO4 and concentrated to give the title compound (21 mg) as a yellow oil. MS (m/e)=451.0 [M+H+].