Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:42])[CH2:10][CH:11]1[O:15][C:14]([CH:16]([NH:21][C:22](=[O:41])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[O:32])=[CH:26][CH:25]=2)[CH2:17][CH:18]([CH3:20])[CH3:19])=[N:13][CH2:12]1)C1C=CC=CC=1>C1COCC1.CO.[OH-].[Pd+2].[OH-]>[CH3:19][CH:18]([CH3:20])[CH2:17][CH:16]([C:14]1[O:15][CH:11]([CH2:10][C:9]([OH:42])=[O:8])[CH2:12][N:13]=1)[NH:21][C:22](=[O:41])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:40])=[O:32])=[CH:26][CH:25]=1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)C2=NCC(CC(=O)OCc3ccccc3)O2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)C2=NCC(CC(=O)O)O2)cc1
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of [2-(3-methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydrooxazol-5-yl]-acetic acid benzyl ester (120 mg) and palladium hydroxide (40 mg) in 10 ml of THF and 10 ml of MeOH was shaken on a Parr Apparatus under 30 p.s.i. H2 for 2 h. The mixture was filtered through Celite and the filtrate concentrated under reduced pressure. The residue was suspended in EtOAc and concentrated under reduced pressure. Trituration with hot EtOAc gave 93 mg of the title compound as a light pink solid. MS [M+1]+ 481.3; 1H nmr (400 MHz, DMSO-d6) δ0.77-0.87 (m, 6H), 1.39-1.59 (m, 3H), 2.10-2.33 (m, 4H, including s at 2.21, 3H), 2.40-5.08 (m, 7H, including q at 3.36, J=14.2 Hz, 2H), 6.90 (t, J=7.4 Hz, 1H), 7.08-7.14 (m, 4H), 7.35 (d, J=6.8 Hz, 2H), 7.79 (d, J=8.1 Hz, 1H), 7.95-8.45 (m, 2H), 9.13-9.23 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][C:8]3[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=3[N:6]=2)[CH2:2]1.[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1Cl>CN(C=O)C.O>[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:1]1[CH2:4][CH:3]([C:5]2[NH:9][C:8]3[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=3[N:6]=2)[CH2:2]1
Reactant: COC(=O)c1cccnc1Cl
Reactant: Clc1ccc2[nH]c(C3CNC3)nc2c1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccnc1N1CC(c2nc3cc(Cl)ccc3[nH]2)C1
Temperature: 100 °C

Procedure:
A mixture of 2-azetidin-3-yl-5-chloro-1H-benzoimidazole (as prepared according to Preparation 5 above) (3.2 g, 15.4 mmol) and 2-chloro-nicotinic acid methyl ester (1.78 g, 10.4 mmol) was dissolved in DMF (10 mL) and heated to 100° C. for 2 h. The mixture was diluted with water (10 mL), and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo to afford the product as yellow solid.
Reaction SMILES: C([CH:5]([NH:9][C:10]1[CH:15]=[C:14]([I:16])[C:13]([Cl:17])=[CH:12][C:11]=1[O:18][CH3:19])[C:6]([OH:8])=[O:7])(C)(C)C.O=S(Cl)Cl.[CH3:24]O>>[Cl:17][C:13]1[C:14]([I:16])=[CH:15][C:10]([NH:9][CH2:5][C:6]([O:8][CH3:24])=[O:7])=[C:11]([O:18][CH3:19])[CH:12]=1
Reactant: CO
Reactant: COc1cc(Cl)c(I)cc1NC(C(=O)O)C(C)(C)C
Solvent: O=S(Cl)Cl
Product: COC(=O)CNc1cc(I)c(Cl)cc1OC

Procedure:
A mixture of tert-butyl 2-(4-chloro-5-iodo-2-methoxyphenylamino)acetic acid (3.0 g, 8.7 mmol), SOCl2 (3 mL) in MeOH (20 mL) was stirred at reflux for 2 h. The mixture was concentrated in vacuo to yield the crude product (3.1 g) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH:8]=[CH:9][CH:10]([C:11]([OH:13])=[O:12])[N:5]2[C:4](=[O:14])[NH:3]1.[CH2:15]=[O:16]>C(O)(C)C>[OH:16][CH2:15][N:3]1[C:2](=[O:1])[N:6]2[CH2:7][CH:8]=[CH:9][CH:10]([C:11]([OH:13])=[O:12])[N:5]2[C:4]1=[O:14]
Reactant: O=C(O)C1C=CCn2c(=O)[nH]c(=O)n21
Reactant: C=O
Solvent: CC(C)O
Product: O=C(O)C1C=CCn2c(=O)n(CO)c(=O)n21
Yield: 44 %

Procedure:
2,3,5,8-Tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylic acid is reacted with formaldehyde in a manner analogous to that described in the preceding paragraph to give in 44% yield 2,3,5,8-tetrahydro-2-hydroxymethyl-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylic acid of melting point 175°-178° C. (from isopropanol). This acid is esterified using diazomethane in ether to give methyl 2-hydroxymethyl-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate of melting point 123°-125° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:5]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[O:20])=[CH:6][NH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16].[O:32]1[CH2:36][CH2:35]OS1(=O)=O>CN(C)C=O>[OH:32][CH2:36][CH2:35][N:7]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:16])[F:17])=[C:4]([CH3:3])[C:5]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[O:20])=[CH:6]1
Reactant: O=S1(=O)OCCO1
Reactant: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c[nH]c1-c1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cn(CCO)c1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.12 g, 3 mmol, 60% dispersion in mineral oil) was dissolved in N,N-dimethylformamide (1.5 mL), and 4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide (0.47 g, 1.1 mmol) was added thereto, and then, the resulting mixture was stirred at room temperature for 30 minutes. Then, 1,3,2-dioxathiolane-2,2-dioxide (0.14 g, 1.2 mmol) was added thereto, and the resulting mixture was stirred at room temperature. After 1 hour, sodium hydride (40 mg, 1.0 mmol, oily, 60%) was added thereto again, and the resulting mixture was stirred for 30 minutes. Then, 1,3,2-dioxathiolane-2,2-dioxide (12 mg, 0.11 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 1 hour. After the mixture was concentrated under reduced pressure, methanol (5 mL) was added to the residue and insoluble substances were removed by filtration, and the filtrate was concentrated again. To the residue, tetrahydrofuran (2 mL) and 6 M hydrochloric acid (2 mL) were added, and the resulting mixture was stirred at 60° C. for 16 hours. The reaction was cooled to room temperature, and then dissolved in ethyl acetate, and washed with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate), whereby the objective compound (0.25 g, 48%) was obtained.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[CH2:7]([O:9][NH2:10])[CH3:8].[C:11]([C:15]1[C:16](=[O:36])[CH2:17][CH:18]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[C:24]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:23]=2[CH3:35])[CH2:19][C:20]=1[OH:21])(=O)[CH2:12][CH3:13]>C(O)C.C(Cl)Cl>[CH2:7]([O:9][N:10]=[C:11]([C:15]1[C:16](=[O:36])[CH2:17][CH:18]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[C:24]([NH:30][S:31]([CH3:34])(=[O:32])=[O:33])[C:23]=2[CH3:35])[CH2:19][C:20]=1[OH:21])[CH2:12][CH3:13])[CH3:8]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(NS(C)(=O)=O)c2C)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)c(NS(C)(=O)=O)c2C)CC1=O
Reaction time: 18 h

Procedure:
Sodium acetate (0.19 g, 2.29 mmol) and ethoxyamine hydrochloride (0.22 g, 2.29 mmol) were added to a solution of 2-propionyl-3-hydroxy-5-(3-methylsulphonamido-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (0.58 g, 1.53 mmol) in ethanol (25 ml) and methylene chloride (25 ml). Stirring was continued at 20° for 18 hrs. The solvent was removed under reduced pressure and the residue partitioned between chloroform and water. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield2-[1-(ethoxyimino)propyl]-hydroxy-5-[3-(methylsulphonamido)-2,4,6-trimethylphenyl]cyclohex-2-en-1-one as a brown oil (0.27 g, 42%). The compound was characterized by proton magnetic resonance spectroscopy. The spectroscopic data are recorded in Table 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.[O:17]=[C:18]1[N:23]([CH2:24][CH2:25][CH2:26][CH:27]=O)[CH2:22][CH2:21][CH2:20][O:19]1.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:14][CH2:15][CH3:16])[CH2:27][CH2:26][CH2:25][CH2:24][N:23]3[CH2:22][CH2:21][CH2:20][O:19][C:18]3=[O:17])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCCNC1CCc2ccc(OC)cc2C1
Reactant: O=CCCCN1CCCOC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCCN(CCCCN1CCCOC1=O)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine (ca.13 mg 50 umole), was added 440 μL solution of 4-(2-oxo-[1,3]oxazinan-3-yl)-butyraldehyde (0.125 M in 1,2 dichloroethane), 30 μL diisopropylethylamine (DIEA) and 300 μL of 0.25 M slurry of sodium triacetoxyborohydride in 1,2 dichloroethane. The reaction was shaken at room temperature for 48 h. After quenching with 2 mL 2% NaOH, the reaction mixture was transferred along with 0.5 mL water and ethyl acetate to workup flasks. The organic phase was washed, dried and concentrated. Purification by chromatography yielded 3-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazinan-2-one 19, MS: 375 ([M+H]+).
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[S:6])[CH2:2][CH3:3].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][NH:17][C@H:18]([C:30]2[NH:31][CH:32]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:34]=2)[CH2:19][C:20]([O:22]CC2C=CC=CC=2)=O)=[CH:8]1>C1COCC1>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][N:17]2[C@H:18]([C:30]3[NH:31][CH:32]=[C:33]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:34]=3)[CH2:19][C:20](=[O:22])[N:4]([CH2:1][CH2:2][CH3:3])[C:5]2=[S:6])=[CH:8]1
Reactant: CCCN=C=S
Reactant: O=C(C[C@H](NCc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1)OCc1ccccc1
Solvent: C1CCOC1
Product: CCCN1C(=O)C[C@@H](c2nc(-c3ccccc3)c[nH]2)N(Cc2c[nH]c3ccccc23)C1=S
Temperature: 40 °C
Reaction time: 15 h
Yield: 82 %

Procedure:
Propylisothiocyanate (25 μl, 1.2 eq.) is added to a solution of benzyl (3S)-3-[(1H-indol-3-ylmethyl)amino]-3(4phenyl-1H-imidazol-2-yl)propanoate (90 mg, 1 eq.) in 2 ml of THF. The mixture is stirred for 15 hours at a temperature of approximately 40° C. then diluted with 2 ml of THF. An aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 125 mg, 2 eq.) is added. The mixture is stirred for 5 hours at a temperature of approximately 20° C. then filtered on frit. The filtrate is concentrated under reduced pressure at 40° C. 1 ml of THF and 1 ml of triethylamine are added to the residue. The mixture is stirred for 15 hours at a temperature of approximately 40° C. then concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: ethyl acetate/heptane 8:2)-yields the expected compound (72 mg, yield 82%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([O:17][CH3:18])[CH:11]=[CH:10]2.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[O:25]>O1CCCC1>[CH3:18][O:17][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([CH:24]([C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([C:20]([F:19])([F:29])[F:30])[CH:22]=3)[OH:25])[CH:8]=2)[N:13]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: COc1ccc2cc(Br)ccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(C(O)c3cccc(C(F)(F)F)c3)ccc2n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 66.1 %

Procedure:
Butyllithium (12.5 ml) was added dropwise at -78° C. to a solution of 6-bromo-2-methoxyquinoline (4 g) in tetrahydrofuran (160 ml). After complete addition the mixture was stirred at -78° C. for 15 minutes. A solution of 3-(trifluoromethyl)-benzaldehyde (3.51 g) in tetrahydrofuran (40 ml) was added dropwise and the mixture was stirred at -78° C. for 30 minutes, then quenched with water (50 ml) and extracted with ethylacetate. The organic layer was separated, washed with brine, dried over MgSO4, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 97/3). The pure fractions were collected and the solvent was evaporated, yielding 3.7 g (66%) of (±)-2-methoxy-α-[3-(trifluoromethyl)phenyl]-6- quinoline methanol (intermediate 28).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C:26]([OH:30])([CH3:29])[CH2:27][OH:28])[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:42][C:32]1[CH:37]=[CH:36][C:35]([S:38]([O:28][CH2:27][C:26]([OH:30])([CH3:29])[CH2:25][O:24][C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][N:13]([C:8]2[CH:7]=[C:6]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:31])[CH:11]=[CH:10][C:9]=2[CH3:12])[C:22]3=[O:23])(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OCC(C)(O)CO)cc2c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(C)(O)COc2ccc3ncn(-c4cc(C(=O)NC5CC5)ccc4C)c(=O)c3c2)cc1
Temperature: 60 °C
Yield: 77 %

Procedure:
To a solution of N-cyclopropyl-3-[6-(2,3-dihydroxy-2-methylpropoxy)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzamide (0.2 g) in pyridine (10 ml) was added p-toluenesulfonylchloride (0.18 g) followed by 4-dimethylaminopyridine (cat.) and the mixture heated at 60° C. for 18 hours. The reaction mixture was concentrated under reduced pressure and redissolved in ethyl acetate. The organics were washed with 1N citric acid, brine, dried (magnesium sulfate) and concentrated to give the crude 3-[(3-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]-2-hydroxy-2-methylpropyl 4-methylbenzenesulfonate (0.21 g) which was used without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:17][C:11]1[CH:10]=[CH:9][C:8]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:7][C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCOc1cccc(OCCCC)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCOc1ccc(Br)c(OCCCC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
80 g of 1,3-dibutoxybenzene (0.36 mol) are dissolved at room temperature in 100 ml of carbon tetrachloride. 64.25 g of N-bromosuccinimide (0.36 mol) are introduced in portions over 30 minutes such that the temperature can be maintained between 20° C. and 30° C. When the addition is complete, the mixture is stirred at room temperature for 1 hour. The reaction mixture is filtered over kieselguhr and the solvent is removed completely by concentration. The crude product (110 g) is fractionated on a 10 cm Vigreux column at 10-1 mbar. In this way, 65 g of 1-bromo-2,4-dibutoxybenzene with a boiling point of 112° C. at 10-1 mbar are obtained as a yellowish oil in 60% yield.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([I:18])[N:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCOCC1>[I:18][C:4]1[CH:5]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:7]=[C:2]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: Nc1ccc(S(=O)(=O)c2cc(I)nc(I)c2)cc1
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: Nc1ccc(S(=O)(=O)c2cc(I)nc(N3CCCC3)c2)cc1
Yield: 75 %

Procedure:
0.127 g (0.000261 Mol) 4-(2,6-Diiodo-pyridine-4-sulfonyl)-phenylamine were dissolved in dioxane (5 ml) and treated with 0.22 ml (0.0026 Mol) pyrrolidine for 6 h at ambiente temperature. Then the solvent was removed, the residue dissolved in ethyl acetate, washed with 1N HCl, sat. bicarbonate and brine, dried over MgSO4 and evaporated. After chromatography on SiO2 with ethyl acetate hexane 1:2 and drying in a high vacuum it was obtained 0.084 g (75%) of 4-(2-iodo-6-pyrrolidin-1-yl-pyridine-4-sulfonyl)-phenylamine as a beige solid; mp.: 218-221° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][N:10]([CH3:20])[S:11]([C:14]2[S:15][C:16]([Br:19])=[CH:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(N(S(F)(F)[F:28])CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[F:28][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][N:10]([CH3:20])[S:11]([C:14]1[S:15][C:16]([Br:19])=[CH:17][CH:18]=1)(=[O:13])=[O:12]
Reactant: CCN(CC)S(F)(F)F
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1ccc(Br)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(CC(F)c1ccc(F)cc1)S(=O)(=O)c1ccc(Br)s1
Temperature: 0 °C

Procedure:
To a solution of 5-bromothiophene-2-sulfonic acid [2-(4-fluorophenyl)-2-hydroxyethyl]-methyl-amide (the compound of Preparation Example 71) (210 mg) in dichloromethane (2 mL) was added dropwise (diethylamino)sulfur trifluoride (DAST) (0.1 mL) at −70° C., After gradually warming slowly to 0° C. over 1.5 hours, an aqueous solution of saturated sodium bicarbonate was added, and the solution was extracted with ethyl acetate. After the organic layer was washed with saturated sodium chloride water and was dried with anhydrous sodium sulfate, the residue that was obtained upon removing the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (169 mg) was obtained as a pale yellow oily substance.
Reaction SMILES: CON(C)[C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[CH:6]=1.[CH3:23][Mg]Br.Cl>C1COCC1.CC(OC)(C)C>[F:20][C:17]([F:18])([F:19])[CH2:16][O:15][C:7]1[CH:6]=[C:5]([C:4](=[O:21])[CH3:23])[CH:10]=[CH:9][C:8]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)c(OCC(F)(F)F)c1
Reactant: C[Mg]Br
Agent: Cl
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(F)(F)F)c(OCC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of N-methoxy-N-methyl-3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzamide from step 7 (10.467 g, 32 mmol) in THF (100 mL) at −5° C. was added methylmagnesium bromide (3 M in Et2O, 21.1 mL, 64 mmol). The mixture was stirred at 0° C. for 15 min, then warmed up to 23° C., stirring was continued for further 1.5 h at 23° C. Cooled to 0° C., 1 N HCl (150 mL) was added drop wise, stirring was continued at 23° C. for 15 min, the mixture was diluted with TBME, the phases were separated, the organic layer was washed with water and brine, dried over MgSO4. Removal of the solvent in vacuum left a yellow solid (9.021 g, 100%), which was used without further purification. MS (EI) 286.1 [M].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][CH2:22][C:23]1[N:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[CH:25]=[N:24][C:23]([CH2:22][F:21])=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1cnc(CF)cn1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Product: C[C@@]1(c2cc(NC(=O)c3cnc(CF)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 5-(fluoromethyl)pyrazine-2-carboxylic acid [J. M. Ellard et al. WO2011009898 (2011)] following General Procedure F yielded the title compound as a colorless amorphous solid. MS: m/z=430.5 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[NH2:33][CH2:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:32])[NH:33][CH2:34][C:35]5[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=5)=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: NCc1cccnc1
Product: O=C(NCc1cccnc1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 72.2 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 3-(aminomethyl)pyridine (available from Aldrich Chemical Company, Inc.; 67 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-[(pyridin-3-ylmethyl)-carbamoyl]-biphenyl-2-carboxylic acid (85 mg, 73%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.16 (br s, 1H), 9.19 (t, J=5.9 Hz, 1H), 8.66 (s, 1H), 8.55 (d, J=3.5 Hz, 1H), 8.47 (s, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 8.25 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.90-8.01 (m, 3H), 7.76 (d, J=8.3 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.45-7.55 (m, 3H), 4.57 (d, J=5.8 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH2:20][C:21](O)=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[S:24]1[CH:28]=[CH:27][N:26]=[C:25]1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[CH2:20][C:21](=[O:22])[N:32]1[CH2:33][CH2:34][N:29]([C:25]2[S:24][CH:28]=[CH:27][N:26]=2)[CH2:30][CH2:31]1
Reactant: c1csc(N2CCNCC2)n1
Reactant: COc1ccccc1C1(CC(=O)O)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccccc1C1(CC(=O)N2CCN(c3nccs3)CC2)C(=O)Nc2ccc(Cl)cc21
Yield: 83.8 %

Procedure:
With 800 mg of [5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetic acid, which is the compound described in Preparation 1.1 of the brochure Publication No. WO03/008407, and 449 mg of 1-(1,3-thiazol-2-yl)piperazine as starting materials, reaction manipulation and post-treatment were carried out by a similar method to Step 45-1, and the obtained residue was crystallized from EtOAc and n-hexane to obtain 976 mg of the title compound (colorless crystal).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.ClC1C=C2C3(CCNC3)C[N:31]([C:38](NC3SC(Cl)=CN=3)=[O:39])[C:28]2=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C@@:10]3([CH2:14][CH2:13][N:12]([C:38]([NH:31][CH3:28])=[O:39])[CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1
Reactant: O=C(Nc1ncc(Cl)s1)N1C[C@@]2(CCNC2)c2cc(Cl)ccc21
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Cl)ccc21
Product: CNC(=O)N1CC[C@@]2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 373, with the exception that the (S)-5-chloro-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide obtained as an intermediate of Example 52 was used instead of 5-chloro-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide.