Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH:10]([CH3:13])[CH:9]([CH2:14][CH:15]([S:17][CH2:18][CH3:19])[CH3:16])[CH2:8][C:7]1=[O:20])(=O)[CH2:2][CH2:3][CH3:4].[CH2:21]([O:23][NH2:24])[CH3:22]>C(O)C>[CH2:21]([O:23][NH:24][C:1](=[C:6]1[C:11](=[O:12])[CH:10]([CH3:13])[CH:9]([CH2:14][CH:15]([S:17][CH2:18][CH3:19])[CH3:16])[CH2:8][C:7]1=[O:20])[CH2:2][CH2:3][CH3:4])[CH3:22]
Reactant: CCON
Reactant: CCCC(=O)C1C(=O)CC(CC(C)SCC)C(C)C1=O
Solvent: CCO
Product: CCCC(NOCC)=C1C(=O)CC(CC(C)SCC)C(C)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
Into 10 ml of ethanol, 2.97 g of 2-butyryl-5-(2-ethylthiopropyl)-4-methylcyclohexane-1,3-dione was dissolved and 0.81 g of ethoxyamine was dropped thereto at 0° C. and the resulting solution was stirred at room temperature for 3 hours. After pouring the reaction solution into ice-cold water, the mixture was extracted with chloroform. The chloroform solution was washed with water and extracted with 1N-sodium hydroxide solution. The sodium hydroxide solution was acidified with 1N-hydrochloric acid and the acidified mixture was extracted with chloroform. The chloroform solution was washed with water and dried over anhydrous magnesium sulfate. The removal of chloroform by distillation under reduced pressure gave 3.0 g of the desired product as yellow oily material. Yield 88%, nD19.5 1.5375.
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:23][C:22]4([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[O:21][C:20]3=[O:29])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH2:30]([N:32](CC)[CH2:33]C)C.CS(Cl)(=O)=O.CNC>C(Cl)Cl>[CH3:30][N:32]([CH3:33])[CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:23][C:22]4([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[O:21][C:20]3=[O:29])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=C1OC2(CCCCC2)CN1Cc1ccc(-c2ccc(COCCO)cc2)cc1
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CN(C)CCOCc1ccc(-c2ccc(CN3CC4(CCCCC4)OC3=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
3-[4′-(2-Hydroxy-ethoxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one (85 mg, 0.215 mmol) was mixed with triethylamine (0.09 mL, 0.644 mmol) in DCM (3 mL). The mixture was cooled in ice-water bath. Methane sulfonylchloride (3.3 uL, 0.49 mmol) was added and the reaction mixture was allowed to warm to room temperature. The stirring was continued for further 2 hours. The reaction mixture was quenched with saturate NaHCO3 aqueous solution (3 mL). The aqueous phase was extracted with DCM (3×3 mL). The combined organic phase was dried over sodium sulfate and concentrated to give a brown oil which was mixed with dimethyl amine (4 mL, 6.44 mmol) in a screw cap vial and heated at 60˜70° C. for 3.5 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL) and stirred with saturated NaHCO3 aqueous solution (3 mL). The aqueous phase was extracted with DCM (3×4 mL). The combined organic phases were dried over sodium sulfate and concentrated to give a pale brown oil, which was purified on silica gel eluting with DCM containing 1˜2.5% 2M ammonia in methanol to give the product as a white solid (74 mg, 82%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.56 (dd, 4H), 7.41 (d, 2H), 7.29 (d, 2H), 4.64 (s, 2H), 4.45 (s, 2H), 3.56 (t, 2H), 3.12 (s, 2H), 2.54 (t, 2H), 2.27 (s, 6H), 1.75 (m, 4H), 1.52 (m, 6H).
Reaction SMILES: ClC1C=C(N2C(C3C=CC(C(F)(F)[F:20])=CC=3)=NOS2=O)C=CC=1.ClC1C=C(N2C(C3C(Cl)=CC=CC=3Cl)=NOS2=O)C=CC=1.[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[N:53]1[C:57]([C:58]2[CH:63]=[CH:62][C:61](Cl)=[CH:60][CH:59]=2)=[N:56][O:55][S:54]1=[O:65].ClC1C=C(Cl)C=CC=1N1C(C2C=CC(Cl)=CC=2Cl)=NOS1=O.ClC1C=C(Cl)C=CC=1N1C(C2C(Cl)=CC=CC=2Cl)=NOS1=O>>[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[N:53]1[C:57]([C:58]2[CH:63]=[CH:62][C:61]([F:20])=[CH:60][CH:59]=2)=[N:56][O:55][S:54]1=[O:65]
Reactant: O=S1ON=C(c2ccc(C(F)(F)F)cc2)N1c1cccc(Cl)c1
Reactant: O=S1ON=C(c2ccc(Cl)cc2)N1c1ccc(Cl)cc1Cl
Agent: O=S1ON=C(c2c(Cl)cccc2Cl)N1c1ccc(Cl)cc1Cl
Agent: O=S1ON=C(c2c(Cl)cccc2Cl)N1c1cccc(Cl)c1
Agent: O=S1ON=C(c2ccc(Cl)cc2Cl)N1c1ccc(Cl)cc1Cl
Product: O=S1ON=C(c2ccc(F)cc2)N1c1ccc(Cl)cc1Cl

Procedure:
3-(3-chlorophenyl)-4-(4-trifluoromethylphenyl)-1,2,3,5-oxathiadiazole-2-oxide; 3-(3-chlorophenyl)-4-(2,6-dichlorophenyl)-1,2,3,5-oxathiadiazole-2-oxide; 3-(2,4-dichlorophenyl)-4-(4-chlorophenyl)-1,2,3,5-oxathiadiazole-2-oxide; 3-(3-chlorophenyl)-4-(2,4-chlorophenyl)-1,2,3,5-oxathiadiazole-2-oxide; 3-(2,4-dichlorophenyl)-4-(4-trifluorophenyl)-1,2,3,5-oxathiadiazole-2-oxide; 3-(2,4-dichlorophenyl)-4-(2,4-dichlorophenyl)-1,2,3,5-oxathiadiazole-2-oxide; 3-(2,4-dichlorophenyl)-4-(2,6-dichlorophenyl)-1,2,3,5-oxathiadiazole-2-oxide.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12](O)=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:20][C:21]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25])([F:23])[F:22].C(C1C=CC(N)=CC=1)(C)(C)C>>[F:20][C:21]([F:23])([F:22])[C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12]([NH:33][C:30]4[CH:31]=[CH:32][C:27]([S:24]([C:21]([F:23])([F:22])[F:20])(=[O:25])=[O:26])=[CH:28][CH:29]=4)=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S1(=O)N=C(O)c2ccc(-c3ncccc3Cl)cc21
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: CC(C)(C)c1ccc(N)cc1
Product: O=S1(=O)N=C(Nc2ccc(S(=O)(=O)C(F)(F)F)cc2)c2ccc(-c3ncccc3C(F)(F)F)cc21

Procedure:
The title compound was prepared using the procedure of Example 1C, substituting the product of Example 7B (0.1476 g, 0.450 mmol) for the product of Example 1B and substituting 4-aminophenyl trifluoromethyl sulphone (0.2571 g, 1.14 mmol) for 4-tert-butylaniline. MS (ESI+) m/z 536 (M+H)+, m/z 534 (M−H)−; 1H NMR (CD3OD) δ 7.73 (dd, J 4.7, 8.1, 1H), 7.99 (d, J 8.2, 1H), 8.12 (s, 1H), 8.19 (d, J 9.2, 2H), 8.38 (m, 3H), 8.46 (d, J 7.8, 1H), 8.92 (d, J 4.4, 1H).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][O:3][CH2:2]1.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[CH3:33][C:34]1[C:39]([Pb+3])=[C:38]([CH3:41])[CH:37]=[C:36]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:35]=1.Cl>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH3:33][C:34]1[CH:35]=[C:36]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:37]=[C:38]([CH3:41])[C:39]=1[CH:9]1[C:10](=[O:12])[CH2:11][C:6]2([CH2:5][CH2:4][O:3][CH2:2][CH2:1]2)[CH2:7][C:8]1=[O:13]
Reactant: Cc1cc(-c2ccccc2)cc(C)c1[Pb+3]
Reactant: O=C1CC(=O)CC2(CCOCC2)C1
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)CC2(CCOCC2)CC1=O
Temperature: 25 °C

Procedure:
To a mixture of 3-oxaspiro[5.5]undecane-8,10-dione (0.182 g, 1 mmol) and 4-dimethylamino-pyridine (0.61 g; 5 mmol) is added dry chloroform (4 ml), and the mixture is stirred under an atmosphere of nitrogen at room temperature until the solid dissolves. To this solution is then added dry toluene (2 ml), and then a solution of 3,5-dimethylbiphen-4-yllead triacetate (1.2 mmol) in chloroform is added. The reaction mixture is heated under reflux for 1 hour, then cooled to room temperature, acidified to pH=1 with 2N aqueous hydrochloric acid, filtered and the filtrate is extracted with dichloromethane (2×40 ml). The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated in vacuo. The residue is purified by column chromatography over silica gel to give 9-(3,5-dimethylbiphenyl-4-yl)-3-oxa-spiro[5.5]undecane-8,10-dione.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6](Cl)=[O:7])[CH2:3][CH2:2]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([NH2:27])=[N:18][N:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[N:21][C:20]=23)=[CH:12][C:11]=1[CH3:28]>C(Cl)Cl.N1C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([NH:27][C:6](=[O:7])[CH2:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[N:18][N:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[N:21][C:20]=23)=[CH:12][C:11]=1[CH3:28]
Reactant: Cc1cc(C)n2nc(N)c(-c3ccc(Cl)c(C)c3)c2n1
Reactant: O=C(Cl)CCC1CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C)n2nc(NC(=O)CCC3CC3)c(-c3ccc(Cl)c(C)c3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
A solution of the product from Example 114D (40.9 mg, 0.308 mmol) in CH2Cl2 (2 mL) was added to a stirring solution of the product from Example 47C (49.5 mg, 0.173 mmol) in pyridine (1.5 mL) at room temperature. The solution was stirred at room temperature for 1 hour, and then concentrated under vacuum. Methanol (2 mL) was added, and the mixture was concentrated under vacuum. The residue was crystallized from 60% EtOH-water (8 mL) to provide the title compound (52 mg). 1H NMR (300 MHz, CD3OD) δ ppm 0.01-0.14 (m, 2H) 0.37-0.52 (m, 2H) 0.66-0.82 (m, 1H) 1.48-1.65 (m, 2H) 2.40 (s, 3H) 2.50 (t, J=7.0 Hz, 2H) 2.57 (s, 3H) 2.72 (s, 3H) 6.88 (s, 1H) 7.37 (d, J=8.1 Hz, 1H) 7.55 (dd, J=8.6, 1.5 Hz, 1H) 7.65 (d, J=1.0 Hz, 1H)); MS (ESI) m/z 383/385 (M+H)+; Anal. Calculated for C21H23N4OCl: C, 65.87; H, 6.05; N, 14.63. Found: C, 65.56; H, 6.08; N, 14.63.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](Br)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Li]CCCC.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)=[O:39])=[CH:34][CH:33]=1>C1COCC1>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:38]([C:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=3)([C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)[OH:39])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C(c1ccc(Cl)cc1)c1cccnc1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)(c1cccnc1)c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
A suspension of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline (214.5 mg, 0.495 mmol, Intermediate 3: step c) in dry THF (5 mL) was heated with a heat gun to form a solution. The solution was cooled in a dry ice-acetone bath for 2 minutes, then a solution of n-BuLi (2.5 M in hexanes, 0.18 mL, 0.45 mmol) was added dropwise by syringe. After 1 minute, a solution of (4-chlorophenyl)(pyridin-3-yl)methanone (0.117 mg, 0.541 mmol) in dry THF (0.2 mL) was added dropwise. The reaction mixture was stirred for 5 minutes in a dry ice-acetone bath, then the reaction flask was placed into an ice-water bath that was allowed to warm to room temperature. The reaction was quenched with saturated ammonium chloride. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 50-100% EtOAc-hexanes) followed by reverse-phase chromatography (acetonitrile with 0.05% TFA in water). Product fractions were mixed with saturated aqueous sodium bicarbonate and DCM, the layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried (Na2SO4), filtered, and concentrated to provide the title compound as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4](P(OCC)(OCC)=O)[CH2:5][CH3:6].[H-].[Na+].[C:18]([O:22][C:23]([C:25]1[S:26][C:27]([CH:30]=O)=[CH:28][CH:29]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1>[C:18]([O:22][C:23]([C:25]1[S:26][C:27](/[CH:30]=[C:4](/[C:3]([O:2][CH3:1])=[O:15])\[CH2:5][CH3:6])=[CH:28][CH:29]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOP(=O)(OCC)C(CC)C(=O)OC
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC/C(=C\c1ccc(C(=O)OC(C)(C)C)s1)C(=O)OC
Reaction time: 0.5 h
Yield: 80 %

Procedure:
2-(Diethylphosphono)butyric acid methyl ester (46 g, 0.193 mol) was dissolved in tetrahydrofuran (300 mL), 60% sodium hydride (6.6 g, 0.165 mol) was added at 0° C., and the mixture was stirred for 30 minutes. To the reaction mixture was added a solution of 5-formyl-2-thiophenecarboxylic acid tert-butyl ester obtained in Example 1, step 2 (32.1 g, 0.15 mol) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was partitioned between ethyl acetate and 1N-hydrochloric acid solution, and washed successively with water and brine. After drying over anhydrous magnesium sulfate, the residue was purified by silica gel column chromatography to give the title compound (35.6 g, 0.12 mol, 80%).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]([CH3:29])[C:9]([C:11]1[C:20]2[O:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:17]([CH3:27])[C:16](=[O:28])[C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:10]>ClCCl.C(OCC)C>[CH3:29][N:8]([CH2:7][CH2:6][Cl:3])[C:9]([C:11]1[C:20]2[O:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:17]([CH3:27])[C:16](=[O:28])[C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)N(C)CCO)cccc2c1=O
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)oc2c(C(=O)N(C)CCCl)cccc2c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1.1 ml of thionyl chloride in 2 ml of dichloromethane was added to a solution of 3.37 g of Intermediate XIII in 20 ml of dichloromethane, and the mixture was stirred for 4 hours at ambient temperature. Removal of the solvent gave an oil which was taken up in diethyl ether. The title compound precipitated as a white solid which was filtered off for use without further purification. m.p. (118) 126°-128° C. (diethyl ether).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:36]=[CH:37][CH2:38][CH3:39])=[C:13]([CH:35]=1)[O:14][CH2:15][CH2:16][C:17]1[N:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[O:20][C:21]=1[CH3:22])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:36]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:35][C:13]=1[O:14][CH2:15][CH2:16][C:17]1[N:18]=[C:19]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)[O:20][C:21]=1[CH3:22])[CH2:37][CH2:38][CH3:39]
Reactant: CCC=Cc1ccc(OCc2ccccc2)cc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCc1ccc(O)cc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C

Procedure:
A solution of 4-[2-(5-Benzyloxy-2-but-1-enylphenoxy)ethyl]-5-methyl-2-biphenyl-4-yl-oxazole (0.34 mmol) in ethanol (10 mL) was treated with 5% Pd/C (30 mg) under a balloon containing hydrogen at ambient temperature for 24 h. The mixture was filtered and concentrated in vacuo to give a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:10]=1)[N:7]([CH2:20][O:21][CH3:22])[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5]2.[H-].[Na+].[CH3:30]N(C)C=O.CI>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N:11]([CH3:30])[S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:14])[CH:10]=1)[N:7]([CH2:20][O:21][CH3:22])[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(F)cc(NS(=O)(=O)c3cccs3)c2n1COC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(F)cc(N(C)S(=O)(=O)c3cccs3)c2n1COC
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
A mixture of ethyl 5-fluoro-1-(methoxymethyl)-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.45 g), 60% sodium hydride (52 mg) and N,N-dimethylformamide (10 mL) was stirred at 4° C. for 30 min. Methyl iodide (0.095 mL) was added to the solution, and the mixture was stirred at room temperature for 2 days. The reaction solution was diluted with ethyl acetate, washed with aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-2:8) to give the title compound (0.20 g, yield 43%) as colorless prism crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:10]([CH2:16][N:17]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:9]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:43][S:44](Cl)(=[O:46])=[O:45].Cl>CCOC(C)=O>[CH3:43][S:44]([O:15][CH2:14][C:12]1[CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]=[C:10]([CH2:16][N:17]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:11]=1)(=[O:46])=[O:45]
Reactant: Cc1ccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2cc(CO)cc(-c3ccc(F)cc3)c2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2cc(COS(C)(=O)=O)cc(-c3ccc(F)cc3)c2)cc1
Reaction time: 1 h

Procedure:
To a solution of N-((4′-fluoro-5-(hydroxymethyl)biphenyl-3-yl)methyl)-N-(4-fluorobenzyl)-4-methylbenzenesulfonamide (100 mg, 0.203 mmol) and Et3N (0.15 mL) in EtOAc (5 mL) at −30° C. was added methanesulfonyl chloride (25 mg, 0.218 mmol) in EtOAc (10 mL) slowly with stirring. After 1 h, a small amount of 1N aq HCl and EtOAc were added to the reaction mixture. The EtOAc layer was separated, dried over MgSO4 and concentrated in vacuo to obtain the product as a viscous material. It was enough pure to use for next step without any further purification. MS (ESI): (M+H)+=572.18.
Reaction SMILES: O[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H][H].O.N>C(O)(=O)C.[Pd]>[CH2:2]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:18]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: [H][H]
Reactant: CCCCCCCCCCC(O)c1ccc(CC(=O)OCC)cc1
Agent: [Pd]
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCCc1ccc(CC(=O)OCC)cc1
Temperature: 0 °C
Yield: 88.8 %

Procedure:
To the solution of ethyl 4-(1-hydroxyundecyl)-phenylacetate (9.7 g, 0.029 mol) in acetic acid (50 ml) was added 10%-palladium on carbon. The reaction mixture was stirred for 18 hours under 1 atmospheric pressure of hydrogen and then poured onto the mixture of concentrated ammonia water (100 ml) and ice (100 g). The resultant precipitate was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure to obtain ethyl 4-undecylphenylacetate (3-w, 8.2 g, 88%) as an oil.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH2:28][O:29][CH2:30][O:31][CH3:32])[CH2:17][O:18][C:19]2[CH:26]=[CH:25][CH:24]=[C:23](F)[C:20]=2[C:21]#[N:22])=[CH:12][CH:11]=1>CC(N(C)C)=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([CH2:28][O:29][CH2:30][O:31][CH3:32])[CH2:17][O:18][C:19]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:20]=2[C:21]([NH2:22])=[N:7][C:6]([NH2:8])=[N:5]3)=[CH:14][CH:15]=1
Reactant: N=C(N)N
Reactant: COCOCC(COc1cccc(F)c1C#N)c1ccc(Cl)cc1
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Product: COCOCC(COc1cccc2nc(N)nc(N)c12)c1ccc(Cl)cc1
Temperature: 135 °C
Reaction time: 24 h
Yield: 24.4 %

Procedure:
Guanidine carbonate (792 mg; 4.4 mmol) is suspended in a solution of 2-[2-(4-Chlorophenyl)-3-methoxymethoxypropoxy]-6-fluorobenzonitrile (769 mg; 2.20 mmol) in DMA, and heated to 135° C. for 8 hours. The solution is cooled to RT overnight and placed in a freezer at 4° C. for 24 hours. The resulting black solids are removed by filtration through paper. The filtrate is concentrated under vacuum, and purified by column chromatography (10% MeOH/EtOAc). The collected fractions are dried to give 209 milligrams of 5-[2-(4-chlorophenyl)-3-methoxymethoxy propoxy]-quinazoline-2,4-diamine.
Reaction SMILES: [I:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].[H-].[Na+].[C:13]([O:17][C:18](=[O:21])[CH2:19]Br)([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[C:13]([O:17][C:18](=[O:21])[CH2:19][O:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[I:1])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cccc(CO)c1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(COCC(=O)OC(C)(C)C)c1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
(2-Iodo-3-methyl-phenyl)-methanol (1608 mg, 6.8 mmol, Example 131: step b) was dissolved into DMF (10 mL). The solution was cooled to 0° C. To this was added sodium hydride in one portion and the reaction continued to stir at 0° C. for 30 minutes. To the cooled solution was added t-butylbromoacetate (1.3 mL, 8.9 mmol) and then the reaction was warmed to RT and then heated to 50° C. for 4 hours. The solvents were removed in vacuo and the resulting residue was dissolved into EtOAc and washed with brine. The combined organic layers were dried (MgSO4) and the solvent was removed in vacuo resulting in the title compound (1.29 g, 53%) that was used with out further purification. 1H-NMR (CDCl3): δ 7.28–7.13 (m, 3H), 4.63 (s, 2H), 4.07 (s, 2H), 2.44 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: C([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[CH2:15][CH2:16][CH2:17][C:18]2[N:19]=[CH:20][N:21]([Si](C)(C)C)[CH:22]=2)=[CH:10][CH:9]=1)=O)(C)(C)C.S(Cl)([Cl:30])=O>>[Cl:30][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]#[N:5])=[CH:9][CH:10]=1)[CH2:15][CH2:16][CH2:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)NC(=O)c1ccc(C(O)CCCc2cn([Si](C)(C)C)cn2)cc1
Product: N#Cc1ccc(C(Cl)CCCc2c[nH]cn2)cc1

Procedure:
A solution of 4.5 g of 4-[4-(p-tert-butylaminocarbonylphenyl)-4-hydroxy-n-butyl]-1-trimethylsilylimidazole in 50 ml of thionyl chloride is refluxed for 1 h, cooled and evaporated. The residue is partitioned between methylene chloride and aqueous sodium bicarbonate solution. The organic phase is separated, dried over sodium sulfate and evaporated to yield the title compound (c).