Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].[OH:8][CH2:9][CH:10](CO)O>>[CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:10][CH2:9][OH:8]
Reactant: OCCOCCO
Reactant: OCC(O)CO
Product: OCCOCCOCCO

Procedure:
The preparation is repeated using a 1:1:1 mole ratio of diethylene glycol, triethylene glycol, and glycerin to obtain the desired approximately 1:1:1 mole ratio mixture of sodium 2-[2-(2-hydroxyethoxy)ethoxy]ethanesulfonate, sodium 2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethanesulfonate, and sodium 2-(2,3-dihydroxypropoxy)ethanesulfonate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:27])[CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:16][CH:15]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:20](=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:19]=1)=[O:8])([O-:3])=[O:2]
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2cccc([N+](=O)[O-])c2)cc1
Yield: 25.7 %

Procedure:
In a manner similar to that described in Example 3, 3-nitro-benzoyl chloride (0.064 g, 0.00035 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.022 g of 4-[4-(3-nitro-benzoylamino)-phenyl]-4-oxo-butyric acid as a yellow solid; MS-(AP+) MH+343.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:19](=[O:20])[CH2:18][C:17]([CH3:22])([CH3:21])[CH2:16][C:14]=4[N:15]=3)[C:6]=2[CH:23]=1.Cl[C:25]1[N:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1.CCN(C(C)C)C(C)C>>[CH3:22][C:17]1([CH3:21])[CH2:16][C:14]2[N:15]=[C:11]([N:7]3[C:6]4[CH:23]=[C:2]([NH:1][C:25]5[N:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=5)[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][CH2:8]3)[S:12][C:13]=2[C:19](=[O:20])[CH2:18]1
Reactant: Cc1ccc(Cl)nn1
Reactant: CC1(C)CC(=O)c2sc(N3CCOc4ccc(N)cc43)nc2C1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Nc2ccc3c(c2)N(c2nc4c(s2)C(=O)CC(C)(C)C4)CCO3)nn1
Reaction time: 20 h
Yield: 26.6 %

Procedure:
A mixture of Example 12 (44 mg, 0.134 mmol), 3-chloro-6-methylpyridazine (15 mg, 0.116 mmol) and DIPEA (0.5 mL, 67.0 mmol) was heated to 180° C. under microwave irradiation for 2 h. A further portion of 3-chloro-6-methylpyridazine (15 mg, 0.116 mmol) was added and heating continued for a further 20 h. The solvent was removed in vacuo and the residue purified by prep HPLC to give the title compound (13 mg, 23%) as a yellow solid. δH (CDCl3) 1.15 (6H, s), 2.42 (2H, s), 2.58 (3H, s), 2.76 (2H, s), 4.13-4.18 (2H, m), 4.32-4.38 (2H, m), 6.93-7.20 (5H, m), 8.03 (1H, d, J 2.4 Hz). LCMS (ES+) 422 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:5]([NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:6].C(N(CC)CC)C.[CH3:28][C:29]1([CH3:36])[C:33]([CH3:35])([CH3:34])[O:32][BH:31][O:30]1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][C:19]1[CH:18]=[CH:17][C:4]([C:5]([NH:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:6])=[CH:3][C:2]=1[B:31]1[O:32][C:33]([CH3:35])([CH3:34])[C:29]([CH3:36])([CH3:28])[O:30]1
Reactant: CC1(C)OBOC1(C)C
Reactant: Cc1ccc(C(=O)NCCCN2CCOCC2)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NCCCN2CCOCC2)cc1B1OC(C)(C)C(C)(C)O1

Procedure:
The procedure used in Example 3: step b was followed using 3-iodo-4-methyl-N-(3-morpholin-4-yl-propyl)-benzamide ((Example 301: step a) 695 mg, 1.79 mmol), PdCl2(PPh3)2 (63 mg, 0.09 mmol), triethylamine (1.25 mL, 9.4 mmol), and 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.91 mL, 6.4 mmol) in dioxane (5 mL). Analogous aqueous workup and purification by SiO2 flash column chromatography (0–10% MeOH in DCM) yielded the title compound contaminated with the product resulting from halide reduction (653 mg, 94%). The material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[CH:42][C:5]2[CH:6]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:7](=[O:37])[N:8]([CH2:23][C:24]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34]CC)=[O:33])[CH2:28][CH2:27]3)=[O:25])[CH2:9][CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]#[C:18][Si](C)(C)C)[C:4]=2[CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO.O>[Cl:1][C:2]1[CH:43]=[CH:42][C:5]2[CH:6]([CH2:38][CH:39]([CH3:40])[CH3:41])[C:7](=[O:37])[N:8]([CH2:23][C:24]([N:26]3[CH2:27][CH2:28][CH:29]([C:32]([OH:34])=[O:33])[CH2:30][CH2:31]3)=[O:25])[CH2:9][CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]#[CH:18])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)C1CCN(C(=O)CN2CC(c3ccccc3C#C[Si](C)(C)C)c3cc(Cl)ccc3C(CC(C)C)C2=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccccc1C1CN(CC(=O)N2CCC(C(=O)O)CC2)C(=O)C(CC(C)C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
12 mg of the compound from Example 31A (0.019 mol) are dissolved in 2.0 ml of THF/methanol (1:1), mixed with 100 μl of 1 N sodium hydroxide solution and stirred at room temperature for 16 h. The reaction solution is acidified with 1 N hydrochloric acid, diluted with water and extracted three times with dichloromethane. The combined organic phases are dried over sodium sulphate, and the residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 6 mg (58% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([O:25][CH2:26][CH:27]=[C:28]([Cl:30])[Cl:29])[CH:22]=[C:21]([Cl:31])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:19][C:18](=O)[O:17][N:16]=2)=[CH:11][CH:10]=1.P(Cl)(Cl)([Cl:34])=O>N1C=CC=CC=1>[Cl:34][C:18]1[O:17][N:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]3[C:21]([Cl:31])=[CH:22][C:23]([O:25][CH2:26][CH:27]=[C:28]([Cl:29])[Cl:30])=[CH:24][C:2]=3[Cl:1])=[CH:14][CH:13]=2)[N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2ccc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)cc2)no1
Solvent: c1ccncc1
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccc(-c3noc(Cl)n3)cc2)c(Cl)c1

Procedure:
90 mg of 3-(4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-4H-[1,2,4]oxadiazol-5-one, 14 mg of pyridine and 0.2 ml of phosphorus oxychloride are stirred for 14 hours at 130° C. The reaction mixture is poured onto ice-water and extracted with ethyl acetate. Concentration of the organic phase and purification over silica gel yield the title compound (compound 1.16).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12](CC(F)=O)[CH:11]3[C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[CH3:35])[C:5]2=[CH:4][CH:3]=1.C(OC(N1CCC(N)CC1)=O)(C)(C)C.CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[CH3:35])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)c1ccncc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 88.8 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.18 mmol) prepared in example 57a was reacted with 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.50 mmol), N-methylmorpholine (0.1 g, 0.99 mmol) and 4-dimethylaminopyridine (2 mg, 0.017 mmol) in tetrahydrofuran to give racemic (2′R,3R,4′S)-1′-[1-tert-butoxycarbonyl-piperidin-4-yl)aminocarbonyl-methyl]-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.075 g, 58.6%).
Reaction SMILES: Cl[C:2]1[S:6][CH:5]=[CH:4][C:3]=1[CH2:7]Br.[Cl-].C[N+](C(=O)CCCCCCC)(C(=O)CCCCCCC)[C:12](=O)[CH2:13][CH2:14]CCCCC.C(Cl)(Cl)Cl>O1CCCC1.[OH-].[Na+]>[S:6]1[CH:5]=[CH:4][C:3]2[CH:7]=[CH:12][CH:13]=[CH:14][C:2]1=2
Reactant: Clc1sccc1CBr
Reactant: CCCCCCCC(=O)[N+](C)(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: c1ccc2sccc2c1

Procedure:
Stir cis-6-chloro-2,3-dihydro-3-hydroxy-2-[(1', 2', 4'-triazolyl)-1'-methyl]benzo(b)thiophene (1.17 gms., 4.37 mmols), 2-chloro-3-thenylbromide (1.06 gms., 5.0 mmol) and methyl tricaprylyl ammonium chloride (0.1 gm.) in tetrahydrofuran (25 ml) and 50% sodium hydroxide (10 ml) at room temperature for one hour. Pour the reaction mixture into chloroform (500 ml.) and extract with two 500 ml. portions of water. Dry the chloroform solution over anhydrous magnesium sulfate, filter and evaporate in vacuo. Chromatograph the resultant residue on silica gel eluting with chloroform. Combine the like eluates as determined by thin layer chromatography and evaporate in vacuo to obtain cis-6-chloro-3-(2'-chloro-3'-thenyloxy)-2,3-dihydro-2-[(1", 2", 4"-triazolyl)-1"-methyl]benzo(b)thiophene, a gum.
Reaction SMILES: C([O:3][CH2:4][CH3:5])=C.Cl[Si:7]([CH3:36])([CH3:35])[CH2:8][CH2:9][C:10]([F:34])([F:33])[C:11]([F:32])([F:31])[C:12]([F:30])([F:29])[C:13]([F:28])([F:27])[C:14]([F:26])([F:25])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18]>>[C:4]([Si:7]([CH3:35])([CH3:36])[CH2:8][CH2:9][C:10]([F:33])([F:34])[C:11]([F:31])([F:32])[C:12]([F:29])([F:30])[C:13]([F:27])([F:28])[C:14]([F:25])([F:26])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])(=[O:3])[CH3:5]
Reactant: C[Si](C)(Cl)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C=COCC
Product: CC(=O)[Si](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
Acetyidimethyl-3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecylsilane was synthesized from ethyl vinyl ether and chlorodimethyl-3,3,4,4,5,5,6,6,7,7,8,8, 9,9,10,10,10-heptadecafluorodecylsilane after the procedure of Cunico and Kuan (J. Org. Chem. 1985, 50, 5410-5413).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:28]=2)=[O:24])[CH:20]=[C:19]([CH3:41])[C:18]=1O.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:18]1[C:19]([CH3:41])=[CH:20][C:21]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][Si:34]([C:37]([CH3:39])([CH3:38])[CH3:40])([CH3:35])[CH3:36])[CH:28]=2)=[O:24])=[CH:22][C:17]=1[Cl:16])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc(Cl)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc(Cl)c1OS(=O)(=O)C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
Trifluoromethanesulfonic anhydride (3 mL, 17.7 mmol) was added to a cooled (−78° C.) solution of 2-chloro-4-[[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-phenyl]methyl]amino]carbonyl]-6-methylphenol (6.00 g,14.8 mmol) and triethylamine (8.24 mL, 59.1 mmol) in dichloromethane (60 mL). After stirring for 2 h at −78° C. , the reaction was quenched with solid ammonium chloride (4 g). The mixture was diluted with ethyl acetate (200 mL) and washed with 1N HCl (100 mL), saturated aqueous sodium bicarbonate and brine. The organic layer was dried (MgSO4), filtered, evaporated and chromatographed (20-30% ethyl acetate/hexanes) to give trifluoromethanesulfonic acid, 2-chloro-4-[[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]methyl]amino]carbonyl]-6-methylphenyl ester (5.00 g, 63%) as pale orange oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:12]=[C:11]([CH2:21][S:22][C:23]2[S:24][C:25]([CH2:28][CH3:29])=[N:26][N:27]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)C1C=CC=CC=1.[CH3:38][O:39]C1C=C(C=CC=1)CBr>>[CH2:28]([C:25]1[S:24][C:23]([S:22][CH2:21][C:11]2[N:10]=[C:9]([NH:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[C:6]([O:39][CH3:38])[CH:7]=3)[CH:14]=[C:13]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[CH:12]=2)=[N:27][N:26]=1)[CH3:29]
Reactant: CCc1nnc(SCc2cc(N3CCOCC3)cc(NCc3ccccc3)n2)s1
Reactant: COc1cccc(CBr)c1
Agent: BrCc1ccccc1
Product: CCc1nnc(SCc2cc(N3CCOCC3)cc(NCc3cccc(OC)c3)n2)s1

Procedure:
The above identified compound was obtained as a vermilion oily substance in the same manner as in Example 1-(6) and (7) except that benzyl bromide was changed to 3-methoxybenzyl bromide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9][CH2:10][CH2:11]O.P(Br)(Br)[Br:14]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9][CH2:10][CH2:11][Br:14]
Reactant: BrP(Br)Br
Reactant: Cc1cccc(C)c1SCCO
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C)c1SCCBr

Procedure:
18.2 g of 2-(2,6-dimethyl phenylthio) 1-hydroxy ethane and 50 ml chloroform are added in a flask and when the mixture is perfectly clear, it is cooled to 0°. To the solution 14.3 g of phosphorous tribromide are added while keeping the temperature to about 0°. After completion of the addition, the inner temperature is let to revert at ambiant temperature then heated to reflux for one hour.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:9](=[O:25])[O:10][C:11]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[C:12]=2[C:13]=1[CH3:14])(=O)=O.[C:26]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(OC)(C)C.C(O)(C)C>[CH3:24][O:23][C:15]1[C:12]2[C:13]([CH3:14])=[C:8]([CH2:7][CH2:6][N:35]3[CH2:36][CH2:37][CH:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:33][CH2:34]3)[C:9](=[O:25])[O:10][C:11]=2[CH:18]=[C:17]([O:19][CH3:20])[C:16]=1[O:21][CH3:22]
Reactant: COc1cc2oc(=O)c(CCOS(C)(=O)=O)c(C)c2c(OC)c1OC
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: COc1cc2oc(=O)c(CCN3CCC(c4ccccc4)CC3)c(C)c2c(OC)c1OC
Yield: 27 %

Procedure:
Process B; starting materials: 3-[2-(methanesulphonyloxy)ethyl]-5,6,7-trimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 34) and 4-phenylpiperidine; yield 27%; m.p. 117°-118° C. (from TBME/isopropanol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[C:28](I)=[CH:27][N:26]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[C:28]([C:13]2[CH:12]=[CH:11][C:10]([CH2:24][NH2:25])=[CH:9][CH:14]=2)=[CH:27][N:26]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(-c2ccc(CN)cc2)c(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)n1
Temperature: 150 °C
Yield: 53.2 %

Procedure:
To a mixture of 3-(2,4-bis-benzyloxy-5-chloro-phenyl)-4-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole (0.1 g, 0.15 mmol) in DMF (3 ml) was added 4-aminomethylboronic acid (0.028 g, 0.30 mmol). 1M sodium bicarbonate solution (0.5 ml, 0.5 mmol) was then added, followed by dichlorobis(triphenylphosphine) palladium 11 (0.011 g, 0.015 mmol). The mixture was degassed and then heated to 150° C., for 600 seconds under microwave irradiation. The mixture was then concentrated in vacuo and purified by column chromatography using dichloromethane and methanol as eluent to give 4-[3-(2,4-bis-benzyloxy-5-chloro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-benzylamine (0.025 g, 26%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2>C1COCC1.C(Cl)Cl>[N:1]1([CH:8]2[C:9]3[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=3[CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: ClC1c2ccccc2CCc2ccccc21
Reactant: C1CNCCN1
Solvent: C1CCOC1
Solvent: ClCCl
Product: c1ccc2c(c1)CCc1ccccc1C2N1CCNCC1
Reaction time: 8 h
Yield: 2915.9 %

Procedure:
Into a solution of partially dissolved piperazine (15.2 g, 0.17 mmol) in THF (130 mL) at more temperature was added dropwise a solution of 5-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (2.3g, 10.3 mmol) in 20 mL THF. The reaction was allowed to stir overnight and then was diluted with CH2Cl2, washed once with 1.0N NaOH solution, once with brine and then dried (Mg SO4). It was then filtered and the solvent removed to give a residue which was flash chromatographed (5% MeOH saturated with NH3 in CH2Cl2) to give 1.38 g of a glassy solid of the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12](I)=[C:11]([N:14]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[N:10]([CH3:34])[N:9]=1)(=[O:3])[CH3:2].[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:11]([N:14]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[N:10]([CH3:34])[N:9]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: COCCOCN(c1c(I)c(OCCOC(C)=O)nn1C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COCCOCN(c1c(-c2ccccc2)c(OCCOC(C)=O)nn1C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C

Procedure:
2-[(5-{{[4-(tert-Butyl)phenyl]sulfonyl}[(2-methoxyethoxy)methyl]amino}-4-iodo-1-methyl-1H-pyrazol-3-yl)oxy]ethyl acetate (Preparation 14) (1.95 g), benzeneboronic acid (0.78 g) and cesium carbonate (5.26 g) were suspended in 1,4-dioxane (50 ml) and water (5 ml). The mixture was degassed (vacuum and nitrogen atmosphere×5) and then tetrakis(triphenylphosphine)palladium(0) (50 mg) was added and the mixture degassed again. The mixture was heated at reflux for 2 hours and cooled to room temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (20 ml×3). The combined organics were washed with saturated aqueous sodium bicarbonate solution, dried with magnesium sulfate, filtered and concentrated under reduced pressure. Chromatography on silica eluting with a gradient elution of ethyl acetate:hexane (1:2 to 2:1) yielded the desired product as an off white solid (1.112 g).
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([O:16][C:17]([F:20])([F:19])[F:18])[CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]#[CH:35])=[N:32][CH:33]=2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]#[C:35][C:2]3[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)=[C:4]([O:16][C:17]([F:20])([F:19])[F:18])[CH:3]=3)=[N:32][CH:33]=2)=[CH:26][CH:27]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: FC(F)(F)Oc1cc(I)ccc1OCCN1CCCC1
Product: FC(F)(F)Oc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
Prepared according to general working method I from 1-[2-(4-iodo-2-trifluoromethoxy-phenoxy)-ethyl]-pyrrolidine (250 mg, 0.62 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (140 mg, 0.65 mmol).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:33][C:34]([N:36]([CH3:44])[C:37]2[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=2)=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:33][C:34]([N:36]([C:37]2[CH:38]=[CH:39][C:40]([NH:43]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:8]4[C:7]\3=[CH:12][CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=4)/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:41][CH:42]=2)[CH3:44])=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CN(C(=O)CN1CCCC1)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CN2CCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(pyrrolidin-1-yl-methylcarbonyl)-N-methyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C30H30N4O4
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@@H:22]4[NH:27][S:28]([CH2:31][C:32](OC)=[O:33])(=[O:30])=[O:29])=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[BH4-].[Na+].CO>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@@H:22]4[NH:27][S:28]([CH2:31][CH2:32][OH:33])(=[O:29])=[O:30])=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: COC(=O)CS(=O)(=O)N[C@H]1CCc2c(-c3cnc(-c4ccc(OC(C)C)c(C#N)c4)s3)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CC[C@@H]4NS(=O)(=O)CCO)s2)cc1C#N
Temperature: 75 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
Prepared using General Procedure 17: To a stirred solution of (S)-methyl 2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate (20 mg, 0.04 mmol) in THF (0.5 mL) was added sodium borohydride (3.6 mg, 0.09 mmol) at room temperature. The reaction was heated to 75° C. and methanol (0.06 mL, 1.4 mmol) was added dropwise. After 1 h, the reaction was cooled and concentrated. Purification of the crude material by preparative HPLC gave 12.2 mg (64%) of (S)-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamide 165. LCMS-ESI (m/z) calculated for C24H25N3O4S2: 483.1; found 484.2 [M+H]+, tR=3.45 min.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24]2)[CH:20]=[CH:19][C:18]=1[Cl:34])=O)(C)(C)C>ClCCl.Cl.CCOCC>[CH2:32]([O:31][C:29]([C@@H:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:21]2[CH:20]=[CH:19][C:18]([Cl:34])=[C:17]([C:9]3[NH:8][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[N:10]=3)[CH:22]=2)[CH2:24]1)=[O:30])[CH3:33]
Reactant: CCOC(=O)[C@@H]1CCCN(c2ccc(Cl)c(-c3nc4ccccc4n3C(=O)OC(C)(C)C)c2)C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
Method 2—Step d To a mixture of 2-[2-Chloro-5-((R)-3-ethoxycarbonyl-piperidin-1-yl)-phenyl]-benzoimidazole-1-carboxylic acid tert-butyl ester (1.30 g, 2.68 mmol) in dichloromethane (2 mL), 2M HCl in Et2O (10 mL) was added and the resulting mixture was stirred overnight at room temperature. The solid was filtered off, then recovered with 10% NaOH (10 mL) and extracted with dichloromethane (3×10 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure, to get 0.81 g of the title compound without further purifications (85%).