Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([CH:10]=O)=[C:4]2[N:3]=[CH:2]1.[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][NH2:17])[CH3:13].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][NH:17][CH2:16][CH:15]([O:18][CH2:19][CH3:20])[O:14][CH2:12][CH3:13])[C:4]=2[N:3]=[CH:2]1
Reactant: O=Cc1cccc2scnc12
Reactant: CCOC(CN)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(CNCc1cccc2scnc12)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Benzothiazole-4-carbaldehyde (1.96 g, 12 mmol) in MeOH (50 mL) was added aminoacetaldehyde diethyl acetal (1.74 mL, 12 mmol) and acetic acid (1.03 mL, 18 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was added to a stirred solution of sodium cyanoborohydride (816 mg, 13 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. Then H2O and ethyl acetate were added to the reaction mixture. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was used next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:31]=[CH:30][CH:29]=[CH:28][C:5]=1[O:6][CH2:7][CH2:8][NH:9][C@H:10]([CH3:27])[CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([C:21]#[N:22])[CH:20]=1)[N:17]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:16][CH2:15]2)[CH3:2].[OH-].[Na+].OO.S([O-])([O-])=[O:37].[Na+].[Na+]>CS(C)=O.O>[CH2:1]([O:3][C:4]1[CH:31]=[CH:30][CH:29]=[CH:28][C:5]=1[O:6][CH2:7][CH2:8][NH:9][C@H:10]([CH3:27])[CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([C:21]([NH2:22])=[O:37])[CH:20]=1)[N:17]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:16][CH2:15]2)[CH3:2]
Reactant: CCOc1ccccc1OCCN[C@H](C)Cc1cc(C#N)c2c(c1)CCN2CCCO
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1ccccc1OCCN[C@H](C)Cc1cc2c(c(C(N)=O)c1)N(CCCO)CC2
Temperature: 27.5 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
(R)-5-[2-[[2-(2-Ethoxyphenoxy)ethyl]amino]propyl]-1-(3-hydroxypropyl)-2,3-dihydro-1H-indole-7-carbonitrile (5.95 g) was dissolved in dimethylsulfoxide (16.4 ml), and 5N sodium hydroxide solution (0.25 ml) was added to the solution. To the mixture was added 30% hydrogen peroxide (1.55 ml) keeping inner temperature below 25° C., and the mixture was stirred overnight at an inner temperature of 25-30° C. A solution of sodium sulfite (2.39 g) in distilled water (82 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution, distilled water and brine subsequently, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, the residue was recrystallized from ethyl acetate to give (R)-5-[2-[[2-(2-ethoxyphenoxy)-ethyl]amino]propyl]-1-(3-hydroxypropyl)-2,3-dihydro-1H-indole-7-carboxamide (4.72 g).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:24](=[O:47])[NH:25][C@H:26]([C:35](=[O:46])[NH:36][C:37]1[S:38][CH:39]=[C:40]([C:42](=[O:45])[CH2:43][CH3:44])[N:41]=1)[C@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:11][CH:10]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][C@H:8]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[CH:13][CH:14]=1)[C:24]([NH:25][C@@H:26]([C@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[C:35]([NH:36][C:37]1[S:38][CH:39]=[C:40]([C:42](=[O:45])[CH2:43][CH3:44])[N:41]=1)=[O:46])=[O:47]
Reactant: CCC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(OCCN3CCCCC3)cc2)[C@@H](C)c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](N)c2ccc(OCCN3CCCCC3)cc2)[C@@H](C)c2ccccc2)n1
Reaction time: 1.5 h

Procedure:
{(R)-[(1S,2S)-2-Phenyl-1-(4-propionyl-thiazol-2-ylcarbamoyl)-propylcarbamoyl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-carbamic acid tert-butyl ester (110 mg, 0.16 mmol) was dissolved in a 30% v/v solution of trifluoroacetic acid in dichloromethane (5 mL) at 0° C. After stirring for 1.5 hours the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was adjusted to pH=8 by the addition of solid sodium bicarbonate. The aqueous layer was again extracted with ethyl acetate (2×). The combined organic layers was dried over sodium sulfate, filtered and concentrated in vacuo to give crude (2S,3S)-2-{(R)-2-amino-2-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetylamino}-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide which was used immediately and without further purification.
Reaction SMILES: N1C=CC=C1.[H-].[Na+].Br[CH2:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:16]([C:20]([F:23])([F:22])[F:21])[O:17]2)=[CH:12][C:11]=1[Cl:29].C[O:31][CH2:32][CH2:33]OC>>[Cl:29][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[CH2:9][O:31][CH2:32][CH3:33])[O:17][CH:16]([C:20]([F:23])([F:22])[F:21])[C:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:14]2
Reactant: COCCOC
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(CBr)cc2OC1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: c1cc[nH]c1
Product: CCOCc1cc2c(cc1Cl)C=C(C(=O)OCC)C(C(F)(F)F)O2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of pyrrole (55 mg, 0.75 mmol) in 1.5 mL DME was added to a mixture of NaH (38 mg, 0.83 mmol) in I mL DME at 0° C. under argon. The mixture was stirred at 0° C. for 10 min and then warmed to 25° C. After 30 min, a solution of ethyl 7-(bromomethyl)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (300 mg, 0.75 mmol), from Example 162 Step 3, was dissolved in 2.5 mL DME was added dropwise. After 3 h, the reaction was filtered through a pad of Celite (1″) and washed with EtOAc (10 mL). The filtrate was concentrated to give a brown oil in 350 mg (100%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@H:17]([OH:18])[CH2:16][C@H:15]2[C@@H:11]1[CH2:12][C:13](=[O:19])[O:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CCOCC.C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@H:10]1[C@H:17]([O:18][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][O:20]2)[CH2:16][C@H:15]2[C@@H:11]1[CH2:12][C:13](=[O:19])[O:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C[C@@H]2[C@@H](COCc3ccccc3)[C@H](O)C[C@@H]2O1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1C[C@@H]2[C@@H](COCc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2O1

Procedure:
A solution of 14.5 g. of (1S,5R,6S,7R)-6-benzyloxymethyl-7-hydroxy-2-oxabicyclo[3,3,0]octan-3-one, 6 ml. of dihydropyran, and 40 mg. of p-toluenesulfonic acid in 300 ml. of absolute methylene chloride as agitated for one hour at 5°. Then the solution is diluted with ether, shaken with 4% sodium bicarbonate solution, washed neutral with water, dried over magnesium sulfate, and evaporated under vacuum. Yield: 21 g. of the tetrahydropyranyl ether as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][CH:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>O1CCCC1.CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][CH:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc([N+](=O)[O-])c2)C1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc(N)c2)C1
Reaction time: 1 h
Yield: 121.9 %

Procedure:
To 10% palladium-carbon (100 mg), a solution of tert-butyl 3-((3-nitrophenyl)amino)pyrrolidine-1-carboxylate (C23, 210 mg) in tetrahydrofuran (10 mL) and methanol (10 mL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour under a hydrogen atmosphere. The insoluble matter was removed by filtration through Cerite, and then the solvent was evaporated under reduced pressure to obtain tert-butyl 3-((3-aminophenyl)amino)pyrrolidine-1-carboxylate (C24, 231 mg).
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:22]([NH2:24])[CH3:23]>>[CH2:22]([NH:24][C:18]([C:14]1[S:13][C:12](/[CH:11]=[CH:10]/[C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20])[CH3:23]
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Reactant: CCN
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NCC)s1
Yield: 55 %

Procedure:
As described for example 104, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using ethylamine (2M solution in THF) instead of rac-2-amino-1-butanol, to the title compound (91 mg, 55%) which was obtained as a light yellow solid after purification by chromatography (silica, 0 to 100% ethyl acetate in heptane). MS: m/e=334.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Cl[C:15]1[CH:27]=[C:19]2[N:20]([CH:24]([CH3:26])[CH3:25])[CH2:21][CH2:22][CH2:23][N:18]2[C:17](=[O:28])[N:16]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:11])[F:9])[CH2:12][O:13][C:15]1[CH:27]=[C:19]2[N:20]([CH:24]([CH3:25])[CH3:26])[CH2:21][CH2:22][CH2:23][N:18]2[C:17](=[O:28])[N:16]=1
Reactant: OCc1ccc(C(F)(F)F)c(F)c1
Reactant: CC(C)N1CCCn2c1cc(Cl)nc2=O
Product: CC(C)N1CCCn2c1cc(OCc1ccc(C(F)(F)F)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3-fluoro-4-(trifluoromethyl)phenyl)methanol and 8-chloro-1-isopropyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@@:3]21[C:17]1[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=1)[O:11][CH2:10][CH2:9]2.[C:20]([C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1)#[N:21]>>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:1])([F:19])[C@@:3]2([C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:28](=[O:29])[C:25]4[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[CH:27][N:26]=4)[CH:16]=3)[O:11][CH2:10][CH2:9]2)[N:4]=1
Reactant: NC1=N[C@@]2(CCOc3ccc(N)cc32)C(F)(F)CO1
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: N#Cc1ccc(C(=O)Nc2ccc3c(c2)[C@@]2(CCO3)N=C(N)OCC2(F)F)nc1
Yield: 74 %

Procedure:
The condensation of (R)-5′,5′-difluoro-5′,6′-dihydrospiro[chroman-4,4′-[1,3]oxazine]-2′,6-diamine (intermediate B7.1) and 5-cyanopicolinic acid yielded the title compound (74% yield) as a yellow solid. MS (ISP): m/z=400.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:38]=[CH:37][C:5]([CH2:6][O:7][C:8]2[CH:36]=[CH:35][CH:34]=[CH:33][C:9]=2[CH2:10][CH2:11][N:12]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1.[Cl:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(COC)OC.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>[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]3[CH:36]=[CH:35][CH:34]=[CH:33][C:9]=3[CH2:10][CH2:11][N:12]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=3)[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:37][CH:38]=2)=[CH:42][CH:41]=1
Reactant: CCOC(=O)CCCCN(CCc1ccccc1OCc1ccc(Br)cc1)Cc1ccc(C(=O)OC)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)CCCCN(CCc1ccccc1OCc1ccc(-c2ccc(Cl)cc2)cc1)Cc1ccc(C(=O)OC)cc1

Procedure:
300.0 mg (0.51 mmol) of methyl 4-{[{2-[(4-bromobenzyl)oxy]phenethyl}(5-ethoxy-5-oxopentyl)amino]methyl}benzoate from Ex. 4 are initially charged in 3 ml of dimethoxyethane and admixed successively with 101.7 mg (0.62 mmol) of 4-chlorophenylboronic acid and 0.57 ml of 2M sodium carbonate solution. 10.0 mg of dichlorobis(triphenylphosphine)palladium(II) are added, and the mixture is then heated at reflux temperature for 18 hours. The reaction solution is cooled, admixed with 20 ml of ethyl acetate and washed successively with 5% strength sodium hydrogen phosphate solution, water and saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and the solvent is distilled off under reduced pressure. The crude product is chromatographed over silica gel using the mobile phase cyclohexane/ethyl acetate=10:1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[O:11]=[S:12]1(=[O:29])[CH2:17][CH2:16][N:15]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:14]2=[N:13]1.C(N(CC)CC)C>CN(C=O)C.C(O[Cu]OC(=O)C)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:28][C:25]2[CH:24]=[CH:23][C:22]([C:21]3[C:14]4=[N:13][S:12](=[O:29])(=[O:11])[CH2:17][CH2:16][N:15]4[CH:18]=[CH:19][CH:20]=3)=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Reactant: OB(O)c1ccc(F)cc1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccc(F)cc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
A mixture of 4-fluorophenylboronic acid (365 mg), 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (240 mg), diacetoxycopper (316 mg), triethylamine (0.60 ml), and powdered 4A MS (1.5 g) in DMF (10 mL) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (139 mg) as a white solid.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[CH2:1]([N:8]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[C:29](=[O:31])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(Cc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of tert-butyl 4-(benzylamino)piperidine-1-carboxylate (8.1 g, 28.0 mmol) and Et3N (7.8 mL, 56.0 mmol) in CH2Cl2 (100 mL) was added acetyl chloride (2.4 mL, 33.5 mmol) and the reaction was stirred at room temperature overnight, then concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 30% to 60% EtOAc/CH2Cl2, afforded tert-butyl 4-(N-benzylacetamido)piperidine-1-carboxylate (9.3 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[C:5]([CH3:8])[O:4][N:3]=1.[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1.ClCCl>[C:9]1([S:15]([N:1]([C:2]2[C:6]([Br:7])=[C:5]([CH3:8])[O:4][N:3]=2)[S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1onc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1onc(N(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 25 h
Yield: 72.9 %

Procedure:
3-Amino-4-bromo-5-methylisoxazole (5.31 g, 30 mmol) was dissolved in dry pyridine (30 ml). Benzenesulfonyl chloride (5.24 ml, 42 mmol) was added dropwise with stirring at ambient temperature. N,N-(Dimethyl)aminopyridine (100 mg) was added and stirring was continued at 50° C. for 25 h. The reaction mixture was diluted with dichloromethane (200 ml), washed with 1N HCl (6×100 ml) and the organic phase was dried over magnesium sulfate. The solvent was removed under reduced pressure to yield a crude product which was purified by column chromatography using 9:1, hexanes/ethyl acetate as eluent to give N-(benzenesulfonyl)-N-(4-bromo-5-methyl-3-isoxazolyl)benzenesulfonamide (7 g, 51% yield, Rf=0.27 using 3:1, hexanes/ethyl acetate as eluent) as a solid.
Reaction SMILES: Cl[C:2]([C:7]1(C)[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][CH3:13])([CH2:5][CH3:6])[CH2:3][CH3:4].[CH3:15][NH:16][CH3:17]>C(O)C>[CH3:15][N:16]([CH3:17])[CH:7]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH3:13])[C:2]1([CH2:5][CH3:6])[CH2:3][CH3:4]
Reactant: CNC
Reactant: CCN1CCCC1(C)C(Cl)(CC)CC
Solvent: CCO
Product: CCN1CCCC(N(C)C)C1(CC)CC
Temperature: 40 °C
Reaction time: 44 h

Procedure:
A four-necked pear-shaped flask (500 mL) was charged with 14.04 g (0.07 mol) of 2-(1-chloro-1-ethylpropyl)methyl-1-ethylpyrrolidine, 54.26 g (0.48 mol) of a 40% aqueous dimethylamine solution, and 100 mL of ethanol, and the mixture was stirred at 40° C. for 44 hours.
Reaction SMILES: [Na].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[CH3:13][OH:14]>>[F:10][C:9]([F:12])([F:11])[C:6]1[CH:7]=[CH:8][C:3]([O:14][CH3:13])=[CH:4][CH:5]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CO
Agent: [Na]
Product: COc1ccc(C(F)(F)F)cc1
Temperature: 130 °C
Yield: 41 %

Procedure:
Sodium (12.78 g; 555 mmol) was added to dry MeOH (100 ml). When the gas evolution ceased, the reaction mixture was evaporated to dryness and dry NMP (250 ml) followed by Cu (s) (35.3; 555 mmol) and 4-bromo-trifluoromethylbenzene (25 g; 111 mmol) was added. The reaction mixture was heated to 130° C. for 4 h, cooled to rt. and filtered. Water (500 ml) was added to the filtrate and it was extracted with Et2O (2×200 ml). The combined organic fractions were washed with H2O (2×100 ml), dried (MgSO4) and evaporated to dryness. Column chromatography gave 8.05 g (41%) of product.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]2[CH:25]=[CH:24][C:12]([O:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:11][CH:10]=2)[N:6]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[N:5]=1)([CH3:3])=[CH2:2]>O1CCCC1.CO.[Pd]>[CH:1]([C:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[CH:24][CH:25]=2)[N:6]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc(-c2ccc(OCCNC(=O)OC(C)(C)C)cc2)n(-c2ccc(OC)cc2)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-n2nc(C(C)C)cc2-c2ccc(OCCNC(=O)OC(C)(C)C)cc2)cc1

Procedure:
A mixture of 10% Pd-C 50% wet (65 mg) and tert-butyl 2-{4-[3-isopropenyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamate obtained by Example 7 (645 mg) in tetrahydrofuran (2 ml) and methanol (4 ml) was hydrogenated under H2 1 atm at room temperature for 3 hrs.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[N:36]=[C:37]=[O:38]>C1COCC1>[CH3:24][CH:22]([CH3:23])[C:21]([NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:37]([NH:36][C:27]3[CH:28]=[CH:29][C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:26]=3)=[O:38])[CH2:9][CH2:10]2)[CH:15]=1)=[O:25]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Reactant: O=C=Nc1ccc2ccccc2c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCNC(=O)Nc3ccc4ccccc4c3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 2-naphthyl isocyanate: ESMS m/e: 515.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([O:12][CH3:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[CH:4]([O:12][CH3:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:7][CH:6]=1
Reactant: ClCc1ccccn1
Reactant: COC(=O)C(OC)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(OC)c1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.4 %

Procedure:
A mixture of 2-methoxy-2-(4-hydroxyphenyl)acetic acid methyl ester (see Example 10) (8g; 40 mmol), potassium carbonate (11.04 g; 80 mmol) and 2-chloromethylpyridine hydrochloride (6.56 g; 40 mmol) in DMF (150 ml) was stirred at room temperature for 16 h, and then poured into icy water. The product was extracted with ethyl acetate, the acetate layer was washed with water, brine, dried with magnesium sulfate ans concentated in vacuo. The residue was purified by column chromatography (hexane-ethyl acetate 3:1) to afford 2.0 g of 2-methoxy-2-[4-(2-pyridylmethoxy)phenyl]acetic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][C:12]=1[CH:13]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[Cl:8][C:3]1[C:2]([NH:1][CH2:13][C:12]2[CH:15]=[C:16]([O:19][C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:18][C:11]=2[O:10][CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ccc(OC(F)(F)F)cc1C=O
Reactant: Nc1cccnc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(OC(F)(F)F)cc1CNc1cccnc1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a 75 mL 3-necked round bottom flask fitted with mechanical stirrer, thermometer, addition funnel, and nitrogen inlet, were charged 29 mL acetic acid and 1.45 grams (11.3 mmoles) 3-amino-2-chloropyridine. The mixture was agitated for 5 minutes at 25° C. for dissolution. To the resulting solution was added 3.10 grams (14.1 mmoles/1.25 equivalents) of 2-methoxy-5-trifluoromethoxy benzaldehyde. Sodium triacetoxyborohydride, (4.79 grams, 22.6 mmoles, 2.0 equivalents) was added in portions while maintaining the temperature below 25° C. The reaction mixture was stirred 22 hours at 25° C. before adding another 0.5 grams of sodium triacetoxyborohydride. After stirring an additional 1 hour and 15 minutes, the reaction mixture was vacuum concentrated to 12.5 mL and partitioned between 26 mL each of methylene chloride and water. The pH was adjusted to 9.5 with 25% sodium hydroxide solution while maintaining a temperature of 25°-30° C. with cooling. The layers were separated, and the aqueous layer was washed with 14.5 mL methylene chloride. The methylene chloride layers were combined and dried with magnesium sulfate. The magnesium sulfate was removed by filtration, and the methylene chloride filtrate was evaporated and displaced with ethyl acetate, which resulted in a yellow oil (3.49 gms/92.8% weight yield). The structure of the product was established by high resolution NMR and GC/MS. 1H NMR (CDCl3) 7.70 (dd, 1H), 7.09 (bs, 1H), 7.02 (m, 2H), 6.85 (m, 2H), 4.95 (t, 1H), 4.36 (d, 2H), 3.88 (s, 3H).