Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18])([O-])=O.[H][H].[S]>C(O)C.[Ni]>[C:11]1([S:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([C:17]([F:20])([F:18])[F:19])[CH:6]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Sc2ccccc2)cc1C(F)(F)F
Agent: [Ni]
Agent: [S]
Solvent: CCO
Product: Nc1ccc(Sc2ccccc2)cc1C(F)(F)F

Procedure:
2-Nitro-5-phenylthiobenzotrifluoride (25.6 g, 0.86 mole) in ethanol (500 ml) is reduced over Raney nickel at about 45 psi of hydrogen gas. After hydrogen uptake is complete the mixture is deactivated with elemental sulfur, filtered, and the filtrate evaporated under reduced pressure to afford product as an oil. The infrared spectrum shows an absorption at 2.9μ (strong NH band). The product crystallizes on standing to give a solid, m.p. 63°-66.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]1)=[O:22].[Cl:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]3)=[O:12])[N:8]2[C:37]2[CH:36]=[CH:35][N:34]=[C:33]([Cl:32])[CH:38]=2)=[CH:4][C:3]=1[C:21]([N:23]1[CH2:24][CH2:25][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:27][CH2:28]1)=[O:22]
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CC(C)N1CCN(C(=O)c2cc3cc(C(=O)N4CCC(F)(F)CC4)[nH]c3cc2Cl)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2cc3cc(C(=O)N4CCC(F)(F)CC4)n(-c4ccnc(Cl)c4)c3cc2Cl)CC1
Yield: 19 %

Procedure:
The title compound was synthesized in analogy to example 66, from [6-chloro-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 227), 2-chloropyridine-4-boronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a colorless foam (19%).
Reaction SMILES: [CH2:1]([CH:5]([CH:9]=[CH2:10])[C:6](=[O:8])[CH3:7])[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:19])C=1.O>ClCCl>[CH2:1]([CH:5]([CH:9]1[O:19][CH2:10]1)[C:6](=[O:8])[CH3:7])[CH2:2][CH2:3][CH3:4]
Reactant: C=CC(CCCC)C(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CCCCC(C(C)=O)C1CO1
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a solution of 3-butyl-4-penten-2-one (14.0 g) in dichloromethane (100 ml) was added m-chloroperbenzoic acid (26.0 g) at 0° to 5° C., and the mixture was stirred at the same temperature for 1 hour and then at 20° C. for 12 hours. The reaction solution was then poured into water, followed by phase separation. The dichloromethane layer was washed with an aqueous sodium hydrogen carbonate solution and then with an aqueous sodium sulfite solution, followed by concentrating. The residue was distilled to obtain 13.3 g of 3-butyl-4,5-epoxy-pentan-2-one.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[Br:22])(=[O:3])[CH3:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[S:24]([O:21][C@@H:8]1[C@H:7]([Br:22])[C@@H:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:10][C@H:9]1[N:11]1[C:20]2[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=2[N:13]=[CH:12]1)([CH3:23])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1Br
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](OS(C)(=O)=O)[C@@H]1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
After 1 g (2.7 mmols) of 5'-O-acetyl-3'-deoxy-3'-bromoadenosine was added to 10 ml of pyridine, 340 mg (1.1 eq.) of methanesulfonyl chloride was added to the mixture. The mixture was stirred at room temperature for 30 minutes and pyridine was distilled off under reduced pressure. The residue was added to 30 ml of water followed by extraction twice with 30 ml of chloroform. After the organic solvent was washed with water and then dried over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to give 1.09 g (yield, 90%) of 2'-O-mesyl-5'-O-acetyl-3'-deoxy-3'-bromoadenosine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)[CH2:6][C:5]2=O.C[Si]([N:28]=[C:29]=[N:30][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)[CH2:6]/[C:5]/2=[N:30]\[C:29]#[N:28]
Reactant: O=C1CC(c2ccc(OC(F)(F)F)cc2)Oc2ccc(Br)cc21
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\CC(c2ccc(OC(F)(F)F)cc2)Oc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a solution of 6-bromo-2-(4-(trifluoromethoxy)phenyl)chroman-4-one (530 mg, 1.37 mmol) in anhydrous DCM (15 mL) was added TiCl4 (1 M solution in DCM, 2.74 mL, 2.74 mmol) dropwise within 15 min at room temperature. After the addition, the reaction mixture was stirred for 1 h. To this mixture was added Bis-trimethylsilylcarbodiimide (561.6 mg, 3 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (80 g) and extracted with DCM (3×50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give (E)-N-(6-bromo-2-(4-(trifluoromethoxy)phenyl)chroman-4-ylidene)cyanamide (540 mg, 90%), which was used in the next step without further purification.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]([CH:25]([CH3:27])[CH3:26])=[C:7]([C:22]([O-:24])=O)[CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:3])[CH3:2].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>O1CCCC1>[CH:1]([C:4]1[NH:5][C:6]([CH:25]([CH3:27])[CH3:26])=[C:7]([C:22]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:24])[CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1=C(C(C)C)NC(C(C)C)=C(C(=O)[O-])C1c1ccc(F)cc1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C(C)C)NC(C(C)C)=C(C(=O)N2CCOCC2)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.05 g (6.5 mmol) of N,N'-carbonylimidazole are added under a nitrogen atmosphere to 1.875 g (5 mmol) of the compound from Example 95 dissolved in 20 ml of dry tetrahydrofuran and the mixture is stirred for 30 minutes at room temperature. It is subsequently heated to reflux for 30 minutes, a solution of 0.87 ml (10 mmol) of morpholine in 5 ml of dry tetrahydrofuran is added and it is heated to boiling for a further 2 hours. After cooling to room temperature, the mixture is concentrated in vacuo and the residue is taken up in dichloromethane and washed successively with 1N hydrochloric acid, 1N sodium hydroxide solution and water. The organic phase is dried over magnesium sulphate and concentrated in vacuo, and the crystalline residue is dried in a desiccator.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[C:6](Cl)(Cl)=[S:7].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[CH2:23][CH2:24][O:25][C:26]1[C:35]2[C:30](=[CH:31][C:32]([Cl:37])=[C:33]([NH2:36])[CH:34]=2)[NH:29][C:28](=[O:38])[C:27]=1[C:39]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([CH3:46])[CH:40]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>O.C(Cl)(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[CH2:23][CH2:24][O:25][C:26]1[C:35]2[C:30](=[CH:31][C:32]([Cl:37])=[C:33]([N:36]=[C:6]=[S:7])[CH:34]=2)[NH:29][C:28](=[O:38])[C:27]=1[C:39]1[CH:40]=[C:41]([CH3:46])[CH:42]=[C:43]([CH3:45])[CH:44]=1)=[O:16])([CH3:11])([CH3:13])[CH3:12]
Reactant: S=C(Cl)Cl
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(N)c(Cl)cc3[nH]c2=O)c1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(N=C=S)c(Cl)cc3[nH]c2=O)c1

Procedure:
To a stirred suspension of calcium carbonate (320 mg) and thiophosgene (120 mg) in 10 mL water:chloroform (1:1) at 0° C. was added 2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (450 mg, prepared essentially as described in Example 1) and the mixture stirred at low temperature. After 2 hours the reaction was quenched by the addition of 10% hydrochloric acid and stirring continued until the gas evolution ceased. The mixture was then extracted with chloroform, the combined organics dried over magnesium sulfate and concentrated in vacuo to provide the crude title compound (480 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([O:20]CC=C)[CH:13]=2)[O:9][N:8]=1.B(Cl)(Cl)Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([OH:20])[CH:15]=[C:16]([C:18]#[N:19])[CH:17]=2)[O:9][N:8]=1
Reactant: C=CCOc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-allyloxy-5-cyanophenyl)-1,2,4-oxadiazole (1.0 g, 3.4 mmol) and tetrabutylammonium iodide (1.4 g, 3.8 mmol) in dichloromethane (18 mL) at −78° C., under argon, was treated with a solution of 1 M boron trichloride in dichloromethane (22 mL, 22 mmol). After 5 minutes at −78° C. the reaction mixture was stirred at ambient temperature for 1 hour. The reaction was then quenched with ice water and stirred for 30 minutes. The mixture was then washed with saturated sodium bicarbonate and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. Silica gel chromatography using a gradient of 10% ethyl acetate in hexanes to 80% ethyl acetate in hexanes afforded 460 mg (51%) of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3/MeOD): δ −8.81 (d, 1H), 8.23 (d, 1H), 8.01 (s, 1H), 7.95 (m, 1H), 7.92 (m, 1H), 7.54 (m, 1H), 7.35 (m, 2H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]3[CH2:18][C:17]4([CH2:23][CH2:22][CH:21]([C:24]([O-:26])=[O:25])[CH2:20][CH2:19]4)[O:16][N:15]=3)=[CH:12][N:11]=[C:10]3[N:27]([CH2:30][CH3:31])[N:28]=[CH:29][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+]>O1CCCC1.O>[CH:1]1([NH:7][C:8]2[C:13]([C:14]3[CH2:18][C:17]4([CH2:19][CH2:20][CH:21]([C:24]([OH:26])=[O:25])[CH2:22][CH2:23]4)[O:16][N:15]=3)=[CH:12][N:11]=[C:10]3[N:27]([CH2:30][CH3:31])[N:28]=[CH:29][C:9]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCC(C(=O)[O-])CC4)C3)cnc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCC(C(=O)O)CC4)C3)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl (cis or trans) 3-[4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylate (130 mg, 0.000286 mole) (example 9) was taken in tetrahydrofuran (5 ml). Aqueous lithium hydroxide (48 mg, 0.00147 mole) in 2 ml water was added to it. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The mixture was acidified with 3N hydrochloric acid to about pH of 6. The extraction was done with ethyl acetate. The organic layer was washed with water and brine, dried and concentrated under reduced pressure to get crude product. The title compound was purified by preparative thin layer chromatography.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)(=[O:12])[CH3:11].C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O>[C:10]([O:13][CH2:14][CH2:15][CH2:16][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)(=[O:12])[CH3:11]
Reactant: c1ccc2[nH]cnc2c1
Reactant: CC(=O)OCCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OCCCn1cnc2ccccc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
In a nitrogen atmosphere, a mixture of 118 g of benzimidazole, 181 g of 3-bromopropyl acetate, 111 g of triethylamine, 2 g of sodium iodide, and 500 g of N,N-dimethylformamide was heated and stirred at 80° C. for 16 hours. The reaction mixture was subjected to conventional aqueous work-up and then purified by column chromatography, obtaining 3-(1H-benzimidazol-1-yl)propyl acetate (yield 70%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:21]3[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16]=3[NH:15][CH:14]=2)=[O:12])=[CH:6][CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:36][CH3:37]>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:21]3[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16]=3[N:15]([CH2:36][CH3:37])[CH:14]=2)=[O:12])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCI
Reactant: CCOc1ccc(NC(=O)c2c[nH]c3c2C(=O)CCC3)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(NC(=O)c2cn(CC)c3c2C(=O)CCC3)cc1
Temperature: 85 °C
Yield: 32 %

Procedure:
A mixture of N-(4-ethoxyphenyl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (204 mg, 0.7 mmol), potassium carbonate (188 mg, 1.4 mmol), cesium carbonate (22 mg, 0.1 mmol), and iodoethane (0.08 mL, 1 mmol) in N,N-dimethylformamide was heated at 85° C. for 1 hour. The mixture was cooled and filtered using ethyl acetate. The solid was set aside; the organic layer was washed with water, dried over magnesium sulfate, filtered, concentrated in vacuo, and triturated with diethyl ether to give N-(4-ethoxyphenyl)-1-ethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (73 mg). The set-aside solid was slurried in aqueous hydrochloric acid, the precipitate collected, rinsed with water and dried to give additional amide (Compound 58) (94 mg). mp. 209-210° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7].[Br:14]Br>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][Br:14])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(C)c(OC)c1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A solution of methyl 3-methoxy-4-methylbenzoate (10 grams) and 2,2-azobis(2-methyl-propionitrile) (25 milligrams) in carbon tetrachloride (200 mL) was heated to gentle reflux. Bromine (9 grams) was added in portions and resulting solution was heated at reflux for 1 hour then stirred at room temperature overnight. The carbon tetrachloride was evaporated and the residue dissolved in ether. The ether solution was washed with water. The ether layer was dried over sodium sulfate then evaporated to give 13.9 grams of crude product. NMR (CDCl3) δ:3.92 (s, 3H), 4.45 (s, 2H), 7.65-7.00 (m, 3H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[N:7]=[C:6]([NH:10][C:11]([N:13]3[C:21]4[C:16](=[CH:17][C:18]([O:22][C:23]5[CH:28]=[CH:27][N:26]=[C:25]([CH2:29][N:30](C)[C:31](=O)OC(C)(C)C)[CH:24]=5)=[CH:19][CH:20]=4)[CH:15]=[CH:14]3)=[O:12])[CH:5]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([C:4]2[N:8]([CH3:9])[N:7]=[C:6]([NH:10][C:11]([N:13]3[C:21]4[C:16](=[CH:17][C:18]([O:22][C:23]5[CH:28]=[CH:27][N:26]=[C:25]([CH2:29][NH:30][CH3:31])[CH:24]=5)=[CH:19][CH:20]=4)[CH:15]=[CH:14]3)=[O:12])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CN(Cc1cc(Oc2ccc3c(ccn3C(=O)Nc3cc(C4CC4)n(C)n3)c2)ccn1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cc(C4CC4)n(C)n3)c2)ccn1
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (4-(1-(5-cyclopropyl-1-methyl-1H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy)pyridin-2-yl)methyl(methyl)carbamate (0.124 g, 0.240 mmol) in DCM (5 ml) is added TFA (2 ml, 0.240 mmol). The reaction is stirred for approximately 30 minutes and then concentrated in vacuo to near dryness. The residue is dissolved in DCM, diluted with water and neutralized via the addition of saturated aqueous NaHCO3. The resulting layers are then separated and the aqueous layer is extracted twice with DCM. The organic layers are combined dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue is purified via FCC (0-15% MeOH/DCM) to provide the title compound. MS (ESI) m/z 417.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.64-0.70 (m, 2 H) 0.96-1.02 (m, 2 H) 1.87-1.96 (m, 1 H) 2.27 (s, 3 H) 3.71 (s, 2 H) 3.80 (s, 3 H) 6.16 (d, J=0.51 Hz, 1 H) 6.73 (dd, J=3.79, 0.51 Hz, 1 H) 6.80 (dd, J=5.56, 2.53 Hz, 1 H) 6.93 (d, J=2.02 Hz, 1 H) 7.09 (dd, J=8.97, 2.40 Hz, 1 H) 7.42 (d, J=2.27 Hz, 1 H) 8.17 (d, J=3.54 Hz, 1 H) 8.33 (d, J=8.84 Hz, 1 H) 8.36 (d, J=5.81 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][C@H:34]([NH:37][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:19]=2)=[O:21])[CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)N[C@H]3CCN(C(=O)OC(C)(C)C)C3)ccc21
Yield: 63.2 %

Procedure:
(S)-3-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester (65 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (70 mg), (S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (46 mg), HBTU (95 mg), and DIEA (70 uL) in DMF (1 mL).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[O:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:17][CH2:16][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)[C:7]=1[NH2:8]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: NCC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Nc1c(Cl)ncnc1NCC1CCOCC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
Charge a microwave reaction vial with 4,6-dichloro-pyrimidin-5-ylamine (12.20 mmoles, 2.00 g), isopropyl alcohol (5 mL), C-(tetrahydro-pyran-4-yl)-methylamine (14.63 mmoles, 1.69 g), and N,N-diisopropylethylamine (15.85 mmoles, 2.76 mL). Irradiate with stirring at 140° C. for 2 hours with high absorbance mode in the microwave. Solvent is evaporated and residue triturated with dichloromethane to afford 6-Chloro-N*4*-(tetrahydro-pyran-4-ylmethyl)-pyrimidine-4,5-diamine
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][S:23]([C:26]1[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=1[CH3:34])(=[O:25])=[O:24].[CH3:35]I.O>CN(C)C=O>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]([CH3:35])[S:23]([C:26]1[C:27]([CH3:34])=[CH:28][C:29]([CH3:33])=[CH:30][C:31]=1[CH3:32])(=[O:25])=[O:24]
Reactant: Cc1cc(C)c(S(=O)(=O)Nc2ccccc2CSc2nccn2-c2ccccn2)c(C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)N(C)c2ccccc2CSc2nccn2-c2ccccn2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100 mg of 60% sodium hydride are suspended in 2 ml of dimethyl formamide, and a solution of one g of 1-(2-pyridyl)-2-[2-(2,4,6-trimethylphenyl)sulfonylaminobenzylthio]imidazole in 2 ml of dimethyl formamide is added thereto under ice-cooling. The mixture is stirred at room temperature for 30 minutes, and 320 mg of methyl iodide are added thereto. The mixture is stirred for 2 hours. The reaction mixture is poured into water, and the resultant oily product is extracted with ethyl acetate. The extract is dried and evaporated. The residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=3:2), whereby 0.76 g of 1-(2-pyridyl)-2-{2-[N-methyl-N-(2,4,6-trimethylphenyl)sulfonylamino]benzylthio}imidazole is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=1.[CH3:25][P:26]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([O:36][C:37]([F:40])([F:39])[F:38])[CH:30]=1)([CH3:28])=[O:27]>>[CH3:28][P:26]([C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=2)=[C:31]([O:36][C:37]([F:38])([F:40])[F:39])[CH:30]=1)([CH3:25])=[O:27]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Cl)ncc1C(F)(F)F
Reactant: CP(C)(=O)c1ccc(N)c(OC(F)(F)F)c1
Product: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Nc2ccc(P(C)(C)=O)cc2OC(F)(F)F)ncc1C(F)(F)F

Procedure:
This compound can be prepared as described in Example 80 by reacting 2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-4-amine with 4-(Dimethylphosphoryl)-2-(trifluoromethoxy)aniline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:12][C:11]([CH2:21][CH:22]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28](COCC[Si](C)(C)C)[CH:27]=3)[C:23]([OH:25])=[O:24])=[N:10]2)=[CH:5][CH:4]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[NH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]([CH:22]([CH2:21][C:11]2[CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:10]=2)[C:23]([OH:25])=[O:24])=[CH:27]1
Reactant: COc1ccc(-n2nc(CC(C(=O)O)c3cn(COCC[Si](C)(C)C)c4ccccc34)cc2-c2ccc(C)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(-n2nc(CC(C(=O)O)c3c[nH]c4ccccc34)cc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
A solution of 3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-3-yl]-propionic acid (Example 70, 0.17 g, 0.29 mmol) and 1.0 M TBAF (2.88 mL) in THF was heated to 60° C. for24 h. The reaction mixture was cooled to rt, diluted with EtOAc (100 mL), and washed with water (3×30 mL) and brine (1×30 mL). The organic layer was dried with Na2SO4, and the solvent was removed under reduced pressure. The crude residue was purified by reversed-phase HPLC giving 111 mg (85%) of 2-(1H-indol-3-yl)-3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-propionic acid. HPLC: Rt=3.0 (Method B). MS (ES+): mass calculated for C28H25N3O3, 451.19; m/z found 452.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 10.97 (s, 1H), 7.64 (d, J=6.3 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.13-7.07 (m, 5H), 7.04 (d, J=8.1 Hz, 2H), 6.98 (t, J=8.0 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 6.36 (s, 1H), 4.22 (dd, J=6.1, 9.0 Hz, 1H), 3.77 (s, 3H), 3.45 (dd, J=9.0, 14.7 Hz, 1H), 3.06 (dd, J=6.2, 14.7 Hz, 1H), 2.27 (s, 3H).