Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]([N:19]=C(C1C=CC=CC=1)C1C=CC=CC=1)([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.Cl>C1COCC1>[CH3:1][O:2][C:3](=[O:33])[C:4]([NH2:19])([CH2:5][C:6]1[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=1)[CH2:12][C:13]1[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C(Cc1ccncc1)(Cc1ccncc1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)C(N)(Cc1ccncc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
2-Benzhydrylideneamino-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propionic acid methyl ester (49.6 g, 113 mmol) was dissolved in anhydrous THF (640 ml). To the reaction was added 227 ml of a solution of 2.0 M aqueous hydrochloric acid (HCl). The mixture was stirred at ambient temperature for one hour. The reaction was subsequently concentrated under vacuum to remove the THF. The reaction was then partitioned between ethyl ether and water. The aqueous layer was washed two more times with ethyl ether. The pH of the aqueous layer was then adjusted to 9 with sodium carbonate (Na2CO3) and the solution is extracted with methylene chloride until virtually no product is left in the methylene chloride (CH2Cl2) layer. The CH2Cl2 extracts were combined, dried over Na2SO4, filtered and concentrated under vacuum to give 25.6 g (94.4 mmol) of the titled compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:23][CH3:24].N1C=CC=CC=1.[C:31]1([CH2:37][S:38](Cl)(=[O:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:38]([CH2:37][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)(=[O:40])=[O:39])=[C:3]([O:23][CH3:24])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1N
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1NS(=O)(=O)Cc1ccccc1
Reaction time: 8 h
Yield: 22.7 %

Procedure:
5-(4-Amino-3-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (27 mg, 0.083 mmol) was dissolved in dichloromethane (0.8 mL). Pyridine (0.8 mL) was added followed by phenylmethanesulfonyl chloride (19 mg, 0.105 mmol). After stirring overnight, another 19 mg of phenylmethanesulfonyl chloride was added and the reaction mixture was stirred overnight. The solvent was removed and the residue was purified by preparative thin layer chromatogram eluted with dichlormethane/Methanol (95:5) to give N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]phenylmethanesulfonamide (9 mg, 0.0188 mmol). 1H NMR (DMSO-d6) δ 1.89 (m, 6H), 2.28 (m, 2H), 3.85 (s, 3H), 4.38 (s, 2H), 5.23 (m, 3H), 6.08 (bs, 1H), 6.99 (m, 2H), 7.27, (m, 2H), 7.33 (m, 3H), 7.58 (d, J=8.17 Hz, 1H), 8.34 (s, 1H). LC/MS MH+=478
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20](=[O:37])[CH2:21][NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=3)[N:26]=[CH:25][N:24]=2)[CH2:16]1.C(O)(C(F)(F)F)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[OH:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:16][CH:17]([NH:19][C:20](=[O:37])[CH2:21][NH:22][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([C:33]([F:34])([F:36])[F:35])[CH:31]=5)[N:26]=[CH:25][N:24]=4)[CH2:18]3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: O=C1CCC(c2ncccc2O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(c3ncccc3O)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-(3-hydroxy-pyridin-2-yl)-cyclohexanone (as prepared in step C, 1 eq.) and N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in the previous step, tris TFA salt, 1 eq.) in DCM was added TEA (3 eq.). After stirring at room temperature 30 minutes, NaBH(OAc)3 (3 eq) was added and the mixture was stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution and partially concentrated. Extraction with ethyl acetate followed by concentration of the organic layer in vacuo yielded a residue which was purified by flash chromatography (silica gel, 0-20% 7 N NH3-MeOH/Ethyl acetate) to afford the product as a solid, mixture of isomers.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](O)=O)=[CH:18][CH:17]=1>>[CH3:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]2[O:11][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[NH:1][CH:2]=[N:3][C:4]=4[CH:9]=3)=[N:12][N:13]=2)=[CH:18][CH:17]=1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: CSc1ccc(CCC(=O)O)cc1
Product: CSc1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol) and 3-(4-methylthiophenyl)propionic acid (197 mg; 1 mmol) as described in method 2;
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.O[C:26]([C:29]1[NH:30][C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[C:33]([C:38]#[N:39])[CH:32]=2)([CH3:28])[CH3:27]>O>[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]2[C:20](=[O:21])[C:37]3[C:36]4[C:31](=[CH:32][C:33]([C:38]#[N:39])=[CH:34][CH:35]=4)[NH:30][C:29]=3[C:26]([CH3:28])([CH3:27])[C:18]=2[CH:17]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(O)c1cc2ccc(C#N)cc2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.1 %

Procedure:
(Method 3) To nitrobenzene (5 ml) and aluminum chloride (400 mg, 3 mmol), 4-methoxybenzoyl chloride (400 mg, 2.3 mmol) was added. After stirring for 30 min at room temperature, 2-(1-hydroxy-1-methyl-ethyl)-1H-indole-6-carbonitrile (Compound AA6, 200 mg, 1 mmol) was added followed by stirring at room temperature for 3 hr. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (127 mg, 40%).
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20])[C:11](Cl)=[O:12].[CH:21]1([CH2:27][NH2:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(N(CC)CC)C>[CH:21]1([CH2:27][NH:28][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]#[CH:20])=[C:8]([O:7][CH3:6])[CH:9]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C#CCOc1ccc(C(=O)Cl)cc1OC
Reactant: NCC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCOc1ccc(C(=O)NCC2CCCCC2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a mixture of 10 ml of THF and 0.20 g of 3-methoxy-4-(2-propynyloxy)benzoyl chloride were added dropwise 0.22 g of cyclohexylmethylamine and 0.20 g of triethylamine in order under ice cooling The mixture obtained was stirred at room temperature for 4 hours. Then, the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.22 g of N-cyclohexylmethyl-4-(2-propynyloxy)-3-methoxybenzamide (hereinafter, described as the compound 17 of the present invention) represented by the formula:
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][C:22]4([C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:26](=O)[O:25]4)[CH:21]([CH3:34])[CH2:20]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.B.C1COCC1.[ClH:41].N>O1CCCC1>[ClH:41].[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][C:22]4([C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][O:25]4)[CH:21]([CH3:34])[CH2:20]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC1CN(CCCC2c3ccccc3CCc3ccccc32)CCC12OC(=O)c1ccccc12
Agent: B
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: CC1CN(CCCC2c3ccccc3CCc3ccccc32)CCC12OCc1ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
(1RS,3'SR)-1'-[3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-propyl]3'-methyl-spiro[isobenzofuran-1,4'-piperidin]-3-one (0.5 mmol) was dissolved in tetrahydrofurane and borane-THF-complex (1M solution in THF, 3 mmol) was added under argon. The resulting mixture was heated at reflux for 18 h. It was cooled to 0° C., and 1M HCl was added dropwise until no more gas evolution was observed. The mixture was concentrated in vacuo and HCl (1N, 5 ml) was added to the white foam obtained, and the resulting mixture was stired at 100° C. for 1 h. The solution was then cooled and basified with concentrated aqueous ammonia solution. The product was extracted into dichloromethane and purified by column chromatography over silicagel (ethylacetate). Addition of HCl in ethanol to a solution of the product in ethylacetate/ethanol yielded (1RS,3'SR)-1'-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-propyl]-3'-methyl-spiro[isobenzofuran-1,4'-piperidine] hydrochloride (0.18 g, 82%) as colorless solid, m.p. 225° C. and MS: m/e=438.4 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([F:14])=[CH:4][C:3]=1[NH:15][N:16]=[C:17]([C:22](=[O:26])[CH2:23][O:24][CH3:25])[C:18]([O:20][CH3:21])=[O:19].[CH3:27]OC(OC)N(C)C>>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([F:14])=[CH:4][C:3]=1[N:15]1[CH:27]=[C:23]([O:24][CH3:25])[C:22](=[O:26])[C:17]([C:18]([O:20][CH3:21])=[O:19])=[N:16]1
Reactant: COCC(=O)C(=NNc1cc(F)c(N2CCOCC2)cc1F)C(=O)OC
Reactant: COC(OC)N(C)C
Product: COC(=O)c1nn(-c2cc(F)c(N3CCOCC3)cc2F)cc(OC)c1=O
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of methyl 2-[(2,5-difluoro-4-morpholin-4-ylphenyl)hydrazono]-4-methoxy-3-oxobutanoate (2.8 g, 7.5 mmol) in N,N-dimethylformamide dimethyl acetal (18 mL) was stirred at 100° C. for 80 min. After cooling to room temperature, the precipitate was collected by filtration and washed with iPr2O to give the title compound (2.7 g, 95% yield) as a brown powder: 1H NMR (300 MHz, DMSO-d6): δ ppm 3.12 (4H, dt, J=4.4, 2.5 Hz), 3.48-4.31 (10H, m), 7.18 (1H, dd, J=12.5, 7.6 Hz), 7.72 (1H, dd, J=12.5, 7.2 Hz), 8.50 (1H, s). LC-MS (ESI) m/z 382 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH2:12][CH3:13])[CH:3]=1.[C:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:12]([O:11][C:4]1[CH:3]=[C:2]([N:20]2[CH2:21][CH2:22][N:17]([C:14](=[O:16])[CH3:15])[CH2:18][CH2:19]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])[CH3:13]
Reactant: CC(=O)N1CCNCC1
Reactant: CCOc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(N2CCN(C(C)=O)CC2)ccc1[N+](=O)[O-]

Procedure:
The compound obtained in Step 1 above (300 mg), N-acetylpiperazine (300 mg), and potassium carbonate (500 mg) were dissolved in dimethylformamide (3 mL) and reacted at 80° C. overnight. The dimethylformamide of the reaction mixture was removed under reduced pressure, and added with water to form a solid. The solid was filtered to obtain a target compound as a yellow solid.
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].O1CCCC1.[N:20]([C@H:23]1[CH2:37][O:36][C@H:26]([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C:25](=[O:38])[CH2:24]1)=[N+:21]=[N-:22].Cl>O1CCCC1>[N:20]([C@@H:23]1[CH2:24][C@@H:25]([OH:38])[C@@H:26]([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])[O:36][CH2:37]1)=[N+:21]=[N-:22]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1OC[C@H](N=[N+]=[N-])CC1=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1OC[C@H](N=[N+]=[N-])C[C@H]1O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 59.6 %

Procedure:
Lithium tri-sec-butylborohydride/tetrahydrofuran solution (1.0 mol/l, 0.83 ml, 0.83 mmol) was added to a tetrahydrofuran (2.5 ml) solution of the compound (169 mg, 0.59 mmol) obtained in Step 1 above at −78° C. and the resulting mixture was stirred at −78° C. for 45 minutes. 1N hydrochloric acid was added, the resulting mixture was subjected to extraction with ethyl acetate and the organic layer was washed with brine. The organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography [n-hexane:ethyl acetate=20:1→12:1 (v/v)] to give 101 mg (59%) of the title compound as a colorless oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[N:9]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[Cl:18])[CH2:8][C:5]2([CH2:7][CH2:6]2)[CH2:4][N:3]1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)(=O)C>[CH3:6][C:5]1([CH3:7])[CH2:8][N:9]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[Cl:18])[S:2](=[O:25])(=[O:1])[N:3]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:4]1
Reactant: CCOC(=O)CN1CC2(CC2)CN(c2c(Cl)cc(Cl)cc2Cl)S1(=O)=O
Solvent: CC(=O)O
Product: CCOC(=O)CN1CC(C)(C)CN(c2c(Cl)cc(Cl)cc2Cl)S1(=O)=O
Reaction time: 14 h

Procedure:
Ethyl 2-(6,6-dioxido-7-(2,4,6-trichlorophenyl)-6-thia-5,7-diazaspiro[2.5]-octane-5-yl)acetate (50 mg, 0.12 mmol) and Pt(IV)O2 (54 mg, 0.24 mmol) were dissolved in acetic acid (10 mL) in a reactor and then air in the reactor was removed by introducing hydrogen gas, followed by shaking for 14 hr under 50 psi. The resultant was washed with ethyl acetate and filtered over celite. To the filtrate, was added water (50 mL) and neutralized using 1 N NaOH, followed by extraction to obtain the organic layer. The resultant was dried over MgSO4, concentrated under reduced pressure, and purified by column chromatography (hexane:ethyl acetate=8:2), giving the compound of interest (46 mg, 77%, light apricot-colored solid). 1H NMR (300 MHz, CDCl3): δ 7.38 (s, 2H), 4.26-4.19 (q, 2H, J=7.1, 7.1, 7.1 Hz), 4.17 (s, 2H), 3.65 (s, 2H), 3.49 (s, 2H), 1.32-1.27 (t, 3H, J=7.1, 7.1 Hz), 1.22 (s, 6H).
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]([Cl:27])=[CH:25][N:26]=1)[C:21](O)=[O:22]>>[NH2:17][C:18]1[CH:19]=[C:20]([C:24]([Cl:27])=[CH:25][N:26]=1)[C:21]([NH:14][CH:12]([C:9]1[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:15])[F:16])=[CH:7][CH:8]=1)[CH3:13])=[O:22]
Reactant: Nc1cc(C(=O)O)c(Cl)cn1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Agent: Cl
Product: CC(NC(=O)c1cc(N)ncc1Cl)c1ccc(OCC(F)(F)F)nc1
Yield: 39 %

Procedure:
The title compound is prepared in 39% yield (213 mg, a white solid) from (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (379 mg, 1.48 mmol, Amine-1, single enantiomer) and 2-amino-5-chloroisonicotinic acid (280 mg, 1.62 mmol) by the similar manner in Step-1 of Example-8.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH:40]([CH3:42])[CH3:41]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:40]([CH3:42])[CH3:41])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1

Procedure:
Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 8.0 mg, 0.018 mmol) in DMF (1.0 ml) was reacted with K2CO3 (8.0 mg, 0.055 mmol) and 2-iodopropane (9.0 μl, 0.092 mmol) to yield the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:4](=[O:20])[N:3]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[F:8][C:7]1[C:2](=[NH:1])[N:3]([CH2:26][C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)[C:4](=[O:20])[N:5]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)(=[O:10])=[O:11])[CH:6]=1
Reactant: COc1ccc(S(=O)(=O)n2cc(F)c(N)nc2=O)cc1
Reactant: OCc1cccs1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2cc(F)c(=N)n(Cc3cccs3)c2=O)cc1
Temperature: 25 °C

Procedure:
To a 25 mL vial with magnetic stirring were added 4-amino-5-fluoro-1-((4-methoxyphenyl)sulfonyl)pyrimidin-2(1H)-one (150 mg, 0.501 mmol), thiophen-2-ylmethanol (172 mg, 1.504 mmol), triphenylphosphine (Ph3P; 394 mg, 1.504 mmol) and dry tetrahydrofuran (THF; 4.204 mL). The reaction mixture was placed under nitrogen (N2) atmosphere and cooled to ice-bath temperature. After cooling 10 minutes (min), diethylazodicarboxylate (DEAD; 0.238 mL, 1.504 mmol) was added dropwise and the mixture was allowed to warm to room temperature overnight. The reaction mixture was evaporated to dryness. The crude residue was purified on SiO2 (EtOAc/hexanes gradient) to provide the title compound as a yellow-white wax (146 mg, 73.8%): 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=9.1 Hz, 2H), 7.84 (d, J=1.8 Hz, 1H), 7.67 (d, J=5.5 Hz, 1H), 7.17 (dd, J=5.2, 1.2 Hz, 1H), 7.13 (d, J=3.5 Hz, 1H), 7.02 (d, J=9.1 Hz, 2H), 6.88 (dd, J=5.1, 3.5 Hz, 1H), 5.28 (s, 2H), 3.91 (s, 3H);. UV (CH2Cl2) λmax: 259 nm; ESIMS m/z 396.5 ([M+H]+). Step 2: 5-Fluoro-4-imino-3-(thiophen-2-ylmethyl)-3,4-dihydropyrimidin-2(1H)-one (2). To a magnetically stirred mixture of 5-fluoro-4-imino-1-((4-methoxyphenyl)sulfonyl)-3-(thiophen-2-ylmethyl)-3,4-dihydropyrimidin-2(1H)-one (130 mg, 0.329 mmol) in dry TFA (2.529 mL) was added dimethyl sulfide (0.122 mL, 1.64 mmol) in a dry 25 mL vial under Argon atmosphere. The reaction mixture was stirred at 23° C. for 16 h. The reaction mixture was evaporated to dryness and the crude residue was diluted with ice-water and aqueous saturated sodium bicarbonate solution and extracted with CH2Cl2 (2×). The layers were separated, the combined organic extracts were evaporated, and the crude residue was purified on SiO2 (EtOAc/CH2Cl2 gradient) to afford the title compound as an off-white wax (15 mg, 19.2%): 1H NMR (400 MHz, CDCl3+D2O) δ 7.22 (br d, J=3.4 Hz, 1H), 7.21 (dd, J=5.2, 1.1 Hz, 1H), 6.94 (dd, J=5.1, 3.5 Hz, 1H), 6.72 (d, J=4.3 Hz, 1H), 5.38 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 152.48 (d, J=30.5 Hz), 151.06 (s), 138.17 (s), 137.82 (s), 128.48 (s), 126.30 (s), 125.76 (s), 115.39 (d, J=35.1 Hz), 39.30 (s); ESIMS m/z 226.3 ([M+H]+), 224.4 ([M−H]−).
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[F:69][C:70]1([F:121])[C:82]2[CH:81]=[C:80]([C:83]3[NH:87][C:86]([C@@H:88]4[CH2:92][CH2:91][CH2:90][N:89]4[C:93](=[O:106])[C@@H:94]([NH:101][C:102](=[O:105])[O:103][CH3:104])[CH:95]4[CH2:100][CH2:99][O:98][CH2:97][CH2:96]4)=[N:85][CH:84]=3)[CH:79]=[CH:78][C:77]=2[C:76]2[C:71]1=[CH:72][C:73]([C:107]1[CH:108]=[CH:109][C:110]3[N:114]=[C:113]([C@@H:115]4[CH2:119][CH2:118][CH2:117][NH:116]4)[NH:112][C:111]=3[CH:120]=1)=[CH:74][CH:75]=2>>[CH3:60][O:59][C:57](=[O:58])[NH:56][C@H:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:48]([N:116]1[CH2:117][CH2:118][CH2:119][C@H:115]1[C:113]1[NH:112][C:111]2[CH:120]=[C:107]([C:73]3[CH:74]=[CH:75][C:76]4[C:77]5[C:82](=[CH:81][C:80]([C:83]6[NH:87][C:86]([C@@H:88]7[CH2:92][CH2:91][CH2:90][N:89]7[C:93](=[O:106])[C@@H:94]([NH:101][C:102]([O:103][CH3:104])=[O:105])[CH:95]7[CH2:100][CH2:99][O:98][CH2:97][CH2:96]7)=[N:85][CH:84]=6)=[CH:79][CH:78]=5)[C:70]([F:69])([F:121])[C:71]=4[CH:72]=3)[CH:108]=[CH:109][C:110]=2[N:114]=1)=[O:61]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6CCCN6)[nH]c5c4)ccc2-3)[nH]1)C1CCOCC1
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]c5c4)ccc2-3)[nH]1)C1CCOCC1

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-2-((S)-2-(5-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 914.51 [M+H]+. (86.2 mg, 53%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14]([NH:20][CH3:21])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+](=[CH2:24])=[N-]>CO.CN(C)C=O.C(OCC)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:12]2[CH:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14]([NH:20][CH3:21])[N:13]=2)[CH3:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(NC)n1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CO
Product: CNc1cc(N(C)S(=O)(=O)c2ccc(N)cc2)nc(NC)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
0.65 g (0.0021 mol) of 4-amino-N-(2,6-bis-methylamino-pyrimidin-4-yl)-benzenesulfonamide was dissolved in a mixture of 100 ml of methanol and 400 ml of dimethylformamide and treated with 60 ml of a solution of diazomethane in diethyl ether. The mixture was stirred at room temperature for 30 minutes. The solvent was distilled off and the residue was chromatographed over 50 g of SiO2 with 5% of methanol in methylene chloride as the eluent. There was obtained 0.24 g (35%) of 4-amino-N-(2,6-bis-methylamino-pyrimidin-4-yl)-N-methyl-benzenesulfonamide as a yellow solid; m.p.: 79-80° C.