Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=O)[CH2:7][C:8]([O:10]CC)=[O:9].[N:14]([C:17]1[CH:27]=[CH:26][C:20]([C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)=[N+:15]=[N-:16].[O-]CC.[Na+].[OH-].[Na+]>C(O)C.O>[CH2:24]([NH:23][C:21]([C:20]1[CH:26]=[CH:27][C:17]([N:14]2[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][F:1])=[C:7]([C:8]([OH:10])=[O:9])[N:16]=[N:15]2)=[CH:18][CH:19]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)CC(=O)CCCCF
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCCCF)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
Ethyl 7-fluoro-3-oxoheptanoate (0.920 g, 4.84 mmol, 1.17 eq.) obtained in Example 108a) and 4-azido-N-ethylbenzamide (0.790 g, 4.15 mmol) were dissolved in ethanol (25 ml), sodium ethoxide (366 mg, 4.84 mmol, 1.17 eq.) was added, and the mixture was stirred at room temperature for 30 min, and then at 60° C. for 11 hr. 1N Aqueous sodium hydroxide solution (4.15 ml, 1.0 eq.) was added to the reaction mixture and the mixture was further stirred for 1 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and washed with ethyl acetate-hexane (1:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, and acidified (pH<3) with 6N hydrochloric acid. The precipitate was collected by filtration, washed with water and dried to give the title compound as a pale-gray powder (1.26 g, 3.77 mmol, 90.8%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][C:31](=[O:46])[C@H:32]([CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:33][CH3:34])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][NH:30][C:31](=[O:46])[C@H:32]([CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[N:33]([C:18](=[O:20])[C@H:9]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:34])=[CH:26][CH:27]=1
Reactant: CN[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Product: CN(C(=O)[C@H](CCc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCc1ccc(F)cc1

Procedure:
Using Procedure D, Boc-homophenylalanine (143 mg) and Nδ-Boc-Nα-methylornithine 2-(4-fluorophenyl)ethylamide (B) (crude product) gave desired compound (195 mg) as a glassy solid which was purified by flash chromatography: 1H NMR (400 MHz, CDCl3) δ1.52 (2 s, 18H).1.71 (m, 2H), 1.82 (m, 4H), 2.62-2.80 (m, 7H), 3.12 (m, 2H), 3.45 (m, 2H), 4.61 (m, 1H), 4.92 (m, 1H), 6.89 (m, 2H), 7.13 (m, 2H), 7.20 (m, 3H), and 7.32 (m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:22][CH2:23][CH2:24][CH3:25])[N:18]([CH2:19][CH2:20][NH2:21])[C:14]=2[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1>ClCCl>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:22][CH2:23][CH2:24][CH3:25])[N:18]([CH2:19][CH2:20][NH:21][C:1](=[O:3])[CH3:2])[C:14]=2[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CC(=O)Cl
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
Under a nitrogen atmosphere, acetyl chloride (50 μL, 0.7 mmole) in dichloromethane (25 mL) was added dropwise to a cooled (ice bath) solution of 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.2 g, 0.7 mmol) in dichloromethane (50 mL). After the addition was complete, the reaction mixture was allowed to warm to ambient temperature. After 30 minutes thin layer chromatography indicated that the reaction was complete. The reaction mixture was washed with 10% sodium hydroxide, water and brine; dried; and concentrated under vacuum to provide 0.25 g of crude product. This material was purified by column chromatography (silica gel eluting with dichloromethane) to provide 0.2 g of a solid. This solid was recrystallized from acetonitrile (30 mL) to provide 0.18 g of N′-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]acetamide as a white powder, m.p.228-230° C. Analysis: Calculated for C17H22N6O: %C, 62.56; %H, 6.79; %N, 25.75; Found: %C, 62.50; %H, 6.59; %N, 26.04. HRMS (EI) calcd for C22H26N6O2 (M+) 326.1855, found 326.1846
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]([O:16]C(C)(C)C)=[O:15])[N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product from step E (5.54 g, 12 mmol) in 30 mL of dichloromethane was added 13 mL of trifluoroacetic acid. The reaction mixture was stirred at ambient temperature for 16 h then was concentrated in vacuo and excess trifluoroacetic acid removed by azeotropic distillation with dichloromethane to provide the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ; 8.00 (d, J=8.2 Hz, 2H); 7.83 (d, J=1.8 Hz, 2H); 7.41 (d, J=1.9 Hz, 1H); 7.36 (d, J=8.3 Hz, 2H); 7.32 (s, 1H); 5.94 (s, 2H); 4.87 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>>[C:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:10])[CH3:9]
Reactant: Nc1ccccc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccccc1

Procedure:
The aminophenyl-β-sulfatoethylsulfone has been produced by reacting aniline with acetic anhydride to produce acetoanilide, followed by chlorosulfonating the latter with a largely excessive quantity of chlorosulfonic acid to produce acetylaminobenzenesulfonyl chloride, reducing the latter with sodium sulfite to produce the corresponding sulfinic acid, reacting the latter with ethylene oxide or ethylene chlorohydrin to produce acetylaminophenyl-β-hydroxyethylsulfone, and then subjecting the latter to hydrolysis and esterification in sulfuric acid to obtain the desired sulfuric ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([Cl:19])[C:10]=1[C:20]1[C:29]2[N:28]=[C:27]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]3)[CH:26]=[N:25][C:24]=2[C:23]([C:39](O)=[O:40])=[CH:22][CH:21]=1>C(Cl)Cl.CO>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:39]([C:23]2[C:24]3[N:25]=[CH:26][C:27]([CH2:30][N:31]4[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]4)=[N:28][C:29]=3[C:20]([C:10]3[C:9]([Cl:8])=[C:14]([O:15][CH3:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=3[Cl:19])=[CH:21][CH:22]=2)=[O:40])[CH:3]=1
Reactant: CCN1CCN(Cc2cnc3c(C(=O)O)ccc(-c4c(Cl)c(OC)cc(OC)c4Cl)c3n2)CC1
Reactant: Nc1cccnc1
Solvent: ClCCl
Solvent: CO
Product: CCN1CCN(Cc2cnc3c(C(=O)Nc4cccnc4)ccc(-c4c(Cl)c(OC)cc(OC)c4Cl)c3n2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 3-aminopyridine, 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-(4-ethyl-piperazin-1-ylmethyl)-quinoxaline-5-carboxylic acid (Step 83.1) and stirring the reaction mixture for 2 days at rt. Title compound: ESI-MS: 581.0/583.2 [M+H]+; tR=3.04 min (System 1); TLC: Rf=0.33 (DCM/MeOH, 9:1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][C:18]([Br:19])=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[C:1]1([S:7]([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][C:18]([Br:19])=[C:13]3[CH:12]=[C:11]2[CH3:20])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)cncc21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2c(Br)cncc2n1S(=O)(=O)c1ccccc1
Temperature: -35 °C
Reaction time: 0.75 h
Yield: 39.1 %

Procedure:
A 50 mL round-bottomed flask, under nitrogen fitted with a thermometer probe, and a condenser/inert gas bubbler (via a Claisen head), was charged with a solution of 1-benzenesulfonyl-4-bromo-1H-pyrrolo[2,3-c]pyridine (0.96 g, 2.84 mmol) in anhydrous THF (10 mL). To the resultant solution, at −35° C., was added dropwise a solution of lithium diisopropylamide (2.0M in heptane/THF/ethyl benzene, 2.84 mL, 5.68 mmol) and the mixture then stirred at −35° C. for 45 min. Methyl iodide (1.06 mL, 17.04 mmol) was added to the reaction mixture dropwise. The resulting solution was allowed to reach room temperature and was stirred for 3 h. The reaction was quenched by addition of a solution of 1N HCl (5 mL); the solution was diluted with water (15 mL) and extracted with EtOAc (2×75 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, 0-100% DCM:cyclohexane). The residue was triturated with EtOAc (2 mL) and the precipitate was collected by filtration to give the title compound as a white solid (0.39 g, 39%). LCMS (Method A): RT=4.47 min, [M+H]+ 351 (79Br), 353 (81Br)
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[C:23]([N:27]1[N:31]=[N:30][C:29]([C:32]2[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=2[CH:34]=O)=[N:28]1)([CH3:26])([CH3:25])[CH3:24]>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:34][C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[C:29]4[N:30]=[N:31][N:27]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:28]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: CC(C)(C)n1nnc(-c2ccccc2C=O)n1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)n1nnc(-c2ccccc2C=Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)n1

Procedure:
Analogously to Example 32, 521 mg (2.00 mmol) of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 343 μl of acetic acid are dissolved in 50 ml of methanol and reacted with 691 mg (3.0 mmol) of 2-(2-tert-butyl-tetrazol-5-yl)-benzaldehyde to form 4-(3-chloro-phenylamino)-3-[(2-(2-tert-butyl-tetrazol-5-yl)-phenyl}-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of the above intermediate in 30 ml of DMEU with 16 ml (16 mmol) of DIBAL-H and analogous working-up yield 4-(3-chloro-phenylamino)-3-[2-(2-tert-butyl-tetrazol-5-yl)-benzylamino]-1H-pyrazolo[3,4d]pyrimidine; TLC: Rf=0.64 (CHCl3/methanol/H2O/acetic acid=85:13:1.5:0.5); HPLC: tRet(grad20-100)=10.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:19](O)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.FC1C=CC([N:41]2C3C(=CC(C(C4C=CC=CC=4)C(C)(C)CN)=CC=3)C=N2)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:19]([NH2:41])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C(c1ccccc1)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: CC(C)(CN)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Product: NC(=O)C(c1ccccc1)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
(c)(d) 3-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2,3-diphenylpropanoic acid (80, mg, 0.154 mmol) was converted into the acid fluoride using the identical procedure to that for Synthetic Intermediate I above. A solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,3-diphenylpropanoyl fluoride in anhydrous THF (5 mL) at −78° C. was bubbled NH3 (g) for 10 minutes. The reaction mixture was sealed and stirred at −78° C. for 15 min and at rt for 1 hr. Water (100 mL) was added, the reaction mixture was extracted with ethyl acetate (100 mL), dried (Na2SO4), and concentrated to give 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,3-diphenylpropan-amide.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.O>CN(C)C=O>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:23][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cccnc1Cl
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccnc1Oc1cccc(Cl)c1

Procedure:
A solution 2-Chloro-nicotinonitrile (5.0 grams, 36.1 mmole), cesium carbonate (23.5 grams, 72.2 mmole) and 3-chlorophenol (4.65 grams, 36.1 mmole) in dimethylformamide (100 ml) was heated to 80° C. over night. The mixture was cooled and poured into 500 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to a white solid (8.21 g). M.P. 88-90° C.; Anal. calcd. for C12H7N2OCl: C, 62.49; H, 3.06; N, 12.15. Found: C, 62.43; H, 3.00; N, 12.13.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[OH:12].[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=O)=[CH:17][CH:16]=1>S(Cl)(Cl)=O>[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]2[O:12][C:3]3[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=3[N:1]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1cccc(N)c1O
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc2nc(-c3ccc(OC)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
Methyl 2-(4-methoxyphenyl)benzoxazole-7-carboxylate was prepared from methyl 3-aminosalicylate and 4-methoxybenzoyl chloride as described in Step A of Example 1. The crude material was suspended in thionyl chloride (15 mL) and the mixture heated to reflux overnight. After this time the reaction was cooled and concentrated to a dark oil. This oil was treated with methanol and the solution stirred at room temperature for 1 h. Subsequent concentration afforded a dark brown solid which was purified by column chromatography to afford a 24% yield of methyl 2-(4-methoxyphenyl)benzoxazole-7-carboxylate as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 8.19 (d, J=8.7 Hz, 2H), 8.04 (d, J=7.8 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.20 (d, J=8.7 Hz, 2H), 3.99 (s, 3H); 3.88 (s, 3H); MS (ESI) m/z 284 [M+H]+.
Reaction SMILES: Cl.[CH3:2][NH:3][CH:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[C:22]3[C:21]4[C@@H:20]([CH2:23][C@H:24]([OH:26])[CH3:25])[CH2:19][CH2:18][C:17]=4[S:16][C:15]=3[N:14]=[CH:13][N:12]=2)[CH2:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)=[O:36]>CN(C=O)C>[OH:26][C@H:24]([CH3:25])[CH2:23][C@H:20]1[CH2:19][CH2:18][C:17]2[S:16][C:15]3[N:14]=[CH:13][N:12]=[C:11]([O:10][CH:7]4[CH2:6][CH2:5][CH:4]([N:3]([CH3:2])[CH2:34][C:35]([N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)=[O:36])[CH2:9][CH2:8]4)[C:22]=3[C:21]1=2
Reactant: O=C(CCl)N1CCCC1
Reactant: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@@H](C)O)CC4)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](O)C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)CC(=O)N5CCCC5)CC4)c3c21
Temperature: 25 °C
Reaction time: 14 h
Yield: 34.1 %

Procedure:
A 50-mL round-bottom flask was charged with a solution of tert-butyl N-(4-[[(3R)-3-[(2R)-2-hydroxypropyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (170 mg, 0.38 mmol, 1.0 equiv) in 5.5 mL of dichloromethane cooled to 0° C. Then hydrochloric acid (12 M, 0.5 mL) was added and the resulting solution was stirred for 3 h at room temperature. The reaction mixture was concentrated under reduced pressure to give (2R)-1-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-3-yl]propan-2-ol hydrochloride (130 mg, crude) as a light yellow oil. The resulting hydrochloride (130 mg, crude) was dissolved in DMF (5 mL). Potassium carbonate (359 mg) and 2-chloro-1-(pyrrolidin-1-yl)ethan-1-one (125 mg) were added at room temperature and the resulting mixture was stirred for 14 h at 25° C. After completion of the reaction, the product was extracted with DCM, washed with brine and concentrated in vacuo. The crude product (160 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): Column: SunFire Prep C18, 19*150 mm, 5 μm; mobile phase: water (with 0.1% HCOOH) and CH3CN (6.0% CH3CN up to 50.0% in 25 min); UV detection at 254/220 nm. The product containing fractions were collected and evaporated to remove the water and CH3CN to give 2-[(4-[[(3R)-3-[(2R)-2-hydroxypropyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)(methyl)amino]-1-(pyrrolidin-1-yl)ethan-1-one (52.7 mg) as a white solid. MS (ES): m/z 473 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 8.46 (1H, s), 5.32-5.18 (1H, m), 3.94-3.92 (1H, m), 3.57 (2H, t), 3.45 (2H, t), 3.36 (3H, m), 3.08-3.10 (1H, m), 2.96-2.98 (1H, m), 2.67-2.62 (2H, m), 2.41-2.29 (6H, m), 2.070-1.97 (5H, m), 1.95-1.87 (2H, m), 1.64-1.52 (5H, m), 1.30 (3H, d).
Reaction SMILES: Cl[C:2]1[C:3](=[O:21])[O:4][C:5]([CH2:19][CH3:20])([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[Cl:22][C:23]1[CH:35]=[CH:34][C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[C:28]([SH:30])=[N:29][C:25]=2[CH:24]=1>>[Cl:22][C:23]1[CH:35]=[CH:34][C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[C:28]([S:30][C:2]3[C:3](=[O:21])[O:4][C:5]([CH2:19][CH3:20])([CH2:9][CH2:10][C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=4)[CH2:6][C:7]=3[OH:8])=[N:29][C:25]=2[CH:24]=1
Reactant: CCC1(CCc2ccc(OC)cc2)CC(O)=C(Cl)C(=O)O1
Reactant: CC(C)n1c(S)nc2cc(Cl)ccc21
Product: CCC1(CCc2ccc(OC)cc2)CC(O)=C(Sc2nc3cc(Cl)ccc3n2C(C)C)C(=O)O1

Procedure:
The title compound was prepared from 3-Chloro-6-ethyl-4-hydroxy-6-[2-(4-methoxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one from Step 1 and 5-Chloro-1-isopropyl-1H-benzoimidazole-2-thiol using the coupling method described in Example C(4),
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[C:4]([C:12]([O:14]C)=[O:13])[CH:3]=1.[OH-].[Li+].O1CCCC1>CO>[Cl:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[C:4]([C:12]([OH:14])=[O:13])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)c2[nH]c(=O)[nH]c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)c2[nH]c(=O)[nH]c2c1
Temperature: 50 °C
Yield: 89.8 %

Procedure:
Methyl 7-chloro-2oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (351 mg, 1.55 mmol), 1 M aqueous lithium hydroxide (0.774 mL, 1.55 mmol) and tetrahydrofuran (5 mL) were combined and heated to 50° C. for 2 hours. To the reaction was added 1 M aqueous lithium hydroxide (0.774 mL, 1.55 mmol) and methanol (10 mL) and the reaction was heated to reflux for 6 hours and then allowed to cool to ambient temperature overnight. The reaction solution was concentrated in vacuo to remove the tetrahydrofuran and methanol. The residual aqueous layer was extracted with ethyl acetate (2 mL). To the aqueous layer was added water (2 mL) ethyl acetate (2 mL) and 3 M aqueous hydrochloric acid. A precipitate formed. The mixture was filtered and the solids were washed with water and ethyl acetate. The solids were dried under a stream of nitrogen to give the title compound (296 mg, 90%). 1H NMR (400 MHz, DMSO-d) 5 ppm 11.54 (s, 1H) 11.12 (s, 1H) 7.54 (d, J=1.37 Hz, 1H) 7.38 (d, J=1.37 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1(Cl)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](Cl)=[CH:3]1.CC(=[O:16])C>O>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:16])[CH:3]=1
Reactant: CC(C)=O
Reactant: ClC1=CC(Cl)(Cl)c2ccccc21
Solvent: O
Product: O=C1C=C(Cl)c2ccccc21

Procedure:
A mixture of 35 parts of 1,1,3-trichloro-1H-indene, 295 parts of 2-propanone, and 375 parts of water is heated at the boiling point under reflux in a nitrogen atmosphere overnight. The resultant dark brown solution is stripped of solvent by vacuum distillation under nitrogen at 35°. The distilland is extracted with 1,1'-oxybisethane. The extract is consecutively washed with water, 10% sodium chloride, and water, then dried over anhydrous magnesium sulfate and thereupon stripped of solvent by vacuum distillation. The oily residue is crystallized from pentane to give 3-chloro-1H-inden-1-one as a red-orange solid, the formula of which is ##STR4##
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[F:18])=[N:5]1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[S:28][CH:29]=[C:30]([C:32](O)=[O:33])[N:31]=2)[CH2:22][CH2:21]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[C:10]([F:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:32]([C:30]3[N:31]=[C:27]([CH2:26][N:23]4[CH2:22][CH2:21][O:20][CH2:25][CH2:24]4)[S:28][CH:29]=3)=[O:33])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1
Reactant: O=C(O)c1csc(CN2CCOCC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1)NC(=O)c1csc(CN2CCOCC2)n1

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile (0.3 g, 1.07 mmol), 2-(morpholinomethyl)-thiazole-4-carboxylic acid (0.29 g, 1.29 mmol), HOBt (0.22 g, 1.61 mmol), DIPEA (0.56 mL, 3.23 mmol) and EDCI (0.31 g, 1.61 mmol) in 10 mL DMF as solvent using the method of Example 34(d). Yield 0.27 g. 1H NMR (400 MHz; d6-DMSO): 1.13 (d, 3H), 3.61 (m, 4H), 3.84 (d, 2H), 4.39 (m, 3H), 6.78 (dd, 1H), 7.84 (dd, 1H), 7.90 (d, 1H), 8.06 (dd, 1H), 8.15 (s, 1H), 8.45 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=2[N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=1)=[O:23]>>[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][N:34]([CH2:13][C:12]3[CH:15]=[CH:16][C:9]([S:8][C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=4)=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=3)[CH2:33][CH2:32]2)[CH:26]=1)=[O:23]
Reactant: Cc1ccc(Sc2ccc(C=O)cc2[N+](=O)[O-])cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: Cc1ccc(Sc2ccc(CN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)cc2[N+](=O)[O-])cc1

Procedure:
Prepared by Procedure F and Scheme R using 4-[(4-methylphenyl)sulfanyl]-3-nitrobenzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/:e 504.2 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1.C(N(CC)CC)C.I.[NH2:16][C:17]1[C:18]([C:25]([NH:27][C:28](=[NH:31])SC)=[O:26])=[N:19][C:20]([Cl:24])=[C:21]([NH2:23])[N:22]=1>O1CCCC1>[NH2:16][C:17]1[C:18]([C:25]([N:27]=[CH:28][NH:31][N:2]2[CH2:7][CH2:6][S:5][CH2:4][CH2:3]2)=[O:26])=[N:19][C:20]([Cl:24])=[C:21]([NH2:23])[N:22]=1
Reactant: C1CSCCN1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: Cl
Agent: I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1nc(N)c(C(=O)N=CNN2CCSCC2)nc1Cl
Temperature: 0 °C

Procedure:
Thiomorpholine hydrochloride (2.10 g., 0.015 mole), triethylamine (2.1 ml., 0.015 mole), and 1-(3,5-diamino-6-chloropyrazinoyl)-2-methyl-2-thiopseudourea hydroiodide (1.94 g., 0.005 mole) are heated in tetrahydrofuran (50 ml.) at reflux for 4 hrs. The reaction mixture is added to ice-water to precipitate 590 mg. of 3,5-diamino-6-chloro-N-[(4-thiomorpholinyl)aminomethylene]-2-pyrazinecarboxamide which melts at 234°-6° C. after reprecipitation from dilute hydrochloric acid with sodium hydroxide.