Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.C(=O)([O-])O.[Na+].[CH:23]1([C:29]2[C:37]3[C:32](=[CH:33][C:34]([C:38]([O:40][CH3:41])=[O:39])=[CH:35][CH:36]=3)[NH:31][C:30]=2B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:23]1([C:29]2[C:37]3[C:32](=[CH:33][C:34]([C:38]([O:40][CH3:41])=[O:39])=[CH:35][CH:36]=3)[NH:31][C:30]=2[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH2:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(B3OC(C)(C)C(C)(C)O3)[nH]c2c1
Reactant: Brc1ccccc1SCCOC1CCCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3SCCOC3CCCCO3)[nH]c2c1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
To a suspension of 2-[2-(2-bromophenylsulfanyl)ethoxy]tetrahydropyran (1.00 g, 3.2 mmol), sodium hydrogen carbonate (1.10 g, 13.2 mmol) and tetrakis(triphenylphosphine)palladium (363 mg, 0.310 mmol) in 1,2-dimethoxyethane (10 ml) and water (5 ml) was added methyl 3-cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6-carboxylate (1.45 g, 3.78 mmol) with heating under reflux and the mixture was heated under reflux for 2.5 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=5:1-3:1) to give methyl 3-cyclohexyl-2-{2-[2-(tetrahydropyran-2-yloxy)ethylsulfanyl]phenyl}-1H-indole-6-carboxylate (1.38 g, yield 74.5%).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:12]1COCC1>>[CH3:12][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:1]([NH2:9])=[O:8]
Reactant: C1CCOC1
Reactant: NC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccccc1C(N)=O
Temperature: 60 °C
Yield: 91 %

Procedure:
Treat the product of step 5 (10.54 g, 23.3 mmol) in THF (170 mL) with 60% NaH (1.87 g, 47 mmol) followed by CH31I (1.9 mL, 30.5 mmol). Heat the reaction mixture at 60° C. for 30 min and then partition between Et2O (250 mL) and H2O (500 mL). Extract the aqueous layer with Et2O (500 mL), wash the combined organic layers with brine (250 mL), dry with MgSO4 and concentrate to give 9.9 g of the methyl benzamide product as a colorless oil (21 mmol, 91%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4](O[C@H](C2C=CC(Cl)=CC=2N2C=CC(C)=N2)C(F)(F)F)[N:3]=1.[Br:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([Br:47])[C:42]=1[CH:48]([OH:53])[C:49]([F:52])([F:51])[F:50]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:53][CH:48]([C:42]2[C:41]([Br:40])=[CH:46][CH:45]=[CH:44][C:43]=2[Br:47])[C:49]([F:50])([F:51])[F:52])[N:3]=1
Reactant: OC(c1c(Br)cccc1Br)C(F)(F)F
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Product: Nc1nc(OC(c2c(Br)cccc2Br)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with 1-(2,6-dibromophenyl)-2,2,2-trifluoroethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7]3[CH2:8][CH2:9][N:10]4[CH:14]([C:15]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12][CH2:11]4.[H-].[Na+].CC1C=CC(S(O[CH2:31][CH2:32][C:33]2[CH:34]=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=2)(=O)=O)=CC=1>CN(C=O)C.O>[CH3:1][C:2]1[CH:17]=[N:16][C:5]2[N:6]([CH2:31][CH2:32][C:33]3[CH:34]=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=3)[C:7]3[CH2:8][CH2:9][N:10]4[CH:14]([C:15]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12][CH2:11]4
Reactant: Cc1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN2CCCC12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 10-methyl-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine (110 mg, 0.484 mmol) in DMF (1 mL) was added a suspension of NaH (60.0 mg, 1.45 mmol) in DMF (1 mL). After stirring for 5 min at RT, a solution of 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (423 mg, 1.45 mmol) in DMF (1 mL) was added dropwise into the reaction mixture and stirring continued for another 2 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 10-methyl-7-(2-(6-methylpyridin-3-yl)ethyl)-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine. 1H NMR (CD3OD, Tri-HCl salt) δ (ppm): 8.7 (s, 1H), 8.4 (d, 1H), 8.25 (s, 2H), 7.8 (d, 1H), 5.1 (m, 1H), 4.8-4.6 (m, 2H), 3.9-3.7 (m, 3H), 3.4 (m, 2H), 3.4-3.2 (m, 2H), 2.9-2.7 (m, 2H), 2.8 (s, 3H), 2.5 (s, 3H), 2.3-2.15 (m, 3H). Separation by chiral HPLC provided enantiomers 74a and 74b.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([O:17]C)=[O:16])=[C:13]([CH3:19])[NH:12][C:11]3[CH2:20][CH2:21][C:22](=[O:23])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].B(Cl)(Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]3[CH2:20][CH2:21][C:22](=[O:23])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)C1=C(C)NC2=C(C(=O)CC2)C1c1ccc(F)c(Br)c1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CC1=C(C(=O)O)C(c2ccc(F)c(Br)c2)C2=C(CCC2=O)N1
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A suspension of the product from Example 10A (1.90 g, 5.0 mmol) in methylene chloride (10 mL) at 5° C. under nitrogen was treated with 1M boron trichloride in methylene chloride (40 mL), stirred overnight, quenched in ice water (100 mL) and ethyl acetate (30 mL), and the aqueous drained off. The suspension of the product in ethyl acetate was filtered, the filter cake was washed with ethyl acetate and dried to provide 1.26 g of the title compound as an orange-pink solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[N:20]([CH2:21][C:22]3[O:23][C:24]([CH2:27][O:28][Si](C(C)(C)C)(C)C)=[CH:25][CH:26]=3)[C:19]3[CH:36]=[CH:37][CH:38]=[CH:39][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[F-].[NH4+].O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([C:16]2[N:20]([CH2:21][C:22]3[O:23][C:24]([CH2:27][OH:28])=[CH:25][CH:26]=3)[C:19]3[CH:36]=[CH:37][CH:38]=[CH:39][C:18]=3[N:17]=2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2Cc2ccc(CO[Si](C)(C)C(C)(C)C)o2)CC1
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2Cc2ccc(CO)o2)CC1
Reaction time: 20 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(5-(t-butyldimethylsilyloxy)methylfur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine (7 mmol) and methanol (40 mL). Add ammonium fluoride (42 mmol). Heat to reflux. After 20 hours, concentrate in vacuo to give a residue. Combine the residue with water and dichloromethane. Separate the layers and extract the aqueous layer twice with dichloromethane. Combine the organic layers and dry over Na2SO4, filter, and concentrate in vacuo to give 1-(t-butoxycarbonyl)-4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CN(C)C=O.[CH:14]1([CH2:17][N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][C:21]([C:33]2[CH:34]=[N:35][C:36]([CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[N:37][CH:38]=2)=[N:22][C:23]=3[N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH2:16][CH2:15]1>C(OCC)(=O)C>[Cl:1][C:26]1[N:18]([CH2:17][CH:14]2[CH2:16][CH2:15]2)[C:19]2[C:24]([N:25]=1)=[C:23]([N:27]1[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1)[N:22]=[C:21]([C:33]1[CH:38]=[N:37][C:36]([CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[N:35][CH:34]=1)[N:20]=2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)NCc1ncc(-c2nc(N3CCOCC3)c3ncn(CC4CC4)c3n2)cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Reaction time: 4.5 h
Yield: 56.1 %

Procedure:
N-Chlorosuccinimide (0.92 g, 6.89 mmol) was added to an N,N-dimethylformamide solution (60 ml) of tert-butyl {5-[9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-yl}methylcarbamate (2.14 g, 4.59 mmol) at room temperature. The resulting mixture was stirred for 4.5 hours followed by the addition of N-chlorosuccinimide (0.12 g, 0.92 mmol) and the resulting mixture was further stirred for 2.5 hours. The reaction mixture was poured into ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=17:3 to 3:1) to give the title compound (1.29 g, 56%, two steps combined) as a colorless amorphous substance.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([O:27]C(C)(C)C)=[O:26])[CH:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1.Cl>C(#N)C>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([OH:27])=[O:26])[CH:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4O)sc3c2)ccn1
Agent: Cl
Solvent: CC#N
Product: O=C(O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4O)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To the solution of tert-butyl 4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)picolinate (250 mg, 0566 mmol) in 10 ml of acetonitrile was added 6 M of hydrochloric acid (1 ml, 6 mmol). The reaction solution was stirred at room temperature for 1 hour and then at 60° C. for 2 hours. The crude reaction solution was concentrated and re-dissolved with 10 ml of acetonitrile. The resulting solution was evaporated in vaccuo to give light brown oily product 4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)picolinic acid (215 mg, 0.56 mmol). ES/MS m/z 386.5 (MH+).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C@@H:3]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:4][C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6].C([O-])(O)=O.[Na+].Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:34]>CC#N>[CH2:8]([NH:7][C:5](=[O:6])[CH2:4][C@H:3]([O:12][Si:13]([C:16]([CH3:18])([CH3:17])[CH3:19])([CH3:14])[CH3:15])[C@@H:2]([NH:1][C:33](=[O:34])[O:35][C:36]1[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=1)[CH2:20][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[CH2:9][CH2:10][CH3:11]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCCCNC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](N)CC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCCNC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CC1CCCCC1)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.8 %

Procedure:
To a stirred solution of crude (3S,4S)-4-amino-N-butyl-3-(tertbutyldimethylsilyloxy)-5-cyclohexylpentanamide (311 mg, 0.81 mmol) in MeCN were added powdered NaHCO3 (203 mg, 2.43 mmol) and p-nitrophenyl chloroformate (244 mg, 1.21 mmol) and the mixture was stirred overnight at rt. The mixture was concentrated under reduced pressure. The residue was taken up in 1:1 EtOAc/Et2O (90 mL), washed with water (20 mL) and brine (20 mL), dried over MgSO4 and concentrated to leave an orange oil. This material was chromatographed on a 40-g silica cartridge eluted with a 0 to 100% ethyl acetate in hexanes gradient to afford 4-nitrophenyl (2S,3S)-5-(butylamino)-3-(tert-butyldimethylsilyloxy)-1-cyclohexyl-5-oxopentan-2-ylcarbamate (39 mg, 8%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[C:8](O)(=[O:10])[CH3:9]>>[CH3:7][C:5]1[CH:6]=[C:2]([NH:1][C:8](=[O:10])[CH3:9])[NH:3][N:4]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CC(=O)O
Product: CC(=O)Nc1cc(C)n[nH]1
Temperature: 120 °C
Yield: 22 %

Procedure:
A solution of 3-amino-5-methylpyrazole (2.3 g, 23.7 mmol) dissolved in glacial acetic acid (15 mL) was refluxed at 120° C. for 16 hours to afford a transparent yellow solution. This solution was cooled to ambient temperature which resulted in the formation of white needles. The crystals were isolated via filtration, washed with water until the pH of the water became neutral and dried under high vacuum to yield 0.73 g (22%) of N-(5-methyl-2H-pyrazol-3-yl)acetamide. This solid (0.43 g, 3.1 mmol) was then suspended in 10 mL of anhydrous THF at 0° C. under argon. Excess lithium aluminum hydride in anhydrous THF (10 mL) was added over 24 hours and was stirred for an additional 48 hours. The reaction mixture was quenched by the careful addition of a saturated sodium bicarbonate solution. The solids were washed with THF and the organics were combined, dried over anhydrous MgSO4 and evaporated to yield 0.29 g (81%) of ethyl-(5-methyl-2H-pyrazol-3-yl)amine as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:13]=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=CC1(c2ccc(Cl)cc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC1(c2ccc(Cl)cc2)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
To a stirred solution of 1-(4-chlorophenyl)-cyclopentanecarbaldehyde (318) (19 g, 91.06 mmol) in methanol (250 mL) was added NaBH4 (6.9 g, 182.13 mmol) portion-wise at 0° C. and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (20 mL). The methanol was removed and the residue was diluted with water (100 mL). The mixture was extracted with ethyl acetate (3×100 mL) and the combined organic parts were dried and concentrated. The crude product was purified by silica CombiFlash column (5% ethyl acetate in hexane was used as eluent) to get [1-(4-chlorophenyl)-cyclopentyl]-methanol (319) (13.3 g, 69%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]2=3)(=[O:10])=[O:9])=[CH:4][C:3]=1[NH:22][C:23](=[O:28])[CH2:24][C:25](=O)[CH3:26].C([O-])(=O)C.[NH4+:33]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]2=3)(=[O:10])=[O:9])=[CH:4][C:3]=1[NH:22][C:23](=[O:28])[CH2:24][C:25](=[NH:33])[CH3:26]
Reactant: [NH4+]
Reactant: CC(=O)CC(=O)Nc1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Agent: CC(=O)[O-]
Solvent: CCO
Product: CC(=N)CC(=O)Nc1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Temperature: 65 °C
Reaction time: 16 h
Yield: 57.2 %

Procedure:
To N-[2-chloro-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-3-oxo-butyramide (0.42 g, 1 mmol) in dry ethanol (4 mL) was added ammonium acetate (0.37 g, 3 mmol). The mixture was heated at 65° C. under stirring for 16 hrs. The filtration of the reaction mixture afforded N-[2-chloro-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-3-imino-butyramide as white solid (0.24 g).
Reaction SMILES: [C:1]1([C:7]2([C:11]#N)[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CC[O:16]CC>CCCCCC>[C:1]1([C:7]2([CH:11]=[O:16])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1(c2ccccc2)CCC1
Reactant: CCOCC
Agent: Cl
Solvent: CCCCCC
Product: O=CC1(c2ccccc2)CCC1
Temperature: 40 °C

Procedure:
A 1M solution of diisobutylaliminohydride in hexane (200 ml) was added under nitrogen to a solution of 1-phenyl-1-cyclobutane carbonitrile (31.4 g) in ether (100 ml) at a temperature below -30° C. The temperature was maintained below 0° C. for thirty minutes and 5N hydrochloric acid (200 ml) at a temperature of -10° C. added. The reaction mixture was washed with petroleum ether (b.p. 60°-80° C.) and then warmed to 40° C. The reaction mixture was extracted with petroleum ether (b.p. 60°-80° C.) and the extract dried and evaporated to yield 1-phenyl-1-cyclobutane-carbaldehyde as an oil.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][O:9][C:10](=[O:37])[C@H:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH2:36])=[CH:26][CH:25]=1)[NH:12][C:13](=[O:22])[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21].CCN(C(C)C)C(C)C.Cl[C:48]([O:50][CH3:51])=[O:49]>C1COCC1>[CH3:8][O:9][C:10](=[O:37])[C@H:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH:36][C:48]([O:50][CH3:51])=[O:49])=[CH:26][CH:25]=1)[NH:12][C:13](=[O:22])[C:14]1[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: COC(=O)Cl
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2N)cc1)NC(=O)c1c(Cl)cccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)Nc1ccccc1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(2-aminophenyl)-L-phenylalanine methyl ester TFA salt (90 mg) was dissolved in THF (5 mL) and to this solution was added DIEA (160 μL) and ClCOOMe (20 μL). The mixture was stirred at room temperature for 12 h. After usual work-up as shown in Example 25, N-(2,6-dichlorobenzoyl)-4-[2-(methoxycarbonylamino)phenyl]-L-phenylalanine methyl ester was obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([SH:11])=[C:4]([CH:12]([CH2:14][CH3:15])[CH3:13])[CH:3]=1.Br[C:17]1C(C(C)C)=CC(S)=C(C(C)C)C=1>>[CH3:17][S:11][C:5]1[CH:6]=[C:7]([CH:8]([CH3:10])[CH3:9])[C:2]([Br:1])=[CH:3][C:4]=1[CH:12]([CH2:14][CH3:15])[CH3:13]
Reactant: CCC(C)c1cc(Br)c(C(C)C)cc1S
Reactant: CC(C)c1cc(Br)c(C(C)C)cc1S
Product: CCC(C)c1cc(Br)c(C(C)C)cc1SC

Procedure:
4-Bromo-2-sec-butyl-5-isopropylphenyl methyl sulfide was prepared using the procedure of Example 1C except that 4-bromo-2-sec-butyl-5-isopropylbenzenethiol was substituted for the 4-bromo-2,5-diisopropylbenzenethiol. The resulting product had a boiling point of 111°C at 0.3 mm Hg.
Reaction SMILES: [N:1]12[CH2:8][C:5]([C:9]3[CH:10]=[CH:11][C:12]([C:15](=[NH:18])[NH:16][OH:17])=[N:13][CH:14]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[C:19](OC(=O)C)(=O)[CH3:20]>N1C=CC=CC=1>[CH3:19][C:20]1[O:17][N:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([C:5]34[CH2:8][N:1]([CH2:7][CH2:6]3)[CH2:2][CH2:3][CH2:4]4)=[CH:14][N:13]=2)[N:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: N=C(NO)c1ccc(C23CCCN(CC2)C3)cn1
Solvent: c1ccncc1
Product: Cc1nc(-c2ccc(C34CCCN(CC3)C4)cn2)no1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.2 %

Procedure:
0.28 g (1.14 mmol) of (−)-5-(azabicyclo[3.2.1]oct-5-yl)-N-hydroxypyridine-2-carboximidamide, prepared in step 7.1, dissolved in 10 ml of pyridine is introduced into a 10 ml reactor. 0.1 ml (1.13 mmol) of acetic anhydride is then added and the medium is stirred at room temperature for 15 hours and then heated at 110° C. for 5 hours. The solvent is concentrated under reduced pressure and the residue is taken up in saturated aqueous sodium carbonate solution. The aqueous phase is extracted with chloroform and the combined organic phases are dried over sodium sulfate, filtered and evaporated under vacuum. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of chloroform, methanol and aqueous ammonia in 96/4/0.4 proportions. 0.077 g of (−)-5-[2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane is thus obtained, and is dissolved in 1 ml of isopropyl alcohol to add 0.05 ml of a 5.7N solution of hydrobromic acid in acetic acid. The crystals obtained are collected by filtration and dried under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C.CN(C)C=O.CS(OC[CH2:44][C:45]1[CH:50]=[C:49]([N+:51]([O-])=O)[CH:48]=[CH:47][C:46]=1[CH3:54])(=O)=O>CN(C)C1C=CN=CC=1.C(#N)C>[NH2:51][C:49]1[CH:48]=[CH:47][C:46]([CH3:54])=[C:45]([CH2:44][CH2:17][N:14]2[CH2:13][CH2:12][CH:11]([C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][CH:6]=3)[CH2:16][CH2:15]2)[CH:50]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1CCOS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N)cc1CCN1CCC(c2c[nH]c3ccc(F)cc23)CC1
Temperature: 90 °C
Reaction time: 20 h
Yield: 221.3 %

Procedure:
A 100 mL round bottom flask was charged with 4-nitrophenyloxycarbonyloxyethyl polystyrene (6.6 g, 7.1 mmol), 5-fluoro-3-(1-tert-butoxycarbonylpiperidin-4-yl)-1H-indole (2.7 g, 8.1 mmol), diisopropylethylamine (6.2 mL, 35.6 mmol), 4-dimethylaminopyridine (0.87 g, 7.1 mmol), and dry dimethyl formamide (85 mL). The mixture was stirred at 90° C. for 20 h. After cooling to room temperature, the resin was filtered off and washed with dry dimethyl formamide (3×25 mL), dry acetonitrile (3×25 mL) and dry dichloromethane (3×25 mL). The resin was transferred to a 250 mL glass cylinder with a fritte and a three way junction in the bottom. The resin was then treated for 20 min with 80 mL of a 1:1 mixture of dichloromethane and trifluoroacetic acid containing anisole (2%, w/w) and methionine (0.2%, w/w), using a flow of nitrogen to agitate the resin (Caution: Generation of carbon dioxide). The resin was filtered off and washed with dry dichloromethane (25 mL), a 1:1 mixture of dichloromethane:triethylamine (3×25 mL) and dry dichloromethane (3×25 mL). The resin was transferred to a 250 mL round bottom flask. Acetonitrile (70 mL), diisopropylethylamine (5.2 mL, 30 mmol) and 2-(2-methanesulfonyloxyethyl)-1-methyl-4-nitrobenzene (3.67 g, 14 mmol) was added. The reaction mixture was heated to 70° C. for 18 h. After cooling to room temperature, the resin was filtered off and washed with dry acetonitrile (3×25 mL) and dry dichloromethane (3×25 mL). The resin was transferred to a 250 mL round bottom flask and treated with tin(II) chloride dihydrate (60 mL of an 0.5 M solution in DMF). The reaction mixture was stirred for 18 h. at room temperature. The resin was filtered off and washed with dry dimethyl formamide (3×25 mL), dry acetonitrile (3×25 mL) and dry dichloromethane (3 ×25 mL). The resin was dried in vacuo (20° C., 20 h) to yield the title resin (6.3 g).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]1([C:29]#[C:30][C:31]2[CH:32]=[N:33][CH:34]=[C:35]([CH:39]=2)[C:36]([NH2:38])=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:23]1([C:29]#[C:30][C:31]2[CH:32]=[N:33][CH:34]=[C:35]([CH:39]=2)[C:36]([NH2:38])=[S:10])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NC(=O)c1cncc(C#Cc2ccccc2)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: NC(=S)c1cncc(C#Cc2ccccc2)c1
Reaction time: 48 h
Yield: 40.3 %

Procedure:
Add Lawesson's Reagent, [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate -2,4-disulfide], (0.42 g, 1.03 mmol) to a suspension of 5-phenylethynyl-nicotinamide (0.12 g, 0.52 mmol) in toluene (3 mL) and stir for 48 h. Concentrate the reaction mixture and purify the residue by silica gel chromatography, eluting with 10:90 to 60:40 with ethyl acetate:hexanes, to give the title compound as a pale yellow solid (0.05 g, 40%).