Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:40]>ClCCl>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)=[O:40])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC
Solvent: ClCCl
Product: COc1cc2ncnc(S(=O)c3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC
Yield: 168 %

Procedure:
To a stirring solution of 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (120 mg, 0.25 mmol) from Example 46 in dichloromethane (2.5 mL) was added 3-chloroperoxybenzoic acid (56 mg, 77% max, 0.25 mmol). The reaction was quenched after 5 minutes with sat. NaHCO3(aq), extracted with EtOAc, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (25-100% EtOAc/hexanes) then repurified (12-100% EtOAc/hexanes) to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylsulfinyl)phenyl)urea (21 mg, 0.42 mmol, 17%). 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.16-9.12 (m, 2H), 8.33-8.28 (m, 2H), 7.49-7.34 (m, 4H), 6.50 (s, 1H), 4.03 (s, 3H), 3.99 (s, 3H), 1.30 (s, 9H); LC-MS (ESI) m/z 496 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:16]2[N:17]([CH3:43])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:21]=[C:20]([N:31]2[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=[C:32]2[CH:40]([CH3:42])[CH3:41])[N:19]=3)([O:14][CH3:15])[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1.CO>[CH:40]([C:32]1[N:31]([C:20]2[N:19]=[C:18]3[C:23]([N:24]=[C:16]([C:10]4([O:14][CH3:15])[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]4)[N:17]3[CH3:43])=[C:22]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:21]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1)([CH3:42])[CH3:41]
Reactant: COC1(c2nc3c(N4CCOCC4)nc(-n4c(C(C)C)nc5ccccc54)nc3n2C)CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: COC1(c2nc3c(N4CCOCC4)nc(-n4c(C(C)C)nc5ccccc54)nc3n2C)CCCNC1
Reaction time: 1.5 h
Yield: 89.2 %

Procedure:
To a solution of 3-[2-(2-isopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-methoxypiperidine-1-carboxylic acid tert-butyl ester (2.47 g, 4.18 mmol) in DCM (100 mL) was added 4M HCl in dioxane (10 mL). The resulting mixture was allowed to stir for 2 h at r.t. before further 1.25M HCl in MeOH (20 mL) was added. The resulting mixture was allowed to stir for 1.5 h then concentrated in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 2-(2-Isopropylbenzoimidazol-1-yl)-8-(3-methoxypiperidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine (1.83 g, 89%). LCMS (method H): RT 2.12 min [M+H]+ 491.4
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32][C:33](O)=[O:34]>>[ClH:16].[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][NH:1][C:33](=[O:34])[CH2:32][CH2:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)=[CH:11][C:12]=1[F:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Reactant: O=C(O)CCc1ccccn1
Product: Cl
Product: O=C(CCc1ccccn1)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and 3-(pyridin-2-yl)propanoic acid, and by a method similar to that of Example 39, the title compound was obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]1[CH2:18][C:19](O)=[O:20].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][OH:46])=[CH:41][CH:40]=1>C(Cl)Cl.CN(C=O)C>[OH:46][CH2:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][CH2:37][NH:36][C:19](=[O:20])[CH2:18][CH:3]2[C:2](=[O:1])[NH:7][CH:6]=[CH:5][N:4]2[S:8]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)(=[O:9])=[O:10])=[CH:40][CH:41]=1
Reactant: NCCc1ccc(CO)cc1
Reactant: Cc1ccc(S(=O)(=O)N2C=CNC(=O)C2CC(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)N2C=CNC(=O)C2CC(=O)NCCc2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of [3-oxo-1-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-pyrazin-2-yl]-acetic acid (620 mg, 2.0 mmol), EDC (Aldrich, 575 mg, 3.0 mmol), HOBt (Aldrich, 270 mg, 2.0 mmol), and [4-(2-amino-ethyl)-phenyl]-methanol (362 mg, 2.4 mmol) was added CH2Cl2 (15 mL) and DMF (2 mL). The reaction mixture was stirred at room temperature overnight and diluted with CH2Cl2 (80 mL). The organic phase was washed with saturated NaHCO3, and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by silica gel chomatography (6%-10% MeOH—CH2Cl2) to afford the title compound. MS (ESI): 444 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1.[H-].[Na+].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:35]Br>CN(C=O)C.C(OCC)(=O)C>[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:35][C:23]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:21][CH2:20][N:19]2[C:15]([C:5]3[CH:6]=[CH:7][C:8]([C:9]4[O:13][C:12]([CH3:14])=[N:11][CH:10]=4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:16][N:17]=[C:18]12
Reactant: Fc1ccc(CBr)cc1F
Reactant: CCOC(=O)C1CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Cc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
Ethyl 3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (3.00 g) was added to a suspension of sodium hydride (60%, 340 mg) in DMF (5 mL) under ice-cooling. The reaction mixture was stirred for 30 min under ice-cooling, 3,4-difluorobenzyl bromide (1.53 g) was added under ice-cooling, and the mixture was stirred for 1 hr under ice-cooling. The reaction mixture was diluted with ethyl acetate, the mixture was washed with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (3.47 g).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([O:21][C:22](=[O:32])[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([OH:3])=[O:2].[N+:33]([C:36]1[CH:41]=[CH:40][C:39]([O:42][C:43](=[O:46])[CH2:44]Br)=[CH:38][CH:37]=1)([O-:35])=[O:34].C(OC(C)C)(C)C>CC(C)=O.C(N(CC)CC)C>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([C:22]([O:21][C@@H:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]([O:3][CH2:44][C:43]([O:42][C:39]2[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:41][CH:40]=2)=[O:46])=[O:2])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:32])=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: O=C(CBr)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCC(CCCCCCCCCCC(=O)O)OC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Product: CCCCCC[C@H](CCCCCCCCCCC(=O)OCC(=O)Oc1ccc([N+](=O)[O-])cc1)OC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-Nitro-benzoic acid 11-carboxy-1-hexyl-undecyl ester (500 g) in dry Acetone, triethylamine (232 mL) at 10-15° C. was added Bromoacetic acid 4-nitro-phenyl ester (347 g). The solution was stirred at room temperature for 8 hours. 75% of the solvent was distilled off and cooled to room temperature. The resulting solid was poured onto cold water and pH was adjusted to 4-5 with dilute HCl. The resulting solid was filtered off and washed with chilled water (100 mL). The slurry was prepared with 1 lit Di Isopropyl Ether and filtered off. The resulting solid was then dried in vacuum oven at 60-80° C. to yield pure (R)-18-(2-(4-nitrophenoxy)-2-oxoethoxy)-18-oxooctadecan-7-yl 4-nitrobenzoate product as off white powder with a melting point of 130-133° C. The resulting compound was characterized by 1H NMR (CDCl3) δ 0.86 (t, 3H, CH3), 1.2-1.5 (m, 28H, 14×CH2), 1.68 (m, 2H, CH2), 2.42 (t, 2H, COCH2), 3.52 (m, 1H, CH), 5.2 (s, 2H, CH2) 7.42 (m, 2H, Ar) 8.4-8.52 (m, 6H, Ar).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([CH:24]([CH3:28])[C:25](O)=[O:26])[CH:18]=[CH:17]2.C(OCC)(=O)C>O>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([CH:24]([CH3:28])[CH2:25][OH:26])[CH:18]=[CH:17]2
Reactant: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2cc(C(C)CO)ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 0.4 g. of lithium aluminum hydride and 100 ml. of ethyl ether, there is added a mixture of 2.3 g. of d 2-(6-methoxy-2-naphthyl)propionic acid and 100 ml. of ethyl ether. The mixture is stirred at 0°C for 30 minutes, and 10 ml. of ethyl acetate is added. After 1 hour, 4 ml. of water is added to the mixture. The resulting mixture is filtered and evaporated under reduced pressure to yield l 2-(6-methoxy-2-naphthyl)-l-propanol.
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[C:22]([Cl:34])=[CH:21][N:20]=1>>[Cl:34][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[N:24][C:19]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][CH:2]([F:17])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:20][CH:21]=1
Reactant: COc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(NCC(F)F)CC2
Product: COc1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)F)CC3)ncc1Cl
Yield: 61 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2-Difluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-phenyl)-amine to yield 5-Chloro-N*2*-[7-(2,2-difluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]-N*4*-(2-methoxy-phenyl)-pyrimidine-2,4-diamine (2.93 mg, 61% yield) as a white powder. 1H-NMR (CDCl3) δ 8.44 (d, J=7.8 Hz, 1H), 8.04 (s, 1H), 7.85 (s, 1H), 7.37 (s, 1H), 7.23 (m, 1H), 7.02 (m, 2H), 6.92 (m, 3H), 5.84 (m, 1H). 3.94 (s, 3H), 2.80 (m, 3H), 2.68 (m, 2H), 2.07 (m, 2H), 1.30 (m, 2H). LC/MS (ESI+)=474 (M+H). MP=191-193° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[Cl:9][C:10]([Cl:18])=[CH:11][CH:12](Br)[C:13](Br)([CH3:15])[CH3:14]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O.C1(C)C=CC=CC=1>[C:1]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:12]([CH:11]=[C:10]([Cl:18])[Cl:9])[C:13]1([CH3:15])[CH3:14])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: CC(C)(Br)C(Br)C=C(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(C#N)C(C=C(Cl)Cl)C1(C)C
Reaction time: 6 h
Yield: 31.2 %

Procedure:
A mixture of ethyl cyanoacetate (12.44 parts), 1,1-dichloro-3,4-dibromo-4-methylpent-1-ene (31.1 parts), cupric acetate monohydrate (20 parts), benzyltriethylammonium chloride (4.54 parts) and water (100 parts) is stirred at 95°-100° C. for 6 hours. The mixture is cooled and diluted with water (100 parts and toluene (100 parts by volume), and filtered to remove insoluble material. The filter-cake is washed twice with toluene (20 parts by volume) and twice with water (50 parts). The filtrates and washes are separated and the toluene layer is washed with concentrated hydrochloric acid (50 parts by volume) diluted with water (50 parts) and then four times with water (50 parts). The toluene is removed by evaporation under reduced pressure to give ethyl 1-cyano-3-(2',2'-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate, strength 53.3% and cis-cyano:trans-cyano ratio 69.2:30.8 in 31.2% yield.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:21])[C@H:10]2[NH:14][C:15]2[S:16][CH:17]=[C:18]([CH3:20])[N:19]=2)[C:7]=1[C:22]([O:24]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:23])(=[O:3])[CH3:2].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>ClCCl>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:21])[C@H:10]2[NH:14][C:15]2[S:16][CH:17]=[C:18]([CH3:20])[N:19]=2)[C:7]=1[C:22]([OH:24])=[O:23])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](Nc3nc(C)cs3)[C@H]2SC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](Nc3nc(C)cs3)[C@H]2SC1
Yield: 84.9 %

Procedure:
A mixture of 210 mg of (6R-trans)-3-[(acetyloxy)methyl]-7-[(4-methyl-2-thiazolyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, trifluoroacetic acid and anisole in dichloromethane was reacted as described in Example 11, giving 123 mg of the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C=O)C.S(Cl)([Cl:18])=O>>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=C(O)c1cccnc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccnc1Cl
Temperature: 70 °C

Procedure:
To 2-chloronicotinic acid (15.7 g, 100 mmol) in thionyl chloride (50 mL) was added DMF (0.2 mL), heated to 70° C. and reacted for 3 h. After reaction was complete, solvent was removed by distillation to obtain crude product 17.5 g.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C:7]([OH:9])=O)(=[O:3])[CH3:2].[CH2:18]([O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH2:30][CH2:31][CH3:32])[NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH2:30][CH2:31][CH3:32])[NH:28][C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)SCC(C(=O)O)C(C)c1ccccc1
Reactant: CCCC[C@H](N)C(=O)OCc1ccccc1
Product: CCCC[C@H](NC(=O)C(CSC(C)=O)C(C)c1ccccc1)C(=O)OCc1ccccc1
Yield: 75 %

Procedure:
Using the procedure described in Example 60, but starting with 2-acetylthiomethyl-3-phenylbutanoic acid and norleucine benzyl ester, and after purifying by chromatography, eluting with a hexane/ethyl acetate (75:25 by volume) mixture, N-(2-acetylthiomethyl-1-oxo-3-phenylbutyl)norleucine benzyl ester is obtained in a 75% yield in the form of an oil, having the following characteristics: Rf =0.46 [hexane/ethyl acetate(6.5:3.5 by volume)].
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH:11](=O)[CH:12]([CH3:14])[CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH2:11]([NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH:12]([CH3:14])[CH3:13]
Reactant: COC(=O)c1ccsc1N
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccsc1NCC(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 2-aminothiophene-3-carboxylate (2.0 g, 12.7 mmol) in dichloromethane (40 mL) and glacial acetic acid (0.72 mL) were added isobutyraldehyde (0.87 g, 12.1 mmol) and sodium triacetoxyborohydride (4.0 g, 18.9 mmol). The reaction mixture was stirred for 18 h at room temperature and concentrated. The residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution and with water, dried over anhydrous sodium sulfate and concentrated. The residual oil was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate-hexane to afford the title compound as a slightly yellow oil (2.19 g, 81% yield). 1H NMR (400 MHz, CDCl3): δ 7.00 (d, 1 H), 6.18 (d, 1 H), 3.80 (s, 3 H), 3.20 (m, 2 H), 1.68 (m, 1 H), 1.00 (d, 6 H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH3:42])[C:20]([N:22]([CH2:32][C:33]1[C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=2[S:36][CH:37]=1)[C@@H:23]([CH3:31])[CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[O:21]>>[S:36]1[CH:37]=[C:33]([CH2:32][N:22]([C@@H:23]([CH3:31])[CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])[C:20](=[O:21])[C@@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:12]([CH3:13])[NH:11][C:9]([NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH3:42])[C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]1=2
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)N
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)NC(=O)CN(C)NC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 98 mg (0.41 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-12) 100 mg (0.27 mmol) to obtain the title compound.
Reaction SMILES: S(=O)(=O)(O)[OH:2].B(F)(F)F.CC[O:12][CH2:13][CH3:14].Br[C:16]12[CH2:25][C:20]3([CH3:26])[CH2:21][CH:22]([CH2:24][C:18]([CH3:27])([CH2:19]3)[CH2:17]1)[CH2:23]2>ClC(Cl)=C>[CH3:27][C:18]12[CH2:24][CH:22]3[CH2:21][C:20]([CH3:26])([CH2:25][C:16]([CH2:14][C:13]([OH:12])=[O:2])([CH2:23]3)[CH2:17]1)[CH2:19]2
Reactant: O=S(=O)(O)O
Reactant: CC12CC3CC(C)(C1)CC(Br)(C3)C2
Reactant: CCOCC
Agent: FB(F)F
Solvent: C=C(Cl)Cl
Product: CC12CC3CC(C)(C1)CC(CC(=O)O)(C3)C2
Temperature: 8 °C
Reaction time: 1 h

Procedure:
Concentrated sulfuric acid (44 mL) and boron trifluoride etherate (3.53 mL) were added to a flask and cooled to 8° C. A solution of 1-bromo-3,5-dimethyladamantane (11.02 g) in 1,1-dichloroethylene (35.3 mL) was added dropwise over a 2 hour period. The temperature was kept between 14 and 18° C. and gas evolution was observed. After stirring 1 hour at 10° C., the reaction was worked up by adding to ice and extracting with diethyl ether. The organic layer was extracted with 1N NaOH (3×), and the combined aqueous solution was acidified with sulfuric acid and re-extracted with ether (3×). The organic layers were combined, dried over magnesium sulfate, filtered and evaporated to dryness to give crude 3,5-dimethyladamantaneacetic acid (6.23 g).
Reaction SMILES: [Cl:1][C:2]1[C:7](F)=[C:6]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:22])[N:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:23][C:24](=[O:32])[C@:25]([OH:31])([CH3:30])[C:26]([F:29])([F:28])[F:27].[OH:33][CH2:34][CH2:35][SH:36].C[O-].[Na+]>CN1C(=O)CCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[C:7]([S:36][CH2:35][CH2:34][OH:33])=[C:6]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:22])[N:19]([CH3:20])[CH3:21])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:23][C:24](=[O:32])[C@:25]([OH:31])([CH3:30])[C:26]([F:28])([F:27])[F:29]
Reactant: CN(C)C(=O)c1ccc(S(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2F)cc1
Reactant: OCCS
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CN(C)C(=O)c1ccc(S(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2SCCO)cc1
Temperature: 120 °C
Yield: 12 %

Procedure:
To (R)-N-{2-chloro-3-fluoro-4-[4-(N,N-dimethylcarbamoyl)phenylsulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 18) (600 mg), as a solution in NMP (5 ml), was added 2-hydroxyethanethiol (0.1 ml) and sodium methoxide (0.65 g), and the reaction mixture was heated at 120° C. overnight under an argon atmosphere. The solution was diluted with saturated brine and extracted with ether (3×30 ml). The ether extracts were combined and dried. The volatile material was removed by evaporation and purified by chromatography on a Mega Bond Elut column (20 g silica) eluting with hexane/EtOAc to yield the title compound as a white solid (60 mg, 12%). NMR: 1.60 (s, 3H), 2.60-2.65 (m, 2H),), 2.85 (s, 3H), 2.95 (s, 3H), 3.10-3.20 (m, 2H), 4.75 (dd, 1H), 7.60 (d, 2H); 7.95 (d, 2N), 8.05 (s, 1H), 8.35 (d, 1H), 8.45 (d, 1H), 9.95 (s, 1H); m/z: 553.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:7]=[C:8]([C:14]#[N:15])[C:9]([C:12]#[N:13])=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.Br[CH:17]([CH2:25][CH3:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[CH:1]1([CH2:4][N:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[C:8]([C:14]#[N:15])[CH:7]=2)[CH:17]([CH2:25][CH3:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:2][CH2:3]1
Reactant: CCC(Br)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(NCC2CC2)cc1C#N
Product: CCC(C(=O)OC(C)(C)C)N(CC1CC1)c1ccc(C#N)c(C#N)c1

Procedure:
Synthesized in a manner similar to example 1B using 4-[(cyclopropylmethyl)amino]-1,2-benzenedicarbonitrile and tert-butyl 2-bromobutanoate: MS (ES) m/z 340 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[N:20]1[C:28]2[CH2:27][CH2:26][NH:25][CH2:24][C:23]=2[NH:22][CH:21]=1>>[N:20]1[C:28]2[CH2:27][CH2:26][N:25]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=4)[N:3]=3)[CH2:24][C:23]=2[NH:22][CH:21]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: c1nc2c([nH]1)CNCC2
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCc4nc[nH]c4C3)n2)c1

Procedure:
B44 was prepared following the general procedure reported for B10 using A1 and 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine. The title compound (B44) was purified by reverse phase RP-HPLC (column: C18), using H2O and MeOH as eluents; yield: 34.3 mg (9%), white amorphous solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 2.59-2.71 (m, 2H), 4.07 (t, J=5.7 Hz, 2H), 4.22 (s, 2H), 4.72 (s, 2H), 6.83 and 6.89 (2 s, 2H), 7.00 (d, J=7.5 Hz, 1H), 7.29 (t, J=7.9 Hz, 1H), 7.51 (s, 1H), 7.58 and 7.65 (2 d, J=7.0 Hz and J=7.5 Hz, 1H), 7.74 and 7.88 (2 s, 1H), 8.26 (s, 1H), 9.70 (s, 1H), 11.86 (bs, 1H). MS (ES) C16H18N8O2S requires: 386. found: 387 (M+H)+.