Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:36]=[CH:35][C:8]([CH2:9][CH:10]([C:21]([NH:23][CH:24]([C:32](O)=[O:33])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:22])[NH:11][C:12](=[O:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][C:6]=1[Cl:37])[CH:2]=[CH2:3].Cl.[CH3:39][O:40][C:41](=[O:44])[CH2:42][NH2:43].C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1.C(Cl)(Cl)Cl>[CH3:39][O:40][C:41](=[O:44])[CH2:42][NH:43][C:32](=[O:33])[CH:24]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:23][C:21](=[O:22])[CH:10]([CH2:9][C:8]1[CH:35]=[CH:36][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[C:6]([Cl:37])[CH:7]=1)[NH:11][C:12](=[O:20])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)CN
Reactant: C=CCOc1ccc(CC(NC(=O)Cc2ccccc2)C(=O)NC(Cc2ccccc2)C(=O)O)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCOc1ccc(CC(NC(=O)Cc2ccccc2)C(=O)NC(Cc2ccccc2)C(=O)NCC(=O)OC)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Allyloxy-3-chloro-phenylacetyl-(DL)-phenylalanyl-(DL)-phenylalanine (1.20 g) was dissolved in dry tetrahydrofuran (10 ml). To the solution was added glycine methyl ester hydrochloride (0.25 g) in dry chloroform (10 ml) containing dry triethylamine (0.28 ml). DCC (0.41 g) was added and the reaction mixture was stirred overnight at room temperature. DCU was then filtered off.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:7]=1.[CH:19](OC)(OC)OC>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][CH2:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:19]=[N:18][C:4]=2[CH:3]=1
Reactant: COC(OC)OC
Reactant: Nc1cc(Br)ccc1NCCCc1ccccc1
Product: Brc1ccc2c(c1)ncn2CCCc1ccccc1

Procedure:
A solution of Example 170A (560 mg, 1.83 mmol) in trimethyl orthoformate (10 mL) at 95° C. was stirred for 16 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50-100% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: C(N(CC)[CH:4]=[C:5]([C:11](=[S:21])[NH:12][C:13]([O:15][CH2:16][C:17]([Cl:20])([Cl:19])[Cl:18])=[O:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[F:24][S:25]([C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=1)[C:31](=[O:34])[CH2:32]Br)(=[O:27])=[O:26]>C(O)(C)C>[F:24][S:25]([C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=1)[C:31]([C:32]1[S:21][C:11]([NH:12][C:13]([O:15][CH2:16][C:17]([Cl:18])([Cl:19])[Cl:20])=[O:14])=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=1)=[O:34])(=[O:27])=[O:26]
Reactant: O=C(CBr)c1cccc(S(=O)(=O)F)c1
Reactant: CCOC(=O)C(=CN(CC)CC)C(=S)NC(=O)OCC(Cl)(Cl)Cl
Solvent: CC(C)O
Product: CCOC(=O)c1cc(C(=O)c2cccc(S(=O)(=O)F)c2)sc1NC(=O)OCC(Cl)(Cl)Cl
Yield: 84.9 %

Procedure:
A mixture of 25 g (0.061 m) of ethyl 3-diethylamino-2-[N-(2,2,2-trichloroethoxycarbonyl)thiocarbamoyl]acrylate, 17.15 g (0.061 m) of m-fluorosulfonylphenacyl bromide, and 125 ml of isopropyl alcohol was heated to reflux for 5 minutes. The reactants dissolved at reflux, and shortly thereafter the product precipitated. The mixture was cooled and the solid collected by filtration. The solid was washed with isopropyl alcohol and then water to give 27.6 g (85 percent) of product, melting point 108° to 110° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[OH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[OH-].[Na+].O>C(O)C>[CH2:2]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCBr
Reactant: O=C(O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCOc1ccc(C(=O)O)cc1
Yield: 65.1 %

Procedure:
1-Bromobutane (22.6 g, 0.165 mol) was added dropwise at room temperature to a stirred mixture of 4-hydroxybenzoic acid (15.0 g, 0.11 mol) in ethanol (60 ml) and sodium hydroxide (10.60 g) in the minimum amount of water. The stirred mixture was heated under reflux overnight (tlc analysis revealed a complete reaction), and then the ethanol was distilled off and an equal volume of water was added. The mixture was boiled to give a solution, cooled, washed with ether and acidified with 36% hydrochloric acid. The cooled mixture was filtered, and the product was washed with water to give a colourless solid (13.9 g) which was recrystallised from ethanol to give colourless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8](SC)[CH:9]=2)[CH:4]=1.Cl[C:16]1C=C(C=CC=1)C(OO)=O.[S:26]([O-:29])([O-])=[O:27].[Na+].[Na+]>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:26]([CH3:16])(=[O:29])=[O:27])[CH:9]=2)[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])[O-]
Reactant: COc1ccc2cc(SC)ccc2c1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2cc(S(C)(=O)=O)ccc2c1
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a solution of 2-methoxy-6-methylthionaphthalene (1.0 g, 4.9 mmol), [prepared as described in Step 1], in methylene chloride (50 ml) was added 3-chloroperoxybenzoic acid (3.5 g, 10.3 mmol, 50-60%) portionwise. After 0.5 h, the reaction mixture was cooled in an ice bath, sodium sulfite (0.53 g, 4.2 mmol) was added and the stirring was continued for another 20 minutes. The reaction mixture was then poured in water and the organic layer was separated and dried over sodium sulfate. The solvent was removed in vacuo and the crude product was purified by flash chromatography (gradient elution 30-50% ethyl acetate/hexanes) to give 930 mg of 2-methoxy-6-methylsulfonylnaphthalene (80% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:7][CH2:8][CH2:9][CH3:10])[CH:3]([OH:6])[C:4]#[CH:5].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C>[CH3:1][C:2]([CH3:11])([CH2:7][CH2:8][CH2:9][CH3:10])[CH:3]([O:6][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1)[C:4]#[CH:5]
Reactant: C1=COCCC1
Reactant: C#CC(O)C(C)(C)CCCC
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: C#CC(OC1CCCCO1)C(C)(C)CCCC
Temperature: 25 °C

Procedure:
To a solution of 23.1 g. (0.150 mole) of 4,4-dimethyl-1-octyn-3-o1 (Example 994) in 126 g. of freshly distilled dihydropyran is added 1 drop of phosphorus oxychloride and the solution is maintained at ambient temperature in a tightly stoppered flask for 20 hours. Five drops of triethylamine are then added and the mixture is evaporated in vacuo to an oil. The oil is chromatographed on 600 g. of silica gel and the product is eluted with 5% ethyl acetate in benzene yielding a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH:16](P(OCC)(OCC)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][CH2:41][CH:42]=O)[CH:35]=1.CCOC(C)=O>C1COCC1>[C:34]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][CH2:41][CH:42]=[C:16]([CH2:15][C:12]2[CH:13]=[N:14][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:10][CH:11]=2)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH:35]=1
Reactant: O=CCCc1cccc(-c2ccccc2)c1
Reactant: CCOP(=O)(OCC)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(CC(=CCCc2cccc(-c3ccccc3)c2)C(=O)OC(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
A solution of tert-butyl 3-{6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}-2-(diethoxyphosphoryl)propanoate (1.058 g, 2.31 mmol) in dry THF (4 mL) was added to a solution of sodium hydride (0.111 g, 60% in mineral oil, 2.77 mmol) in dry TBF (3 mL) at 0° C. and the mixture was stirred at 0° C. for 60 min. To this mixture a solution of 3-(1,1′-biphenyl-3-yl)propanal (0.582 g, 2.77 mmol) in dry TBF (3 mL) was added, and the reaction mixture was allowed to attain room temperature over 22 h. EtOAc was then added, and the organic phase was washed with saturated aqueous NH4Cl and water, dried (Na2SO4) and concentrated. Flash chromatography (toluene/EtOAc, 15:1) of the residue gave tert-butyl 5-(1,1′-biphenyl-3-yl)-2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)pent-2-enoate (1.105 g, 93%) as a mixture of E/Z-isomers.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:13]([O:15][CH3:16])=O)[N:4]=1.O[C:18]1[CH:23]=[CH:22][CH:21]=C[C:19]=1[C:24](=[O:26])[CH3:25].Cl>N1C=CC=CC=1>[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:13]2[O:15][C:16]3[C:19]([C:24](=[O:26])[CH:25]=2)=[CH:18][CH:23]=[CH:22][CH:21]=3)[N:4]=1
Reactant: CC(=O)c1ccccc1O
Reactant: COC(=O)c1cc2ccccc2cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: O=c1cc(-c2cc3ccccc3cn2)oc2ccccc12
Temperature: 90 °C
Yield: 88.9 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 227 mg, 5.7 mmol) in dry pyridine (4 ml) was added dropwise a solution of methyl isoquinoline-3-carboxylate (390 mg, 2.08 mmol) and 2′-hydroxy-acetophenone (257 mg, 1.89 mmol) in dry pyridine (4 ml). The mixture was heated at 90° C. for 15 min., cooled to room temperature and poured into an ice cooled 1N hydrochloric acid aqueous solution. The product was extracted in dichloromethane. The organic layers were washed with a 1N hydrochloric acid solution, brine, dried over sodium sulfate and concentrated to dryness. The residue was dissolved in acetic acid (10 ml) and treated with sulfuric acid (40 μl). The solution was heated to 100° C. for 30 min. and cooled to room temperature. The solvents were removed under vacuum distillation. The solid was triturated in water, filtered, washed with a saturated solution of sodium hydrogenocarbonate and water. The solid was dried under vacuum to yield 2-Isoquinolin-3-yl-chromen-4-one (459 mg, 89%) as beige solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH2:25][NH2:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:26][CH2:25][C:19]1([C:16]2[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ncc(C2(CN)CCOCC2)cn1
Product: Cc1ncc(C2(CNC(=O)c3cccc(Cl)c3Cl)CCOCC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and (4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine. LCMS (MH+): m/z=380.1, tR (minutes, Method F)=1.80
Reaction SMILES: CN1CCN(C2C=CC(N[C:15]([C:17]3[C:18]4[N:19]=[CH:20][CH:21]=[N:22][C:23]=4[C:24]([C:27]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=[CH:29][CH:28]=4)=[CH:25][CH:26]=3)=[O:16])=CC=2)CC1.CO.C1COCC1.CO.[CH3:46][N:47]1[CH2:52][CH2:51][N:50]([CH2:53][C:54]2[N:55]=[C:56]([N+:59]([O-])=O)[NH:57][CH:58]=2)[CH2:49][CH2:48]1>[Ni].C(Cl)Cl.CO>[CH3:46][N:47]1[CH2:52][CH2:51][N:50]([CH2:53][C:54]2[N:55]=[C:56]([NH:59][C:15]([C:17]3[C:18]4[N:19]=[CH:20][CH:21]=[N:22][C:23]=4[C:24]([C:27]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=[CH:29][CH:28]=4)=[CH:25][CH:26]=3)=[O:16])[NH:57][CH:58]=2)[CH2:49][CH2:48]1
Reactant: CN1CCN(Cc2c[nH]c([N+](=O)[O-])n2)CC1
Reactant: CN1CCN(c2ccc(NC(=O)c3ccc(-c4cccc5ccccc45)c4nccnc34)cc2)CC1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1CCN(Cc2c[nH]c(NC(=O)c3ccc(-c4cccc5ccccc45)c4nccnc34)n2)CC1

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 8-naphthalen-1-yl-quinoxaline-5-carboxylic acid (Example 46) in Step 14.1, Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2 and 1-methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine (Step 20.1) instead of 2-nitroimidazole in Step 14.3. Title compound: ESI-MS: 478.1 [M+H]+; tR=3.36 min (System 1); TLC: Rf=0.15 (DCM/MeOH, 9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18](O)=[O:19])[N:9]=2)=[CH:4][CH:3]=1.[C:21]1([C:27]([NH2:30])([CH3:29])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:30][C:27]([CH3:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:28])=[O:19])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: CC(C)(N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)c1ccccc1
Reaction time: 0.17 h

Procedure:
70.0 mg (0.238 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 88A and 32.2 mg (0.238 mmol) of 2-phenylpropan-2-amine are placed in 2 ml of dimethylformamide and treated with 38.7 mg (0.286 mmol) of HOBt. After 10 mins' stirring, 59.4 mg (0.310 mmol) EDC hydrochloride are added and the mixture is stirred overnight at room temperature. After this, 32.2 mg (0.238 mmol) of 2-phenylpropan-2-amine, 38.7 mg (0.286 mmol) of HOBt and 59.4 mg (0.310 mmol) of EDC hydrochloride are again added to the reaction mixture and stirred for a further for two hours at room temperature. Without further workup, the mixture is purified directly by preparative HPLC [Method 10]. 44 mg (45% of theory) of the target compound are thus obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:23]=[CH:22][C:10]([CH2:11][NH:12][C:13]3[S:14][C:15]([C:18]([O:20]C)=[O:19])=[CH:16][N:17]=3)=[CH:9][CH:8]=2)[CH:2]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1.[H-].[Na+].[OH-].[Na+]>CN(C)C=O.O>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:12]([CH2:11][C:10]2[CH:22]=[CH:23][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:8][CH:9]=2)[C:13]2[S:14][C:15]([C:18]([OH:20])=[O:19])=[CH:16][N:17]=2)=[CH:27][CH:28]=1
Reactant: COC(=O)c1cnc(NCc2ccc(-c3cccnc3)cc2)s1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cnc(N(Cc2ccc(F)cc2)Cc2ccc(-c3cccnc3)cc2)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a 250 mL round-bottomed flask was added methyl 2-(4-(pyridin-3-yl)benzylamino)thiazole-5-carboxylate (3 g, 9.22 mmol) and 1-(bromomethyl)-4-fluorobenzene (1.264 ml, 10.14 mmol) in dimethylformamide (46.1 ml). The mixture was cooled to 0° C., sodium hydride (0.738 g, 18.44 mmol) was added carefully; and the mixture was warmed to room temperature. After the mixture was stirred for about 30 minutes, it was found to be predominantely carboxylic acid. 1 N NaOH was added to complete the conversion; and a water work up followed by chromatography provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][C:17]([F:20])([F:19])[F:18])/[CH:5]=[N:6]/[S@@:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8].[CH2:21]1COC[CH2:22]1.C([Mg]Br)C>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:5]([NH:6][S@@:7]([C:9]([CH3:10])([CH3:11])[CH3:12])=[O:8])[CH2:21][CH3:22])[CH:13]=[CH:14][C:15]=1[O:16][C:17]([F:20])([F:18])[F:19]
Reactant: C1CCOC1
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc(OC(F)(F)F)c(Cl)c1
Agent: CC[Mg]Br
Solvent: CCOCC
Product: CC[C@@H](N[S@](=O)C(C)(C)C)c1ccc(OC(F)(F)F)c(Cl)c1
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of 218 (3.8 g, 12 mmol) and THF (40 mL) cooled to −78° C. was added dropwise a solution of ethylmagnesium bromide (5.8 mL, 17 mmol) in ether and the solution was stirred for 1 h, quenched with water, and extracted with Et2O. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (35 to 40% EtOAc) to afford 3.5 g (84%) of (R)—N—((R)-1-(3-chloro-4-(trifluoromethoxy)phenyl)propyl)-2-methylpropane-2-sulfinamide (220).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:11](=[S:12](=[O:14])=[O:13])[C:10]([NH2:15])=[C:9]([CH2:16][CH3:17])[CH:8]=[C:4]1[C:5]([OH:7])=O.[CH3:18]C(C)=O.ClC(OCC)=O.[CH:28]1([N:35]2[CH2:39][CH2:38][CH2:37][C:36]2(C)[CH2:40][NH2:41])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(N(CC)CC)C.O>[CH:28]1([N:35]2[CH2:39][CH2:38][CH2:37][CH:36]2[CH:40]([CH3:18])[NH:41][C:5](=[O:7])[C:4]2[CH:3]([O:2][CH3:1])[C:11](=[S:12](=[O:14])=[O:13])[C:10]([NH2:15])=[C:9]([CH2:16][CH3:17])[CH:8]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CC(C)=O
Reactant: CC1(CN)CCCN1C1CCCCCC1
Reactant: CCC1=C(N)C(=S(=O)=O)C(OC)C(C(=O)O)=C1
Agent: CCOC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC1=C(N)C(=S(=O)=O)C(OC)C(C(=O)NC(C)C2CCCN2C2CCCCCC2)=C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4.9 g of 2-methoxy-4-amino-5-ethyl sulphonyl benzoic acid, 57 ml of acetone, 10 ml of water and 2.6 ml of triethylamine (density 0.726) are placed in a 250 ml flask fitted with an agitator, a thermometer, a condenser and a dropping funnel. The solution is cooled to between 0° and +5° C. and 2.1 g of ethyl chloroformate is added drop by drop. The reaction medium is agitated for 45 minutes at room temperature then cooled to 0° C. and 5.3 g of 1-cycloheptyl methyl-2-amino methyl pyrrolidine is poured in drop by drop. The medium is agitated for 4 hours then left to stand overnight. The solvents are evaporated to dryness and the residue is dissolved in 60 ml of water and 15 ml of hydrochloric acid (density 1.18). Extraction is carried out 3 times with 50 ml of methylene chloride, the organic phase is dried over magnesium sulphate and filtered, and the solvent is evaporated under vacuum. The residue is dissolved in 100 ml of water. The solution is filtered in the presence of carbon black and the filtrate is made alkaline with about 7 ml of ammonia (density 0.91). A gum is precipitated. It is extracted 3 times with 50 ml of methylene chloride. The organic phase is washed twice with 50 ml of water, dried over magnesium sulphate and filtered. The solvent is evaporated under vacuum and the residue is re-crystallised in 100 ml of isopropanol.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:10])([CH3:9])[C:4](=O)[CH2:5][C:6]#[N:7].Cl[NH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:20](O)C>>[NH2:7][C:6]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[N:12]=[C:4]([C:3]([CH3:10])([CH3:9])[CH2:2][OH:1])[CH:5]=1
Reactant: CCO
Reactant: ClNNc1ccccc1
Reactant: CC(C)(CO)C(=O)CC#N
Product: Cc1ccc(-n2nc(C(C)(C)CO)cc2N)cc1
Temperature: 90 °C

Procedure:
5-hydroxy-4,4-dimethyl-3-oxopentanenitrile (0.32 g, 2.27 mmol) and 1-chloro-2-phenylhydrazine (0.361 g, 2.49 mmol) were combined in ethanol and heated at 90° C. for 8 hours. The reaction was cooled and concentrated, and the residue was triturated with ethyl acetate. The solids were collected by filtration, triturated with acetone and rinsed to isolate 36 mg of the title compound as a pure white solid. MS M+1(246).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([Br:12])[CH:11]=1)[CH:7]=[O:8]>CO.C(OCC)(=O)C.C(Cl)Cl>[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([Br:12])[CH:11]=1)[CH2:7][OH:8]
Reactant: O=Cc1cc(Br)cc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: OCc1cc(Br)cc(Br)c1
Reaction time: 0.5 h

Procedure:
1.14G(30 mM) of sodium borohydride was added slowly to a suspension of 3,5-dibromobenzaldehyde (7.92G; 30 mM), from step (a), in 50 mL of methanol at 0° under nitrogen. After stirring 30 mins., the reaction mixture was diluted with 150 mL of ethyl acetate and washed with 5×50 mL of saturated sodium chloride solution, dried over anhydrous magnesium sulfate. Solvent removal afforded a crude product, which was dissolved in minimum amount of CH2Cl2 and applied on silica gel. Elution with 1:2 mixture of EtOAc:hexane gave 7.2G of the desired alcohol as white solid.
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.[CH3:13][O:14][C:15]([C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][CH2:22][NH:23]2)=[C:19]([O:26][CH3:27])[CH:18]=1)=[O:16].C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:13][O:14][C:15]([C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][CH2:22][N:23]2[C:1]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:12])=[C:19]([O:26][CH3:27])[CH:18]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: COC(=O)c1cc2c(c(OC)c1)CCN2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC)c2c(c1)N(C(=O)OC(C)(C)C)CC2
Yield: 47 %

Procedure:
Di-tert-butyl carbonate (2.9 g, 13.5 mmol, 1 equiv.) was added to a stirred mixture of 4-methoxy-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester (2.8 g 13.5 mmol, 1 equiv.) and diisopropyl ethyl amine (4.7 mL, 27 mmol, 2 equiv.) in tetrahydrofuran (30 mL) and the mixture was heated at reflux for 16 hours. The solvent was evaporated under vacuum and the residue purified by column chromatography (SiO2, 1:8 EtOAc:heptane). The fractions were combined to afford 4-methoxy-2,3-dihydro-indole-1,6-dicarboxylic acid 1-tert-butyl ester 6-methyl ester, 1.96 g (47% yield). δH (250 MHz; d6-DMSO) 7.80 (1H, s), 7.10 (1H, s), 3.96 (2H, t), 3.78 (6H, s), 3.03 (2H, t), 1.45 (9H, m).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]#[N:21])[CH:16]=[CH:17][CH:18]=1.[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+].O>CN(C)C=O.C(OCC)(=O)C>[NH:22]1[C:20]([CH2:19][C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[O:12][CH2:11][C:2]2[N:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[N:21][N:24]=[N:23]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1cccc(OCc2ncc3ccccc3n2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: c1cc(Cc2nnn[nH]2)cc(OCc2ncc3ccccc3n2)c1
Temperature: 135 °C
Yield: 54.6 %

Procedure:
To a solution of 6.3 g (0.023 mol) of 3-(2-quinazolinylmethoxy)benzenacetonitrile in 150 ml of dimethylformamide are added 7.5 g (0.115 mol) of sodium azide and 6.2 g (0.115 mol) of ammonium chloride, and the slurry is heated to 135° C. for 72 hours. The slurry is poured into 500 ml of water/500 ml of ethyl acetate, and the layers are separated. The aqueous phase is twice extracted with 250 ml of ethyl acetate, and the combined ethyl acetate solution is twice washed with 500 ml of water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain 4 g of crystals, m.p. 129°-131° C. Recrystallization from ethanol gives 2.5 g (34%) of crystals, m.p. 129°-131° C., MS(CI) 319 (M+H).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]([NH2:17])[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[CH3:11])=[O:5])C.S(O)(C1C=CC(C)=CC=1)(=O)=O.O.C1CCN2[C:33](=[N:34]CCC2)[CH2:32][CH2:31]1.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12]([C:9]1[C:10]([CH3:11])=[C:6]2[C:4](=[O:5])[C:32]([C:33]#[N:34])=[CH:31][NH:17][N:7]2[CH:8]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1cn(N)c(C(=O)OCC)c1C
Reactant: C1CCC2=NCCCN2CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cn2[nH]cc(C#N)c(=O)c2c1C
Temperature: 25 °C
Yield: 40 %

Procedure:
To a solution of 1-amino-3-methyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester (1.08 g, 4.50 mmol) in toluene (15 mL) were added 1,1-diethoxypropionitrile (2.02 mL, 1.93 g, 13.5 mmol) and TsOH-H2O (171 mg, 0.90 mmol). The reaction mixture was heated at reflux for 12 h and then cooled to 25° C. DBU (0.18 mL, 0.822 g, 5.40 mmol) was added and the resulting dark brown mixture was heated at 80° C. for 1 h and then coded to room temperature. The reaction mixture was poured onto dichloromethane (50 mL) and NH4Cl (sat. aq., 50 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2×30 mL) and the combined organic extracts were washed with water (30 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (10-30% methanol/dichloromethane) to provided 441 mg (40%) of compound 1C as a brown solid. HPLC: 100% at 3.383 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 246.09 [M+H]+. D Preparation of 4-Chloro-3-cyano-5-methylpyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester (1D)