Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C1(C)C=CC=CC=1.C(OP([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(OCC)=O)C.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[C:31](=O)[CH2:30][CH2:29]2>O>[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)/[C:31](=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])/[CH2:30][CH2:29]2
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1ccc2c(c1)CCC2=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)/C=C1\CCc2cc(OC)ccc21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed sodium hydride (1 g, 46.00 mmol, 2.50 equiv), toluene (150 mL), ethyl 2-(diethoxyphosphoryl)acetate (7 g, 31.22 mmol, 1.69 equiv). This was followed by the addition of 5-methoxy-2,3-dihydro-1H-inden-1-one (3 g, 18.50 mmol, 1.00 equiv) at 30° C. The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 3×100 mL of toluene and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (30:70). This resulted in 2 g (47%) of ethyl 2-[(1E)-5-methoxy-2,3-dihydro-1H-inden-1-ylidene]acetate as yellow oil.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][CH2:2]1.N#N.F[C:10](F)(F)[C:11](O)=[O:12].[CH2:16]([Cl:18])[Cl:17]>C(Cl)(Cl)Cl>[C:2]1([O:12][CH3:11])[CH:16]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][CH:16]([Cl:18])[CH3:10]
Reactant: C1=CCNC=C1
Reactant: ClCCl
Reactant: O=C(O)C(F)(F)F
Agent: N#N
Solvent: ClC(Cl)Cl
Product: CC(Cl)Cl
Product: COc1ccccc1

Procedure:
Dihydropyridine 2 (R8 =CH2 -C6H5 or ##STR4## Y=O or S, n=0 or 1) (Reaction Scheme I) is treated under an inert atmosphere (Ar or N2) with about 5-50 meq (preferably 10 meq trifluoroacetic acid neat or in the presence of a solvent (anisole, CH2Cl2, CHCl3, dichloroethane) at 25°-100° C. (preferably 25° C.) for about 10-60 minutes to obtain the Formula 1 compound. ##STR5##
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si](C(C)C)(C(C)C)C(C)C)[CH:9]=[CH:10][C:3]=12.[C:21]([O-])([O-])=O.[K+].[K+].Cl.[CH2:28]([O:30][C:31](=[O:35])[CH2:32][NH:33][CH3:34])[CH3:29]>CN(C=O)C>[CH2:28]([O:30][C:31]([C:32]1[N:33]([CH3:34])[C:2]2[C:7]([CH:21]=1)=[CH:6][N:5]=[C:4]1[C:3]=2[CH:10]=[CH:9][NH:8]1)=[O:35])[CH3:29]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CNC
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cnc3[nH]ccc3c2n1C
Temperature: 65 °C
Reaction time: 36 h

Procedure:
4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (700 mg, 2.08 mmol) is dissolved in DMF. After the addition of K2CO3 (573 mg, 4.16 mmol) followed by sarcosine ethyl ester hydrochloride (383.3 mg, 2.49 mmol) the reaction mixture is stirred at 65° C. for 36 hours. The reaction mixture is then cooled down and poured onto ice cold water. The residue is collected by filtration and is dried to give the crude product which is then purified by silica gel column chromatography to yield the desired compound: 1H NMR 400 MHz (DMSO-d6) δ 12.41 (s, 1H), 8.68 (s, 1H), 8.57 (s, 1H), 7.75 (d, 1H, J=3.0 Hz), 6.73 (d, 1H, J=3.1 Hz), 4.32 (q, 2H, J=6.8 Hz), 4.28 (s, 3H), 1.35 (t, 3H, J=6.8 Hz); MS m/z 244.1 (M+1).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[C:12]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])[N:11]=[C:10]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[N:9]=1.[Cl:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[Cl:32][CH2:33][C:34]([NH:7][C:8]1[CH:13]=[C:12]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])[N:11]=[C:10]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=2)[N:9]=1)=[O:35]
Reactant: O=C(Cl)CCl
Reactant: N#Cc1ccc(Nc2nc(N)cc(Cc3c(Cl)cccc3Cl)n2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(Nc2nc(Cc3c(Cl)cccc3Cl)cc(NC(=O)CCl)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
Pyridine (1 ml) was added to a mixture of 4-[[4-amino-6-[(2,6-dichloro-phenyl)-methyl]-2-pyrimidinyl]amino]benzonitrile (0.00135 mol) in CH2Cl2 (19 ml). A solution of chloroethanoyl chloride (0.001375 mol) in CH2Cl2 (0.5 mol) was added dropwise on an ice bath. The mixture was stirred at room temperature for 2 hours. More chloroethanoyl chloride (0.00625 mol) in CH2Cl2 (0.5 ml) was added. The mixture stood in the refrigerator overnight. The solvent was evaporated. The residue was treated with a saturated Na2CO3 solution and the mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and concentrated. The residue was purified by flash column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 99/1/0.1). The desired fractions were collected and the solvent was evaporated, yielding 0.22 g (36.5%) of 2-chloro-N-[6-[(2,6-dichloro-phenyl)methyl]-2-[(4-cyano-phenyl)amino]-4-pyrimidinyl]acetamide (interm. 13).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[N:14]([C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2)=[C:15]=[O:16]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:15]([NH:14][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:19]=[CH:20][NH:21]3)=[O:16])=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13]
Reactant: O=C=Nc1cccc2[nH]ccc12
Reactant: NCc1ccc(Cl)c(C(F)(F)F)c1
Product: O=C(NCc1ccc(Cl)c(C(F)(F)F)c1)Nc1cccc2[nH]ccc12

Procedure:
4-Chloro-3-(trifluoromethyl)benzylamine (0.27 g, 1.1 mmol) and the product of Example 80A (0.16 g, 1 mmol) were treated as described in Example 80B to provide the title compound. mp 197° C.; 1H NMR (300 MHz, DMSO-d6) δ 4.42 (d, 2H), 6.52 (m, 1H), 6.96 (m, 3H), 7.25 (m, 1H), 7.56 (dd, 1H), 7.67 (dd, 1H), 7.70 (t, 1H), 7.81 (s, 1H), 8.37 (s, 1H), 11.06 (s, 1H); MS (DCI+) m/z 368 (M+H). Anal. Calcd. for C17H13N3ClF3O: C, 55.52, H, 3.56; N, 11.43. Found C, 55.46; H, 3.65; N, 11.58.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48](O)=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)C(C)C)(C)C.[NH2:60][CH:61]([C:69]1[CH:74]=[CH:73][C:72]([Cl:75])=[CH:71][CH:70]=1)[CH2:62][CH2:63][NH:64][S:65]([CH3:68])(=[O:67])=[O:66]>CN1C(=O)CCC1>[Cl:75][C:72]1[CH:71]=[CH:70][C:69]([CH:61]([NH:60][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:38][CH2:37][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:35][CH2:34]2)=[O:49])[CH2:62][CH2:63][NH:64][S:65]([CH3:68])(=[O:67])=[O:66])=[CH:74][CH:73]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: CS(=O)(=O)NCCC(N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CCNS(C)(=O)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (245 mg, 0.65 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (155 mg, 0.43 mmol) and N,N-diisopropylethylamine (0.213 mL, 1.29 mmol) in NMP (2 mL) at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 5 minutes. N-(3-amino-3-(4-chlorophenyl)propyl)methanesulfonamide (Intermediate 116) (113 mg, 0.43 mmol) in NMP (2 mL) was then added to the reaction and stirred for 18 hours. The reaction mixture was concentrated and diluted with EtOAc (20 mL) and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford tert-butyl 4-(1-(4-chlorophenyl)-3-(methylsulfonamido)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (261 mg, 100%).
Reaction SMILES: CC[O:3][C:4]([CH2:6][CH:7]1[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5].[Br:14]Br.O.C(OCC)(=O)C>C(COC)OC>[C:4]([OH:5])(=[O:3])[CH3:6].[CH2:6]([CH:7]1[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH:8]1[Br:14])[CH3:4]
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CC(=O)O
Product: CCC1C(=O)CCCC1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
To a solution of ethyl 2-cyclohexanone acetate (1.0 g) in dimethoxyethane (15 ml) was added bromine (911 mg) at ice-cooling. After stirring at room temperature for 1 hour, the solution was poured into a mixture of water and ethyl acetate. The separated organic layer was washed with aqueous sodium hydrogen sulfite, sodium hydrogen carbonate and saturated sodium chloride orderly, and dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent: ethyl acetate/n-hexane) to give ethyl 2-bromo-6-cyclohexanone acetate (258 mg).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[CH:31]=[CH:30]C(C=C)=[CH:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[C:34]([OH:38])(C)([CH3:36])[CH3:35].CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:60]C)C=C4)N(CC2)C1.S([O-])([O-])=O.[Na+].[Na+]>C(OC)(=O)C.O>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:27]=[CH:28][C:35]([CH:34]([OH:38])[CH2:36][OH:60])=[CH:30][CH:31]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: CC(C)(C)O
Reactant: C=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: COC(C)=O
Solvent: O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(C(O)CO)cn3)[nH]2)cc1)C1CC1
Yield: 40 %

Procedure:
To a solution of 2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-5-ethenylpyridine (110 mg) in a mixed solvent of tert-butyl alcohol (1.5 mL) and water (1.5 mL) was added AD-mix-α (350 mg; Aldrich), and the mixture was stirred under ice-cooling for 4 hr. Sodium sulfite (30 mg) was added and the mixture was stirred for 30 min. The reaction mixture was diluted with methyl acetate, washed with water and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give the title compound (47 mg, yield 40%) as a yellow amorphous solid. MS: 497 (MH+).
Reaction SMILES: N[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[OH-:17].[Na+].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:20].[Na+].[Na+]>O>[C:2]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)([OH:20])=[O:17]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: [OH-]
Reactant: NCc1cccc2cc(S(=O)(=O)O)ccc12
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cccc2cc(S(=O)(=O)O)ccc12
Temperature: 240 °C

Procedure:
118.6 g (0.5 mol) of 1-aminomethylnaphthalene-6-sulphonic acid (100%) are stirred with 375 ml of water and about 50 g of 45% strength NaOH; the pH value of the mixture is brought to 7-7.5. After addition of 149 g of sodium dichromate (0.5 mol), the mixture is heated at 240° C. in an autoclave for 15 hours. After cooling, the green chromium hydroxide residue is filtered off and washed with hot water. The filtrate is acidified to pH 2 with hydrochloric acid (30% strength) under the influence of heat and then cooled to 20° C. The 1-carboxynaphthalene-6-sulphonic acid which precipitates out in the form of its sodium salt is filtered off and washed with 100 ml of saturated NaCl solution.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C[O-].[Na+:27].CO.CC(C)=O>C(C(C)=O)C(C)C>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[Na+:27]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)CC(C)C
Solvent: CO
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Reaction time: 0.25 h

Procedure:
A solution of esomeprazole (18.8 g, 54.4 mmol; 2.0% sulfone) in methyl isobutyl ketone (120 mL) was cooled to 15° C. 30% sodium methoxide in methanol (10.3 mL, 55.5 mmol) was added in 15 min. The mixture was stirred for 15 min and acetone (60 mL) was added slowly over 10 min. Subsequently, the solution was stirred at 26° C. A solid started to crystallize. After 20 min stirring, methyl tert-butyl ether (30 mL) was added dropwise. The resulting slurry was stirred overnight. The solid was collected by filtration, rinsed with acetone (2×20 mL) and dried under reduced pressure at 50° C. to yield esomeprazole sodium. Yield: 14.4 g (72%). Sulfone content: 0.19%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[O:6].[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)=[CH:8][CH:9]=1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Cc1ccc(C(=O)CCCCl)cc1
Product: CCC(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccc(C)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-(4-methylphenyl)-1-butanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 393.2 (M+H)+.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[O:20]([CH2:27][CH2:28][CH2:29]O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:20]([CH2:27][CH2:28][CH2:29][O:17][C:16]([C@@H:11]1[CH2:12][S:13][CH2:14][CH2:15][N:10]1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=1)(=[O:9])=[O:8])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCCCOc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)OCCCOc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.5 %

Procedure:
0.301 g (1 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.190 g (1.5 mmol) of (3-phenoxy)-propanol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL of CH2Cl2. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: ethyl acetate:cyclohexane=1:4) to obtain the product as a oil (0.39 g).
Reaction SMILES: C(OC([N:8]1[CH2:24][CH2:23][C@@H:11]2[N:12]([CH3:22])[C:13]3[C:14]([C:20]#[N:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[Br-].[CH3:26][CH:27]([CH3:31])[CH2:28][CH2:29][Zn+]>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>[CH3:22][N:12]1[C:13]2[C:18](=[CH:17][C:16]([CH2:29][CH2:28][CH:27]([CH3:31])[CH3:26])=[CH:15][C:14]=2[C:20]#[N:21])[C@@H:10]2[CH2:9][NH:8][CH2:24][CH2:23][C@H:11]12
Reactant: CC(C)CC[Zn+]
Reactant: CN1c2c(C#N)cc(Br)cc2[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CC(C)CCc1cc(C#N)c2c(c1)[C@@H]1CNCC[C@@H]1N2C

Procedure:
Following the general procedure for Example 127–146, the title compound was prepared (11 mg, 39%) as a light yellow oil using (4aS,9bR)-8-bromo-6-cyano-5-methyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 158, 40 mg, 0.10 mmol), 3-methyl-butylzinc bromide (0.5 M in THF, 2.5 mole equivalent) and Pd(PPh3)4 (0.06 mole equivalent).: MS (ESI): 284 (base, M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:14]2(OCC[O:15]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:14](=[O:15])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 18 h
Yield: 92 %

Procedure:
To a stirred solution 8-benzyloxycarbonyl 1,4-dioxa-8-azaspiro[4,5]decane (0.037 mol, 10 g) in tetrahydrofuran (150 mL) was added a solution of hydrochloric acid 5% (20 mL) dropwise a room temperature. The solution was stirred for 18 h (TLC control) and then evaporated under vacuum to small volume (20 mL) and neutralized with saturated sodium bicarbonate solution. The aqueous solution was extracted with ethyl acetate (3×100 mL) and the organic layers were dried on sodium sulfate and finally evaporated under vacuum to give 1-benzyloxycarbonyl piperidin4-one practically pure which was then used in the next step without any further purification (92% yield). 1H-NMR (CDCl3): 1.63 (m, 4H); 3.56 (m,4H); 5.09 (s, 2H); 7.28 (s, 5H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][S:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25][NH2:26]>O1CCOCC1.CC#N>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25][NH:26][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([S:14][CH3:13])[CH:16]=1)(=[O:11])=[O:10]
Reactant: NCc1c(F)cccc1Cl
Reactant: CSc1cccc(N)c1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Solvent: CC#N
Solvent: C1COCCO1
Product: CSc1cccc(NS(=O)(=O)c2cc(F)ccc2NCc2c(F)cccc2Cl)c1
Yield: 5.2 %

Procedure:
The title compound (119 mg, 0.26 mmol) was prepared in two steps from 2,5-difluorobenzenesulfonyl chloride (1.07 g, 5.0 mmol) and 3-(methylsulfanyl)aniline (769 mg, 5.5 mmol) in 1,4-dioxane at 70° C.; followed by 2-chloro-6-fluorobenzyl amine (762 uL, 5.9 mmol) in MeCN (1.5 mL) at 180° C. in a Biotage Initiator microwave reactor using the methods of (IntB1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[NH:5][C:4](=[O:18])[C:3]=1[C:19]([OH:21])=[O:20].OS(O)(=O)=O.[CH3:27]O>>[CH3:27][O:20][C:19]([C:3]1[C:4](=[O:18])[NH:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=2)=[CH:7][C:2]=1[CH3:1])=[O:21]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)[nH]c(=O)c1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)[nH]c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
A solution of 0.30 g (1.0 mmol) of 4-methyl-2-oxo-6-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid in 15 ml of MeOH was treated with 0.06 ml=0.01 g (0.1 mmol) of H2SO4 (98%) and the reaction mixture was heated up to reflux. After 4 hours, it was cooled down to RT, poured into crashed ice and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 0.24 g (77%) of the title compound as off-white solid. MS: 312.0 (MH+).
Reaction SMILES: [Cl:1][CH:2]([S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[Cl:3].ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[Cl:1][CH:2]([S:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:20])[Cl:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: ClC(Cl)SCc1ccccc1
Solvent: ClCCl
Product: O=S(Cc1ccccc1)C(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The reactant benzyl dichloromethyl sulfoxide was prepared by dissolving 15.4 grams (g) of benzyl dichloromethyl sulfide in 100 milliliters (ml) of methylene chloride. The solution was cooled in an ice-bath and 15 g of 85% 3-chloroperbenzoic acid was added. After stirring overnight at room temperature, the solution was washed with a 5% solution of potassium carbonate. It was then dried and the solvent evaporated, yielding 15.5 g of solid white benzyl dichloromethyl sulfoxide (m.p. 84°-90° C.). Structure was confirmed by infrared spectraphotometric analysis (IR), and nuclear magnetic resonance spectrum (NMR).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]N)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.C=O.[C:26]([BH3-])#[N:27].[Na+].[C:30](O)(=O)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:27]([CH3:26])[CH3:30])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Reactant: NCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 0.42 h
Yield: 37.6 %

Procedure:
A solution of the crude 8-chloro-1-[(aminomethyl)]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in acetonitrile is treated successively with 37% formalin (1.5 ml) and sodium cyanoborohydride (0.375 g). During the next 1 hour 20 minutes, 2 ml. of a 10% (v/v) solution of acetic acid in acetonitrile is added periodically, dropwise in such a manner that the temperature of the mixture remains between 25°-30° without external cooling. When the reaction is complete, the pH of the solution is about 6.8 and no further rise in temperature is noted after the addition of acid. The mixture is stirred for an additional 25 minutes and concentrated in vacuo. The residue is dissolved in methanol and concentrated. This residue is dissolved in methanol (30 ml), treated with 25% aqueous ethylenediamine (15 ml) and refluxed for 45 minutes. The mixture is cooled, diluted with water, saturated with sodium chloride and extracted with chloroform. The extract is washed (brine), dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on silica gel (100 g) with 2% methanol-98% chloroform. The resulting product is crystallized from ethyl acetate-Skellysolve B hexanes to give 8-chloro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in 2 crops: 330 mg. of melting point 170°-172.5°C; 67 mg. of melting point 168°-171°C (total yield 37.6%).