Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][C:11]([OH:29])([C:25]([F:28])([F:27])[F:26])[CH2:12][C:13]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24])([CH3:15])[CH3:14])[CH:5]=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[CH2:10][C:11]([OH:29])([CH2:12][C:13]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24])([CH3:15])[CH3:14])[C:25]([F:28])([F:27])[F:26]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1ccc(C=O)cc1Cl)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1ccc(CO)cc1Cl)C(F)(F)F
Temperature: 25 °C
Yield: 88.3 %

Procedure:
To a chilled (0° C.) solution of 30 mg (0.069 mmol) of 3-chloro-4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]benzaldehyde in 1 mL THF was added 4 mg (0.104 mmol) lithium aluminum hydride in one portion. The reaction was warmed to room temperature. The reaction was monitored by TLC, cooled to 0° C., quenched with water, diluted with ethyl acetate, dried over magnesium sulfate, and filtered through diatomaceous earth filter agent. The filtrate was concentrated and chromatographed on silica gel eluting with hexanes-ethyl acetate (97:3 to 8:2) to afford 26.5 mg (88%) of the title compound as an oil.
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10]([C:12]1[C:17](F)=[CH:16][CH:15]=[CH:14][C:13]=1F)=O)[C:4]([O:6][CH2:7]C)=[O:5])#[N:2].C(OCC)(=O)C.[ClH:26]>C(OCC)(=O)C>[Cl:26][C:1]1[NH:2][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cl
Reactant: CCOC(=O)C(C#N)CC(=O)c1c(F)cccc1F
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2ccccc2)[nH]c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
To a suspension of methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate (4.66 g) synthesized from methyl cyanoacetate and phenacyl bromide in the same manner as in Reference Example 95 and Reference Example 97 in acetonitrile (200 mL) was added 2,6-dichloro-N-fluoropyridinium triflate (6.26 g) over 10 min under ice-cooling. The reaction mixture was stirred at the same temperature for 2 hr and at room temperature for 2 hr, and concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→7:3) to give the title compound as a pale-yellow solid (yield 815 mg, 16%). More specifically, to a solution of methyl cyanoacetate (41 g) and diisopropylethylamine (117 g) in tetrahydrofuran (2600 mL) was added dropwise a solution of phenacyl bromide (75 g) in tetrahydrofuran (370 mL). The mixture was stirred at room temperature for 12 hr. The reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with 1 mol/L hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give methyl 2-cyano-4-phenyl-4-oxobutanoate as a brown oil (yield 77.4 g, 95%). To a solution (125 mL) of ethyl 2-cyano-4-(2,6-difluorophenyl)-4-oxobutanoate (25 g) in ethyl acetate was added dropwise 4 mol/L hydrogen chloride-ethyl acetate solution (25 mL). The mixture was stirred at room temperature for 18 hr, and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with 6% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate as colorless crystals (yield 10.0 g, 37%). The title compound was synthesized from the thus-obtained methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH:22]([O:23][C:24](OC3C=CC=CC=3)=[O:25])[C:21]3[S:33][CH2:34][CH:35]([O:38][CH3:39])[CH2:36][S:37][C:20]=3[C:19]2=[O:40])=[N:16][CH:17]=1>C(#N)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH:22]([O:23][C:24]([N:8]3[CH2:9][CH2:10][N:5]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:6][CH2:7]3)=[O:25])[C:21]3[S:33][CH2:34][CH:35]([O:38][CH3:39])[CH2:36][S:37][C:20]=3[C:19]2=[O:40])=[N:16][CH:17]=1
Reactant: COC1CSC2=C(SC1)C(OC(=O)Oc1ccccc1)N(c1ccc(Cl)cn1)C2=O
Reactant: CCC(=O)N1CCNCC1
Solvent: CC#N
Product: CCC(=O)N1CCN(C(=O)OC2C3=C(SCC(OC)CS3)C(=O)N2c2ccc(Cl)cn2)CC1
Temperature: 2 °C
Yield: 9.8 %

Procedure:
A solution of 1-propionylpiperazine (6.8 g) in anhydrous acetonitrile (50 cc) is added, at 20° C., to a suspension of 7-(5-chloropyrid-2-yl)-3-methoxy-8-oxo-6-phenoxycarbonyloxy-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (11.15 g) in anhydrous acetonitrile (80 cc). The reaction mixture is heated under reflux for 6 hours. The acetonitrile is evaporated off under reduced pressure (20 mm Hg; 2.67 kPa). The residue is treated with water (100 cc) and extraction is carried out three times with methylene chloride (total 210 cc); the organic extracts are washed twice with distilled water (total 200 cc), dried over anhydrous sodium sulphate and evaporated to dryness. The resulting residue (14.7 g; oily) is dissolved in a mixture of chloroform and methanol (97:3 by volume; 50 cc). The solution is chromatographed on silica (0.04-0.063 mm; 400 g) contained in a column of diameter 6 cm, under a pressure of 140 kPa. Elution is carried out with the solvent mixture mentioned above under a pressure of 140 kPa. 1800 cc of eluate are collected and discarded, and then 600 cc of eluate are collected and evaporated to dryness under reduced pressure (20 mm Hg; 2.67 kPa). The resulting partially crystalline residue (11.0 g) is dissolved in a boiling mixture of acetonitrile (10 cc) and diisopropyl ether (50 cc). After cooling the solution for 2 hours at 2° C., the resulting crystals are filtered off, washed twice with diisopropyl ether (total 20 cc) and dried under reduced pressure (20 mm Hg; 2.67 kPa) at 20° C. The resulting product (4.1 g; m.p. 160° C.) is dissolved in boiling acetonitrile (60 cc). After cooling the solution for 2 hours at 2° C., the resulting crystals are filtered off, washed twice with diisopropyl ether (total 80 cc) and dried under reduced pressure (0.2 mm Hg; 0.026 kPa) at 50° C. 7-(5-Chloropyrid-2-yl)-3-methoxy-8-oxo-6-(4-propionylpiperazin-1-yl)carbonyloxy-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (1.2 g), melting at 226° C., is obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]([C:13]([OH:15])=O)=[CH:11][C:10]([Br:16])=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:44][C@H:45]1[CH2:50][CH2:49][CH2:48][CH2:47][C@@H:46]1[OH:51].C(N(CC)CC)C>ClCCl.CN(C=O)C>[NH2:2][C:3]1[C:12]([C:13]([NH:44][C@H:45]2[CH2:50][CH2:49][CH2:48][CH2:47][C@@H:46]2[OH:51])=[O:15])=[CH:11][C:10]([Br:16])=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2
Reactant: Nc1c(C(=O)O)cc(Br)c2cnccc12
Reactant: N[C@H]1CCCC[C@@H]1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1c(C(=O)N[C@H]2CCCC[C@@H]2O)cc(Br)c2cnccc12
Reaction time: 3 h

Procedure:
To a solution of 5-amino-8-bromoisoquinoline-6-carboxylic acid hydrochloride (1.00 g, 3.29 mmol) in 10 mL of dichloromethane and 2 mL of DMF was added (1H-1,2,3-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (1.65 g, 3.74 mmol), (1S,2S)-2-aminocyclohexanol (0.430 g, 3.74 mmol), and triethylamine (1.20 mL, 8.62 mmol). After 3 h, the mixture was diluted with additional dichloromethane, washed with water, saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-3% methanol in dichloromethane, to provide crude 5-amino-8-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]isoquinoline-6-carboxamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:10])[C:5]([CH3:9])=[C:6]([F:8])[CH:7]=1.[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:14])[CH:12]=[CH2:13].C1N2CCN(CC2)C1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC>[CH2:16]([O:15][C:11](=[O:14])[CH:12]=[CH:13][C:2]1[CH:3]=[C:4]([F:10])[C:5]([CH3:9])=[C:6]([F:8])[CH:7]=1)[CH2:17][CH2:18][CH3:19]
Reactant: Cc1c(F)cc(Br)cc1F
Reactant: C=CC(=O)OCCCC
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCOC(=O)C=Cc1cc(F)c(C)c(F)c1
Temperature: 120 °C

Procedure:
To a solution of 5-bromo-1,3-difluoro-2-methyl-benzene (6.910 g; 33.379 mmol) in anhydrous DMF (200 ml) were added successively butyl acrylate (7.15 ml; 50.062 mmol), DABCO (157 mg; 1.333 mmol), potassium carbonate (4.612 g; 33.379 mmol), and palladium acetate (150 mg; 0.669 mmol). The resulting brown suspension was heated to 120° C. for 1 h. The reaction mixture was allowed to cool to rt before ether (400 ml) was added. This mixture was then washed with water (2×200 ml), and the mixed aq. layers were further extracted with ether (150 ml). The combined organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/heptane=1/1=>DCM) gave the pure product 3-(3,5-difluoro-4-methyl-phenyl)-acrylic acid butyl ester as a yellow oil which was further dried under HV (4.690 g; 55%). LC-MS: tR=1.10 min.; [M+H]+: no ionisation.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[N:24]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:29]([N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:30])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(Cl)N1CCCC1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)N4CCCC4)nc3cc21

Procedure:
Pyrrolidine-1-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (140 mg, 0.45 mmol) and 1-pyrolidine carbonyl chloride (154 μl, 1.40 mmol). The title compound was obtained as light grey powder (50 mg, 275).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([C:14](O)=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)C>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH2:14][OH:15])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccc(Cl)cc2)cc1C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(Cl)cc2)cc1CO
Reaction time: 18 h
Yield: 57.2 %

Procedure:
To a solution of 5-(4-chlorophenyl)-2-methylfuran-3-carboxylic acid (0.104 g, 0.44 mmol) in THF (2 mL) and MeOH (2 mL) was added TMSCHN2 (2.0 M in Et2O, 0.250 mL). The reaction mixture was stirred for 18 hours at which time it was concentrated in vacuo. The residue was dissolved in 1 ml of THF at 0° C., and a solution of LAH (1.0 M in THF, 0.8 mL) was added. After addition, the reaction was stirred at room temperature for 2 hours, and then water (0.24 mL), 15% aqueous NaOH (0.24 mL), and water (0.72 mL) were added sequentially to the reaction. After 30 minutes, the reaction mixture was filtered through celite, and the filtrate was concentrated to give 53.1 (0.056 g). 1H NMR (400 MHz, CDCl3) δ ppm 7.53-7.63 (m, 2H), 7.31-7.40 (m, 2H), 6.64 (s, 1H), 4.52 (s, 2H), 2.37 (s, 3H).
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][C:4]([OH:6])=[O:5].C(N(CC)CC)C.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][C:4]([O:6][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: CCCCCCCCCCCC(O)CC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCC(O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxymyristic acid (5.00 g) and triethylamine (2.85 g) in DMF (50 ml) was added benzyl bromide (2.43 ml) and the mixture was stirred at room temperature overnight. After the solvent was removed in vacuo, to the residue were added ethyl acetate and water. The separated ethyl acetate layer was washed twice with water and then dried over anhydrous sodium sulfate. After the ethyl acetate was removed in vacuo, purification was carried out by a silica gel column chromatography (silica gel 30 g, chloroform:methanol=100:0-10) to afford 3.69 g of benzyl 3-hydroxymyristate.
Reaction SMILES: [Br:1][C:2]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[C:8](=O)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.CSC.B.[ClH:19]>O1CCCC1>[ClH:19].[Br:1][C:2]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)Oc2c(Br)cccc2NC1=O
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: CC1(C)CNc2cccc(Br)c2O1
Reaction time: 0.17 h
Yield: 92 %

Procedure:
8-Bromo-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one from step 2 (768.30 mg, 3.0 mmol) was dissolved in dry tetrahydrofuran (THF) and the solution was heated to reflux. 0.3 ml of 10M borane dimethyl sulfide (BH3.DMS) in THF was added drop-wise to the reaction mix, and the reaction mix was kept heated under reflux for 1 hour. A solution of 10% ethanolic HCl was then added drop-wise to the reaction mix until a white precipitate appeared, after which refluxing was continued for 10 minutes. The reaction mix was cooled, and the precipitate was removed by filtration, washed with ether, and air dried to yield 770 mg of 8-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazine hydrochloride (92%) as a white solid. MS: (M+H) 280.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH:14]([C:20]([O:22]CC)=[O:21])[CH2:15][S:16]C(=O)C)[CH2:9]1)=O)(C)(C)C>Cl>[SH:16][CH2:15][CH:14]([CH2:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)C(CSC(C)=O)CC1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Product: O=C(O)C(CS)CC1CCNC1
Temperature: 25 °C

Procedure:
A solution of 3-(3-acetylsulfanyl-2-ethoxycarbonyl-propyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.52 g; 1.45 mmol) in concentrated HCl (15 mL) was refluxed under argon for 1 h. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to afford a diasteromeric mixture of the title compound as the hydrochloride salt (0.33 g; 100%).
Reaction SMILES: N[C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[C:15]2[CH2:14][CH2:13][C@@H:12]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH2:11][C:10]3=2)=[N:4][N:3]=1.C(ON=O)CC(C)C>CN(C=O)C>[F:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][N:16]1[C:15]2[CH2:14][CH2:13][C@@H:12]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH2:11][C:10]=2[C:9]2[C:17]1=[CH:18][CH:19]=[C:7]([C:5]1[S:6][CH:2]=[N:3][N:4]=1)[CH:8]=2
Reactant: CC(C)C(=O)N[C@@H]1CCc2c(c3cc(-c4nnc(N)s4)ccc3n2Cc2cccc(F)c2)C1
Agent: CC(C)CCON=O
Solvent: CN(C)C=O
Product: CC(C)C(=O)N[C@@H]1CCc2c(c3cc(-c4nncs4)ccc3n2Cc2cccc(F)c2)C1
Yield: 79.6 %

Procedure:
Add (R)-N-[6-(5-Amino[1,3,4]thiadiazole-2-yl)-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]isobutyramide (Example 126) (0.104 g, 0.224 mmol) to a solution of isoamylnitrite (0.039 g, 0.337 mmol) in DMF at 60° C. and heat for 1 h. Quench reaction onto water and extract with EtOAc to give 80 mg of a yellow solid. Purify over silica eluting with 25-90% EtOAc/hexanes gradient to give 20 mg (20%). MS (ES) m/z 449 (M+1); 1H NMR (DMSO-d6): δ 9.56 (s, 1H), 8.08 (s, 1H), 7.89 (d, 1H), 7.77 (d, 1H), 7.57 (d, 1H), 7.38 (dd, 1H), 7.12 (dd, 2H), 6.84-6.94 (m, 2H), 5.44 (s, 2H), 4.05 (m, 1H), 3.07 (dd, 1H), 2.70-2.84 (m, 2H), 2.63 (m, 2H), 2.41 (septet, 1H), 2.00 (m, 1H), 1.88 (m, 1H), 1.04 (dd, 6H).
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:12][CH2:13][C:14]1[S:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[C:15]=1[Cl:23])[C:10]#[CH:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[I:24]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([Si:5]([O:8][CH:9]([CH2:12][CH2:13][C:14]1[S:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[C:15]=1[Cl:23])/[CH:10]=[CH:11]/[I:24])([CH3:6])[CH3:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: C#CC(CCc1sc2ccccc2c1Cl)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(/C=C/I)CCc1sc2ccccc2c1Cl
Reaction time: 0.75 h
Yield: 86.2 %

Procedure:
A solution of alkyne 19 (5.547 g, 15.2 mmol) in dichloromethane (50 mL) was treated with Cp2ZrHCl (5.794 g, 22.5 mmol). The reaction was stirred for 45 min. and then N-iodosuccinimide (4.966 g, 22.1 mmol) was added. After 15 min., saturated sodium bicarbonate solution (200 mL) was added and the mixture was extracted with dichloromethane (2×100 mL). The combined dichloromethane solution was dried (MgSO4), filtered and evaporated. Purification by flash chromatography on silica gel (0-5% ethyl acetate/hexanes) gave 6.608 g (13.1 mmol, 86%) of the vinyl iodide (32).
Reaction SMILES: [C:1]1([N:7]2[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([C:16]([O:18]C)=[O:17])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CO>[CH3:15][O:14][C:12]([C:10]1[C:9]([C:16]([OH:18])=[O:17])=[N:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:11]=1)=[O:13]
Reactant: COC(=O)c1nn(-c2ccccc2)nc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1nn(-c2ccccc2)nc1C(=O)O
Temperature: 23 °C
Reaction time: 17 h
Yield: 84.9 %

Procedure:
A solution of dimethyl 2-phenyl-2H-1,2,3-triazole-4,5-dicarboxylate (0.522 g, 2.00 mmol) in methanol (40 mL) at 23° C. was treated with a solution of KOH (0.236 g, 4.20 mmol) in methanol (5 mL). The resulting solution was stirred at 23° C. for 17 h and partitioned between NaHCO3 (sat. aq. sol.) and ether. The aqueous layer was washed with ether and acidified carefully to pH 1 with HCl (conc.). The resulting mixture was extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by radial chromatography (2 mm plate, CH2Cl2-methanol-acetic acid 90:10:1) to afford 0.42 g (85%) of 5-methoxycarbonyl-2-phenyl-2H-1,2,3-triazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][N:10]=[CH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)[N:4]([CH2:23][CH2:24][CH3:25])[C:3]1=[O:26].C([NH:31][S:32]([C:35]1[CH:39]=[C:38]([CH:40]=O)[N:37]([CH3:42])[CH:36]=1)(=[O:34])=[O:33])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[C:12]2[CH2:11][N:10]1[C:40]([C:38]2[N:37]([CH3:42])[CH:36]=[C:35]([S:32]([NH2:31])(=[O:34])=[O:33])[CH:39]=2)=[C:6]2[C:5]([N:4]([CH2:23][CH2:24][CH3:25])[C:3](=[O:26])[N:2]([CH3:1])[C:7]2=[O:8])=[N:9]1
Reactant: CCCn1c(NN=Cc2ccnc3ccc(Cl)cc23)cc(=O)n(C)c1=O
Reactant: Cn1cc(S(=O)(=O)NC(C)(C)C)cc1C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCn1c(=O)n(C)c(=O)c2c(-c3cc(S(N)(=O)=O)cn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21

Procedure:
Following the method of Example 180, this compound was made by preparation of 6-chloroquinoline-4-carbaldehyde (1-methyl-2,6-dioxo-3-propyl-1,2,3,6-tetrahydropyrimidin-4-yl)hydrazone, condensation with N-(tert-butyl)-5-formyl-1-methyl-1H-pyrrole-3-sulfonamide and treatment with TFA.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[C:11](S(Cl)(=O)=O)[CH:12]=[CH:13][C:7]=2[O:6]1>[Pd].O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6]1
Reactant: COC(=O)CC1Cc2cc(S(=O)(=O)Cl)ccc2O1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)CC1Cc2ccccc2O1
Yield: 99 %

Procedure:
Compound 4B was prepared by hydrogenation of the corresponding tetrahydrofuran derivative catalyzed by 10% Pd/C in 99% yield. MS: MS: 193 (M+1)+. Preparation of (5-Chlorosulfonyl-2,3-dihydro-benzofuran-2-yl)-acetic acid methyl ester (Compound 4C)
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH:24]2[CH2:33][CH2:32][C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[CH:29][CH:30]=3)[CH2:25]2)[CH2:21][CH2:22][CH3:23])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.Cl>C(Cl)Cl.C(OCC)C>[CH3:35][O:34][C:28]1[CH:27]=[C:26]2[C:31]([CH2:32][CH2:33][CH:24]([N:20]([CH2:21][CH2:22][CH3:23])[CH2:19][CH2:18][CH2:17][CH2:16][N:11]3[C:12](=[O:15])[CH2:13][CH2:14][NH:8][CH2:9][CH2:10]3)[CH2:25]2)=[CH:30][CH:29]=1
Reactant: CCCN(CCCCN1CCN(C(=O)OC(C)(C)C)CCC1=O)C1CCc2ccc(OC)cc2C1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CCCN(CCCCN1CCNCCC1=O)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 115.2 %

Procedure:
To 4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (800 mg, 1.64 mmol) in methylene chloride (15 mL) was added trifluoroacetic acid (5 mL) in a single portion and the reaction was stirred at room temperature for 30 min. The mixture was concentrated to dryness in-vacuo, dissolved in water (40 mL) and treated with 15% aq. KOH (20 mL). The solution was extracted with ethyl acetate, washed with brine, dried (MgSO4) and concentrated in-vacuo. The free base (636 mg, 1.64 mmol) was taken up in diethyl ether (30 mL) and treated with 1M M HCl in ether (3.3 mL). The solid was collected and dried under vacuum to afford 732 mg of 4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one 5 as a dihydrochloride salt. MS: 374 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[O:8]C.[Br-].[Li+].N1CCNCC1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]([F:24])([F:26])[F:25])=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[OH:8]
Reactant: COc1c(Br)cc(C(=O)N2CCOc3ncc(C(F)(F)F)cc32)cc1Br
Agent: C1CNCCN1
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(c1cc(Br)c(O)c(Br)c1)N1CCOc2ncc(C(F)(F)F)cc21
Reaction time: 1 h
Yield: 85 %

Procedure:
In a 5 ml flask, (3,5-dibromo-4-methoxy-phenyl)-(7-trifluoromethyl-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl)-methanone (30 mg, 0.061 mmol) was dissolved in N,N-dimethyl formamide (0.3 ml), and then lithium bromide (10 mg, 0.12 mmol) and piperazine (7.8 mg, 0.091 mmol) were added thereto. After stirring for 1 hour, the solvent was removed by evaporation under reduced pressure. The residue was neutralized with water and 1N hydrochloric acid. The resulting solid was filtered to obtain the target compound 22-2 as white solid (25 mg, 86%).
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Cl:15][CH2:16][C:17]([O:5][CH2:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1])=[O:18]
Reactant: C[Si](C)(C)CCO
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOC(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine 2-(trimethylsilyl)ethanol (7.3 mL) and triethylamine (25 mL) in dichloromethane (80 mL). Cool in an ice bath. Add dropwise chloroacetyl chloride (6.9 g). After the addition is complete warm the reaction mixture to ambient temperature After 5 hours, add chloroacetyl chloride (2.8 g), After 2 hours, filter the reaction mixture and extract with a saturated aqueous solution of sodium bicarbonate and then water. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Distill the residue to give 2-(trimethylsilyl)ethyl chloroacetate: bp 150° C. at 28 mm of Hg.