Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][CH:28]=2)=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].Cl.CN.ON1C2C=CC=CC=2N=N1.[CH2:49]([N:51]=[C:52]=NCCCN(C)C)C>ClCCl.C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[S:6][C:7]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([N:51]([CH3:52])[CH3:49])=[O:33])=[CH:34][CH:35]=2)=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(Cc2ccc(C(=O)O)cc2)s1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(Cc2ccc(C(=O)N(C)C)cc2)s1

Procedure:
To a solution of 4-{[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]methyl}benzoic acid (50 mg) in 0.5 ml of dichloromethane were added methylamine hydrochloride (10.7 mg), 1-hydroxybenzotriazole (20.4 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (55.3 μl), then, the mixture was stirred for 3. hrs. at 25° C. The reaction mixture was diluted with 10 ml of chloroform and washed with water and brine. The organic layer was dried over magnesium sulfate and evaporated under vaccum. The residue was triturated with ethyl acetate and diisopropylether, and collected by filtration to give tert-butyl {4-[2-(2-(acetylamino)-5-{4-[(dimethylamino)carbonyl]benzyl}-1,3-thiazol-4-yl)ethyl]phenyl}carbamate as a pale yellow solid.
Reaction SMILES: C1N=CN([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])C=1.NC1C=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[OH:23]>CN(C=O)C>[N+:20]([C:18]1[CH:17]=[CH:16][C:15]2[O:23][C:6](=[O:7])[NH:8][C:9]=2[CH:10]=1)([O-:22])=[O:21]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2o1
Reaction time: 0.5 h
Yield: 434.9 %

Procedure:
CDI (1.57 g, 19.4 mmol) was added at 0° C. to a stirred solution of 2-amino-4-nitro-phenol (500 mg, 0.6 mmol) in DMF (5 mL) and the resultant was stirred for 30 mins. The mixture was poured onto ice and stirred for 10 minutes. The resulting precipitate was isolated by filtration to afford 470 mg (80%) of 5-nitro-3H-benzooxazol-2-one. 1H NMR: (DMSO-d6): δ 12.4 (b s, 1H), 8.05 (dd, 1H), 7.85 (d, 1H), 7.54 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14]C(=S)N(C)C)=[CH:10][C:8]=2[CH:9]=1)=[O:4]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(OC(=S)N(C)C)ccc2o1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cc2cc(O)ccc2o1
Yield: 64.2 %

Procedure:
A solution of 5-dimethylthiocarbamoyloxy-benzofuran-2-carboxylic acid methyl ester (1.3 g, 4.7 mmol) in 25 mL diphenyl ether was heated at reflux for 2.5 hours. The reaction mixture was then cooled and the resulting precipitate collected. Purification by flash column chromatography (gradient elution: 100% hexanes to 45% EtOAc/hexanes), gave the title compound (0.58 g, 45%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1.CC([O-])=O.[K+].CC(O)=O>CO.O>[C:22]([O:21][CH2:20][C@H:18]1[O:19][C@@H:7]([N:6]2[C:5]3[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:4]=3[N:3]=[C:2]2[Cl:1])[C@H:8]([OH:9])[C@@H:13]1[OH:14])(=[O:24])[CH3:23]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 42 (0.48 g, 1.0 mmol) and KOAc (0.49 g, 5.0 mmol) in MeOH/H2O (20 ml/2 mL) was stirred at room temperature for 24 h. AcOH (0.286 mL 5.0 mmol) was added and stirring was continued at room temperature for 15 min. The reaction mixture was evaporated and the residue was partitioned between H2O/CHCl3 (50 mL/50 mL). The CHCl3 layer was washed with sat. NaCl solution (50 mL), dried (Na2SO4), and evaporated. The residue was chromatographed on a silica column (1.9×20 cm, eluted with CHCl3, 1%, 2%, 4% MeOH/CHCl3). Evaporation of fractions 42-51 (15 mL per fraction) and recrystallization from MeOH gave 0.178 g (2 crops, 45%) of 42a as white crystals. MP: 82°-87° C. MS: (EI) m/e 393.9875 (20%, M+ =393.9890). 1H NMR (DMSO-d6): d 8.00, 7.96 (2×s, 2, 7-H and 4-H), 5.91 (d, 1, 1'-H, J1'-2' =7.5 Hz), 5.59 (d, 1, 2'-OH, J2'-2'OH =6.0 Hz), 5.45 (d, 1, 3'-OH, J3'-3'OH =4.5 Hz), 4.44 (dd, 1, 5'-H, J5'-4' =4.5 Hz, J5'-5" =12.5 Hz), 4.42 (m, 1, 2'-H, J2'-3' =6.0 Hz), 4.25 (dd, 1, 5"-H, J5"-4' =2.5 Hz), 4.17 (m, 1, 4'-H, J3'-4' =3.5 Hz), 4.11 (m, 1, 3'-H), 2.14 (s, 3, 5'-OAc). 13C NMR (DMSO-d6): d 169.95 (COCH3), 142.03 (C2), 140.92 (C3a), 132.30 (C7a), 125.96, 125.86 (C5 and C6), 120.28 (C4), 113.47 (C7), 89.32 (C1'), 82.63 (C4'), 71.41 (C2'), 69.03 (C3'), 63.35 (C5'). 20.56 (COCH3). Anal. Calcd. for C14H13Cl3N2O5 : C, 42.50; H, 3.31; N, 7.08. Found: C, 42.45; H, 3.20; N, 6.97.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[CH:11][C:10](Br)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[CH:11][C:10]([C:35]1[CH:36]=[C:31]([Cl:30])[C:32]([OH:47])=[C:33]([Cl:46])[CH:34]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-(3-acetyl-6-bromoquinolin-4-ylamino)cyclohexylcarbamate (40 mg, 0.087 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (50 mg, 0.195 mmol) to afford the crude product (46 mg) as a yellow solid: ESI MS m/z 544 [C28H31Cl2N3O4+H]+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.C([O:26][B:27]([O:32]C(C)C)[O:28]C(C)C)(C)C.Cl>C(OCC)C>[C:2]1([O:26][B:27]([OH:32])[OH:28])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2ccccc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OB(O)Oc1cccc2ccccc12
Temperature: -40 °C
Reaction time: 6 h

Procedure:
To one liter egg-plant type flask were added 55 g (0.27 mmol) of 1-bromonaphthalene and 300 ml of diethyl ether. The mixture was cooled to −70° C. on a dry ice/methanol bath, to which 170 ml (0.27 mmol) of a n-butyllithium/hexane solution (1.56 mol/l) was added dropwise. After addition was completed, the mixture was stirred for 6 hours while it was gradually brought to room temperature. The mixture was further cooled to −40° C. and to this were added dropwise 70 ml (0.30 mmol) of triisopropylborate and 100 ml of diethyl ether, and stirred overnight. To the reaction solution was added 200 ml of 2 N hydrochloric acid to cause hydrolysis. Diethyl ether (200 ml) was added to the reaction solution, which was washed with brine until it turned neutral. After drying over anhydrous sulfate, the solvent was distilled off under reduced pressure to give light yellow crystals of naphthyl boric acid.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.[CH:22]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28])=O>>[F:19][C:18]([F:20])([F:21])[C:15]1[N:13]2[N:14]=[C:9]([N:2]3[CH2:3][CH:4]4[CH2:8][N:7]([CH2:22][C:24]5[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=5)[C:27]#[N:28])[CH2:6][CH:5]4[CH2:1]3)[CH:10]=[CH:11][C:12]2=[N:17][N:16]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Reactant: N#Cc1cccc(C=O)c1
Product: N#Cc1cccc(CN2CC3CN(c4ccc5nnc(C(F)(F)F)n5n4)CC3C2)c1

Procedure:
Reductive amination of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-formylbenzonitrile was carried out according to General Synthetic Method 10. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 3-[[5-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2-yl]methyl]benzonitrile.
Reaction SMILES: [F:1][CH:2]([F:13])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[N:6]=[C:5]1[CH3:12].[NH2:14][C@@H:15]([CH3:32])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[C:28]([F:30])[C:25]([C:26]#[N:27])=[C:24]([Cl:31])[CH:23]=2)=[N:18]1.C1C=CC2N(O)N=NC=2C=1.CN(C=O)C>O>[Cl:31][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@@H:15]([NH:14][C:9]([C:7]3[N:6]=[C:5]([CH3:12])[N:4]([CH2:3][CH:2]([F:1])[F:13])[CH:8]=3)=[O:11])[CH3:32])[N:18]=2)[CH:29]=[C:28]([F:30])[C:25]=1[C:26]#[N:27]
Reactant: Cc1nc(C(=O)O)cn1CC(F)F
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1CC(F)F
Yield: 5.6 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) using 1-(2,2-difluoro-ethyl)-2-methyl-1H-imidazole-4-carboxylic acid (0.926 mmol, 176 mg), (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile (0.617 mmol, 172 mg) and only a catalytic amount of HOBt (0.062 mmol, 8.34 mg). DMF was used as the solvent. Water was added to the reaction mixture and the mixture was extracted it three times with DCM. The combined organics were washed twice with water. The organic phase was evaporated and the residue was purified by flash chromatography and preparative HPLC, respectively. 15.5 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.07 (d, 3H), 2.36 (s, 3H), 4.23-4.55 (m, 5H), 6.19-6.51 (m, 1H), 7.02 (d, 1H), 7.53 (s, 1H), 7.86 (d, 1H), 7.90-7.95 (m, 1H), 8.00 (s, 1H), 8.12 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@@H:14]3[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[NH:9]1.I[CH:23]([CH3:25])[CH3:24]>CN(C)C=O.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@@H:14]3[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[N:9]1[CH:23]([CH3:25])[CH3:24]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3F)c(=O)c12
Reactant: CC(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c2c(c(=O)n1-c1ccccc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Reaction time: 18 h
Yield: 4.1 %

Procedure:
A mixture of a (4S,7R)-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 12; 150 mg, 0.52 mmol) and 2-iodopropane (105 μL, 1.05 mmol) in N,N-dimethylformamide (2 mL) in a microwave reaction tube was heated to 100° C. and stirred for 18 h. The reaction mixture was allowed to cool, diluted with saturated sodium bicarbonate, and extracted twice with ethyl acetate. The organic extracts were combined, washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO CombiFlash® Sg100c chromatography system with an Isco 12 g column, eluting with 25-100% ethyl acetate/hexanes followed by crystallization from dichloromethane to give (4S,7R)-2-(2-fluoro-phenyl)-1-isopropyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (7 mg, 4%) as an yellow solid. ES(+)-MS (M+H) 329.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[C:14](=O)([O-])[O-].[Na+].[Na+].IC>CN(C)C=O>[CH3:14][N:11]1[C:10](=[O:12])[O:9][C:7](=[O:8])[C:6]2=[CH:13][C:2]([CH3:1])=[CH:3][CH:4]=[C:5]12
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1ccc2c(c1)c(=O)oc(=O)n2C
Temperature: 0 °C

Procedure:
A solution of 26.6 g of 5-methylisatoic anhydride in 150 ml of dimethylformamide is treated with 17.5 g of anhydrous sodium carbonate, then with 32 g of iodomethane, and the mixture is stirred at 20°-25° C. for 18 hrs. The reaction mixture is poured into 1.25 liter of ice water and the resulting precipitate of N,5-dimethylisatoic anhydride is collected by filtration, washed with water and dried; mp 166°-169° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:12][CH3:13].C([Li])CCC.CN(C)[CH:21]=[O:22]>O1CCCC1.[Cl-].[NH4+].C(#N)C>[CH3:13][O:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:21]=[O:22])[CH:3]=2)[N:8]=[CH:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: COc1ccnc2ccc(Br)cc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccnc2ccc(C=O)cc12
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a solution of 6-bromo-4-methoxy-quinoline (8.91 g, 37.42 mmol) in THF (tetrahydrofuran) (155 mL) was added dropwise a 2.5M solution of n-butyllithium in hexanes (16.46 mL, 4.16 mmol, 1.1 equiv.) at −70° C. During the addition, the temperature of the reaction mixture was raised slightly to −60° C. and it gave a very dark brown solution. The resulting colored solution was stirred for 30 min at this temperature. Then, a solution of dimethylformamide (5.78 mL, 74.84 mmol) in THF (10 mL) was added dropwise. After addition, the mixture was allowed to warm to room temperature and stirred for 15 h. Then, the mixture was diluted with saturated ammonium chloride solution and the two layers were separated. The aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude brown solid. This solid was dissolved in acetonitrile (˜50 mL) at hot condition and then stored in the refrigerator overnight. The solids were collected by filtration and washed with diethyl ether. After drying in air, 4.47 g (64% yield) of 4-methoxy-quinoline-6-carbaldehyde was isolated as a white solid: EI-HRMS m/e calcd for C11H9NO2 (M+) 187.0633, found 187.0638.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[N:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=2)=[CH:13][CH:12]=1
Reactant: COc1cnc(Cl)nc1
Reactant: OB(O)c1ccc(Cl)cc1
Product: COc1cnc(-c2ccc(Cl)cc2)nc1
Yield: 40 %

Procedure:
The title compound was prepared according to the method described for Preparation 17 using 2-chloro-5-methoxy-pyrimidine and 4-chlorophenylboronic acid to afford the title compound as an off-white solid (4.05 g, 40%)
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28]([N:30]1[CH2:35][C@H:34]2[C@H:32]([CH2:33]2)[C@H:31]1[CH2:36][OH:37])=[O:29])([CH3:26])([CH3:25])[CH3:24].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:23]([O:27][C:28]([N:30]1[CH2:35][C@H:34]2[C@H:32]([CH2:33]2)[C@H:31]1[CH:36]=[O:37])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1C=O

Procedure:
Dess-Martin periodinane (3.18 mmol) is added to a solution of (1S,2S,5R)-2-Hydroxymethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (3.24 mmol) in DCM (45 mL, saturated with water). Additional periodinane (0.80 mmol) is added after 2 h. After additional 2.5 h a sat. NaHCO3 solution is added, the layers are separated and the organic layer is washed with aq. Na2S2O3 solution. The aq. layer is extracted twice with DCM, the combined organic layers are concentrated in vacuo and the residue is purified by FC (pentane to pentane/ether 4/1) to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH2:23][CH2:24][CH3:25])[N:14]([CH2:15][CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[CH:27]([B-](F)(F)F)=[CH2:28].[K+]>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH2:23][CH2:24][CH3:25])[N:14]([CH2:15][CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH:27]=[CH2:28])=[CH:5][C:4]=2[N:3]=1
Reactant: CCCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCNS(C)(=O)=O
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Product: C=Cc1ccc2c(c1)nc(N)c1nc(CCCC)n(CCNS(C)(=O)=O)c12

Procedure:
N-[2-(4-Amino-7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]methanesulfonamide was coupled with potassium vinyltrifluoroborate according to the procedure described in Part D of Examples 440-455 and recrystallized from acetonitrile to provide N-[2-(4-amino-2-butyl-7-vinyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]methanesulfonamide as an off-white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2/[C:14](/[NH:17][OH:18])=[N:15]\[H])=[N:2]1.[CH2:23]([CH:25](CC(Cl)=O)[C:26](Cl)=[O:27])[CH3:24].[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>N1C=CC=CC=1.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[C:14]2[N:15]=[C:24]([CH2:23][CH2:25][CH2:26][OH:27])[O:18][N:17]=2)=[N:2]1
Reactant: CCC(CC(=O)Cl)C(=O)Cl
Reactant: [H]/N=C(/NO)c1ccccc1C=Cc1n[nH]c2ccccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: O
Solvent: c1ccncc1
Product: OCCCc1nc(-c2ccccc2/C=C/c2n[nH]c3ccccc23)no1
Temperature: 90 °C
Reaction time: 1 h
Yield: 17.9 %

Procedure:
(E)-2-[2-(1H-indazol-3-yl)vinyl]-N-hydroxybenzamidine (0.08 g, 0.29 mmol) obtained in Step 1 of Example 175 was dissolved in pyridine (5.0 mL) and the solution was added with ethylsuccinyl chloride (47 μL, 0.33 mmol), followed by stirring at 90° C. for 1 hour. The reaction mixture was added with water and extracted with ethyl acetate. After the organic layer was concentrated, the residue was added to acetonitrile (5.0 mL) and stirred at 80° C. for 3.5 hours. The reaction mixture was added with water and extracted with ethyl acetate. After the organic layer was concentrated, the residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 1/2) and the residue was dried. Further, the residue was dissolved in a mixed solvent of methylene chloride (1.0 mL)/THF (1.0 mL), cooled to −78° C. and diisobutylaluminum hydride (1.0 mol/L toluene solution, 1.0 mL, 1.0 mmol) was added, followed by stirring for 30 minutes. The reaction mixture was added with saturated aqueous Rochelle salt solution, extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=2/1) to obtain Compound 180 (18 mg, 24%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][C:20]2=[O:32])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:33]>C(OCC)(=O)C>[ClH:33].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][NH:22][CH2:21][C:20]2=[O:32])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3ccc(OCc4ccccc4)cc23)C(=O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1CNCCN1c1cccc2ccc(OCc3ccccc3)cc12
Reaction time: 0.5 h

Procedure:
Through a solution of the product from Step D (1.244 g, 2.88 mmol) in 50 mL of ethyl acetate at 0° C. was bubbled anhydrous HCl gas for 5 minutes. After 30 minutes, the solution was concentrated in vacuo to provide the titled salt as a brown powder (1.064 g) which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[C:4](=[O:13])[CH2:3]1.Cl[C:15]1C2CCC(C)C(C(O)=O)=CC=2C=CC=1.[I-].[Na+].C(N(CC)CC)C.CN(C)CCN(C)C.C([Li])CCC.CI>CCCCCC.C(#N)C>[CH3:15][C:12]1[C:5]2[C:4](=[O:13])[CH2:3][CH:2]([CH3:1])[CH2:8][CH2:7][C:6]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CC1CCc2c(Cl)cccc2C=C1C(=O)O
Reactant: CC1CCc2ccccc2C(=O)C1
Agent: CN(C)CCN(C)C
Agent: [I-]
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: CI
Solvent: CC#N
Product: Cc1cccc2c1C(=O)CC(C)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.8 %

Procedure:
A mixture of the 7-methyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (6.63 g, 38.1 mmol) synthesized in Reference Example 10, (d), trimethylsilane chloride (7.25 ml, 57.1 mmol), sodium iodide (8.56 g, 57.1 mmol), triethylamine (7.95 ml, 57.0 mmol) and acetonitrile (80 ml) was stirred at room temperature for 4 hours. Then, the solvent was distilled off under reduced pressure and the resulting residue was extracted with a mixed solvent of n-hexane/diethyl ether (1/1). The extract solution was concentrated under reduced pressure and the resulting residue was dissolved in n-hexane (150 ml), followed by adding thereto tetramethylethylenediamine (13.5 ml, 89.4 mmol), and the reaction mixture was cooled to 0° C. Then, n-butyllithium (a 3.0 M n-hexane solution; 30 ml, 90.6 mmol) was added dropwise to the reaction mixture and the resulting mixture was stirred at room temperature for 20 minutes and then at 60° C. for 2.5 hours. The reaction mixture was cooled to room temperature and methyl iodide (3.55 ml, 57.0 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. The reaction mixture was diluted with n-hexane and the dilution was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography to obtain 3.43 g of 4,7-dimethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:13][S:12][C:11]([NH2:19])=[N:10]2.[Br:20]N1C(=O)CCC1=O.CCOCC.C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[Br:20][C:5]1[C:6]([F:8])=[CH:7][C:2]([F:1])=[C:3]([C@:9]23[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[CH2:13][S:12][C:11]([NH2:19])=[N:10]3)[CH:4]=1
Reactant: NC1=N[C@@]2(c3ccc(F)cc3F)CCCC[C@H]2CS1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Product: NC1=N[C@@]2(c3cc(Br)c(F)cc3F)CCCC[C@H]2CS1
Reaction time: 2 h
Yield: 95.6 %

Procedure:
(±)-(4aR*,8aS*)-8a-(2,4-Difluoro-phenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-ylamine (270 mg) was dissolved in concentrated sulfuric acid (3 mL). N-Bromosuccinimide (170 mg) was added in an ice bath, and the mixture was stirred at the same temperature for two hours. Ice was added to terminate the reaction, followed by dilution with ether. The reaction solution was neutralized with a sodium bicarbonate solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (330 mg).