Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26](F)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CN1[C:36]([C:37](Cl)=[O:38])=[CH:35]N=C1>>[CH2:15]1[C:26]2[C:27](=[CH:28][CH:29]=[C:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[C:8]([C:4]5[CH:3]=[C:2]([NH:1][C:37](=[O:38])[C:36]6[CH:35]=[CH:6][CH:7]=[CH:2][CH:3]=6)[CH:7]=[CH:6][CH:5]=5)=[N:9][N:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=45)[CH:22]=[CH:21][N:20]=3)[CH:25]=2)[CH2:12][CH2:11][NH:10]1
Reactant: Cn1cncc1C(=O)Cl
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluorophenyl)-2-pyrimidinamine and 1-methyl-1H-imidazole-5-carbonyl chloride in a manner analogous to Example 66. 1H NMR (400 MHz, DMSO-d6): δ 10.14 (s, 1H), 9.80 (s, 1H), 8.84 (d, 1H), 8.50 (d, 1H), 8.30 (d, 1H), 8.04 (s, 1H), 7.87-7.76 (m, 4H), 7.52-7.41 (m, 3H), 7.29-7.22 (m, 2H), 7.13 (m, 1H), 6.72 (m, 1H), 6.57 (d, 1H), 3.83 (s, 3H); HRMS: calc. C28H22N8OF (M+H)+ 505.1901 found 505.1903.
Reaction SMILES: [F:1][C:2]1[C:7]2[S:8][CH2:9][CH:10]([NH:11][C:12]([NH:14][CH2:15][CH2:16][OH:17])=[S:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>CN(C1C=CN=CC=1)C.C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[C:7]2[S:8][CH2:9][CH:10]([NH:11][C:12](=[S:13])[NH:14][CH2:15][CH2:16][O:17][C:24](=[O:26])[CH3:25])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCCNC(=S)NC1CSc2c(F)cccc21
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OCCNC(=S)NC1CSc2c(F)cccc21
Reaction time: 16 h
Yield: 54.8 %

Procedure:
To a solution of 1-(7-Fluoro-2,3-dihydro-benzo[b]thiophen-3-yl)-3-(2-hydroxy-ethyl)-thiourea (200 mg, 0.73 mmol), pyridine (0.07 mL, 0.88 mmol) and DMAP (20 mg, 0.16 mmol) in THF (5 mL) was added a solution of acetyl chloride (0.06 mL, 0.81 mmol) in THF (2 mL) and the reaction mixture stirred for 16 h. The mixture was diluted with ethyl acetate (20 mL) and extracted with water (4 times). The organic phase was dried over Na2SO4, solvents evaporated and the residue purified by column chromatography to yield Acetic acid 2-[3-(7-fluoro-2,3-dihydro-benzo[b]thiophen-3-yl)thioureido]-ethyl ester (125 mg, 0.40 mmol, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][CH2:14][CH:15]([CH3:18])[CH2:16][CH3:17])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH2:7].C(N(CC)CC)C.C1(C(Cl)=[O:30])CC1.[C:32]1([CH3:38])[CH:37]=[CH:36][CH:35]=CC=1>>[Cl:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][CH2:14][CH:15]([CH3:18])[CH2:16][CH3:17])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH:7][C:38]([CH2:32][CH:37]1[CH2:36][CH2:35]1)=[O:30]
Reactant: CCC(C)COCc1ccc(OCCN)c(Cl)c1
Reactant: Cc1ccccc1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Product: CCC(C)COCc1ccc(OCCNC(=O)CC2CC2)c(Cl)c1
Reaction time: 2 h

Procedure:
To a mixture of 181 g (0.667 mol) of 2-[2-chloro-4-(2-methylbutoxymethyl)phenoxy]ethylamine, 81 g (0.80 mol) of triethylamine and 8 liter of toluene, there is added dropwise a solution of 70 g (0.67 mol) of cyclopropane carbonyl chloride in 2 liter of toluene with stirring at a temperature of from 5° C. to 10° C. After 2 hours, the reaction mixture is stirred at a room temperature for 15 hours. After the reaction is completed, the resultant mixture is washed twice with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel chromatography to give N-{2-[2-chloro-4-(2-methylbutoxymethyl)phenoxy]ethyl}-cyclopropane carboxyamide.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[CH2:16][C:15](=[O:19])[NH:14][C:13]2[C:20]3[C:25]([CH:26]=[CH:27][C:12]1=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].[I:40][C:41]1[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=1C(Cl)=O>ClCCl>[I:40][C:41]1[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=1[C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[CH2:16][C:15](=[O:19])[NH:14][C:13]2[C:20]3[C:25]([CH:26]=[CH:27][C:12]1=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:7]
Reactant: O=C(Cl)c1ccccc1I
Reactant: CC(C)(C)OC(=O)NCCN1C(=O)CC(=O)Nc2c1ccc1ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(=O)N(CCNC(=O)c2ccccc2I)c2ccc3ccccc3c2N1
Temperature: 25 °C
Reaction time: 19 h
Yield: 41.9 %

Procedure:
5-[2-(tert-Butoxycarbonyl)aminoethyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (16 mg, 0.043 mmol) was dissolved in dichloromethane (4 mL), the solution was added with trifluoroacetic acid (0.1 mL), and the mixture was stirred at room temperature for 19 hours. This reaction mixture was added with saturated aqueous sodium hydrogencarbonate (8 mL) with stirring under ice cooling, and the mixture was stirred for 5 minutes. Further, the mixture was added with 2-iodobenzoyl chloride (0.22 mmol) dissolved in dichloromethane (4 mL) with stirring under ice cooling. This reaction mixture was stirred under ice cooling for 30 minutes, and then at room temperature for 30 minutes. The dichloromethane layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (methanol/chloroform=1/50), and then recrystallized from ethyl acetate/hexane to give the title compound (9 mg, yield 42%) as white crystals. The structure was confirmed by NMR and MS.
Reaction SMILES: [CH3:1][I:2].[CH3:3][O:4][C:5]1[C:14]2[CH:13]=[N:12][CH2:11][CH:10]3[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:8]([C:9]=23)=[CH:7][C:6]=1[O:23][CH3:24]>CC(C)=O.C(OCC)C>[I-:2].[CH3:3][O:4][C:5]1[C:14]2[CH:13]=[N+:12]([CH3:1])[CH2:11][CH:10]3[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:8]([C:9]=23)=[CH:7][C:6]=1[O:23][CH3:24]
Reactant: COc1cc2c3c(c1OC)C=NCC3c1ccccc1CC2
Reactant: CI
Solvent: CCOCC
Solvent: CC(C)=O
Product: COc1cc2c3c(c1OC)C=[N+](C)CC3c1ccccc1CC2
Product: [I-]
Temperature: 0 °C

Procedure:
The organic halide, methyl iodide (5 mL), was added to a solution of 4,5-dimethoxy-1,7,8,12b-tetrahydrobenzo[6,7]cyclohepta[1,2,3-de]isoquinoline (3.0 g, 10 mmol; described in example 2) in acetone (75 mL). The mixture was heated at reflux (reflux time=1 hr.), cooled to 0° C. and diluted with diethyl ether. The solid (isoquinolinium salt) was collected and dried under vacuum to give 4,5-dimethoxy-2-methyl-1,7,8,12b-tetrahydrobenzo[6,7]cyclohepta[1,2,3-de]isoquinolinium iodide, mp 179°-182° C.
Reaction SMILES: [CH:1]1([C:4]([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][C:6]#[CH:7])[CH2:3][CH2:2]1.[CH2:17]([SnH:21]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20].N(C(C)(C)C#N)=NC(C)(C)C#N>>[CH:1]1([C:4]([O:12][Si:13]([CH3:16])([CH3:14])[CH3:15])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5]/[CH:6]=[CH:7]/[Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:2][CH2:3]1
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCC(CCCC)(O[Si](C)(C)C)C1CC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCC(C/C=C/[Sn](CCCC)(CCCC)CCCC)(O[Si](C)(C)C)C1CC1
Temperature: 85 °C

Procedure:
A stirred mixture of 23.8 g of 4-cyclopropyl-4-trimethylsiloxy-1-octyne (Example 10), 28 ml of tri-n-butyltin hydride, and 50 mg of azobisisobutyronitrile under nitrogen is heated to 85° C. After the resulting exothermic reaction subsides the mixture is heated at 130° C. for 1 hour. The crude product is evaporatively distilled to give a liquid, p.m.r. spectrum (C D Cl3): δ0.10 (trimethylsiloxy group), 2.33 (doublet, =CHCH2), and 6.02 (vinyl hydrogens).
Reaction SMILES: CCOCC.[N:6]([C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:13])[C:10]([O-:12])=O)=[C:7]=[S:8].[C:20]1([NH:26]N)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C(C)=CC=CC=1>[C:20]1([N:26]2[C:10](=[O:12])[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([CH3:13])[NH:6][C:7]2=[S:8])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NNc1ccccc1
Reactant: CC(N=C=S)(C(=O)[O-])c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: CC1(c2ccccc2)NC(=S)N(c2ccccc2)C1=O
Temperature: 25 °C
Yield: 81.5 %

Procedure:
4.7 g (20 mmol) of ether 2-isothiocyanato-2-phenylpropionate are dissolved in 40 ml of xylene. 2.16 g (20 mmol) of phenylhydrazine are added and the mixture is heated for 4 hours at reflux. The mixture is cooled to room temperature and a beige solid precipitates. The precipitate is filtered, washed with 5 ml of diisopropyl ether and then dried under vacuum. 4.6 g (yield=77%) of 3,5-diphenyl-5-methyl-2-thiohydantoin are thus obtained in the form of a beige powder melting at 164° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[CH:12]=[C:11](B3OC(C)(C)C(C)(C)O3)[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)=[N:9]2)=[CH:5][CH:4]=1.[CH3:33][S:34][C:35]1[N:40]=[C:39](Cl)[CH:38]=[CH:37][N:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:37]3[CH:38]=[CH:39][N:40]=[C:35]([S:34][CH3:33])[N:36]=3)[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)=[N:9]2)=[CH:31][CH:32]=1
Reactant: CSc1nccc(Cl)n1
Reactant: COc1ccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(-c3ccnc(SC)n3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Temperature: 100 °C
Yield: 88.4 %

Procedure:
2.6 g (6 mmol) of 1-(4-methoxybenzyl)-3-(3-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were dissolved in a mixture of 520 ml of dioxane and 130 ml of water under a nitrogen atmosphere. 709 μl (6 mmol) of 2-methylthio-4-chloro-pyrimidine, 3.9 g (12 mmol) of cesium carbonate and 650 mg (0.6 mmol) of palladium tetrakis were added consecutively to the resulting solution under stirring. The reaction mixture was heated at 100° C. for 6 hours, then filtered through a celite pad and concentrated under reduced pressure. The residue was partitioned between dichloromethane and water, the organic layer dried over sodium sulphate and evaporated to dryness. The crude was finally purified by flash-chromatography on a silica gel column (cyclohexane-ethylacetate; from 9/1 to 4/1), giving 2.3 g (88%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl.C(=O)([O-])[O-].[K+].[K+].C[N:23](C)C=O>>[O:15]1[CH2:14][CH:13]1[CH2:11][O:1][CH:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH2:5][CH2:4][C:3]1=[NH:23]
Reactant: ClCC1CO1
Reactant: CN(C)C=O
Reactant: O=C1CCCc2sccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N=C1CCc2sccc2C1OCC1CO1

Procedure:
A mixture of 100 g. (0.60 mol) of the E-oxime of 4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene, 330 g. (3.6 mols) of epichlorohydrin and 391.2 g. (2.8 mols) of potassium carbonate in one liter of dimethylformamide is heated to 110° C. for 6 hours.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.C([O-])(=O)C.[Ca+2:37].C([O-])(=O)C.CCCCCCC>C(#N)C.O>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[Ca:37]
Reactant: [Ca+2]
Agent: CC(=O)[O-]
Agent: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Solvent: CCCCCCC
Solvent: O
Solvent: CC#N
Product: [Ca]
Temperature: 67.5 °C
Reaction time: 6 h

Procedure:
Raltegravir (10 gm) was suspended in acetonitrile (40 ml) and then added a solution of calcium acetate (4 gm) in water (2 ml) at 25 to 30° C. The contents were heated to 65 to 70° C. and distilled off solvent completely under vacuum at 45° C. to obtain residue. To the residue was added n-heptane (50 ml) and again distilled to obtain residue. n-Heptane (100 ml) was added to the residue and stirred for 6 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 9.8 gm of raltegravir calcium.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]1[C:17]([Cl:18])=[C:16](N(CCCl)C)[CH:15]=[CH:14][N:13]=1.[N+:24]([C:27]1[N:31]2[N:32]=[C:33]([SH:36])[CH:34]=[CH:35][C:30]2=[N:29][CH:28]=1)([O-:26])=[O:25].C1CCN2[C:40](=[N:41][CH2:42]CC2)[CH2:39]C1>CN(C)C=O>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[S:10][CH2:11][C:12]1[C:17]([Cl:18])=[C:16]([CH2:42][NH:41][CH2:40][CH2:39][S:36][C:33]2[CH:34]=[CH:35][C:30]3[N:31]([C:27]([N+:24]([O-:26])=[O:25])=[CH:28][N:29]=3)[N:32]=2)[CH:15]=[CH:14][N:13]=1
Reactant: O=[N+]([O-])c1cnc2ccc(S)nn12
Reactant: CN(CCCl)c1ccnc(CSc2nc3ccccc3[nH]2)c1Cl
Reactant: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2ccc(SCCNCc3ccnc(CSc4nc5ccccc5[nH]4)c3Cl)nn12
Yield: 66.4 %

Procedure:
0.44 g (1.0 mmol) of [2-(1H-benzimidazol-2-ylsulfanylmethyl)-3-chloropyridin-4-yl]-(2-chloroethyl)methyl-amine, 0.24 g (1.2 mmol) of 3-nitroimidazo[1,2-b]pyridazine-6-thiol and 0.52 ml (3.5 mmol) of DBU are reacted in 10 ml of dimethylformamide by the procedure described in Example 16. After crystallization from diisopropyl ether, 0.35 g (66%) of the title compound is obtained as a pale beige solid. M.p. 184-185° C.
Reaction SMILES: [CH2:1]([C:3]12[CH2:18][CH2:17][C:16](=[O:19])[CH:15]=[C:4]1[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=12)[CH3:2].N1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[CH2:1]([C@:3]12[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][C@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=12)[CH3:2].[CH2:1]([C@@:3]12[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][C@@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=12)[CH3:2]
Reactant: CCC12CCC(=O)C=C1CCCc1cc(O)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC[C@@]12CCC(=O)C[C@@H]1CCCc1cc(O)ccc12
Product: CC[C@]12CCC(=O)C[C@H]1CCCc1cc(O)ccc12
Yield: 56.9 %

Procedure:
To a suspension of 11b-ethyl-9-hydroxy-1,2,5,6,7,11b-hexahydro-dibenzo[a,c]cyclohepten-3-one (17, R2=Ethyl) (11.25 g, 43.9 mmol) and 10% Pd—C (1.40 g, 1.32 mmol) in THF (80 mL) was added pyridine (20 mL) and the mixture was hydrogenated at rt under about 40 psi of hydrogen for about 18 h. The catalyst was removed by filtration through Celite®, and the filtrate was concentrated. The residue was dissolved in DCM (200 mL) and washed with 2N aq. HCl (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was re-dissolved in EtOAc (100 mL) and DCM (100 mL), filtered through a short pad of silica gel, and concentrated until product began to precipitate. Product was collected by filtration, rinsed with EtOAc (10 mL) and dried under reduced pressure to yield (4aS,11bR)-11b-ethyl-9-hydroxy-1,2,4,4a,5,6,7,11b-octahydro-dibenzo[a,c]cyclohepten-3-one; compound with (4aR,11bS)-11b-ethyl-9-hydroxy-1,2,4,4a,5,6,7,11b-octahydro-dibenzo[a,c]cyclohepten-3-one (18, R2=Ethyl) (6.45 g, 57%) as a white solid. LC/MS, method 1, 0.80 min, 319 (M−H)−. 1H NMR (400 MHz, DMSO) 9.14 (s, 1H), 7.11-7.05 (m, 1H), 6.60-6.54 (m, 2H), 2.96-2.86 (m, 1H), 2.65-2.54 (m, 2H), 2.47-2.36 (m, 1H), 2.29-2.20 (m, 1H), 2.20-2.05 (m, 4H), 1.89-1.79 (m, 1H), 1.71-1.51 (m, 3H), 1.49-1.31 (m, 2H), 0.61 (t, J=7.4 Hz, 3H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:13][O:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([NH2:23])[CH2:19][CH2:18]1)=[O:16].C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCCl.CO>[CH3:13][O:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:23][CH2:11][C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH2:19][CH2:18]1)=[O:16]
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2,3-Dihydro-benzo[1,4]dioxine-6-carbaldehyde (198 mg, 1.21 mmol, 1.0 eq) is added at room temperature to a stirred solution of trans-4-amino-cyclohexanecarboxylic acid methyl ester (200 mg, 1.21 mmol, 1.0 eq) in 1,2-dichloroethane (8 mL) and methanol (2 mL), followed by acetic acid (80 μL, 1.39 mmol, 1.15 eq) and sodium cyanoborohydride (99 mg, 1.57 mmol, 1.3 eq). After 15 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×20 mL) and a saturated sodium hydrogen carbonate aqueous solution (20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexanecarboxylic acid methyl ester as an orange oil (359 mg, 92% yield).
Reaction SMILES: [N+:1]([C:4]1[C:5](O)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[CH3:21][N:22]([CH3:28])[CH2:23][CH2:24][CH2:25][NH:26][CH3:27].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:21][N:22]([CH3:28])[CH2:23][CH2:24][CH2:25][N:26]([CH3:27])[C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1O
Reactant: CNCCCN(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CN(C)CCCN(C)c1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
A solution of 3-nitro-5-(trifluoromethyl)pyridin-2-ol (500 mg, 2.4 mmol), CHCl3 (25 mL), oxalyl chloride (0.42 mL, 4.8 mmol) and DMF (1 drop) was allowed to reflux for 16 h. Once consumption of starting material was complete the reaction was concentrated under reduced pressure. A portion of the crude material (182 mg, 0.8 mmol) was removed and added to a mixture of N1,N1,N3-trimethylpropane-1,3-diamine (0.13 mL, 0.88 mmol), K2CO3 (221 mg, 1.6 mmol) and heated at 90° C. for 10 min. The mixture was concentrated under reduced pressure and reconstituted in CH2Cl2 (20 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford N-(3-(dimethylamino)propyl)-N-methyl-3-nitro-5-(trifluoromethyl)pyridin-2-amine. MS m/z=307 [M+H]+. Calc'd for C12H17F3N4O2: 306.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:36])[C:15](=[O:35])[CH:16]([O:18][C:19]2[N:24]=[C:23]([CH3:25])[C:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:21]([CH3:34])[N:20]=2)[CH3:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][Si]([N-][Si](C)(C)C)(C)C.[K+].CI.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:36])[C:15](=[O:35])[CH:16]([O:18][C:19]2[N:24]=[C:23]([CH3:25])[C:22]([N:26]([CH3:37])[C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[C:21]([CH3:34])[N:20]=2)[CH3:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1nc(OC(C)C(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1nc(OC(C)C(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1N(C)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
To a tetrahydrofuran (1 mL) solution of Compound 56 (72 mg), potassium bis(trimethylsilyl)amide (0.5M toluene solution: 273 μL) was added at −78° C. The mixture was stirred at −78° C. for 30 min and methyl iodide (9 μL) was added portionwise. The mixture was then stirred overnight as it was allowed to be slowly warmed to room temperature (20 to 30° C.). Subsequently, a saturated aqueous ammonium chloride solution was added to the reaction mixture and the mixture was extracted twice with chloroform. The organic layer was concentrated under reduced pressure and the resulting residue was purified by amino-coated silica gel (Fuji Sylysia Chemical Ltd.; NH-DM1020) column chromatography (ethyl acetate:hexane=1:19 to 1:1) to give 7.7 mg (10% yield) of tert-butyl 2-(1-((1-benzylpiperidine-4-yl)(methyl)amino)-1-oxopropane-2-yloxy)-4,6-dimethylpyrimidine-5-yl(methyl)carbamate. 2.6 mg (42% yield) of the title compound was synthesized from tert-butyl 2-(1-((1-benzylpiperidine-4-yl)(methyl)-amino)-1-oxopropane-2-yloxy)-4,6-dimethylpyrimidine-5-yl(methyl)-carbamate in the same manner as in Example 71.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH2:10])=[O:4].[N:17]1([CH:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)[CH:21]=[CH:20][N:19]=[N:18]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH:10][CH:25]1[CH2:24][CH2:23][CH:22]([N:17]2[CH:21]=[CH:20][N:19]=[N:18]2)[CH2:27][CH2:26]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N
Reactant: O=C1CCC(n2ccnn2)CC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCC(n2ccnn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-amino-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (example 9)(0.387 g, 1.6 mmol) and 4-[1,2,3]triazol-1-yl-cyclohexanone (0.27 g, 1.6 mmol) in dry THF is added dibutyltin dichloride (0.024 g, 0.080 mmol) followed by phenylsilane (0.276 ml, 2.2 mmol). The mixture is stirred overnight at room temperature. Solvent is evaporated under reduced pressure, and the residue is diluted with ethyl acetate. The organic layer is washed with water and brine, dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel using gradient 50-100% ethyl acetate in hexane to afford 5-(3,3-dimethyl-but-1-ynyl)-3-(4-[1,2,3]triazol-1-yl-cyclohexylamino)-thiophene-2-carboxylic acid methyl ester.