Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=O)[CH2:9]1.Cl.[NH2:17][CH2:18][C:19]#[C:20][CH3:21].O1CCCC1>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][C:10]2[N:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:11]=2[C:12](=[O:14])[CH2:13]1
Reactant: O=C1CC(=O)CC(c2ccccc2Cl)C1
Reactant: CC#CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccnc2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.5 %

Procedure:
A mixture of 5-(2-chlorophenyl)-1,3-cyclohexanedione (1.1 g), 1-amino-2-butyne hydrochloride (0.5 g), molecular sieve 4A (2 g) and tetrahydrofuran (20 ml) was combined with triethylamine (0.48 g), stirred at room temperature for 1 hour, and then heated under reflux for 12 hours. After cooling, insolubles were filtered off, and the solvent was distilled off under reduced pressure. The residue was stirred at 220° C. for 4 hours. Ethyl acetate and aqueous sodium hydrogen carbonate were added, and the organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was subjected to a column chromatography on a silica gel (EtOAc/hexane) to obtain a crystal which was then recrystallized from ethyl acetate-hexane to obtain 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinoline-5-one (0.20 g) as a colorless crystal.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([C:19]([OH:21])=[O:20])=[CH2:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([OH:25])(=[S:24])[CH3:23]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH:17]([C:19]([OH:21])=[O:20])[CH2:18][S:24][C:22](=[O:25])[CH3:23])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C(=O)O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(O)=S
Product: CC(=O)SCC(C(=O)O)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 95 %

Procedure:
4-(1-Carboxy-vinyl)-piperidine-1-carboxylic acid benzyl ester (15.6 g) was dissolved in thioacetic acid (15 ml) and heated to reflux for 3 h. The thioacetic acid was evaporated under reduced pressure and azeotroped with 1:1 hexane-dichloromethane (4×30 ml) to give the title compound (20.32 g, 95%) as an orange oil.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:28]=3)[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][C:34]6[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=6)[CH:28]=5)[CH:23]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: OC1(c2ccc3cc(OCc4ccccc4)ccc3c2)CCNCC1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2ccc3cc(OCc4ccccc4)ccc3c2)CC1
Yield: 82.5 %

Procedure:
Beginning with 0.170 gm (0.90 mmol) (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 0.300 gm (0.90 mMol) 4-hydroxy-4-(6-benzyloxynaphth-2-yl)piperidine, 0.388 gm (83%) of the title compound were recovered as a white solid by the procedure described in Example 9.
Reaction SMILES: BrN1C(=[O:7])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:21]([O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)[CH3:22]>C(Cl)(Cl)Cl>[CH2:21]([O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=[O:7])[CH:27]=1)[CH3:22]
Reactant: CCOC(=O)Cc1cccc(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1cccc(C=O)c1
Temperature: 100 °C

Procedure:
N-bromosuccinimide (1.78 g) and 2,2′-azobis(2-methylpropionitrile) (16 mg) were added to a solution of ethyl-3-methylphenylacetate (1.76 mL) in chloroform (18 mL) and heated to reflux for 3 hours. On cooling the mixture was diluted with chloroform (40 mL), washed sequentially with saturated aqueous sodium bicarbonate solution (2×50 mL), brine (50 mL), dried (sodium sulfate) and concentrated. The residue was dissolved in nitrogen degassed dimethylsulfoxide (50 mL) and sodium bicarbonate (13.5 g) added. The mixture was heated at 100° C., under nitrogen for 30 min. The reaction was cooled in an ice-bath and poured into brine (300 mL). The aqueous phase was extracted with diethyl ether (3×300 mL). The combined organics were dried (sodium sulfate) and concentrated. Purification on silica, eluting with 10% diethyl ether in iso-hexane, to afford the subtitle compound as a yellow oil (1.23 g).
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.CCCCCC.[CH:20]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])[CH3:21].Br[CH2:33][CH:34]([CH2:37][CH3:38])[CH2:35][CH3:36].Cl>C1COCC1.O>[CH:20]([O:23][C:24]([C:26]1([CH2:33][CH:34]([CH2:37][CH3:38])[CH2:35][CH3:36])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])[CH3:21]
Reactant: CC(C)OC(=O)C1CCCCC1
Reactant: CCC(CC)CBr
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(CC)CC1(C(=O)OC(C)C)CCCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88.1 %

Procedure:
To a solution of dicyclohexylamine (4.263 g, 23.5 mmol) in THF (10 mL) 1.6 M n-BuLi in hexane (13.23 mL, 21.15 mmol) was added with stirring over 20 min at temperature between −20° C. and −15° C. This orange suspension was stirred 10 min at −20° C. and then warmed up to 0° C. To this orange suspension a solution of cyclohexanecarboxylic acid isopropyl ester (3.0 g, 17.63 mmol) in THF (22 mL) was added over 15 min at 0° C. The resulting solution was stirred 30 min at 0° C., then 1-bromo-2-ethylbutane (4.073 g, 24.7 mmol) in THF (11 mL) was added at the same temperature over 15 min. Stirring at 0° C. was continued overnight and for an additional 2 h at room temperature. At 5° C. cold water (20 mL) was added, followed by 2N HCl (50 mL). The white suspension was filtered and the filter cake was washed with water and ethyl acetate. The organic phase of the filtrate was washed with sat. aq. NaHCO3 and with aq. NaCl. The aqueous phases were extracted with ethyl acetate. The organic phases were combined, dried over sodium sulfate and concentrated. The crude product (4.7 g) was distilled at 50° C. (0.01 mbar) to give 3.95 g (88%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid isopropyl ester as colorless oil, purity 97% (GC area).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([C:12]2[NH:13][S:14](=[O:25])(=[O:24])[C:15]3[CH:21]=[C:20]([O:22]C)[CH:19]=[CH:18][C:16]=3[N:17]=2)=[C:8]([OH:26])[C:7]([CH:27]([CH3:29])[CH3:28])=[N:6]1)[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]([C:12]2[NH:13][S:14](=[O:25])(=[O:24])[C:15]3[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[C:8]([OH:26])[C:7]([CH:27]([CH3:28])[CH3:29])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(C(C)C)c(O)c(C2=Nc3ccc(OC)cc3S(=O)(=O)N2)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCn1nc(C(C)C)c(O)c(C2=Nc3ccc(O)cc3S(=O)(=O)N2)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
2-Butyl-5-hydroxy-6-isopropyl-4-(7-methoxy-1, 1-dioxo-1,2-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-2H-pyridazin-3-one (5e) (56 mg) was dissolved in 3 mL of methylene chloride. BBr3 (466 μL, 1.0 M in methylene chloride) was added and the mixture was stirred at room temperature for 1.5 hours. LC-MS result showed the incompletion of the reaction. BBr3 (0.5 mL, 1.0 M) was added and the reaction mixture was continued to shake at room temperature overnight. LC-MS confirmed that the reaction was close to completion. The reaction mixture was poured onto ice (10 mL), extracted with CHCl3 (20 mL×3). The organic layer was dried over MgSO4, filtered, concentrated under reduced pressure and further purified by flash chromatography on silica gel to give the desired product (5f) (42.2 mg) in 78.0% yield. 1H NMR (400 MHz, CDCl3): δ 7.46 (d, 1H, J=2.8 Hz), 7.16-7.26 (m, 2 H), 4.20 (t, 2H, J=7.2 Hz), 3.34 (m, J=6.8 Hz, 1H), 1.81 (m, 2H), 1.41 (m, 2H), 1.29 (d, 6H, J=6.8 Hz), 1.00 (t, 3H, J=7.4 Hz); LC-MS (ESI+): m/e=407.1 [M+1]+ (exact MS: 406.13).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Br:26])[CH:24]=3)[N:19]([S:27]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33]([O:40][CH3:41])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH:18]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[Br:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]([S:27]([C:30]1[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]([O:40][CH3:41])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH:18]=[C:17]2[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1)=[O:16]
Reactant: COc1ccc(S(=O)(=O)n2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)c3cc(Br)ccc32)c2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)n2cc(C(=O)N3CCCNCC3)c3cc(Br)ccc32)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
To a solution of 4-[5-Bromo-1-(4-methoxy-naphthalene-1-sulfonyl)-1H-indole-3-carbonyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (A) (45 mg, 0.07 mmol) in dichloromethane (5 cm3) was added trifluoroacetic acid (2 cm3). The solution was shaken at room temperature for 1 h before the solvent was removed under reduced pressure. The residue was dissolved in N,N-dimethylformamide (DMF) (1 cm3) and purified using reverse phase HPLC (Agilent Technologies, CombiHT SB-C18, Preparative cartridge 21.2×100 mm, 5-micron) using a linear gradient of water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid). The desired peak was then evaporated under reduced pressure to afford the title compound (83) (45.9 mg, 27%). Positive ion APCI (M+H)+ 543.4.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=1[CH:16]=[O:17].C[O-].[Na+].[C:21](O)(=[O:23])C.C(Cl)Cl>CO>[CH:16]([C:3]1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[C:6]([C:8]([O:10][CH3:11])=[O:9])=[N:7][C:2]=1[O:23][CH3:21])=[O:17]
Reactant: COC(=O)c1cc(C=O)c(Cl)nc1C(=O)OC
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(C=O)c(OC)nc1C(=O)OC
Temperature: 90 °C
Reaction time: 15 h
Yield: 63 %

Procedure:
A solution of dimethyl 6-chloro-5-formylpyridine-2,3-dicarboxylate (1.0 g, 0.0039 mol) in methanol (10 mL) is added to sodium methoxide (0.42 g, 0.0078 mol) in methanol (2 mL). The resulting mixture is stirred for 15 hours at 90° C. After cooling to room temperature, the reaction mixture is acidified to pH 3.0 with acetic acid. The reaction is poured into methylene chloride, washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the title compound (0.62 g, 63%) as an orange oil, identified by IR and NMR spectral analyses.
Reaction SMILES: [CH3:1][C@H:2]([CH2:7][CH2:8][O:9][Si](C(C)(C)C)(C)C)[CH2:3][CH:4]=[CH:5][CH3:6].[H][H]>[OH-].[OH-].[Pd+2].CO>[CH3:1][C@@H:2]([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:7][CH2:8][OH:9]
Reactant: CC=CC[C@H](C)CCO[Si](C)(C)C(C)(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCC[C@H](C)CCO

Procedure:
To a solution of 74.8 g. of 5-(S)-methyl-7-(t-butyldimethylsilyloxy)-2-heptene in 500 ml. of methanol was added 7.5 g. of 10% palladium hydroxide on carbon and the mixture shaken in a hydrogen atmosphere for 1.5 hours at 50 psi. The catalyst was filtered and the solvent removed under vacuum, 30 g.
Reaction SMILES: [C:1]([C:4]1[C:5]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:37])[C@H:20]([NH:29]C(=O)OC(C)(C)C)[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:15][CH2:14]2)=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1)(=O)[NH2:2]>O=P(Cl)(Cl)Cl>[NH2:29][C@H:20]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[C:19]([N:16]1[CH2:17][CH2:18][N:13]([C:5]2[C:4]([C:1]#[N:2])=[CH:9][N:8]=[C:7]3[NH:10][CH:11]=[CH:12][C:6]=23)[CH2:14][CH2:15]1)=[O:37]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(C(N)=O)cnc3[nH]ccc23)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc2[nH]ccc2c1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Temperature: 70 °C
Yield: 7.4 %

Procedure:
(R)-tert-Butyl 1-(4-(5-carbamoyl-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)-3-(4-chlorophenyl)-1-oxopropan-2-ylcarbamate (0.035 g, 0.066 mmol) was placed in POCl3 (2 mL) and heated to 70° C. for 2 hours. The reaction was then concentrated, diluted with DCM, and washed with saturated NaHCO3. The organic fraction was dried, filtered and concentrated to give a crude residue. The residue was purified (SP4, 12+M, water/CAN 95/5→60/40, 20CV) to give (R)-4-(4-(2-amino-3-(4-chlorophenyl)propanoyl)piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (0.002 g, 7.4% yield). MS ESI (+) m/z 409 detected.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][C@H:9]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([F:20])[CH:19]=[C:14]2[CH:13]=[C:12]1[CH2:21]O)[CH3:10])([CH3:4])([CH3:3])[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6]([N:7]1[CH2:8][C@@H:9]([CH3:10])[N:11]2[C:12](=[CH:13][C:14]3[C:15]2=[N:16][CH:17]=[C:18]([F:20])[CH:19]=3)[CH2:21]1)=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](CNC(=O)OC(C)(C)C)n1c(CO)cc2cc(F)cnc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)Cc2cc3cc(F)cnc3n21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of 5.4 g (R)-[2-(5-fluoro-2-hydroxymethyl-pyrrolo[2,3-b]pyridin-1-yl)-propyl]-carbamic acid tert-butyl ester in 55 mL dichloromethane was added 7.40 g manganese dioxide and the mixture was stirred at room temperature for 1 h. Another 7.40 g manganese dioxide was added and the mixture was stirred at room temperature for 4 h. The solids were removed by filtration over dicalite. The mother liquor was evaporated and the residue was taken up in 50 mL dichloromethane and 3.0 mL acetic acid and 10.62 g sodium triacetoxyborohydride was added. An instantaneous gas evolution took place and the mixture warmed up to ca 35° C. The mixture was stirred at ambient temperature for 18 h. To the reaction mixture was added 50 mL water. A marked gas evolution took place. The mixture was stirred at room temperature for 15 min. The phases were separated and the organic phase was evaporated to dryness and purified by chromatography on silica gel with heptane:ethyl acetate=1:1 as eluent to yield a slightly yellow oil which crystallized on standing to yield 3.80 g (R)-7-fluoro-4-methyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester as slightly yellow crystals; m.p.: 85–87° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:33])([CH3:32])[C:4]2[C:9]([C:10](=[O:23])[C:11]=1[C:12]([NH:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[O:13])=[CH:8][CH:7]=[C:6]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:5]=2>C(O)(C(F)(F)F)=O>[OH:1][C:2]1[C:3]([CH3:33])([CH3:32])[C:4]2[C:9]([C:10](=[O:23])[C:11]=1[C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])=[CH:8][CH:7]=[C:6]([CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH:5]=2
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C(C)(C)c2cc(CCc3ccccc3)ccc2C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(O)=C(C(=O)NCC(=O)O)C(=O)c2ccc(CCc3ccccc3)cc21

Procedure:
Tert-butyl 2-(2-hydroxy-1,1-dimethyl-4-oxo-7-phenethyl-1,4-dihydronaphthalene-3-carboxamido)acetate (130 mg, 289 μmol) was dissolved and stirred in TFA (2 mL) at ambient temperature for 30 minutes. The mixture was then concentrated to give the title compound. MS (ESI) m/z: Calculated; 393.4: Observed; 394.0
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][C:23]([C:25]1[CH:30]=[CH:29][C:28](F)=[CH:27][CH:26]=1)=[O:24].N1C=C(C2C(C3C=CC=CC=3)=NOC=2C(F)(F)F)N=C1.FC1C=CC(C(F)(F)F)=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:28]4[CH:29]=[CH:30][C:25]([C:23](=[O:24])[CH3:22])=[CH:26][CH:27]=4)[CH:17]=3)=[C:11]([C:18]([F:21])([F:19])[F:20])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: Fc1ccc(-c2noc(C(F)(F)F)c2-c2c[nH]cn2)cc1
Agent: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Agent: Fc1ccc(C(F)(F)F)cc1
Product: CC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Yield: 50 %

Procedure:
As described for Example 4, 3-(4-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (100 mg, 0.34 mmol) and 4-fluoroacetophenone, instead of 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole and 4-fluorobenzotrifluoride, was converted to the title compound (70 mg, 50%) which was obtained as a white solid. MS: m/e=416.3 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[C:4]([CH3:12])[CH:3]=1.[CH:13]([Sn](CCCC)(CCCC)CCCC)=[CH2:14]>O1CCOCC1>[CH3:12][C:4]1[CH:3]=[C:2]([CH:13]=[CH2:14])[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(=O)Nc1cc(C)cc(Br)n1
Solvent: C1COCCO1
Product: C=Cc1cc(C)cc(NC(C)=O)n1
Temperature: 100 °C

Procedure:
37.5 g of N-(6-bromo-4-methyl-pyridin-2-yl)-acetamide (compound G4) is dissolved in 750 ml anoxic dioxane under a nitrogen atmosphere. Subsequently, 70.3 ml of vinyl tributylstannane and 11.5 g trans-dichloro-bis(triphenylphosphane)palladium-(II) are added. The reaction mixture is heated to 100° C. for 65 h. Thereafter, the volatile components are removed in vacuo and the remaining residue is purified by chromatography on silica gel (eluent: toluene/ethyl acetate 6:1) to afford 21.0 g of the title compound. M.p. 140° C. GC-MS: 176.2 (M+). TLC: Rf=0.40 (toluene/ethyl acetate 4:1).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[C:11](#[N:13])[CH3:12].[H-].[Na+:15].C(OC)(C)(C)C>C1COCC1>[C:11]([CH:12]=[C:3]([C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1)[O-:4])#[N:13].[Na+:15]
Reactant: COC(=O)c1cnccn1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: N#CC=C([O-])c1cnccn1
Reaction time: 0.5 h

Procedure:
A solution of 1.5 g (10.9 mmol) of methylpyrazine-2-carboxylate and 446 mg (10.9 mmol) of acetonitrile in 16.5 ml of THF was added dropwise to a suspension, heated under reflux, of 434 mg of sodium hydride (60% strength suspension in mineral oil) in 10 ml of THF. The reaction mixture was heated under reflux for 20 h. After cooling, 50 ml of methyl tert-butyl ether were added and the mixture was stirred for 30 minutes. The precipitate formed was filtered off with suction over a frit and dried under oil pump vacuum. This gave 1.77 g (96% of theory) of the title compound which was used without further characterization for the next step.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1)(C)(C)C>O1CCOCC1>[ClH:1].[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CO)cc1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1ccc(CO)cc1
Temperature: 50 °C

Procedure:
Add 4N hydrogen chloride in 1,4-dioxane (25 mL) to a solution of (4-hydroxymethyl-benzyl)-carbamic acid tert-butyl ester (3.0 g, 12.6 mmol) in 1,4-dioxane (25 mL). Heat the reaction mixture at 50° C. for 1 hr. Filter the solid and wash it with ethyl acetate to give the title compound (2.1 g, 12.1 mmol).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([NH:11][C:12]([C:14]2[N:15]=[C:16]([CH3:19])[S:17][CH:18]=2)=[O:13])[CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[C:29]=2[NH2:35])O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[NH2:34][C:30]1[C:29]([NH2:35])=[CH:28][CH:33]=[CH:32][C:31]=1[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([NH:11][C:12]([C:14]2[N:15]=[C:16]([CH3:19])[S:17][CH:18]=2)=[O:13])[CH:3]=1
Reactant: Cc1nc(C(=O)Nc2cc(Br)cc3[nH]ncc23)cs1
Reactant: CC1(C)OB(c2cccc(N)c2N)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nc(C(=O)Nc2cc(-c3cccc(N)c3N)cc3[nH]ncc23)cs1
Temperature: 150 °C
Yield: 115.7 %

Procedure:
N-(6-Bromo-1H-indazol-4-yl)-2-methyl-1,3-thiazole-4-carboxamide (200 mg,), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-benzenediamine (167 mg) (which may be prepared as described in WO2006005915), Pd(dppf)Cl2 (43 mg) and sodium carbonate (890 μl) were added to a microwave vial followed by 1,4-dioxane (2 ml) and water (2 ml). The mixture was heated under microwave irradiation at 150° C. for 15 min. The reaction was diluted with DCM (30 ml) and the layers separated. The aqueous layer was extracted further with DCM (2×30 ml) and the combined organic extracts were evaporated to dryness to give the title compound (250 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si](C)(C)C)=[CH:9][C:8]=2[CH:19]([CH3:21])[CH3:20])[CH2:6][CH2:5]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][C:8]=2[C:19]([CH3:21])=[CH2:20])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC1(c2ccc(C#C[Si](C)(C)C)cc2C(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(OCC)CC2)c(C(=C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; [4-(1-ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-trimethylsilane (Intermediate 102, 210.0 mg, 0.70 mmol) in methanol (10 mL) was treated with potassium carbonate (100.0 mg, 0.72 mmol) and stirred overnight at ambient temperature. The crude alkyne was used directly in the next reaction.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][C:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)([CH3:12])[CH2:9]2)C=CC=CC=1.[ClH:24]>C(O)C.[OH-].[OH-].[Pd+2]>[ClH:24].[ClH:24].[CH3:12][C:10]1([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:11][NH:8][CH2:9]1
Reactant: CC1(N2CCCC2)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: CC1(N2CCCC2)CNC1
Yield: 86 %

Procedure:
A mixture of 1-[1-(diphenylmethyl)-3-methyl-3-azetidinyl]pyrrolidine (0.94 g, 3.07 mmol) and 20% Pd(OH)2 (0.11 g) in ethanol (30 ml) and 1N HCl (7 ml) was treated with H2 at 60 psi overnight. The catalyst was removed by filtration, and the filtrate was evaporated under vacuum. The residue was washed with benzene (3×5 ml) and dried under high vacuum to provide 1-(3-methyl-3-azetidinyl)pyrrolidine dihydrochloride (0.76 g, presumed 86% pure). LCMS: (M+H)+: 141.0.
Reaction SMILES: CN1CCCCC1.[CH:8]([O:11][C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[Cl:30][C:31]1[CH:41]=[CH:40][C:34]([NH:35][CH2:36][CH:37]([NH2:39])[CH3:38])=[CH:33][CH:32]=1>C(Cl)Cl.O>[Cl:30][C:31]1[CH:41]=[CH:40][C:34]([NH:35][CH2:36][CH:37]([NH:39][C:19](=[O:21])[C@H:15]([CH:16]([CH3:17])[CH3:18])[NH:14][C:12]([O:11][CH:8]([CH3:9])[CH3:10])=[O:13])[CH3:38])=[CH:33][CH:32]=1
Reactant: CC(N)CNc1ccc(Cl)cc1
Reactant: CC(C)OC(=O)N[C@H](C(=O)O)C(C)C
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CN1CCCCC1
Solvent: ClCCl
Product: CC(CNc1ccc(Cl)cc1)NC(=O)[C@@H](NC(=O)OC(C)C)C(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
1.9 g of N-methylpiperidine was added to a solution containing 3.8 g of N-isopropoxycarbonyl-L-valine dissolved in 80 ml of methylene chloride, at -20° C. After the mixture was stirred for 15 minutes at the same temperature, 2.6 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20° C. 3.5 g of 2-(4-chloroanilino)-1-methylethylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 3.3 g of the desired product in the form of a white crystal (yield: 47%).