Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O>C1(C)C=CC=CC=1>[CH:22]1([CH2:21][N:20]2[C@@H:7]3[C@@H:8]([C:9]4[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=4[CH2:5][CH2:6]3)[CH2:13][C:14]2=[O:16])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NCC1CCCCC1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CC1CCCCC1
Reaction time: 10 h
Yield: 79.9 %

Procedure:
4.0 g (0.01525 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 80 ml of toluene, 1.98 ml (0.01525 mol) of aminomethyl-cyclohexane were added thereto and the mixture was boiled for 23 hours on a water separator. After concentration the residue was hydrogenated with 1.5 g of Raney-nickel in 150 ml of ethanol at 120° and 140 bar for 10 hours. After chromatography over silica gel with cyclohexane/ethyl acetate 3:1 the product was dissolved in hot isopropyl ether and crystallized at room temperature. There were obtained 3.82 g (80%) of rac-cis-3-cyclohexylmethyl-1,3,3a, 4, 5,9b-hexahydro-6-methoxy-2H-benzo[e]indol-2-one as white crystals with m.p. 136°-137°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH2:23][CH3:24])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[C:27]([C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=2)=[O:34])=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH2:23][CH3:24])[CH:19]=[CH:18][C:14]=1[C:15]([NH:25][C:26]1[C:27]([C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=2)=[O:34])=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1)=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(N)c(C(=O)Nc2ccc(Cl)cn2)n1
Reactant: CCSc1ccc(C(=O)O)c(OCCCNC(=O)OC(C)(C)C)c1
Product: CCSc1ccc(C(=O)Nc2ccc(C)nc2C(=O)Nc2ccc(Cl)cn2)c(OCCCNC(=O)OC(C)(C)C)c1
Yield: 67 %

Procedure:
Using a procedure analogous to Example 1-G, 2-(3-t-butoxycarbonylaminopropoxy)-4-(ethylthio)benzoic acid and 3-amino-N-(5-chloropyridin-2-yl)-6-methylpyridine-2-carboxamide gave the title compound as a solid (2.2 g, 67%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][CH:10]([CH3:26])[CH2:11][CH:12]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]1=[O:25].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>C1COCC1>[CH3:9][CH:10]([CH3:26])[CH2:11][C:12]1([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1=[O:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)CC1CCN(CCc2ccccc2)C1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CC1(CC(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 67.7 %

Procedure:
LDA (2.0M, 11.5 mL, 23.0 mmol) is added to a solution of 3-(2-methylpropyl)-1-(2-phenylethyl)-2-pyrrolidinone (4.70 g, 19.2 mmol) and THF (80 mL) at -78° C. The solution is stirred at -78° C. for 45 minutes, and tert-butyl bromoacetate (3.4 mL, 23 mmol) is added. The solution is allowed to warm to 0° C. over 2 hours and is allowed to stir overnight at room temperature. After quenching with saturated aqueous ammonium chloride, aqueous workup (EtOAc, MgSO4) and purification by column chromatography (10% EtOAc/5% CH2Cl2 /hexane) to give 4.67 g (68%) of the title compound as a colorless oil. An analytical sample is crystallized from hexane (mp 50° C.).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:10]([CH2:11][C:12]([N:14]([CH:23]([CH3:25])[CH3:24])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[O:13])[C:9]2[CH:26]=[CH:27][CH:28]=[CH:29][C:8]=2[N:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:6](=[O:36])[CH2:5]1.Br[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:41]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[N:40]=1.O>CN(C=O)C>[C:51]([O:50][C:48]([N:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39]([CH2:38][CH:5]2[C:4](=[O:3])[N:10]([CH2:11][C:12]([N:14]([CH:23]([CH3:25])[CH3:24])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[O:13])[C:9]3[CH:26]=[CH:27][CH:28]=[CH:29][C:8]=3[N:7]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:6]2=[O:36])=[N:40]1)=[O:49])([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Reactant: COc1ccccc1N(C(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
45 mg of Sodium Hydride (60% in oil, 1.12 mmol) is added to a solution of 2-(-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(2-methoxy-phenyl) acetamide, prepared as in Part D, (430 mg. 0.934 mmol) in DMF (10 mL) and the resultant mixture stirred at RT for 0.5 h prior to the addition of 3-Bromomethyl-1-tert-butoxycarbonyl-1H-indazole (291 mg, 0.934 mmol) to the reaction mixture. After stirring 22 h at RT, water (10 mL) is added and the resultant mixture extracted into ethyl acetate (3×10 mL). The combined organics were washed with water (3×10 mL), brine (10 mL), dried (MgSO4), and concentrated in vacuo to afford the crude product which is purified by silica gel flash column chromatography using 3% methanol in methylene chlorideas eluent to give the desired product (260 mg) as a beige solid, which exists as 3:2 mixture of rotamers (major rotamer recorded): 1H NMR (300 MHz, CDCl3) δ8.1 (t, 1H, J=8.0), 7.90 (m, 1H), 7.60-6.90 (m, 15H), 5.05 (m, 1H, J=6.9), 4.60-3.40 (m, 8H), 1.7 (s, 9H), 1.16 (m, 6H).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[CH2:5]([CH:7]1[O:9][CH2:8]1)[Cl:6]>[Ag]>[Cl:6][CH2:5][CH:7]([OH:9])[CH2:8][O:4][CH2:1][CH:2]=[CH2:3]
Reactant: C=CCO
Reactant: ClCC1CO1
Agent: [Ag]
Product: C=CCOCC(O)CCl
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
A mixture of 87 grams (1.5 mols) of allyl alcohol and 1 milliliter of boron trifluoride-diethyl etherate is heated to 60° C. in a reaction vessel provided with reflux condenser, thermometer and dropping funnel. Within 45 minutes, 46.25 grams (0.5 mol) of epichlorohydrin are constantly added to said mixture. The reaction is exothermic. Thereafter the reaction mixture is rectified via a 40 centimeter silver-coated column, whereupon at first 55 grams of unreacted allyl alcohol are distilled off at 24° C. and a pressure of 15 millibars. By subsequent distillation at 0.08 millibars there are obtained 59.7 grams (79.3% of the theory) of (3-chloro-2-hydroxy-propyl)-allyl ether with a boiling point of 57° C. and a refractive index nD20 =1.4630.
Reaction SMILES: [C:1](=[O:23])([O:20][CH2:21][CH3:22])[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[CH:10]1[CH:17]2[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:19][CH:11]1[CH2:12]3)[CH2:16]2.[N+:24]([O-])([O-:26])=[O:25].[K+]>OS(O)(=O)=O>[C:1](=[O:23])([O:20][CH2:21][CH3:22])[O:2][C:3]1[CH:8]=[C:7]([N+:24]([O-:26])=[O:25])[C:6]([CH3:9])=[CH:5][C:4]=1[CH:10]1[CH:11]2[CH2:19][CH:15]3[CH2:14][CH:13]([CH2:18][CH:17]1[CH2:16]3)[CH2:12]2
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)Oc1ccc(C)cc1C1C2CC3CC(C2)CC1C3
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)Oc1cc([N+](=O)[O-])c(C)cc1C1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a cooled solution of 2-admantyl-4-methyl-phenyl ethyl carbonate (1.32 g, 4.2 mmol) in H2SO4 (98%, 10 mL) was added KNO3 (510 mg, 5.0 mmol) in small portions at 0° C. The mixture was stirred for 3 h while warming to room temperature, poured into ice and then extracted with dichloromethane. The combined organic layers were washed with NaHCO3 and brine, dried over MgSO4 and concentrated to dryness. The residue was purified by column chromatography (0-10% EtOAc-Hexane) to yield 2-admantyl-4-methyl-5-nitrophenyl ethyl carbonate (378 mg, 25%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[OH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: OCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCCc2ccccn2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-(2-hydroxyethyl)pyridine and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C[Al](C)C.C[O:14][C:15]([C:17]1[N:18]=[C:19]([CH3:23])[S:20][C:21]=1[Br:22])=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15]([C:17]2[N:18]=[C:19]([CH3:23])[S:20][C:21]=2[Br:22])=[O:14])=[N:3][CH:4]=1
Reactant: COC(=O)c1nc(C)sc1Br
Reactant: Nc1ccc(F)cn1
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(C(=O)Nc2ccc(F)cn2)c(Br)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
A solution of 2-amino-5-fluoropyridine (6.0 g, 53 mmol) in 40 ml dry dioxane was treated at 0° C. with trimethylaluminium (2M in hexane, 26.8 ml, 53 mmol). The mixture was stirred at room temperature for 1 h. A solution of 5-bromo-2-methyl-thiazole-4-carboxylic acid methyl ester (4.2 g, 18 mmol) in 40 mL dry dioxane was added and the reaction mixture was refluxed for 4 h. 10 ml water and 10 g sodium sulfate were sequentially added and filtered. The filtrate was evaporated and the residue purified by flash chromatography (hetane, ethyl acetate) to yield 5-bromo-2-methyl-thiazole-4-carboxylic acid (5-fluoro-pyridin-2-yl)-amide (3.0 g, 53%) as a white solid, MS (ISP): m/e=318.0 (M+H+).
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH2:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1)([O-:30])=[O:29]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:40][S:37]([C:34]3[CH:33]=[CH:32][C:31]([N+:28]([O-:30])=[O:29])=[CH:36][CH:35]=3)(=[O:38])=[O:39])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 4-nitrobenzenesulfonamide in accordance with Procedure 1, Method A described hereinabove. Yield (32%); 1H NMR (d6-DMSO) δ 8.33 (d, J=8.8 Hz, 2H), 8.08 (d, J=8.8 Hz, 2H), 7.38-7.07 (m, 13H), 6.82 (d, J=8.0 Hz, 2H), 6.35 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.3 Hz, 2H), 0.81 (t, J=7.3 Hz, 3H); APCI m/z: 538 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.[Br:11]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Br:11])=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCc1ccc(Br)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrCCc1ccc(Br)cc1
Reaction time: 1 h
Yield: 157.7 %

Procedure:
To a solution of 2-(4-bromophenyl)ethanol (1.00 g) and tetrabromomethane (3.96 g) in tetrahydrofuran (10 ml) was added triphenylphosphine (2.87 g) at room temperature and the mixture was stirred at the same temperature for 1 hour under nitrogen. The mixture was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-bromo-4-(2-bromoethyl)benzene (2.07 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]O.S(Cl)([Cl:12])=O.[OH-].[Na+]>C(Cl)Cl.O>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][Cl:12]
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(I)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: ClCc1cccc(I)c1

Procedure:
A solution of 3-iodobenzyl alcohol (600 mg, 2.56 mmol) in DCM (3 ml) was treated with thionyl chloride (3 ml, 41.3 mmol) and stirred at ambient temperature for 18 h, before addition of further thionyl chloride (1 ml, 13.7 mmol) and heating to reflux for 12 h. The cooled solution was basified with 50% NaOH, diluted with water and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated to afford a clear syrup which crystallises on standing to give 3-iodobenzyl chloride as a white solid (650 mg, quant.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:9]=1)[CH2:5][OH:6].CCN(C(C)C)C(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[S:25]([O:6][CH2:5][C:4]1[CH:7]=[C:8]([O:10][C:11]([F:12])([F:13])[F:14])[CH:9]=[C:2]([Cl:1])[CH:3]=1)(=[O:27])(=[O:26])[CH3:24]
Reactant: OCc1cc(Cl)cc(OC(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1cc(Cl)cc(OC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 100.1 %

Procedure:
To a solution of 3-chloro-5-trifluoromethoxybenzyl alcohol (6.1 g, 26.9 mmol; see Example 6(v) above) in CH2Cl2 (250 mL) at 0° C. under a nitrogen atmosphere was added DIPEA (4.2 g, 32.3 mmol) and methanesulfonyl chloride (3.4 g, 29.6 mmol). The solution was stirred at 0° C. for 1.5 hours and quenched with H2O. The organics were separated and then washed with H2O (1×), 1N HCl (1×), H2O (1×) and aqueous NaHCO3 (1×) and then dried (Na2SO4), filtered and concentrated to afford the sub-title compound (8.2 g, 99%) as an oil.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.Cl.NC1CCN(CCN2CC[C@H]([OH:53])[C@@H](C)C2)CC1>>[OH:53][C@H:5]1[CH2:6][CH2:7][N:1]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:14][CH2:15]2)[CH2:2][C@@H:3]1[CH3:4]
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Reactant: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(OCc3ccoc3)cccc2[nH]1
Agent: Cl
Product: C[C@H]1CN(CCN2CCC(NC(=O)c3cc4c(OCc5ccoc5)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid 95 (preparation see example 36) and amine 14.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([CH3:16])([CH3:15])[C:13](=[O:17])[N:12]([CH:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:33])[CH2:25][N:26]4[C:30](=[O:31])[CH2:29][CH2:28][C:27]4=[O:32])[CH2:20][CH2:19]3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH2:35][CH:36]1[CH2:38][CH2:37]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:36]1([CH2:35][O:1][C:2]2[CH:3]=[C:4]([C:10]3[C:14]([CH3:15])([CH3:16])[C:13](=[O:17])[N:12]([CH:18]4[CH2:23][CH2:22][N:21]([C:24](=[O:33])[CH2:25][N:26]5[C:27](=[O:32])[CH2:28][CH2:29][C:30]5=[O:31])[CH2:20][CH2:19]4)[N:11]=3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:38][CH2:37]1
Reactant: BrCC1CC1
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C2(C)C)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C2(C)C)cc1OCC1CC1

Procedure:
A mixture of 1 g 1-(2-{4-[3-(3-hydroxy-4-methoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione (compound A4), 0.7 g of bromomethylcyclopropane and 1 g of potassium carbonate in 100 ml of acetonitril is refluxed for 8 h after which the solvent is evaporated. The residue is partitioned between water and ethyl acetate, the organic layer is dried over magnesium sulfate and the EA evaporated. The residue is crystallized from ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:11]([OH:13])[CH3:12]>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:13][CH2:11][CH3:12])=[O:5]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CCO
Product: CCOC(=O)c1ccccc1F
Reaction time: 3 h

Procedure:
A mixture of 35 g of 2-fluoro-benzoyl chloride and 400 ml of ethanol was stirred for three hours and was allowed to stand overnight. The mixture was distilled to dryness at 50° C. and 30-40 mm Hg and the residue was taken up in methylene chloride The solution was washed with 5% aqueous sodium bicarbonate and then with water, dried and evaporated to dryness under reduced pressure. The product was rectified at 14 mm Hg to obtain 34 g of ethyl 2-fluoro-benzoate with a boiling point of 90°-91° C. at 14 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[CH:5]2.Cl.[NH2:17][C@@H:18]([CH3:22])[C:19]([NH2:21])=[O:20].C(N(CC)CC)C.CO>>[Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:17]([C@@H:18]([CH3:22])[C:19]([NH2:21])=[O:20])[CH:6]=[CH:5]2
Reactant: O=c1occc2c([N+](=O)[O-])c(Cl)ccc12
Reactant: C[C@H](N)C(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@@H](C(N)=O)n1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 6-chloro-5-nitro-1H-isochromen-1-one (230 mg, 0.00102 mol), (S)-2-aminopropanamide hydrochloride (127 mg, 0.00102 mol), triethylamine (142 μL, 0.00102 mol) and methanol (20 mL, 0.5 mol) was stirred at 60° C. for 3 hours. the solvent was removed under reduced pressure and the residue was purified by flash chromatography to afford the product as a yellow solid.
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[C:12]([C:13](=[O:14])[N:5]2[CH2:4][CH2:3][NH:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].O>C1C=CC=CC=1>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][CH:1]1[CH:6]2[C:7]3[C:12]([C:13](=[O:14])[N:5]2[CH2:4][CH2:3][NH:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: O=C1c2ccccc2C2CNCCN12
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)CC1NCCN2C(=O)c3ccccc3C12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
A solution of 1,2,3,4,6,10b-hexahydropyrazino[2,1-a]isoindol-6-one (described in Example 8, 7.5 g, 0.04 mol) in 150 ml of benzene is added to sodium hydride (1.7 g of a 50% dispersion in mineral oil, 0.036 mol) in 200 ml of benzene and stirred at room temperature for 30 min. A solution of ethyl bromoacetate (8.8 g, 0.044 mol) in 150 ml of benzene is added and the reaction is refluxed with stirring for 3 hr and cooled. Water is cautiously added and the benzene layer is separated, washed with water, dried, and evaporated. The residue is chromatographed on silica gel using 50% acetone in benzene and the eluates are evaporated to give 6-oxo-1,2,3,4,6,10b-hexahydropyrazino[2,1-a]isoindole-1-acetic acid ethyl ester (5.5 g), nmr (CDCl3) δ1.3(t), 2.4-2.6(m), 2.8-3.5(m), 4.2(q), 4.6(m) and 7.3-7.7(m).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OCC)=O)=N\C(OCC)=O.[Cl:32][C:33]1[C:34]([OH:40])=[CH:35][C:36](=[O:39])[NH:37][CH:38]=1.[F:41][C:42]([F:57])([F:56])[C:43]1[CH:44]=[N:45][C:46]([N:49]2[CH2:54][CH2:53][CH:52](O)[CH2:51][CH2:50]2)=[N:47][CH:48]=1>C(OCC)(=O)C.CN(C=O)C>[Cl:32][C:33]1[C:34]([O:40][CH:52]2[CH2:53][CH2:54][N:49]([C:46]3[N:45]=[CH:44][C:43]([C:42]([F:41])([F:56])[F:57])=[CH:48][N:47]=3)[CH2:50][CH2:51]2)=[CH:35][C:36](=[O:39])[NH:37][CH:38]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: OC1CCN(c2ncc(C(F)(F)F)cn2)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1cc(OC2CCN(c3ncc(C(F)(F)F)cn3)CC2)c(Cl)c[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a 100 mL recovery flask under nitrogen was added triphenylphosphine (1285 mg, 4.90 mmol), DMF (10 mL), and then (E)-diethyl diazene-1,2-dicarboxylate (0.67 mL, 4.20 mmol). The mixture was stirred at room temperature for 5 minutes at which point 5-chloro-4-hydroxypyridin-2(1H)-one (509 mg, 3.50 mmol) was added. After stirring for an additional 5 minutes, 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-ol (1865 mg, 3.50 mmol) was added. The reaction was placed in a 100° C. oil bath under a nitrogen atmosphere with a vent line for two hours. The clear amber reaction mixture was cooled to room temperature and added to 600 mL of ethyl acetate. After washing the ethyl acetate with water (2×200 mL), the solvent was removed in vacuo from the slightly cloudy, pale pink solution to provide 3.06 g of a red, oily foam. This material was purified using a 65 mm id×120 mm silica gel column and eluting as follows:
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:13]3[NH:14][CH:15]=[CH:16][C:12]3=[N:11][C:4]=1[CH:5]=[N:6]2.[H-].[Na+].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>O1CCCC1.C(OC)(C)(C)C>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:14]2[N:13]3[C:3]4[C:2]5[C:7](=[CH:8][CH:9]=[CH:10][CH:1]=5)[N:6]=[CH:5][C:4]=4[N:11]=[C:12]3[CH:16]=[CH:15]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: c1ccc2c(c1)ncc1nc3cc[nH]n3c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3nc4cnc5ccccc5c4n32)cc1
Reaction time: 0.17 h
Yield: 28.2 %

Procedure:
A solution of 10H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]quinoline (1.00 g, 4.80 mmol) in tetrahydrofuran (24 mL), under a nitrogen atmosphere, was chilled in an ice-water bath. The solution was treated with NaH (0.29 g, 7.20 mmol, 60%) in small portions over 2 min. After 10 min, the mixture was treated with p-toluenesulfonyl chloride (1.01 g, 5.28 mmol), and allowed to come to ambient temperature. After 1.5 h the reaction was quenched with slow addition of water (5 mL). The reaction mixture was concentrated under reduced pressure to yield a brown solid. The solid was purified by prep. HPLC (100 g silica gel eluted with 1-10% CMA in chloroform) to give a tan foam. The foam was dissolved in methyl tert-butyl ether (25 mL) and filtered through filter paper. The filtrate was concentrated under reduced pressure to yield 0.49 g of 10-[(4-methylphenyl)sulfonyl]-10H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]quinoline as a tan solid.
Reaction SMILES: [CH2:1]([C:4]#[N:5])[CH:2]=[CH2:3].[CH2:6]([SiH:9]([Cl:11])[Cl:10])[CH:7]=[CH2:8]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:10][Si:9]([Cl:11])([CH2:3][CH2:2][CH2:1][C:4]#[N:5])[CH2:6][CH:7]=[CH2:8]
Reactant: C=CC[SiH](Cl)Cl
Reactant: C=CCC#N
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: C=CC[Si](Cl)(Cl)CCCC#N
Yield: 60081.9 %

Procedure:
Using the same apparatus and procedure described in EXAMPLE 1, 97.9 g (1.46 mol) of allyl cyanide and 350 μl of 1% chloroplatinic acid in isopropanol were added to the flask. Through the dropping funnel was added dropwise 20.6 g (0.15 mmol) of allyldichlorosilane for 30 min at 80° C. and the solution was further reacted for 17.5 hrs to complete the reaction. Vacuum distillation (76-78/0.5 torr) of the product mixture gave 18.76 g (62%) of 4,4-dichloro-7-cyano-4-sila-1-heptene.