Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].C([O-])([O-])=O.[Cs+].[Cs+].[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>C(C(C)=O)C>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])=[CH:31][CH:30]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: O=C1N(Cc2ccc(F)cc2)c2ccccc2C12COc1cc3c(cc12)OCO3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
To a solution of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.16 g, 0.57 mmol) in ethylmethylketone (5.00 mL) was added Cs2CO3 (0.40 g, 1.20 mmol). The reaction mixture was stirred at ambient temperature for 15 min followed by the addition of 4-fluorobenzyl bromide (0.20 g, 1.0 mmol). The reaction mixture was refluxed for 4 h. After the completion of the reaction, the mixture was filtered and the solvent was removed under reduced pressure. The residue was recrystallized from EtOAc/Hexane to yield the title compound (0.111 g) as a white solid in 50% yield: MS (ES+) m/z 390.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][CH2:7]2.[Li+].CC([N-]C(C)C)C.CS([C:24]1[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[N:25]=1)(=O)=O.[NH4+].[Cl-]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][CH:7]2[C:24]1[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[N:25]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: O=C1OCc2cccc(Cl)c21
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)nc(C2OC(=O)c3c(Cl)cccc32)n1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
1.68 g (0.0 mol) of 7-chlorophthalide is added to 100 ml of dry THF and the mixture cooled to -70° C. 6.8 ml (0.01 mol) of 1.5M LDA is then added over 3 minutes and the reaction mixture stirred at -70° C. for 15 minutes. 2.18 g (0.01 mol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine in 50 ml of THF is then added and the mixture stirred for 4 hrs with temperature being maintained at -75° to -70° C. The reaction mixture is neutralized with 1.5 g of NH4Cl in 5 ml of water, warmed and concentrated on a rotovaporator. The concentrate is partitioned between CH2Cl2 /H2O (50 ml each) and the aqueous phase separated and treated with further 30 ml of CH2Cl2. The combined CH2Cl2 phases are washed with 30 ml of water, separated and concentrated. The concentrate was flash chromatographed on silica gel using 80/20 hexane/ethyl acetate (500 ml), 50/50 hexane/ethyl acetate (500 ml) and 80/20 acetone/methanol (500 ml) (30 fractions×50 ml). The title compound (fractions 9-23) was obtained after recrystallization from hexane/CH2Cl2 as a white solid, m.p. 148°-149° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12](=[O:14])[CH3:13])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:15]([O:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27](Cl)=[CH:28][CH:29]=[N:30]2)=[CH:25][C:24]=1[O:34][CH3:35])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH2:15]([O:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27]([O:1][C:2]3[C:3]([C:12](=[O:14])[CH3:13])=[N:4][C:5]4[C:10]([CH:11]=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:28][CH:29]=[N:30]2)=[CH:25][C:24]=1[O:34][CH3:35])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: CC(=O)c1nc2ccccc2cc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
(3-Hydroxy-quinolin-2-yl)-ethanone (878 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (7.03 g), and 4-dimethylaminopyridine (3.44 g) were suspended in o-dichlorobenzene (20 ml), and the mixture was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-acetone to give 1-[3-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-quinolin-2-yl]-ethanone (758 mg, yield 36%).
Reaction SMILES: C(OC(N1[C@H](CN2C(C(OCC)=O)=CC(COC3C=CC=CC=3)=N2)COC1(C)C)=O)(C)(C)C.OC[C@@H]1CN2N=C(COC3C=CC=CC=3)C=C2C(=O)N1.[O:54]([CH2:61][C:62]1[CH:77]=[C:65]2[C:66](=[O:76])[NH:67][C@H:68]([CH2:70][O:71][Si:72]([CH3:75])([CH3:74])[CH3:73])[CH2:69][N:64]2[N:63]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>>[O:54]([CH2:61][C:62]1[CH:77]=[C:65]2[C:66](=[O:76])[NH:67][C@@H:68]([CH2:70][O:71][Si:72]([CH3:73])([CH3:75])[CH3:74])[CH2:69][N:64]2[N:63]=1)[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: C[Si](C)(C)OC[C@@H]1Cn2nc(COc3ccccc3)cc2C(=O)N1
Agent: CCOC(=O)c1cc(COc2ccccc2)nn1C[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: O=C1N[C@H](CO)Cn2nc(COc3ccccc3)cc21
Product: C[Si](C)(C)OC[C@H]1Cn2nc(COc3ccccc3)cc2C(=O)N1

Procedure:
The compound was prepared from (R)-4-(5-ethoxycarbonyl-3-phenoxymethyl-pyrazol-1-ylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester using the methods described in the preceding examples 31 ((S)-6-hydroxymethyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one) and 32 ((S)-2-phenoxymethyl-6-trimethylsilanyloxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([C:21]([F:32])([F:31])[F:20])[CH:27]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(-c3cccc(C(F)(F)F)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-trifluoromethyl-phenylboronic acid to give [6-methoxy-1-(3-trifluoromethyl-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 385(MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([NH:22][S@@](C(C)(C)C)=O)[C:10]1[CH:15]=[CH:14][C:13]([P:16]([CH3:21])(=[O:20])[O:17][CH2:18]C)=[CH:12][CH:11]=1.[ClH:29].O1CCOCC1>>[ClH:29].[NH2:22][C@@H:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:10]1[CH:11]=[CH:12][C:13]([P:16]([CH3:21])(=[O:20])[O:17][CH3:18])=[CH:14][CH:15]=1
Reactant: CCOP(C)(=O)c1ccc([C@@H](N[S@](=O)C(C)(C)C)c2ccc(F)cc2F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COP(C)(=O)c1ccc([C@@H](N)c2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Ethyl 4-((R)-(2,4-difluorophenyl)((R)-1,1-dimethylethylsulfinamido)methyl)-phenyl(methyl)phosphinate, 20-d, (866 mg, 2.5 mmol) was dissolved in HCl/dioxane (5 ml) and the mixture was stirred at room temperature for 1 h. Then it was concentrated under vacuum and the residue was washed with ethyl acetate to provide the product 20-e (781 mg, 96%).
Reaction SMILES: [Na+].[C:2]1([S:8]([O-:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:12][C:13]#[N:14]>CN(C)C=O>[C:2]1([S:8]([CH2:12][C:13]#[N:14])(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S([O-])c1ccccc1
Reactant: N#CCCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCS(=O)(=O)c1ccccc1
Temperature: 40 °C

Procedure:
Benzene sulfinic acid sodium salt, 49.2 g. (0.3 mole) was combined with 400 ml. of dimethyl formamide in a 1 liter flask. The mixture was stirred at 40° C. Chloroacetonitrile, 22.5 g. (0.3 mole) was added over a period of 5 minutes. The resulting mixture was stirred and heated at 40°-45° C. for 2 hours. The reaction mass was then poured into 600 ml. of water, and the solid insoluble product was collected by suction filtration and dried. There was obtained a yield of 29.8 g. of the title compound, m.p. 111°-112° C.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][C:6](=[O:14])[C:7]([C:12]#[N:13])=[CH:8]OCC)C.[CH2:16]([O:18][C:19]([O:24][CH2:25][CH3:26])([CH3:23])[CH2:20][CH2:21][NH2:22])[CH3:17]>O>[CH2:25]([O:24][C:19]([O:18][CH2:16][CH3:17])([CH3:23])[CH2:20][CH2:21][N:22]1[CH:8]=[C:7]([C:12]#[N:13])[C:6](=[O:14])[NH:5][C:4]1=[O:3])[CH3:26]
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Reactant: CCOC(C)(CCN)OCC
Solvent: O
Product: CCOC(C)(CCn1cc(C#N)c(=O)[nH]c1=O)OCC
Temperature: 80 °C
Yield: 83 %

Procedure:
(2-Cyano-3-ethoxy-acryloyl)-carbamic acid ethyl ester (Prep32, 500 mg, 2.3 mmol) was suspended in water (20 mL) and 3,3-diethoxybutylamine (816 μl, 4.7) was added and the mixture warmed at 80° C. for 10 minutes. The reaction mixture was lyophilized and the residue was purified by flash chromatography with petroleum ether-ethyl acetate (1-1) to give 553 mg of the title compound as a white solid (83% yield).
Reaction SMILES: [CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2].[CH:29](=O)[CH2:30][CH2:31][CH2:32][CH2:33]C>>[CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[C:21]=4[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2]
Reactant: CCCCCC=O
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(F)cc3nc2-1
Product: CCCCCc1c2c(nc3cc(F)ccc13)-c1cc3c(c(=O)n1C2)COC(=O)C[C@]3(O)CC

Procedure:
The product of Example 84 is treated with hexanal according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)(=O)=O.[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[C:24]#[CH:25].C([O-])(=O)C.[Na+]>CN(C)C=O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:19][CH3:20])[CH:8]=[C:7]([C:25]#[C:24][C:23]([O:27][CH2:28][CH3:29])=[O:26])[CH2:16][CH2:15]2
Reactant: COc1cc2c(cc1OC)CCC(OS(=O)(=O)C(F)(F)F)=C2
Reactant: C#CC(=O)OCC
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C#CC1=Cc2cc(OC)c(OC)cc2CC1

Procedure:
To a solution of 178 mg (0.53 mmol) of (3,4-dihydro-6,7-dimethoxy-2-naphthyl) trifluoromethane-sulfonate in dimethylformamide (2 ml) were added 0.39 ml (3.9 mmol) of ethyl 2-propynoate, 84.8 mg (1.0 mmol) of sodium acetate and 14.8 mg (0.020 mmol) of bis(triphenylphosphine)palladium (II) acetate with stirring under nitrogen, and the mixture was stirred for 1 hour and 30 minutes at 60° C. A saturated saline solution was added to the reaction mixture to conduct extraction with benzene-hexane (1:2). An organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel to obtain 76.5 mg (yield: 51%) of crude crystals of the title compound. The crude crystals were recrystallized from diethyl ether-hexane, thereby obtaining a pale yellow crystalline powder.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-]>[Cu]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: COC(=O)c1ccc2c(Br)nn(C(C)C)c2c1
Agent: Cl[Cu]
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(-c3ccccc3Cl)nn(C(C)C)c2c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
To a mixture of methyl 3-bromo-1-isopropyl-1H-indazole-6-carboxylate (0.32 g, 1.08 mmol), 2-chlorophenylboronic acid (0.51 g, 3.29 mmol), cessium carbonate (1.15 g, 3.52 mmol), copper(I) chloride (0.11 g, 1.09 mmol), 1,1′-bis(diphenylphosphino)ferrocene (61.1 mg, 0.11 mmol) and palladium(II) acetate (12.6 mg, 0.06 mmol) under argon was added N,N-dimethylformamide (4.3 mL). The mixture was stirred in a sealed tube at 90° C. for 18 h. After 18 h, the mixture was cooled to ambient temperature and quenched with saturated aqueous sodium bicarbonate (15 mL). The mixture was extracted with ethyl acetate (3×15 mL). The combined organic layer was washed with saturated aqueous ammonium chloride (4×10 mL), saturated aqueous sodium chloride (1×10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (100% hexanes→85% hexanes/ethyl acetate) gave the title compound (0.11 g): LC-MS [M+1]=329.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13](F)[CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][CH:5]2[NH2:16].[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH2:28][C:29](O)=[O:30])=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH2:28][C:29]([NH:16][CH:5]3[C:4]4[C:12](=[CH:13][CH:14]=[C:2]([F:1])[CH:3]=4)[O:11][C:7]4([CH2:10][CH2:9][CH2:8]4)[CH2:6]3)=[O:30])=[CH:26][C:21]=2[O:20][CH:19]=[CH:18]1
Reactant: NC1CC2(CCC2)Oc2c(F)cc(F)cc21
Reactant: O=C(O)CCc1ccc2c(c1)OCCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccc2c(c1)OC=CO2)NC1CC2(CCC2)Oc2ccc(F)cc21

Procedure:
The title compound was prepared from Intermediate 6 (200 mg, 0.963 mmol) and 3-(2,3-dihydro-1,4-benzodioxin-6-yl)propanoic acid (187 mg, 0.963 mmol) in presence of EDCI.HCl (276 mg, 1.441 mmol), HOBt (221 mg, 1.441 mmol) and triethylamine (403 μl, 2.891 mmol) in dichloromethane (10 ml) as described in Example 1 to give 16 mg of the product as a white solid; IR (KBr) 3307, 2951, 1869, 1643, 1508, 1257, 1071, 817 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 1.13-1.23 (m, 1H), 1.66-1.78 (m, 3H), 2.04-2.13 (m, 3H), 2.18-2.27 (m, 2H), 2.42-2.49 (m, 1H), 2.72-2.79 (m, 2H), 4.17 (s, 4H), 5.01 (br s, 1H), 6.54 (d, J=11.1 Hz, 1H), 6.38-6.74 (m, 4H), 6.93 (t, J=8.1 Hz, 1H), 8.25 (d, J=8.4 Hz, 1H); ESI-MS (m/z) 396.66 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:7]2[O:8][C@@H:6]2[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3]1.O1CCCC1.[OH-].[NH4+:22]>C(O)C>[NH2:22][C@@H:6]1[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3][C:2]([CH3:15])([CH3:1])[C@H:7]1[OH:8]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@H]2O[C@H]21
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Temperature: 50 °C

Procedure:
To a solution of (1aR-cis)-1a,7b-dihydro-2,2-dimethyl-2H-oxireno-[c][1]benzopyran-6-carbonitrile (3.0 g, 15.0 mmol, compound of example 1, part A) in ethanol (30 mL) and tetrahydrofuran (30 mL) was added ammonium hydroxide (30 mL) and the reaction mixture was heated at 50° C. in a pressure bottle for 16 hours. Most of the solvent was evaporated and the residue was dissolved in 1N hydrochloric acid. It was extracted with ether and the organic extracts were discarded. The aqueous layer was made basic by the addition of 1N sodium hydroxide and extracted with chloroform. The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to yield (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H- 1-benzopyran-6-carbonitrile (2.8 g), as a colorless foam. This material was used for the next reaction without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH2:33][CH3:34])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:35]1[CH2:38][CH2:37][CH2:36]1>>[N:35]1([C:2]2[N:7]=[CH:6][C:5]([S:8]([N:11]3[CH2:20][CH2:19][C:18]4[C@:13]([CH2:31][O:32][CH2:33][CH3:34])([CH2:14][C:15]5[CH:23]=[N:22][N:21]([C:24]6[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=6)[C:16]=5[CH:17]=4)[CH2:12]3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:38][CH2:37][CH2:36]1
Reactant: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reactant: C1CNC1
Product: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCC3)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 4b using (R)-6-(6-chloropyridine-3-sulfonyl)-4a-ethoxymethyl-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene and azetidine. LCMS (Method C): 524 (M+H)+, Retention time 11.6 minutes.
Reaction SMILES: [CH2:1]([N:13]([CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:20](OS(C(F)(F)F)(=O)=O)[CH:19]=1)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:38](C([Sn])=C(CCCC)CCCC)[CH2:39]CC.[Cl-].[Li+].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>O1CCOCC1.C(OCC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:13]([CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:20]([CH:38]=[CH2:39])[CH:19]=1)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)OC)c(OS(=O)(=O)C(F)(F)F)c1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: [Pd]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: C=Cc1cc(OCCN(C)CCCCCCCCCCCC)ccc1CCC(=O)OC
Temperature: 100 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
To a solution of 3-[4-[2-(N-dodecyl-N-methylamino)ethoxy]-2-[trifluoromethanesulfonyloxy]-phenyl]propanoic acid, methyl ester (250 mg, 0.48 mmol) in 1,4dioxane (2.5 ml) were added tributylvinyltin (1.2 ml, 4.0 mmol), lithium chloride (123 mg, 1.44 mmol), tetrakis(triphenylphosphine)-palladium(0) (10 mg) and 2,6-di-tert-butyl-4-methylphenol (10 mg). The resulting mixture was then stirred at 100° C. for 5 h. After cooling to r.t., the mixture was diluted with diethyl ether, washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (diethyl ether/acetone 100:0 to 80:20) to afford the title compound (170 mg, 80%) as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.C(N(CC)CC)C.[O:27]=[C:28]1[C:37]2[C:32](=[CH:33][C:34]([CH2:38][CH:39]=O)=[CH:35][CH:36]=2)[CH2:31][CH2:30][O:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[O:1]=[C:2]1[CH2:7][N:6]([CH2:39][CH2:38][C:34]2[CH:33]=[C:32]3[C:37](=[CH:36][CH:35]=2)[C:28](=[O:27])[O:29][CH2:30][CH2:31]3)[CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1
Reactant: O=CCc1ccc2c(c1)CCOC2=O
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: N#Cc1ccc2c(c1)CCC(N1CCN(CCc3ccc4c(c3)CCOC4=O)CC1=O)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (51 mg, 0.17 mmol) and triethylamine (65 mg, 0.64 mmol) was dissolved in dichloroethane then (1-oxo-3,4-dihydro-1H-isochromen-6-yl) acetaldehyde (60 mg, 0.26 mmol) was added followed by sodium triacetoxyborohydride (270 mg, 1.28 mmol). The reaction mixture was stirred at RT for 16 hours. The reaction mixture was poured into water then extracted with dichloromethane. The organic layer was washed with brine then dried over Na2SO4, filtered and concentrated. The compound was purified by preparative TLC plate to yield the title product. 1H-NMR (500 MHz, CDCl3) δ ppm 8.07 (d, J=7.8 Hz, 1H), 7.43 (s, 1H), 7.42 (d, J=7.5 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.18 (d, J=7.61 Hz, 1H), 7.14 (s, 1H), 4.90 (b, 1H), 4.57 (t, J=5.7 Hz, 2H), 3.27-3.36 (m, 4H), 3.08 (t, J=5.8 Hz, 2H), 3.02-2.74 (m, 10H), 2.01 (b, 1H), 1.92-1.95 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)=[N:6][C:7]=1Cl.[CH2:20](COC)[O:21]C.C[O-].[Na+]>CO.C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)=[N:6][C:7]=1[O:21][CH3:20]
Reactant: Cn1nc(-c2ccc(Cl)c(Cl)n2)c(Cl)c1C(F)(F)F
Reactant: COCCOC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: COc1nc(-c2nn(C)c(C(F)(F)F)c2Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 48 h

Procedure:
1.0 g of 3-(5,6-dichloro-2-pyridyl)-4-chloro-5-trifluoromethyl-1-methyl-[1 H]-pyrazole (Example H20) is initially introduced into 5 ml of dry dimethoxyethane. After the solution has been cooled to 0° C., 0.61 ml of a 5.4 molar solution of sodium methylate in methanol is added dropwise and the mixture is subsequently stirred at 25° C. for 2 days. The reaction mixture is taken up in diethyl ether and washed successively with 0.5 N hydrochloric acid, water and brine. After drying over sodium sulfate, the mixture is filtered and the filtrate is concentrated to dryness in vacuo. 0.94 g of the desired title compound is obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([OH:9])=O.[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[NH2:20]>>[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[NH:20][C:7]([CH:3]1[C:4]([CH3:5])([CH3:6])[C:2]1([CH3:1])[CH3:10])=[O:9]
Reactant: Nc1nc2ccccc2s1
Reactant: CC1(C)C(C(=O)O)C1(C)C
Product: CC1(C)C(C(=O)Nc2nc3ccccc3s2)C1(C)C
Yield: 27.1 %

Procedure:
A mixture of 2,2,3,3-tetramethylcyclopropanecarboxylic acid (0.50 g, 3.5 mmol) and benzothiazol-2-ylamine (0.58 g, 3.9 mmol) were processed as in Example 9A. Purification by column chromatography (SiO2, 20-40% ethyl acetate/hexanes gradient) afforded 0.26 g (27%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 1.22-1.27 (m, 6H), 1.36 (s, 6H), 1.67 (s, 1H), 2.07-2.18 (m, 2H), 3.34 (s, 3H), 3.41 (t, J=5.8 Hz, 2H), 4.39-4.53 (m, 2H), 7.20-7.26 (m, 1H), 7.37-7.42 (m, 2H), 7.60 (d, J=7.5 Hz, 1H); MS (DCI/NH3) m/z 275 (M+H)+.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12](Br)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]1C2C(=CC=CC=2)C=C[CH:16]=1>>[C:1]([C:9]1[S:13][C:12]([C:16]#[N:15])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)s1
Reactant: c1ccc2ncccc2c1
Product: N#Cc1ccc(C(=O)c2ccccc2)s1
Temperature: 25 °C

Procedure:
5-Benzoyl-2-bromothiophene (8 g., 30 mmoles) and cuprous cyanide (3.2 g., 36 mmoles) were combined in 75 ml. of quinoline and refluxed for 3 hours. The reaction mixture was cooled to room temperature and solids removed by filtration with 15 ml. of quinoline and 15 ml. of water wash. The combined filtrate and washings were poured into approximately 300 g. of ice, acidified with conc. hydrochloric acid and product extracted into 300 ml. of ether. The ether extract was back-washed with 150 ml. of water, filtered from insolubles and concentrated to yield solid 5-benzoyl-2-cyanothiophene (5.7 g., m.p. 85°-89° C., m/e 213).