Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[C:25]3[CH2:24][CH2:23][CH:22]=[CH:21][C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][CH:4]=1)#[N:2].ClC1C=C(C=CC=1)C(OO)=[O:31]>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[CH2:24][CH2:23][CH:22]2[O:31][CH:21]23)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N(C(=O)C(F)(F)F)c2cccc3c2CCC=C3)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: N#Cc1ccc(N(C(=O)C(F)(F)F)c2cccc3c2CCC2OC32)cc1

Procedure:
A solution of a 3:1 mixture of N-(4-cyanophenyl)-N-(7,8-dihydro-1-naphthyl)-2,2,2-trifluoro acetamide and the corresponding 5,6-dihydro isomer (4.3 g, 13 mmol) and m-chloroperoxybenzoic acid (80-85%, 4.0 g, 19 mmol) (Aldrich) in methylene chloride (60 ml) was stirred for 50 minutes at room temperature. The solution was diluted with methylene chloride (100 ml), washed with saturated NaHCO3 solution (2×30 ml), dried (K2CO3), and concentrated in vacuo. The epoxide isomers were separated by chromatography on silica gel eluting with diethyl ether:hexane (7:13 to 9:11) and recrystallization of the enriched isomer from diethyl ether:hexane. The mother liqour was combined with some mixed fractions from the chromatography and purified by repeating the procedure. The combined solid was dried under high vacuum to give N-(4-cyanophenyl)-2,2,2-trifluoro-N-(1a,2,3,7b-tetrahydronaphth[1,2-b]oxiren-4-yl)acetamide (2.8 g). 1H NMR (CDCl3, 200 MHz) δ: 1.69 (dt, J=14,5 Hz, 1H, CH2), 2.03-2.25 (m, 1H, CH2), 2.31-2.69 (m, 2H, CH2), 3.70-3.78 (m, 1H, OCH), 3.90 (d, J=4 Hz, 1H, OCH), 7.29-7.42 (m, 4H, Ar), 7.50-7.60 (m, 1H, Ar), 7.63 (d, J=9 Hz, 2H, Ar). Anal. Calculated for C19H13F3N2O2: C, 63.69; H, 3.66; N, 7.82. Found: C, 63.70; H, 3.66; N, 7.76.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([CH3:36])[CH:29]=3)=[C:20]([C:37]([F:40])([F:39])[F:38])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:42]>C(O)C>[ClH:42].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([CH3:36])[CH:29]=2)=[C:20]([C:37]([F:38])([F:39])[F:40])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: COc1ccc(CCCOc2ccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2C(F)(F)F)cc1C
Agent: Cl
Solvent: CCO
Product: COc1ccc(CCCOc2ccc(CCC(N)(CO)CO)cc2C(F)(F)F)cc1C
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Compound 42-5 (810 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (570 mg) as a white powder.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[NH:10][C:3]=12.O=P(Cl)(Cl)[Cl:19]>C(#N)C>[CH2:15]([O:14][C:12]([C:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([Cl:19])=[C:3]2[NH:10][C:9]=1[CH3:11])=[O:13])[CH3:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C)[nH]c2c(O)ccnc12
Solvent: CC#N
Product: CCOC(=O)c1c(C)[nH]c2c(Cl)ccnc12

Procedure:
Ethyl 7-hydroxy-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (44.0 g, 0.20 mol) is suspended in dry acetonitrile (400 mL). After addition of POCl3 (47 mL, 0.50 mol) the stirred reaction mixture is heated to reflux for 4 hours. The volatiles are removed under reduced pressure. The residue is suspended in ice-cold water (500 mL) and carefully neutralized to pH 8 by dropwise addition of 6N NaOH. Stirring is continued at ambient temperature over night. The pH is readjusted to 8, the product is filtered, washed with several small portions of water and dried in vacuum at 50° C. for 24 hours to yield the title compound as off-white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][S:29](=[O:42])(=[O:41])[NH:30][C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[CH:27][C:21]=2[S:20](=[O:44])(=[O:43])[N:19]=1.[CH3:45][Si](C=[N+]=[N-])(C)C>O1CCCC1.CO>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][S:29](=[O:42])(=[O:41])[N:30]([CH3:45])[C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[CH:27][C:21]=2[S:20](=[O:43])(=[O:44])[N:19]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)NC(=O)OCc4ccccc4)ccc3N2)c(O)c2cccnc21
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)N(C)C(=O)OCc4ccccc4)ccc3N2)c(O)c2cccnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.3 %

Procedure:
A solution of the product of Example 436 (0.032 g, 0.05 mmol) in 1:1 tetrahydrofuran/methanol (2 ml) at −10° C. was treated dropwise with trimethylsilyl diazomethane (2.0 M in hexanes, 50 μL, 0.1 mmol), then stirred at 25° C. for 16 hours and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 3% methanol in dichloromethane to provide the title compound (5 mg, 15% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.99 (d, J=6.25 Hz, 6 H) 1.58 (m, 2 H) 1.69 (m, 1 H) 3.21 (s, 3 H) 4.49 (m, 2 H) 5.19 (s, 2 H) 7.32 (m, 5 H) 7.46 (m, 1 H) 7.51 (dd, J=7.91, 4.60 Hz, 1 H) 7.58 (d, J=2.21 Hz, 1 H) 7.68 (d, J=8.82 Hz, 1 H) 8.57 (dd, J=8.09, 1.84 Hz, 1 H) 8.90 (dd, J=4.78, 1.47 Hz, 1 H) 11.29 (s, 1 H) 14.09 (s, 1 H). MS (ESI−) m/z 653 (M−H)−.
Reaction SMILES: C(OC([NH:11][CH2:12][C@H:13]([N:29]([CH3:42])[C:30]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:35]=1[Cl:41])=[O:31])[CH2:14][O:15][C:16](=[O:28])[NH:17][C:18]1[N:19]=[CH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=O)C1C=CC=CC=1.[Si](I)(C)(C)C>CC#N>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[C:18]([NH:17][C:16](=[O:28])[O:15][CH2:14][C@@H:13]([N:29]([CH3:42])[C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:35]=2[Cl:41])=[O:31])[CH2:12][NH2:11])[N:19]=1
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CNC(=O)OCc1ccccc1)COC(=O)Nc1cc2ccccc2cn1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CN)COC(=O)Nc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 275.6 %

Procedure:
To a solution of isoquinolin-3-yl-carbamic acid (S)-3-benzyloxycarbonylamino-2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-propyl ester (1.3 g, 2.13 mmol) in CH3CN (20.0 mL) was added TMSI (0.35 mL, 2.56 mmol). The mixture was stirred at RT for 15 min and quenched with MeOH (20.0 mL). The resulting mixture was stirred for another 15 min, concentrated to dryness, and partitioned in between ether (30 mL) and HCl (2 N, 20 mL). The aqueous layer was separated, basified to pH 9, and extracted with EtOAc (200 mL×2). The combined organic layers were washed brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (S)-3-amino-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)propyl isoquinolin-3-ylcarbamate (2.7 g) as a light yellow foam solid, which was used without further purification. LRMS (M+H+) m/z 460.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:12][C:13]([C:15]2[CH:16]=[N:17][N:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:19]=2)=O)[CH:8]=[C:9]([CH3:11])[CH:10]=1)=O)C.C([O-])(=O)C.[NH4+:28].O>C(O)(=O)C>[C:20]([N:18]1[CH:19]=[C:15]([C:13]2[NH:28][C:4](=[O:3])[C:6]3[N:7]([CH:8]=[C:9]([CH3:11])[CH:10]=3)[CH:12]=2)[CH:16]=[N:17]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: [NH4+]
Reactant: CCOC(=O)c1cc(C)cn1CC(=O)c1cnn(C(C)(C)C)c1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c(=O)[nH]c(-c3cnn(C(C)(C)C)c3)cn2c1
Temperature: 25 °C

Procedure:
A solution of 375 mg (1.18 mmol) 1-[2-(1-tert-butyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester and 4.89 g (63.5 mmol) ammonium acetate in 4.15 ml acetic acid is stirred for 28 hours at 110° C. The reaction mixture is allowed to cool to room temperature and excess water is added. The resulting precipitate is filtered off, washed with water and dried. It is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 3-(1-tert-butyl-1H-pyrazol-4-yl)-7-methyl-2H-pyrrolo[1,2-a]pyrazin-1-one as light yellow solid; HPLC/MS 2.27 min (B), [M+H] 271;
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[CH:8]1([O:16][CH2:17]CO)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:8]1([O:16][CH2:17][CH2:1][O:2][C:3]2[S:4][CH:5]=[CH:6][CH:7]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: OCCOC1CCCCCCC1
Reactant: COc1cccs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: c1csc(OCCOC2CCCCCCC2)c1
Yield: 61.9 %

Procedure:
As in Example 1, a solution of 2-methoxythiophene (11.4 g) and 2-(cyclooctyloxy) ethanol (13.78 g) in benzene (200 mL) containing para-toluenesulfonic acid (0.1 g) was stirred at reflux for 3 days in a flask equipped with a Soxhlet extractor charged with 4 Å molecular sieves. After the reaction was worked up in the usual manner, the crude product was purified by HPLC (hexane-diethyl ether; 2.4: 1) to give 12.6 g of 2-[[2-(cyclooctyloxy) ethyl]oxy]thiophene as a colorless oil. A small portion was distilled in a Kugelrohr apparatus (~130 ° C./0.02 mm) to furnish the analytical specimen.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:19])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[Cl:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: COc1cc2c(cc1Cl)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1Cl)C(C)CNCC2
Reaction time: 8 h
Yield: 109.3 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.399 g, 1.24 mmol) in methanol (20 mL) was treated with 15% aqueous NaOH (20 mL), and stirred overnight at 20 C. The product mixture was diluted with water (100 mL), extracted twice with EtOAc (100 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4 and concentrated to give 0.306 g of a yellow solid. 1H NMR (400 MHz, CDCl3) d 7.05 (s, 1 H), 6.59 (s, 1 H), 3.80 (s, 3 H), 3.0-2.8 (m, 6 H), 2.62 (m, 1 H), 2.16 (bs, 1 H), 1.24 (d, J=7 Hz, 3 H). MS calculated for C12H16ClNO+H: 226, observed: 226.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].Cl.[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:29]=[C:28]4[C:23]([CH2:24][CH2:25][N:26]([C:30](=[O:37])[CH2:31][CH:32]5[CH2:36][CH2:35][NH:34][CH2:33]5)[CH2:27]4)=[CH:22][CH:21]=3)[N:17]=[C:16]([NH2:38])[N:15]=2)[CH2:10][CH2:9]1.C(N(CC)CC)C>C(#N)C>[NH2:38][C:16]1[N:17]=[C:18]([C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][N:26]([C:30](=[O:37])[CH2:31][CH:32]4[CH2:36][CH2:35][N:34]([C:2]([O:4][CH3:5])=[O:3])[CH2:33]4)[CH2:27]3)=[CH:22][CH:21]=2)[CH:19]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH3:7])[CH2:13][CH2:12]2)[N:15]=1
Reactant: COC(=O)Cl
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCNC3)CC4)nc(N)n2)CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(CC(=O)N2CCc3ccc(-c4cc(N5CCN(C)CC5)nc(N)n4)cc3C2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (2.1 uL, 0.028 mmol) was added to a mixture of 4-(4-methylpiperazin-1-yl)-6-[2-(pyrrolidin-3-ylacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyrimidin-2-amine HCl salt (10 mg, 0.02 mmol) and triethylamine (0.013 mL, 0.092 mmol) in acetonitrile (0.5 mL). The reaction mixture was stirred at r.t. for 30 min The mixture was purified by RP-LCMS (pH=10) to afford the desired product. Analytic LCMS (M+H)+: m/z=494.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C:16]([C:17]#[N:18])=[C:12]2[NH:11][CH2:10][CH2:9]1.Br[CH2:27][CH:28]1[CH2:30][CH2:29]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:27][CH:28]4[CH2:30][CH2:29]4)=[CH:23][CH:24]=3)[C:16]([C:17]#[N:18])=[C:12]2[NH:11][CH2:10][CH2:9]1
Reactant: N#Cc1c(-c2ccc(O)cc2)nn2c1NCCC2c1ccccc1N
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1c(-c2ccc(OCC3CC3)cc2)nn2c1NCCC2c1ccccc1N
Temperature: 56 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
To a solution of 7-(2-aminophenyl)-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (331 mg, 1.0 mmol) in acetone (15 mL) was added (bromomethyl)cyclopropane (135 mg, 1.0 mmol) and K2CO3 (276 mg, 2.0 mmol). After stirring at 56° C. for 16 hr, the mixture was filtered. The cake was washed with acetone (20 mL×2). The filtrate was concentrated to afford 300 mg of desired product (78%) as a yellow solid. MS (ESI) m/e [M+1]+ 386.0.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:26])[O:17][CH2:18][CH2:19][NH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:27]([N:26]=[C:16]([N:7]1[CH2:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[O:17][CH2:18][CH2:19][NH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)NCCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=O)NCCOC(=NC(=O)c1ccccc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 2-ethoxycarbonylamino-ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and benzoyl chloride, there is obtained 2-ethoxycarbonylamino-ethyl N-benzoyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 457 (6), 341 (18), 194 (100), 116 (75), 105 (75);
Reaction SMILES: [BH4-].[Na+].C12CCC(CC1)C([CH2:11][OH:12])C2.[ClH:13].[CH3:14][N:15]([CH2:17][CH:18]1[CH:23]2[CH2:24][CH2:25][CH:20]([CH2:21][CH2:22]2)[CH:19]1[C:26]1[CH:31]=[CH:30][C:29]([N+]([O-])=O)=[CH:28][CH:27]=1)[CH3:16]>>[ClH:13].[CH3:14][N:15]([CH2:17][CH:18]1[CH:23]2[CH2:24][CH2:25][CH:20]([CH2:21][CH2:22]2)[CH:19]1[C:26]1[CH:31]=[CH:30][C:29]([O:12][CH3:11])=[CH:28][CH:27]=1)[CH3:16]
Reactant: CN(C)CC1C2CCC(CC2)C1c1ccc([N+](=O)[O-])cc1
Reactant: OCC1CC2CCC1CC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(C2C3CCC(CC3)C2CN(C)C)cc1

Procedure:
Ethyl trans-2-p-methylphenylbicyclo[2,2,2]octane-3-carboxylate (0.025 mole) was added to lithium aluminium hydride (0.03 mole) in tetrahydrofuran (60 ml.) at 0°C. and after 3 hours, water was added and the mixture extracted with ether. Evaporation of the ether extract gave the corresponding bicyclo[2,2,2]oct-3-yl methanol as an oil. The latter was dissolved in dichloromethane (50 ml.) and methylamine (10 ml.) and methanesulphonyl chloride (3.6 g.) added at 0°C. After 2 hours, dimethylamine (25 ml. of a 33% solution in water) was added to the resultant methyl sulphonate and the mixture refluxed for 1 week. A large excess of water was added and the mixture extracted with ether. Evaporation of the dried ether extract yielded a solid which, on addition of ethanolic hydrochloric acid, gave N,N-dimethyl-2-p-methylphenylbicyclo[2,2,2]oct-3-yl methylamine hydrochloride as a white solid (2 g.) which had a satisfactory C, H, N and Cl analysis. Similarly, N,N-dimethyl-2-p-methoxyphenylbicyclo[2,2,2]oct-3-yl methylamine hydrochloride was prepared. Also by reduction of trans-2-p-nitrophenylbicyclo[2,2,2]octane-3-carboxyaldehyde, using sodium borohydride, followed by treatment of the resultant methanol as described above, N,N-dimethyl-2-p-nitrophenylbicyclo[2,2,2]oct-3-yl methylamine hydrochloride was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:27][C:28]3[NH:29][CH:30]=[CH:31][CH:32]=3)[C:18]2=[O:33])[CH2:13][CH:14]([OH:16])[CH3:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:27][C:28]3[NH:29][CH:30]=[CH:31][CH:32]=3)[C:18]2=[O:33])[CH2:13][C:14](=[O:16])[CH3:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc([C@@H](CC(C)O)N2C(=O)c3cccc(Cc4ccc[nH]4)c3C2=O)ccc1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOc1cc([C@@H](CC(C)=O)N2C(=O)c3cccc(Cc4ccc[nH]4)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.2 %

Procedure:
A mixture of 2-[(1R)-1-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutyl]-4-(pyrrolylmethyl)isoindoline-1,3-dione (1.26 g, 2.81 mmol), pyridinium chlorochromate (1.21 g, 5.62 mmol), and celite (0.6 g) in methylene chloride (35 mL) was stirred at room temperature for 4 hours. The mixture was filtered through celite and the filtrate was washed with water (30 mL), brine (30 mL). The organic layer of the filtrate was dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (Silica gel, Hexane:ethyl acetate 6:4) to give 2-[(1R)-1-(3-ethoxy-4-methoxyphenyl)-3-oxobutyl]-4-(pyrrolylmethyl)isoindoline-1,3-dione (0.83 g, 66%) as a white solid: mp 143-145° C.; 1H NMR (CDCl3) δ 7.66 (d, J=7.3 Hz, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.10-7.06 (m, 2H), 6.93 (d, J=7.7 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.73-6.71 (m, 2H), 6.22-6.21 (m, 2H), 5.78-5.72 (dd, J=5.4, 9.8 Hz, 1H), 3.32-3.23 (dd, J=5.4, 18.0 Hz, 1H), 2.18 (s, 3H), 1.46 (t, J=6.9 Hz, 3H); 13C NMR (CDCl3) δ 205.31, 168.53, 167.83, 149.11, 148.33, 138.31, 134.43, 132.37, 132.04, 131.55, 127.05, 122.34, 121.46, 120.14, 112.59, 111.29, 109.08, 64.39, 55.91, 50.01, 48.53, 44.88, 30.17, 14.72; Anal. Calcd. for C26H26N2O5; C, 69.94; H, 5.87; N, 6.27. Found: C, 70.01; H, 6.01; N, 6.08.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=1[O:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[OH:11])[CH3:4].Cl[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCCC1>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][O:11][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:9][O:8][C:7]1[CH:18]=[CH:19][CH:20]=[CH:21][C:6]=1[O:5][CH2:3][CH3:4])[CH3:28]
Reactant: CCOc1ccccc1OCC(O)c1ccccn1
Reactant: CCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC(COc1ccccc1OCC)c1ccccn1
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
A mixture of sodium hydride (50%, 9.79 g, 0.204 mole, washed with hexane) in tetrahydrofuran (THF) was prepared. α-[(2-Ethoxyphenoxy)methyl]-2-pyridinemethanol (52.96 g, 0.204 mole) in 175 ml of THF was added dropwise under nitrogen with stirring over 1/2 hr. Stirring was continued for 1 hr at room temperature. Ethyl chloroacetate (24.98 g, 0.204 mole) in THF was added dropwise over 10 min. The resulting solution was heated at reflux for 2 hr and stirred at room temperature (72 hr). THF was removed, and the residue partitioned between diethyl ether and water. Removal of diethyl ether gave 57.9 g (0.168 mole, 82.4% yield) of the desired 2-[2-(2-ethoxy-phenoxy)-1-(2-pyridinyl)ethoxy]acetic acid ethyl ester as an oil. This structure of the product was confirmed by NMR.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[CH2:12]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH2:20]([N:19]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=C(O)Cc1ccccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Product: O=C(Cc1ccccn1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.6 %

Procedure:
To a solution of 413 mg of 2-pyridylacetic acid hydrochloride, 470 mg of dibenzylamine and 321 mg of 1-hydroxybenzotriazole in 5 ml of dry pyridine was added 637 mg of 1,3-dicyclohexylcarbodiimide, and the mixture was stirred for 15 hours at room temperature. Precipitates were filtered off, the filtrate was concentrated under reduced pressure. The residue was dissolved in a 1N-hydrochloric acid and washed twice with 25 ml of diethyl ether, and then a 2N-aqueous hydroxide was added to the solution to a pH of 11. A separated oil was extracted with 50 ml of dichloromethane, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 486 mg of N,N-dibenzyl-2-pyridylacetamide as an oil.
Reaction SMILES: [CH2:1]([CH:9]1[C:17]([C:19]([F:22])([F:21])[F:20])(O)[C:16]2[C:11]3=[C:12]([O:23][CH2:24][CH2:25][N:10]13)[CH:13]=[CH:14][CH:15]=2)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(Cl)(Cl)=O>N1C=CC=CC=1>[CH2:1]([C:9]1[N:10]2[CH2:25][CH2:24][O:23][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]=1[C:19]([F:22])([F:20])[F:21])[C:11]2=3)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: OC1(C(F)(F)F)c2cccc3c2N(CCO3)C1CCc1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: FC(F)(F)c1c(CCc2ccccc2)n2c3c(cccc13)OCC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5-phenethyl-6-(trifluoromethyl)-2,3,5,6-tetrahydro-[1,4]oxazino[2,3,4-hi]indol-6-ol (208 mg, 0.60 mmol) in pyridine (3 mL) was added thionyl chloride (142 mg, 1.2 mmol) at 0° C. After stirring for 2 h at 0° C., the resulting mixture was concentrated to yield 5-phenethyl-6-(trifluoromethyl)-2,3-dihydro-[1,4]oxazino[2,3,4-hi]indole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][C:9]=1[NH2:17])([CH3:4])([CH3:3])[CH3:2].C([O:23][C:24](=O)[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]#[N:35])[CH:29]=1)=[O:27])(C)(C)C>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:15])[CH3:16])=[CH:10][C:9]=1[NH:17][C:24](=[O:23])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]#[N:35])[CH:29]=1)=[O:27])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Reactant: CC(C)c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Product: CC(C)c1ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)c1

Procedure:
Prepared from (2-amino-4-isopropyl-phenyl)-carbamic acid tert.-butyl ester (Example G47) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example H10) according to the general procedure K. Obtained as a light brown solid (183 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]([CH:22]2[CH2:24][CH2:23]2)[CH2:20][CH3:21])[C:13]=1[NH2:25].[C:26](OC)(=[O:30])[C:27]([CH3:29])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]2[N:25]=[C:27]([CH3:29])[C:26](=[O:30])[N:18]([CH:19]([CH:22]3[CH2:24][CH2:23]3)[CH2:20][CH3:21])[C:14]=2[N:15]=[CH:16][CH:17]=1
Reactant: COC(=O)C(C)=O
Reactant: CCC(Nc1nccc(-c2ccc(OC(F)F)cc2Cl)c1N)C1CC1
Product: CCC(C1CC1)n1c(=O)c(C)nc2c(-c3ccc(OC(F)F)cc3Cl)ccnc21

Procedure:
4-(2-Chloro-4-difluoromethoxy-phenyl)-N2-(1-cyclopropyl-propyl)-pyridine-2,3-diamine (0.284 g, 0.77 mmol) and methyl pyruvate (140 μL, 1.54 mmol) were treated substantially as described in Part F of Example 113 to give 8-(2-Chloro-4-difluoromethoxy-phenyl)-4-(1-cyclopropyl-propyl)2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 115b): 1H NMR (300 MHz, CDCl3) δ 8.52–8.46 (2d, 1H, J=4.8), 7.37–7.32 (m, 2H), 7.26–7.14 (m, 2H), 6.85–6.37(t,1H, J=73.3 Hz), 5.09–4.95, 4.75–4.2 (2m, 1H), 2.48 (s, 3H), 2.4–2.25 (m, 1H), 2.23–2.16 (m, 1H), 2.13–1.93 (m, 1H), 0.90–0.85 (t, 3H, J=7.3 Hz), 0.80–0.67 (m, 1H), 0.57–0.42 (m, 1H), 0.40–0.29 (m, 1H), 0.24–0.18 (m, 1H). MS (AP) m/z 420.2 [(M+H)+, 100], 461.3 [(M+H+CH3CN)+, 20].