Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:17])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[C:8](Cl)=[C:7]([CH:14]=O)[C:6]=2[CH:16]=1.[SH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:3]([F:17])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[C:8]3[S:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][C:7]=3[C:6]=2[CH:16]=1
Reactant: CCOC(=O)CS
Reactant: O=CC1=C(Cl)C2CC(C2)c2cc(F)c(Br)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(s1)C1CC(C1)c1cc(F)c(Br)cc1-2
Temperature: 60 °C
Yield: 27 %

Procedure:
Into a pressure tube containing a solution of 2-bromo-8-chloro-3-fluoro-6,7-dihydro-5H-5,7-methanobenzo[7]annulene-9-carbaldehyde (125 mg at 79% purity LCMS-UV215) in anhydrous N,N-dimethylformamide (0.5 mL) was introduced ethyl mercaptoacetate (46 mg, 0.38 mmol as a solution in 0.5 mL of anhydrous N,N-dimethylformamide) and finely powdered potassium carbonate (53 mg, 0.38 mmol). After warming to 60° C. for 4 hr, the reaction mixture was concentrated in vacuo, the residue suspended in ethyl acetate (15 mL) and washed with water (2×10 ml) and brine (10 ml). The organic extract was dried over sodium sulfate, filtered and the filtrate adsorbed onto silica gel in vacuo. Purification of the dry-loaded material by silica gel flash column chromatography (eluent: heptane/ethyl acetate gradient) furnished the title compound (39 mg, 0.10 mmol, 27% over 2 steps) as a colorless solid: 1H NMR (500 MHz, CDCl3) δ 1.40 (t, J=7.09 Hz, 3H), 1.71 (d, J=8.83 Hz, 2H), 2.86-2.95 (m, 2H), 3.57 (m, 2H), 4.37 (q, J=7.04 Hz, 2H), 6.91 (dd, J=9.14, 2.21 Hz, 1H), 8.06 (dd, J=6.94, 2.21 Hz, 1H), 8.22 (d, J=1.89 Hz, 1H); M+1=381/383.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.CN(C)C=O.[NH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]([C:26]([OH:28])=[O:27])[C:19]2=[O:29].C(N(CC)CC)C.Cl[Si](C)(C)C>ClCCl>[O:29]=[C:19]1[C:18]2[C:23](=[CH:24][CH:25]=[C:16]([NH:15][C:7]([CH:5]3[CH2:4][CH2:3][C:2](=[O:1])[NH:6]3)=[O:9])[CH:17]=2)[NH:22][CH:21]=[C:20]1[C:26]([OH:28])=[O:27]
Reactant: Nc1ccc2[nH]cc(C(=O)O)c(=O)c2c1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(C(=O)Nc2ccc3[nH]cc(C(=O)O)c(=O)c3c2)N1
Reaction time: 1 h
Yield: 57.4 %

Procedure:
A mixture of 1.94 g (15 mmol) of 5-oxo-L-proline, 1.1 ml (15 mol) dimethylformamide, and 30 ml of dichloromethane is stirred 0°-5° for 1 hour. A mixture of 2.04 g (10 mmol) of 6-amino-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, [J. Pharm. Sci., 11, 1051 (1963)] 4.2 ml (30 mmol) of triethylamine, 3.8 ml (30 mmol) of chlorotrimethylsilane, and 75 ml of dichloromethane is stirred at room temperature for 40 minutes and then is cooled at 0°. The cold acid chloride solution is added to the cold silylated quinoline and is stirred at 5° for 4 hours and overnight at room temperature. The reaction mixture is evaporated and the residue is treated with water to give 1.81 g of 1,4-dihydro-4-oxo-6-[[(5-oxo-2-pyrrolidinyl)carbonyl]-amino]-3-quinolinecarboxylic acid.
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[C:13]([CH2:15][C@:16]4([CH3:22])[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]4[C@@H:11]3[CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2)=[O:14].C(N(CC)CC)C.FC(F)(F)S(O[Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])(=O)=O>ClCCl>[O:6]([C:5]1[CH2:4][CH2:3][C@@:2]2([CH3:1])[C:8](=[CH:9][CH2:10][C@@H:11]3[C@@H:12]2[C:13](=[O:14])[CH2:15][C@@:16]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C:20]2=[O:21])[CH:7]=1)[Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1=CC2=CC[C@@H]3[C@H](C(=O)C[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of adrenosterone (6.0 g, 20 mmol) in dry, dichloromethane (120 ml) was added triethylamine (8.4 ml, 60 mmol) followed by tert-butyldimethylsilyl trifluoromethanesulfonate (5.0 ml, 22 mmol) and the mixture stirred at room temperature for 3 h. The dichloromethane was evaporated and the residue redissolved in diethyl ether (100 ml), then allowed to stand for 30 min, after which time an oil separated. The ether phase was decanted off the oil and the solvent evaporated to give the title compound which was used directly in step (b). IR νmax 1705, 1747 cm-1 ; 1H-NMR(CDCl3) inter alia δ0.12 (6H,s,Me2Si), 0.85 (3H,s,18-CH3), 0.92 (9H,s,tBuSi) 1.17(3H,s, 19-CH3), 4.73 (1H,dm, J 6.9Hz, 6-H), 5.36 (1H,m,4-H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N+:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]=1[CH3:21].[Cl-:22].[Br-].F[C:25]1C=CC(C[N+]2C(C)=C(C)N(CC3C=CC(F)=CC=3)C=2)=CC=1>CC(C)=O>[CH3:21][C:3]1[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([CH3:25])=[N+:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]=1[CH3:1].[Cl-:22]
Reactant: Cc1c(C)[n+](Cc2ccc(F)cc2)cn1Cc1ccc(F)cc1
Reactant: Cc1c(C)[n+](Cc2ccccc2)cn1Cc1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: CC(C)=O
Product: Cc1c(C)[n+](Cc2ccccc2)c(C)n1Cc1ccccc1

Procedure:
The novel compound 1 was obtained as white needles in acetone, and its molecular formula of C19H19N2 was determined by HRFABMS. The IR spectrum of 1 showed a strong aromatic absorbance at 1560 cm−1. In 13C NMR spectrum of 1, only eight carbon signals were observed at δ 8.1 (q), 49.6 (t), 127.2 (s), 127.8 (d), 128.6 (d), 129.1 (d), 134.3 (s), and 135.5 (d), suggesting that the molecule of 1 is symmetrical to match the mass spectral data. Analysis of the 1H NMR signals at δ 5.41 (s), 7.31 (dd, J=8.8, 2.2 Hz), and 7.37-7.46 (m) and corresponding 13C NMR signals (gHMQC) at δ 49.6 (t), 127.8 (d), 128.6 (d), 129.1 (d), and 134.3 (s), indicated the appearance of a phenylmethylene group. This is supported by the COSY and gHMBC spectral data. A proton signal due to methyl group was observed as a singlet at δ 2.18, but the correlative carbon appeared in a very high field at δ 8.1 (q) in the gHMQC NMR experiment, similar to those of 1,3-di(4-fluorobenzyl)-4,5-dimethylimidazolium bromide, a synthesized product for the application as probes for intracellular pH determination. In the gHMBC NMR experiments of (1), the proton signal at 5.41 (s) exhibited other relevant cross-peaks at 127.2 (s) and 135.5 (d) attributable to C-2 and C-4 (5), respectively, apart from the ones of phenylmethylene moiety. On the other hand, H-2 showed two relevant cross-peaks at 49.6 (t) and 127.2 (s), assignable to the methylene group and C-4 (5), respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2CCN(CCCC(O)=O)[C:11](=[O:21])[C@H:10]2C)C=[CH:6][C:7]=1Cl.C1C2(CCNC[C@H]2O)C1>>[ClH:1].[CH2:7]1[C:2]2([CH2:3][CH2:4][NH:9][CH2:10][C@H:11]2[OH:21])[CH2:6]1
Reactant: C[C@@H]1C(=O)N(CCCC(=O)O)CCN1c1ccc(Cl)c(Cl)c1
Agent: O[C@@H]1CNCCC12CC2
Product: Cl

Procedure:
In analogy to the procedure described in Example 15, 4-[(R)-4-(3,4-dichloro-phenyl)-3-methyl-2-oxo-piperazin-1-yl]-butyric acid (62% ee) and 1.1 eq. of (S)-6-aza-spiro[2.5]octan-4-ol; hydrochloride (intermediate 2) gave after precipitation (Et2O/n-pentane) the titled compound in 77% yield as light yellow foam. MS: 454.16 (MH+, 2Cl).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15]CC1C=CC=CC=1)=[O:6]>CO>[OH:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])=[O:6]
Reactant: O=C(NCCO)NCc1ccccc1OCc1ccccc1
Solvent: CO
Product: O=C(NCCO)NCc1ccccc1O
Reaction time: 2 h

Procedure:
59.6 g of N-(2-hydroxyethyl)-N'-(2-benzyloxybenzyl)urea are dissolved in 600 ml of methanol and hydrogenated in the presence of 6 g of Pd/C-catalysyt (5%). After 2 hours the hydrogenation ceases. The catalyst is suction-filtered, and the filtrate concentrated by evaporation in vacuo. The residue is recrystallised from 350 ml of ethyl acetate; the pure product melts at 100°-101°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=3[O-])[C:7]=2[CH:21]=1)#[N:2]>C(OC(=O)C)(=O)C>[CH3:12][C:10]1([CH3:13])[CH:9]=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:7]2[CH:21]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11]1
Reactant: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C#N)ccc2O1
Solvent: CC(=O)OC(C)=O
Product: CC1(C)C=C(c2ccccn2)c2cc(C#N)ccc2O1
Yield: 69.1 %

Procedure:
280 mg of 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide were heated at 120° C. in 3 ml of acetic anhydride for 24 hours. After cooling the mixture was evaporated and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated. The residue was recrystallized from cyclohexane to give 181 mg of 2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH:7]=[N:8][OH:9])([O-:3])=[O:2].ClN1C(=O)CCC1=O.[Cl:21][C:22]1[CH:23]=[C:24]([C:29]([C:31]([F:34])([F:33])[F:32])=[CH2:30])[CH:25]=[C:26]([Cl:28])[CH:27]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:21][C:22]1[CH:23]=[C:24]([C:29]2([C:31]([F:34])([F:32])[F:33])[O:9][N:8]=[C:7]([C:6]3[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=3)[CH2:30]2)[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: O=[N+]([O-])c1cccc(C=NO)c1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1cccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
In N,N-dimethylformamide (15 ml), 3-nitrobenzaldoxime (249 mg) was dissolved, and thereto was added N-chlorosuccinimide (201 mg) at room temperature. The mixture was stirred at 60° C. for 1 hour, and then cooled to room temperature. To the reaction solution were added 2-(3,5-dichlorophenyl)-3,3,3-trifluoro-1-propene (362 mg), followed by triethylamine (152 mg), and the mixture was stirred at room temperature for 6 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 3-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]nitrobenzene (232 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:21][C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[C:17]([CH:20]=1)[CH:18]=O.N1CCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:18]/[C:17]3[CH:20]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=3[O:21][C:22]3[N:23]=[CH:24][CH:25]=[CH:26][N:27]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Cl)ccc1Oc1ncccn1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cc(Cl)ccc1Oc1ncccn1
Temperature: 70 °C
Yield: 52.9 %

Procedure:
To a mixture of 6-chlorooxindole (1.1 g, 6.4 mmol) and 5-chloro-2-(pyrimidin-2-yloxy)-benzaldehyde (1.5 g, 6.4 mmol) in methanol (10 mL) was added pyrrolidine (0.5 mL, 6.4 mmol) dropwise. The mixture was then heated at 70° C. for 3 h. After cooled to 4° C., the mixture was filtered and the precipitate was collected, dried to give the title compound as a bright yellow solid (1.3 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:27]2[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:14](=[O:15])[N:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:12]([CH3:23])=[N:11][C:10]=1[CH2:24][CH2:25][CH3:26].Br[C:36]([CH3:42])([CH3:41])[C:37]([O:39][CH3:40])=[O:38].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:14](=[O:15])[N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:36]([CH3:42])([CH3:41])[C:37]([O:39][CH3:40])=[O:38])=[CH:18][CH:17]=3)[C:12]([CH3:23])=[N:11][C:10]=2[CH2:24][CH2:25][CH3:26])=[C:2]([F:1])[CH:3]=1)#[N:34]
Reactant: COC(=O)C(C)(C)Br
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)C(=O)OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 80 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
To a solution of 3′-fluoro-4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.50 g) and methyl 2-bromo-2-methylpropanoate (1.0 g) in N,N-dimethylformamide (10 mL) was added cesium carbonate (0.72 g), and the mixture was stirred at 80° C. for 12 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.58 g, 96%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([S:15][CH2:16][C:17]([NH:19][CH3:20])=[O:18])[CH:12]=[C:11]([Cl:21])[N:10]=2)[CH2:5][CH2:4]1.[Br:22][C:23]1[CH:24]=[C:25]([C:29](O)=[O:30])[NH:26][C:27]=1[CH3:28]>>[Br:22][C:23]1[CH:24]=[C:25]([C:29]([NH:2][CH:3]2[CH2:4][CH2:5][N:6]([C:9]3[CH:14]=[C:13]([S:15][CH2:16][C:17]([NH:19][CH3:20])=[O:18])[CH:12]=[C:11]([Cl:21])[N:10]=3)[CH2:7][CH2:8]2)=[O:30])[NH:26][C:27]=1[CH3:28]
Reactant: Cc1[nH]c(C(=O)O)cc1Br
Reactant: CNC(=O)CSc1cc(Cl)nc(N2CCC(N)CC2)c1
Agent: Cl
Product: CNC(=O)CSc1cc(Cl)nc(N2CCC(NC(=O)c3cc(Br)c(C)[nH]3)CC2)c1

Procedure:
The title compound was prepared by analogous method to Example 18 starting from 2-{[2-(4-aminopiperidin-1-yl)-6-chloropyridin-4-yl]thio}-N-methylacetamide hydrochloride salt (Intermediate 220) and 4-bromo-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 18).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5]>CO.O>[OH:5][CH:4]([C:3]1[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=1[Cl:1])[C:6]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)C1(C(=O)c2ccccc2Cl)CCCC1
Solvent: O
Solvent: CO
Product: CCOC(=O)C1(C(O)c2ccccc2Cl)CCCC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 80.3 %

Procedure:
tBuBisP*RuBr2 (28 mg) was placed in a reactor and deaerated and substituted with argon. A mixture of deaerated methanol/water (10/1) (33 ml) and ethyl 1-(2-chlorobenzoyl)cyclopentanecarboxylate (3.2 g, 11.4 mmol) was added. Under a hydrogen pressure (6 atm), the mixture was stirred at 70° C. for 7 h and concentrated to dryness. This was dissolved in ethyl acetate, dried over anhydrous sodium sulfate and purified by silica gel column chromatography to give the title compound (2.59 g, yield; 80.9%) as a colorless oil. The enantiomer excess of this product was measured by high performance liquid chromatography (Condition F) and found to be 90% ee.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]1[O:10][C:9]([C:15]#[C:16][CH:17]2[CH2:19][CH2:18]2)([C:11]([F:14])([F:13])[F:12])[C:8]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:7]=2[N:6](CC2C=CC(OC)=CC=2)[C:5]1=[O:34].O>C(#N)C>[Br:1][CH2:2][CH2:3][C@@H:4]1[O:10][C@:9]([C:15]#[C:16][CH:17]2[CH2:18][CH2:19]2)([C:11]([F:13])([F:14])[F:12])[C:8]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:7]=2[NH:6][C:5]1=[O:34]
Reactant: COc1ccc(CN2C(=O)C(CCBr)OC(C#CC3CC3)(C(F)(F)F)c3cc(Cl)ccc32)cc1
Solvent: CC#N
Solvent: O
Product: O=C1Nc2ccc(Cl)cc2[C@@](C#CC2CC2)(C(F)(F)F)O[C@H]1CCBr
Reaction time: 0.5 h

Procedure:
To a room temperature solution of 1.13 g of 3-(2-bromoethyl)-7-chloro-5-cyclopropylethynyl-1,5-dihydro-1-(4-methoxybenzyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one in 50 mL of acetonitrile was added 25 mL of water and 5.7 g of ceric ammonium nitrate. After 30 min, the reaction mixture was partitioned between water and ether, and the organic layer was washed with aqueous bicarbonate and brine, dried and evaporated. This produced two diastereomeric products which were separated by column chromatography over silica gel (elution with 10-25% ethyl acetate in hexanes). The first diastereomer eluted (270 mg) was the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11](OCC)(=O)[C:12]([O:14]CC)=[O:13].[O-]CC.[Na+].C(OCC)C>C(O)C>[O:10]=[C:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1][C:11]([C:12]([OH:14])=[O:13])=[CH:9]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccccc1O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: O=C(O)c1cc(=O)c2ccccc2o1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
2'-hydroxyacetophenone (25.7 g) and diethyl oxalate (33.1 g) were added to a solution of sodium ethoxide in ethanol (prepared from 13.0 g of sodium and 375 ml of ethanol), and the mixture was heated for 1 hour while refluxing. After the reaction mixture was cooled to room temperature, ethyl ether (500 ml) was added, and the separating crystals were collected by filtration. To this crystal, 2N hydrochloric acid (600 ml) was added, followed by ethyl ether extraction. The ethyl ether layer was washed with water and dried (MgSO4), after which it was concentrated under reduced pressure. The residual oily substance was dissolved in acetic acid-concentrated hydrochloric acid (1:1,200 ml) and heated for 1 hour while refluxing. The reaction mixture was poured over water (1 liter); the separated crystals were collected by filtration and then washed by sequential additions of water, ethanol and ethyl ether in that order, to yield 4-oxo-4H-1-benzopyran-2-carboxylic acid (83.5%), which was then recrystallized from ethanol to yield colorless needles having a melting point of 240° to 241° C. (decomposed).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][C:11]([C:13]([OH:15])=[O:14])=[N:10][CH:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1=NC(c2ccc(Cl)cc2Cl)N(c2ccc(Cl)cc2)C1
Temperature: 90 °C
Yield: 97 %

Procedure:
To a solution of ethyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (1.1 g, 2.79 mmol) in MeOH (20 mL), a solution of KOH (2.2 g, 39 mmol) in H2O (20 mL) was added. The mixture was heated at 90° C. for 3 h. The reaction mixture was cooled to rt and the MeOH was evaporated. HCl (1N) was added until a white precipitate formed. The solid was filtered off, and dried under vacuum. The product (1.0 g, 98% yield) was obtained as a white solid: LC-MS m/z 367 (MH+), retention time is 3.43 min (method 1); mp 150-151° C.; 1H NMR (300 MHz, CDCl3) δ 7.24-7.65 (7H, m), 8.26 (1H, s).
Reaction SMILES: F[C:2](F)(F)C1C=C(C=C(C(F)(F)F)C=1)CN(C1CCCNC2C(C)=CC(C(F)(F)F)=CC1=2)C(=O)C.[CH:36]([O:39][C:40]([N:42]1[C:48]2[C:49]3[CH2:50][CH2:51][CH2:52][C:53]=3[C:54](Br)=[CH:55][C:47]=2[CH:46]([N:57]([C:73](=[O:75])[CH3:74])[CH2:58][C:59]2[CH:64]=[C:63]([C:65]([F:68])([F:67])[F:66])[CH:62]=[C:61]([C:69]([F:72])([F:71])[F:70])[CH:60]=2)[CH2:45][CH2:44][CH2:43]1)=[O:41])([CH3:38])[CH3:37]>>[CH:36]([O:39][C:40]([N:42]1[C:48]2[C:49]3[CH2:50][CH2:51][CH2:52][C:53]=3[C:54]([CH3:2])=[CH:55][C:47]=2[CH:46]([N:57]([C:73](=[O:75])[CH3:74])[CH2:58][C:59]2[CH:64]=[C:63]([C:65]([F:68])([F:67])[F:66])[CH:62]=[C:61]([C:69]([F:72])([F:71])[F:70])[CH:60]=2)[CH2:45][CH2:44][CH2:43]1)=[O:41])([CH3:38])[CH3:37]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2c(C)cc(C(F)(F)F)cc21
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c1cc(Br)c1c2CCC1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c1cc(C)c1c2CCC1

Procedure:
The titled compound was prepared in a manner analogous to the procedure for the preparation of N-(3,5-Bis-trifluoromethyl-benzyl)-N-(9-methyl-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-acetamide (example 123, step 3) by replacing N-(3,5-Bis-trifluoromethyl-benzyl)-N-(9-bromo-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-acetamide with (+/−)-6-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-4-bromo-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic acid isopropyl ester (example 144, step 2)
Reaction SMILES: O.O.O.O.O.C(=O)([O-])[O-:7].[La+3:10].C(=O)([O-])[O-].C(=O)([O-])[O-].[La+3].[OH:20][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22]>O>[OH2:7].[F:25][C:24]([F:27])([F:26])[S:21]([O-:23])(=[O:22])=[O:20].[La+3:10].[F:25][C:24]([F:27])([F:26])[S:21]([O-:23])(=[O:22])=[O:20].[F:25][C:24]([F:27])([F:26])[S:21]([O-:23])(=[O:22])=[O:20]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [La+3]
Solvent: O
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
Lanthanum (III) carbonate pentahydrate (2.74) was suspended in water (20 mL), and triflic acid (9.0 g) was added dropwise. Once the exothermic addition was complete, a clear colorless solution remained which yielded lanthanum (III) trifluoromethanesulfonate hydrate (14.3 g, as a glassy wet solid) after water removal in vacuo.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=O)[C:6]=2[N:7]=1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.CN(C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([NH:23][CH:20]3[CH2:22][CH2:21]3)=[O:16])[C:6]=2[N:7]=1
Reactant: NC1CC1
Reactant: O=C(O)c1cccc(-c2csc3cnc(Cl)nc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1cccc(-c2csc3cnc(Cl)nc23)c1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
3-(2-Chlorothieno[3,2-d]pyrimidin-7-yl)benzoic acid (600 mg, 2.06 mmol) was dissolved in N,N-dimethylformamide (20 mL) and then cyclopropylamine (234 mg, 4.12 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (589 mg, 3.09 mmol), hydroxybenzotriazole (417 mg, 3.09 mmol) and trimethylamine (574 mL, 4.12 mmol) were added. The reaction mixture was stirred at room temperature for a day, diluted with ethyl acetate, and washed with ammonium chloride aqueous solution. The organic layer was dried with magnesium sulfate, filtered with celite, and then concentrated. Purification by chromatography (20% ethyl acetate/hexane) yielded the target compound (580 mg, 85% yield).
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[N:15]2[CH2:20][CH2:19][CH2:18][C@@H:17]([N:21](C)[C:22](=O)O)[CH2:16]2)[N:8]([CH3:26])[C:7]1=[O:27])#[N:2].[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[CH3:26][N:8]1[C:9]2=[N:10][CH:11]=[CH:12][C:13]([N:15]3[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][CH3:22])[CH2:16]3)=[C:14]2[N:6]([CH2:5][C:4]2[CH:28]=[CH:29][CH:30]=[CH:31][C:3]=2[C:1]#[N:2])[C:7]1=[O:27]
Reactant: CN(C(=O)O)[C@@H]1CCCN(c2ccnc3c2n(Cc2ccccc2C#N)c(=O)n3C)C1
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H]1CCCN(c2ccnc3c2n(Cc2ccccc2C#N)c(=O)n3C)C1
Yield: 31.3 %

Procedure:
The specific operation referred to the step (6) described in Example 1 for details. 247.5 mg (R)-1-[1-(2-cyano-benzyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]piperidin-3-yl(methyl)carbamic acid ter.-butyl ester (0.52 mmol) and 2 mL trifluoroacetic acid were charged to afford 80 mg titled product with a yield of 31.3%.