Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:4]([CH3:6])([CH3:5])[CH:3]1[CH2:7][OH:8].CC(C)([O-])C.[K+].[Cl:16][C:17]1[C:18](F)=[CH:19][C:20]([F:30])=[C:21]([CH:29]=1)[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[O:23]>CS(C)=O>[Cl:16][C:17]1[C:18]([O:8][CH2:7][CH:3]2[C:4]([CH3:6])([CH3:5])[C:2]2([CH3:9])[CH3:1])=[CH:19][C:20]([F:30])=[C:21]([CH:29]=1)[C:22]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[O:23]
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: CC1(C)C(CO)C1(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)C(COc2cc(F)c(C(=O)NS(C)(=O)=O)cc2Cl)C1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 9.3 %

Procedure:
To a stirred solution of (2,2,3,3-tetramethylcyclopropyl)methanol (48 mg, 0.37 mmol) in dry DMSO (5 mL) was added potassium t-butoxide (124 mg, 1.11 mmol) at room temperature. After stirring for 30 min, 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (50 mg, 0.20 mmol) was added and the reaction mixture was stirred at room temperature for 16 hrs. The mixture was cooled to 0° C., quenched by hydrochloride acid (1N, 30 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with water (40 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by prep HPLC (20%-50% MeCN in 0.1% formic acid) to afford the title compound as a white solid (7 mg, 10%). LCMS (ESI) Method A: RT=5.28 min, m/z: 268.1 [M-109]+; 1H-NMR (500 MHz, DMSO-d6): δ 8.13 (br s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.21-7.10 (m, 1H), 4.18 (d, J=7.0 Hz, 2H), 3.02 (s, 3H), 1.10 (s, 6H), 1.03 (s, 6H), 0.74 (t, J=7.5 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:29]3[C:30]([CH3:39])=[C:31]4[C:36](=[CH:37][CH:38]=3)[O:35][CH2:34][CH2:33][CH2:32]4)=[C:14]([C:20](C)(C)[O:21][SiH2]C(C)(C)C)[O:15][C:16]2=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40][NH2:41].CCO>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:29]3[C:30]([CH3:39])=[C:31]4[C:36](=[CH:37][CH:38]=3)[O:35][CH2:34][CH2:33][CH2:32]4)=[C:14]([CH2:20][OH:21])[N:41]([CH3:40])[C:16]2=[O:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cc1c(-c2c(C(C)(C)O[SiH2]C(C)(C)C)oc(=O)c3cc(OCc4ccccc4)ccc23)ccc2c1CCCO2
Solvent: CCO
Product: Cc1c(-c2c(CO)n(C)c(=O)c3cc(OCc4ccccc4)ccc23)ccc2c1CCCO2
Temperature: 80 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
The mixture of 7-Benzyloxy-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-(5-methyl-chroman-6-yl)-isochromen-1-one (5.0 g, 9.21 mmol) and CH3NH2/EtOH (10 mL) was stirred at 80° C. for 1 hour. The solvent was removed in vacuo and the resulting mixture was acidified by HCl-EA solution to pH 1-2. The mixture was diluted with water and extracted with EA (3*100 mL) and dried over sodium sulfate and concentrated to dryness. The residue was purified by chromatography column on silica gel to afford title product (3.5 g, 86%).
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:13])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:14](#[N:17])[CH:15]=[CH2:16].N12CCN(CC1)CC2>[OH-].[Na+]>[C:1]([C:5]1[CH:12]=[CH:11][CH:10]=[C:7]2[C:6]=1[O:13][CH2:16][C:15]([C:14]#[N:17])=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC#N
Reactant: CC(C)(C)c1cccc(C=O)c1O
Agent: C1CN2CCN1CC2
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1cccc2c1OCC(C#N)=C2

Procedure:
3-tert-butyl-2-hydroxybenzaldehyde (Aldrich, 4.0 mL, 23.4 mmol), acrylonitrile (7.7 mL, 117 mmol), and 1,4-diazabicyclo[2.2.2]octane (0.66 g, 5.8 mmol) were heated in a microwave Personal Chemistry at 95° C. for 5 hours. Sodium hydroxide (1N, 200 mL) was added and the mixture was extracted twice with ethyl acetate (200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrate under reduced pressure. The residue was chromatographed on silica gel eluting with 0-to-30% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.31 (s, 9H), 4.85 (d, J=1.36 Hz, 2H), 6.97 (t, J=7.63 Hz, 1H), 7.16 (dd, J=7.63, 1.53 Hz, 1H), 7.29 (dd, J=7.80, 1.70 Hz, 1H), 7.58 (s, 1H). MS (DCI) m/z 231.10 (M+NH4)+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:13]([O:15][C:16](=[O:35])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:35])[CH2:17][C:18]1[CH:19]=[C:20]([C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[CH:4]=[O:5])[C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH3:14]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Br
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc([N+](=O)[O-])cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 2-bromo-5-nitro-benzaldehyde and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: Cl.C([O:6][C:7](=[O:17])[C@H:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])(C)(C)C.[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([S:27](Cl)(=[O:29])=[O:28])=[C:22]([CH3:31])[C:21]=1[CH3:32].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([S:27]([NH:9][C@@H:8]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:7]([OH:6])=[O:17])(=[O:28])=[O:29])=[C:22]([CH3:31])[C:21]=1[CH3:32]
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)O)c(C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a solution of 0.5 g of L-phenylalanine t-butyl ester hydrochloride in 4 mL of N,N-dimethylformamide were added 0.67 g of 4-methoxy-2,3,6-trimethylphenylsulfonylchloride and 0.96 mL of N,N-diisopropylethylamine. After stirring for 2 hours at room temperature the reaction mixture was concentrated and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed with aqueous potassium hydrogensulfate (5%), water, aqueous sodium hydrogencarbonate (5%) and brine, dried over magnesium sulfate and concentrated. The residue was dissolved in 16 mL of dichloromethane and 4 mL of trifluoroacetic acid was added. After stirring for 2 h at room temperature the reaction mixture was concentrated. Dichloromethane and aqueous sodium hydrogencarbonate (5%) were added to the residue (the mixture was basic), the aqueous layer separated and washed with dichloromethane. The aqueous layer was made acid (pH 2) using 2 N hydrochloric acid and several times extracted with dichloromethane. The combined dichloromethane layers were washed with brine, dried over magnesium sulfate and concentrated to give 0.65 g of (2S)-2-[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]-3-phenylpropanoic acid. This acid (80 mg) was coupled with deprotected 5a (75 mg) according to the procedure described for 5c to afford compound 55 (55 mg) as a mixture of diastereomers (1:1). 1H-NMR 400 MHz (CD3OD) δ: 1.25-1.67 (6H, m), 1.97 and 1.99 (3H, 2× s), 2.12 and 2.17 (3H, 2× s), 2.45-3.54 (8H, m), 2.49 (3H, s), 3.81 and 3.85 (3H, 2× s), 3.82-3.92 (1H, m), 5.13-5.28 (1H, m), 6.61 (1H, s), 6.84-7.07 (5H, m), 7.17-7.21 (1H, m), 7.50-7.56 (1H, m), 7.65-7.69 (1H, m), 7.76-7.82 (1H, m), 8.30-8.35 (1H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:22][CH3:23])=[C:6]([CH:8]2[C:16](=[O:17])[CH:15]3[CH:10]([C:11]4([CH3:20])[O:18][C:14]3([CH3:19])[CH:13]=[CH:12]4)[C:9]2=[O:21])[CH:7]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[C:27]([F:34])[CH:26]=1.[F-].[Cs+]>COCCOC.ClCCl>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[CH:4][C:5]([CH2:22][CH3:23])=[C:6]([CH:8]3[C:9](=[O:21])[CH:10]4[CH:15]([C:14]5([CH3:19])[O:18][C:11]4([CH3:20])[CH2:12][CH2:13]5)[C:16]3=[O:17])[CH:7]=2)=[C:27]([F:34])[CH:26]=1
Reactant: CCc1ccc(Br)cc1C1C(=O)C2C(C1=O)C1(C)C=CC2(C)O1
Reactant: OB(O)c1ccc(Cl)cc1F
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: COCCOC
Product: CCc1ccc(-c2ccc(Cl)cc2F)cc1C1C(=O)C2C(C1=O)C1(C)CCC2(C)O1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A mixture of (1RS,2SR,6RS,7SR)-4-(5-bromo-2-ethylphenyl)-1,7-dimethyl-10-oxatricyclo[5.2.1.02,6]dec-8-en-3,5-dione (113 mg, 0.3 mmol), 4-chloro-2-fluorophenylboronic acid (103 mg, 0.6 mmol) and cesium fluoride (449 mg, 3.0 mmol) in degassed 1,2-dimethoxyethane (1.5 ml) are stirred under nitrogen at room temperature for 40 minutes. [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (48 mg, 0.06 mmol) is added, followed by a further quantity of 1,2-dimethoxyethane (1 ml) and reaction mixture is heated to 80° C. for 18 hours. The mixture is cooled to room temperature, then diluted with dichloromethane and filtered through a small plug of diatomaceous earth. The filtrate is evaporated and the residue is purified by column chromatography on silica gel, to give (1RS,2SR,6RS,7SR)-4-(4′-chloro-4-ethyl-2′-fluorobiphen-3-yl)-1,7-dimethyl-10-oxatricyclo-[5.2.1.02,6]decane-3,5-dione.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:14][C@@H:15]([C:20]2[S:21][C:22]([C:25]3[C:33]4[C:28](=[N:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:16][C:17](O)=[O:18])=[O:13])[C:7]1=[O:34].CN(C)C=O.[CH:44]1([NH2:47])[CH2:46][CH2:45]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[CH:44]1([NH:47][C:17]([CH2:16][C@@H:15]([NH:14][C:12]([C:8]2[C:7](=[O:34])[N:6]([CH2:5][C:4]3[CH:35]=[CH:36][C:37]([F:38])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][CH:9]=2)=[O:13])[C:20]2[S:21][C:22]([C:25]3[C:33]4[C:28](=[N:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)=[CH:23][CH:24]=2)=[O:18])[CH2:46][CH2:45]1
Reactant: NC1CC1
Reactant: O=C(O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2c[nH]c3ncccc23)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2c[nH]c3ncccc23)s1)NC1CC1
Reaction time: 2 h

Procedure:
(R)-3-{[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-3-[5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiophen-2-yl]-propionic acid (0.040 g, 0.000075 mol;) was dissolved in N,N-Dimethylformamide (3 mL, 0.04 mol;) and Cyclopropylamine (20 uL, 0.0004 mol;) then N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.037 g, 0.000097 mol;) was added. The reaction was allowed to stir for 2 hours and LC-MS showed disappearance of starting material and appearance of product at 1.28 573.87. The reaction was purified by Gilson Preparative HPLC and the pure fractions were concentrated. ES (+) MS m/e=573.87; NMR (400 MHz, DMSO-d6) δ ppm 0.28 (m, 2H), 0.54 (m, 2H), 2.55 (m, 1H), 2.72 (m, 2H), 5.22 (m, 2H), 5.66 (m, 1H), 6.60 (t, 1H, J=8 Hz), 6.96 (d, 1H, J=3 Hz), 7.14-7.21 (m, 3H), 7.38-7.49 (m, 2H), 7.79 (m, 1H), 8.2-8.25 (m, 2H), 8.29 (m, 1H), 8.4 (dd. 1H), 10.22 (d, 1H), 11.95 (s, 1H)
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:21][C:22]([F:52])([C:48]([F:51])([F:50])[F:49])[C:23]([F:47])([F:46])[C:24]([F:45])([F:44])[O:25][C:26]([F:43])([F:42])[C:27]([F:41])([F:40])[O:28][C:29]([F:39])([F:38])[CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Br>>[CH2:1]([O:7][C:8]1[CH:13]=[N:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][O:31][CH2:30][C:29]([O:28][C:27]([F:40])([F:41])[C:26]([F:42])([F:43])[O:25][C:24]([F:44])([F:45])[C:23]([F:46])([F:47])[C:22]([F:21])([F:52])[C:48]([F:51])([F:50])[F:49])([F:39])[F:38])=[CH:18][CH:19]=2)=[N:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(COCCCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CCCCCCOc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-hexyloxy-2-(4-hydroxyphenyl)pyrimidine (8.0 g, 29.4 mmol) and 5-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromopentane (18.6 g, 32 mmol, Example 2). The resulting crude product was isolated and further purified essentially as described in Example 1 (b.p. 210-25° C. at 0.3 torr).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[NH:24][CH2:23][CH2:22][C:21]2[C:16]1=[CH:17][CH:18]=[C:19]1[O:27][CH2:26][O:25][C:20]1=2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:24]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]5[O:27][CH2:26][O:25][C:20]5=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c1ccc1c2OCO1
Product: CC1c2ccc3c(c2CCN1C(=O)c1cc2ncc(Br)cn2n1)OCO3

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Methyl-6,7,8,9-tetrahydro-1,3-dioxa-7-aza-cyclopenta[a]naphthalene to provide the title compound in moderate yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17](=[O:19])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1ccccc1
Reactant: O=C(O)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: O=C(Nc1ccccc1)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 84 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxy-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0.92 mmol) and aniline (93 mg, 1.0 mmol) to give 31 0 mg of the title compound (84%): mp>250° C.; 1H NMR (270 MHz, DMSO-d6) δ12.25 (s, 1H), 10.36 (s, 1H), 7.56 (d, 2H, J=8 Hz), 7.33 (t, 2H, J=8.0 Hz), 7.24 (bs, 1H), 7.22 (bs, 1H), 7.09 (t, 1H, J=8 Hz), 5.32~5.36 (m, 1H), 2.89 (dm, 1H, J=16.8 Hz), 2.58~2.81 (m, 2H), 2.05~2.22 (m, 1H).
Reaction SMILES: B(F)(F)F.CCOCC.[CH3:10][O:11][C:12](=[O:35])[C@H:13]1[O:22][C@@H:17](OC(=O)C)[C@H:16]([O:23][C:24](=[O:26])[CH3:25])[C@@H:15]([O:27][C:28](=[O:30])[CH3:29])[C@@H:14]1[O:31][C:32](=[O:34])[CH3:33].[Cl:36][C:37]([Cl:41])([Cl:40])[CH2:38][OH:39]>ClCCl>[CH3:10][O:11][C:12](=[O:35])[C@H:13]1[O:22][C@H:17]([O:39][CH2:38][C:37]([Cl:41])([Cl:40])[Cl:36])[C@H:16]([O:23][C:24](=[O:26])[CH3:25])[C@@H:15]([O:27][C:28](=[O:30])[CH3:29])[C@@H:14]1[O:31][C:32](=[O:34])[CH3:33]
Reactant: COC(=O)[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: OCC(Cl)(Cl)Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@H]1O[C@H](OCC(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
BF3-Et2O (15 ml) was added dropwise to a cooled solution at 0° C. of 1,2,3,4-tetra-O-acetyl-β-D-glucopyranuronic acid methyl ester (11.23 g, 0.03 mol) and 2,2,2-trichloroethanol (20 ml) in anhydrous dichloromethane (250 ml) under inert atmosphere. The mixture was stirred at room temperature overnight and then washed with 1N HCl (100 ml), water (100 ml) and brine (100 ml). The organic phase was dried over sodium sulphate, filtered and concentrated to dryness. 1-O-trichloroethyl-2,3,4-tri-O-acetyl-α-D-glucopyranuronic acid methyl ester 1 (8.95 g) was obtained after recrystallization of the crude product from ether.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19][C:7]1=2)C.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.ClCCl>[OH:3][CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19][C:7]1=2
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCO)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A chilled (0° C. ) mixture of tert-butyl 6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate in tetrahydrofuran (30 mL) was treated over 1 h with 1 M diisobutylaluminum hydride (19.0 mL, 19.0 mmol) in dichloromethane. After 1.5 h, ice was added and the mixture was allowed to warm to rt. The mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was filtered through celite, dried, and evaporated in vacuo to provide 2.479 g of the title compound, the structure of which is shown in FIG. 6 as (24) (where n=1).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1>CS(C)=O.ClCCl>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]2)=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Temperature: 95 °C

Procedure:
5-Fluoro-2-nitrobenzotrifluoride (400 mg, 1.91 mmol) and trans-4-aminocyclohexanol (220 mg, 1.91 mmol) were dissolved in dimethylsulfoxide (10 mL). The resulting mixture was heated at 95° C. for 3.5 hr. After cooling at room temperature, the mixture was diluted with dichloromethane (15 mL) and washed with water (3×10 mL). The organic phase was collected and dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was re-crystallized from petrol ether. The desired product was then isolated as a yellow solid (490 mg, 84% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([NH:13][CH3:14])[CH2:10][CH:9]1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]#[N:26])[CH2:19][CH2:18]1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[Cl:40])[CH:35]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH:11]([N:13]([CH2:35][C:34]2[CH:37]=[CH:38][C:39]([Cl:40])=[C:32]([Cl:31])[CH:33]=2)[CH3:14])[CH2:10][CH:9]1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]#[N:26])[CH2:19][CH2:18]1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC1CC(C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(Cl)c(Cl)c1)C1CC(C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1
Reaction time: 8 h
Yield: 4.4 %

Procedure:
To a mixture of 2-[4-(1-benzyl-4-methylamino-pyrrolidine-2-carbonyl)-piperazin-1-yl]-benzonitrile (0.1 mmol) and 3,4-dichloro-benzaldehyde (0.15 mmol) in 2 mL of CH2Cl2 stirring at rt, was added NaBH(OAc)3 (0.15 mmol) and NEt3 (0.3 mmol), and then the resulting mixture was stirred overnight. After purification through preparative HPLC, 2.5 mg of 2-(4-{1-benzyl-4-[(3,4-dichloro-benzyl)-methyl-amino]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile was obtained as colorless oil in 4.8% yield.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9](OCC)(=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>CCOCC.C1COCC1>[CH:1]1([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(=O)C1CCCCC1
Temperature: 0 °C
Yield: 86 %

Procedure:
Cyclohexyl magnesium bromide (Aldrich) in ether (2 M, 150 mL) was pumped under vacuum to remove ethyl ether, at rt, the residue obtained was then dissolved in anhydrous THF (100 mL) while cooled with an ice water bath. The solution was then added to a solution of diethyl oxalate (60 g) in THF (150 mL) at -30--40° C. in 10 min. The reaction mixture was warmed to 0° C. for 5 min, and quenched with 10% HCl (100 mL), extracted with ethyl acetate (200 mL), the extract was washed with water (30 mL), brine (50 mL) and dried with sodium sulfate, then filtered. The filtrate was concentrated to give an oil. It was distilled 40-50° C. at 1 mm Hg to remove the starting material and the left over is the product (total of 46 g, 86% yield, purity>90%, it can be distilled at 1 mm Hg, 75-80° C.): 1H NMR δ 1.20-1.40 (m, 8H), 1.62-1.94 (m, 5H), 3.02 (broad s, 1H), 4.30 (q, J=8 Hz, 2H). 13C-NMR δ 13.91, 25.11, 25.58, 27.36, 46.13, 62.07, 161.84, 197.51.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: N#Cc1cc(N)ccc1OCCCN1CCOCC1
Product: Cc1c(C(=O)Nc2ccc(OCCCN3CCOCC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 25.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.74 g) and 5-amino-2-(3-morpholinopropoxy) benzonitrile (0.76 g), the title compound (0.35 g) was obtained, melting point: 155–157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:23]([OH:25])=[O:24])[CH2:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH2:9][N:8]=[C:7]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:6]=2[CH:32]=1.[N+](=[CH2:35])=[N-]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:23]([O:25][CH3:35])=[O:24])[CH2:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH2:9][N:8]=[C:7]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:6]=2[CH:32]=1
Reactant: CCN(CC)CCCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: CCN(CC)CCCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)C(=O)OC

Procedure:
A solution of 7-chloro-2-[[1-carboxy-4-(diethylamino)butylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine in CH2Cl2 (10 ml.) is treated with stirring under N2, with an ethereal solution of diazomethane (5 ml., 0.3 M). After 1/2 hour the solution is concentrated in vacuo giving 7-chloro-2-[[1-(methoxycarbonyl)-4-(diethylamino)-butylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine as an oil, the nmr of which confirmed the structure. Nmr (CDCl3) δ 0.95 (t, 3, CH2CH3) 1.82 (m, 2, CH2CH2CH2); 2.50 (m, 6, CH2CH3 and CH2CH2N), 2.27 (m, z, CCH2CH2), 3.77 (s, 3, OCH3), 4.50 (broad s, z, 3--CH2), between 6.80 and 7.85 (m, 8, arom H's).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16]>>[CH3:16][O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: COCCCCCCCl
Product: COCCCCCCN1CCC(=O)CC1

Procedure:
1-(6-Methoxyhexyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-6-methoxyhexane essentially as described above in Example 38, Scheme C, step a.