Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[BH3-][C:15]#N.[Na+].CC(O)=O>C(#N)C>[CH3:15][N:7]([CH2:8][C:9]([OH:11])=[O:10])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [BH3-]C#N
Reactant: O=C(O)CNc1ccccc1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a solution of N-phenylglycine (5 g, 33 mmol) and formaldehyde (37% aqueous solution, 20 mL) in acetonitrile (100 mL) was added NaBH3CN (6.8 g) and AcOH (2 mL) and the reaction mixture was stirred at room temperature overnight. Volatiles were removed in vacuo, the residue was acidified to pH=3-4 and extracted with CHCl3 several times. The combined organic extracts were dried and concentrated to afford a crude product (5.73 g), which was purified by chromatography on silica gel (EtOAc) to afford the title compound (3.96 g, 73%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[O:7][CH2:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=1)([O-])=O.Cl.[OH-].[NH4+]>O.C(OCC)(=O)C>[C:15]1([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][C:6]3[CH:5]=[C:4]([NH2:1])[CH:23]=[CH:22][CH:21]=3)[N:14]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1cccc(OCc2cccc(-c3ccccc3)n2)c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cccc(OCc2cccc(-c3ccccc3)n2)c1
Yield: 86.9 %

Procedure:
A supension of 6.2 g (0.02 mol) of 6-[(3-nitrophenoxy)methyl]-2-phenylpyridine in a solution of 50.0 g (0.18 mol) of ferrous sulfate heptahydrate and 0.3 ml of concentrated hydrochloric acid in 100 ml of water is heated on a steambath of 90° C. Concentrated ammonium hydroxide is added in 3 increments of 10 ml over a period of 10 minutes. Heating is discontinued and the reaction mixture is allowed to cool over a period of 45 minutes while vigorously stirring. The reaction mixture is diluted with 300 ml of water/300 ml of ethyl acetate and filtered through Celite. The filter cake is extracted once with 300 ml of ethyl acetate, and the combined ethyl acetate solution is concentrated in vacuo to obtain an oil (4.8 g). The oil is chromatographed with ethyl acetate/hexane as eluent. Fractions 8-11 are combined and concentrated to obtain 2.0 g (37%) of an oil, MS (CI) 277 (N+H). The product is used without further purification in subsequent reactions.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:37])[CH2:5][CH2:6][C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([C:27]4[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[S:29][N:28]=4)[CH2:23][CH2:22]3)=[C:15]([Cl:18])[CH:16]=2)[CH2:11][C:10]1=[O:36])=[O:8].[CH2:38](O)C.Cl>O>[ClH:18].[CH2:2]([O:3][C:4](=[O:37])[CH2:5][CH2:6][C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([C:27]4[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[S:29][N:28]=4)[CH2:23][CH2:22]3)=[C:15]([Cl:18])[CH:16]=2)[CH2:11][C:10]1=[O:36])=[O:8])[CH3:38]
Reactant: COC(=O)CCC(=O)N1C(=O)Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc21
Reactant: CCO
Agent: Cl
Solvent: O
Product: CCOC(=O)CCC(=O)N1C(=O)Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc21

Procedure:
The product of Example 5, (611 mg, 1.1 mmol) was mixed with ethanol (27 mL) and concentrated hydrochloric acid (0.5 mL) and the mixture boiled under reflux for 24 h in the temperature range 78-80° C. Distilled water (20 mL) was added to the hot reaction mixture and solids removed during the hot filtration. The filtrate was cooled further and product solids were isolated by filtration, washed with distilled water (20 mL), and dried under vacuum to yield 200 mg (32%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([NH:18][C@H:19]([C:24](O)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[C:27]([O:31][C:32](=[O:46])[C@H:33]([CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)[NH2:34])([CH3:30])([CH3:29])[CH3:28].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:27]([O:31][C:32](=[O:46])[C@H:33]([CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)[NH:34][C:24](=[O:25])[C@H:19]([CH2:20][CH:21]([CH3:22])[CH3:23])[NH:18][CH:9]([P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1cccc2ccccc12
Reactant: CCOP(=O)(OCC)C(CCc1ccccc1)N[C@@H](CC(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(CCc1ccccc1)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc1cccc2ccccc12)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 61 mg of N-(1-diethoxyphosphoryl-3-phenylpropyl) -leucine and 39 mg of 3-(α-naphthyl) -L-alanine tert-butyl ester in 1.0 ml of dichloromethane was cooled to 0° C. Then 26 mg of 1-hydroxybenzotriazole monohydrate and 34 mg of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride was added to the solution which was stirred at 0° C. for 1 hour and then at room temperature for 3 hours. The reaction mixture was diluted with 15 ml of dichloromethane, and the diluted solution was washed with 15 ml of a saturated aqueous solution of sodium bicarbonate and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel chromatography (hexane: ethyl acetate=1:1) to yield the title compound as two mixtures each of which are composed of two stereoisomers (42 mg of a/b mixture, 35 mg of c/d/mixture). (iv) N-[N-(3-phenylphosphonopropyl)leucyl]-3-(α-naphthyl)-L-alanine
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13](Cl)(=[O:20])[CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:13](=[O:20])[CH2:14][CH2:15][CH2:16][C:17]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[O:18])=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: O=C(Cl)CCCC(=O)Cl
Product: CCOC(=O)c1ccc(OC(=O)CCCC(=O)Oc2ccc(C(=O)OCC)cc2)cc1

Procedure:
A similar procedure to Example 1 is carried out by using 16.6 g of ethyl p-hydroxybenzoate and 8.5 g of glutaric acid dichloride to yield di(p-ethyloxycarbonylphenyl)glutarate, m.p. 81°-82° C., as white crystals.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:1]([O:9][C:21]([C:20]1[CH:19]=[CH:18][C:17]([C:14]2[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=2)=[CH:25][CH:24]=1)=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Yield: 87.5 %

Procedure:
Fifteen grams of n-octanol, 7.5 g of 4-(4'-hydroxyphenyl)benzoic acid and 7.0 g of p-toluenesulfonic acid were dissolved with 100 ml of toluene in a three necked flask with a dehydration apparatus, and the mixture was refluxed for 15 hours. Water was added to the mixture to separate a toluene layer. Ten grams of 4-(4'-octyloxycarbonylphenyl)phenol (AB) were obtained by removing the toluene layer under reduced pressure followed concentration. (s)-4-(1-chloro-2-methylpropylcarbonyloxy)benzoic acid dispersed in 20 ml of carbon tetrachloride was reacted with 5 ml of thionyl chloride by refluxing for 3 hours. After removing the solvent (s)-4-(1-chloro-2-methylpropylcarbonyloxy)benzoic chloride (AC) was obtained. 1.5 g of (AC) was dissolved with mixed solvent of 80 ml of carbon tetrachloride and 10 ml of pyridine, and then 1.7 g of (AB) was added to the mixed solution with cooling and the mixture was allowed to stand overnight to obtain crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8].N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25].Cl>ClCCl>[C:24]([O:17][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:16][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8])(=[O:26])[CH3:25]
Reactant: Cc1ccc(C(=O)c2cc(Br)ccc2O)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Br)cc1C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16.75 h

Procedure:
To a yellow solution of 229 mg (0.8 mmol) of 5-bromo-2-hydroxy-4′-methylbenzophenone (Compound K) in 15 mL of dichloromethane (under a blanket of argon) was added 0.07 mL (69 mg, 0.9 mmol) of pyridine followed by 0.07 mL (74 mg, 0.9 mmol) of acetyl chloride. The resultant reaction mixture was stirred at ambient temperature overnight (16.75 hours), poured into 10% HCl (aq.) solution and extracted with ethyl acetate. The layers were separated and the aqueous phase was washed with ethyl acetate. The organic phases were combined and then sequentially washed with sat. NaHCO3 (aq.) solution, water and brine, dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. Purification by flash chromatography (silica, 20% ethyl acetate in hexane) gave the title compound as a clear, colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[O:16][CH3:17].C(O[C:27](=[NH:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])C.C(O)(=O)C>C(O)C>[NH2:34]/[C:27](/[N:6]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[O:16][CH3:17])[CH2:5][C:4]1[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:3]=1[O:2][CH3:1])=[CH:28]\[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: COc1ccc(CNCc2ccc(OC)cc2OC)c(OC)c1
Reactant: CCOC(=N)CC(=O)OCC
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)/C=C(\N)N(Cc1ccc(OC)cc1OC)Cc1ccc(OC)cc1OC
Yield: 156.7 %

Procedure:
A mixture of bis(2,4-dimethoxybenzyl)amine (8 g), ethyl 3-ethoxy-3-iminopropanoate (8.02 g), acetic acid (1.44 mL) and ethanol (420 mL) was refluxed overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (17 g).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6].CN([P+](Br)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:74][C:75]1([C:81](O)=[O:82])[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]1>ClCCl>[NH2:74][C:75]1([C:81]([NH:41][C@@H:40]([CH:42]([CH3:44])[CH3:43])[C:39]([N:38]([C@@H:33]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([N:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:6])[CH3:46])=[O:45])=[O:82])[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: NC1(C(=O)O)CCCCC1
Agent: CN(C)[P+](Br)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C1(N)CCCCC1)C(C)C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
To a solution of #50 (120 mg, 0.18 mmol, 1 eq.), Brop (84 mg, 0.21 mmol, 1.2 eq.) and diisopropylethylamine (0.1 mL, 0.54 mmol, 3 eq.) in dichloromethane (15 mL, 0.009 M) at 0° C. was added 1-aminocyclohexanecarboxylic acid (31 mg, 0.21 mmol, 1.2 eq.). After 2 hours, the mixture was quenched with water and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane) to give #52 (50 mg, 35%). Rf 0.6 (10% methanol in dichloromethane). LC-MS (Protocol K): m/z 783.79 [M+H+]; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [8.64 (br d, J=8 Hz) and 8.87 (br d, J=9 Hz), total 1H], 8.18-8.28 (m, 1H), [7.77 (d, J=3.5 Hz) and 7.80 (d, J=3.3 Hz), total 1H], [7.63 (d, J=3.3 Hz) and 7.66 (d, J=3.3 Hz), total 1H], 7.12-7.31 (m, 5H), 5.35-5.43 and 5.49-5.57 (2 m, total 1H), [4.51 (dd, J=9, 8 Hz), and 4.61 (dd, J=9, 7 Hz), total 1H], 3.16, 3.19, 3.21 and 3.25 (4 s, total 6H), 2.93 and 3.02 (2 br s, total 3H), [1.05 (d, J=6.8 Hz) and 1.10 (d, J=6.8 Hz), total 3H].
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][C:16]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[CH:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[F:30][C:31]([F:36])([F:35])[C:32]([CH3:34])=[O:33]>O1CCCC1>[F:30][C:31]([F:36])([F:35])[C:32]([OH:33])([CH3:34])[C:29]#[C:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([C:16]2[CH:15]=[CH:14][N:13]=[CH:18][CH:17]=2)(=[O:20])=[O:21])=[CH:23][CH:24]=1
Reactant: C#Cc1ccc(S(=O)(=O)c2ccncc2)cc1
Reactant: CC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)(C#Cc1ccc(S(=O)(=O)c2ccncc2)cc1)C(F)(F)F
Temperature: -20 °C
Reaction time: 0.42 h
Yield: 49.4 %

Procedure:
To a solution of diisopropylamine (0.37 mL, 2.66 mmol) in tetrahydrofuran (11 mL) at -20° C. was added n-butyllithium (0.9 mL of 2.5M solution in hexanes, 2.25 mmol) and the resulting solution was stirred for 25 minutes at -20° C. before being cooled to -78° C. To this was added a solution of 4-(4-pyridylsulfonyl)phenylacetylene (0.5 g, 2.05 mmol) in tetrahydrofuran (3 mL) over a five minute period. The mixture was stirred for an additional 15 minutes at -78° C. To this was added 1,1,1-trifluoroacetone (0.20 mL, 2.25 mmol) in one portion. After stirring the mixture at -78° C. for 20 minutes, it was quenched with water, warmed to ambient temperature and the pH adjusted to 7.0 with saturated aqueous NH4Cl . The solution was evaporated and the resulting residue was partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed (brine), dried and evaporated. The resulting brown oil was purified by chromatography, with ethyl acetate:dichloromethane as the eluent (1:5), to give the title compound as a white solid (0.36 g, 50%); mp 122°-125° C.; NMR (CDCl3): 1.73 (s,3, CH3), 3.37 (s,1, OH), 7.61 (d,2, J=8.2, At), 7.76 (d,2, J=5.1, Ar), 7.93 (d,2, J=4); MS: m/z=356(M+ 1). Analysis for C16H12F3NO3S: Calculated: C, 54.08; H, 3.40; N, 3.94; Found: C, 53.99; H, 3.41; N, 3.75.
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:18][CH3:19])[C:16]=1[OH:17])[CH:12]=O.S([O-])([O-])(=O)=O.O[NH3+:26].O[NH3+].ClC1C2C(=CC=CC=2)C=CC=1>ClCCl>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:18][CH3:19])[C:16]=1[OH:17])[C:12]#[N:26]
Reactant: [NH3+]O
Reactant: COc1cc(C=O)cc(Br)c1O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Clc1cccc2ccccc12
Product: COc1cc(C#N)cc(Br)c1O
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
With stirring (20 rpm), a turbine dryer is charged at room temperature with 1280 parts by weight of anhydrous sodium sulfate, 462 parts by weight of 3-bromo-4-hydroxy-5-methoxybenzaldehyde, 172 parts by weight of hydroxylammonium sulfate and 298 parts by weight of 1-chloronaphthalin. Following evacuation to 70 mbar, the mixture is heated to 130° C. and kept at this temperature for 31/2 hours. The reaction mixture is then cooled to 30° C. and nitrogen is introduced until atmospheric pressure is reached. After 2650 parts by weight of dichloromethane are added, the suspension is kept for 20 min at room temperature while further stirred and then filtered. The filter cake is extracted three times each with 2000 parts by weight of dichloromethane. The solvent extracts are combined with the first filtrate and evaporated to 1/3 of their volume. The solution of the raw product in dichloromethane is subjected to column chromatography using 1400 parts by weight of silica gel 60 [70-230 mesh (Merck)] and 26500 parts by weight of dichloromethane as eluent. After a portion corresponding to the dead volume of the column is first discarded, the next 17000 parts by weight are collected in one fraction and evaporated to dryness. The residue is freed from traces of adsorbed 1-chloronaphthalin at 80° C. in the vacuum. 334.5 parts by weight of 3-bromo-4-hydroxy-5-methoxybenzonitrile are obtained with a purity of over 98% (TLC) and a melting point of 144°-145° C.
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([NH2:16])=[O:15])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH2:4]1.N1C=CC=CC=1.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:31]([O:30][C:28]([O:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([NH2:16])=[O:15])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH2:4]1)=[O:29])[CH3:32]
Reactant: CCOC(=O)Cl
Reactant: NC(=O)N1c2ccccc2CC(=NO)c2ccccc21
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)ON=C1Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 0.2 g (0.74 mmol) of 10,11-dihydro-10-hydroxyimino-5H-dibenz[b,f]azepine-5-carboxamide and 0.01 g (0.08 mmol) of 4-dimethylaminopyridine in 10 mL of dichloromethane and 0.29 g (3.7 mmol) of pyridine was added 0.28 g (2.6 mmol) of ethyl chloroformate dropwise. The resulting mixture was stirred at room temperature for 2 hours whereupon it was extracted with 20 mL of 1M aqueous HCl and a saturated solution of NaHCO3, then dried by sodium sulphate and filtered. The solvent was removed by evaporation under reduced pressure and the residue was crystallised from a mixture of dichloromethane and ethyl acetate to give white crystals of m.p. 188.9°-190° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:21]([NH2:23])=[O:22].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:31](C)=O.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:31])[CH2:17][CH2:16]3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:21]([NH2:23])=[O:22]
Reactant: NC(=O)c1cc2c(C3CCNCC3)cccc2n1Cc1cccc(F)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN1CCC(c2cccc3c2cc(C(N)=O)n3Cc2cccc(F)c2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(3-Fluoro-benzyl)-4-piperidin-4-yl-1H-indole-2-carboxylic acid amide (50 mg, 0.14 mmol) in CH2Cl2 (5 ml) were added formaldehyde (20 μl, 0.24 mmol, 37% in H2O solution) and NaBH(OAc)3 (74 mg, 0.35 mmol). After stirring at room temperature for 4 hours, the reaction mixture was added to a saturated solution of sodium bicarbonate, followed by a mixture of CH2Cl2/H2O. The organic fraction was separated, washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo to give 1-(3-Fluoro-benzyl)-4-(1-methyl-piperidin-4-yl)-1H-indole-2-carboxylic acid amide as a brown oil. This oil was dissolved in 4 ml ethanol, and 2 M ethanolic hydrochloric acid solution (1 ml) was added. The reaction mixture is heated at 100° C. for 20 minutes, then cooled to room temperature, and 14 mg of 1-(3-Fluoro-benzyl)-4-(1-methyl-piperidin-4-yl)-1H-indole-2-carboxylic acid amide hydrochloride salt was collected. MS: 366 (M+H)+.
Reaction SMILES: BrBr.[OH-:3].[Na+].[Cl:5][C:6]1[C:11]([CH3:12])=[C:10]([F:13])[CH:9]=[CH:8][C:7]=1[C:14](=[O:16])C>O.O1CCOCC1>[Cl:5][C:6]1[C:11]([CH3:12])=[C:10]([F:13])[CH:9]=[CH:8][C:7]=1[C:14]([OH:16])=[O:3]
Reactant: CC(=O)c1ccc(F)c(C)c1Cl
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(F)ccc(C(=O)O)c1Cl
Temperature: 10 °C
Reaction time: 2 h

Procedure:
Bromine (7.61 mL, 148 mmol) was added dropwise to sodium hydroxide (19.70 g, 492 mmol) dissolved in Water (80 mL) maintaining temperature<10° C. 1-(2-chloro-4-fluoro-3-methylphenyl)ethanone (I73) (9.19 g, 49.2 mmol) dissolved in 1,4-dioxane (80 mL) was added dropwise at 0° C. and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with chloroform (2×20 mL) and the aqueous phase acidified to pH1 with concentrated hydrochloric acid. The resulting precipitate was filtered, washed with water, a little diethyl ether (Note: product has some ether solubility) and dried to afford product in 8.89 g. This was recrystalised from toluene to afford product in 6.25 g as fine white needles.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH2:9][C@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1>C(O)(C)C>[Br:8][C:5]1[CH:4]=[N:3][C:2]([N:12]2[CH2:13][CH2:14][C@H:10]([NH2:9])[CH2:11]2)=[N:7][CH:6]=1
Reactant: Clc1ncc(Br)cn1
Reactant: N[C@H]1CCNC1
Solvent: CC(C)O
Product: N[C@H]1CCN(c2ncc(Br)cn2)C1
Reaction time: 4 h

Procedure:
Combine 2-chloro-5-bromopyrimidine (20.0 g, 1.0 eq) and isopropanol (200 mL). Add (S)-3-aminopyrrolidine (8.91 g, 1.0 eq) dropwise over about 30 minutes. Add isopropanol (10 mL) and heat to 50° C.-60′. After 4 hours, cool to 20° C.-25° C. over about 1 hour, stir for about 1 hour, and then collect the solid by filtration. Rinse the solid with isopropanol (2×25 mL) and dry under vacuum at about 40° C. to give (S)-1-(5-bromopyrimidin-2-yl)-pyrrolidine-3-amine as its hydrochloride salt.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14]1[CH:23]=[CH:22][C:17](/[CH:18]=[CH:19]/[CH:20]=[O:21])=[CH:16][CH:15]=1.[N:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25]>ClCCl>[OH:25][N:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20](=[O:21])/[CH:19]=[CH:18]/[C:17]1[CH:22]=[CH:23][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: O=Nc1ccccc1
Reactant: COc1ccc(/C=C/C=O)cc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(/C=C/C(=O)N(O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (7.5 mg, 0.05 mmol) was added under argon to a solution of (E)-4-methoxycinnamaldehyde (162 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (18.2 mg, 0.05 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH3:44])[C:18](=[O:43])[C:19]3[CH:29]=[C:28]([CH2:30][CH2:31][O:32][C:33]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:36]=[CH:35][CH:34]=4)[CH:27]=[N:26][C:20]=3[N:21]([CH2:24][CH3:25])[C:22]=2[N:23]=1>C(Cl)Cl>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH3:44])[C:18](=[O:43])[C:19]3[CH:29]=[C:28]([CH2:30][CH2:31][O:32][C:33]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N+:36]([O-:9])=[CH:35][CH:34]=4)[CH:27]=[N:26][C:20]=3[N:21]([CH2:24][CH3:25])[C:22]=2[N:23]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCN1c2ncc(CCOc3ccnc4ccccc34)cc2C(=O)N(C)c2ccc(C)nc21
Solvent: ClCCl
Product: CCN1c2ncc(CCOc3cc[n+]([O-])c4ccccc34)cc2C(=O)N(C)c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.6 %

Procedure:
Solid mCPBA (80-85%, m-chloroperbenzoic acid) (60 mg, 0.28 mmol) was added to a solution of 5,11-dihydro-2,5-dimethyl-11-ethyl-8-{2-(4-quinolinyloxy)ethyl}-6H-dipyrido[3,2-b:2′,3′-e] [1,4]diazepin-6-one (55 mg, 0.13 mmol) in CH2Cl2 (1.3 mL) at room temperature. The mixture was stirred at room temperature for 2.5 h then diluted with CH2Cl2. The resulting solution was successively washed with aqueous 10% Na2S2O3, aqueous saturated NaHCO3 and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (MeOH/EtOAc,2% to 5%) to give the title compound (59 mg, 99% yield) as a white solid: MS (ES) m/z 456 (MH)+.