Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15](C(OCC4C5C=CC=CC=5C5C4=CC=CC=5)=O)[CH2:14][CH2:13]3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.N1CCCCC1>C(Cl)Cl>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC(c2csc(-c3ccccc3)n2)CC1
Solvent: CO
Solvent: ClCCl
Solvent: C1CCNCC1
Product: c1ccc(-c2nc(C3CCNCC3)cs2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a stirred solution of (9H-fluoren-9-yl)methyl 4-(2-phenylthiazol-4-yl)piperidine-1-carboxylate (2 g, 4.29 mmol) in CH2Cl2:MeOH (15:5 mL) was added piperidine (5 mL). This reaction mixture was stirred at RT for 8 h. The reaction mixture was concentrated under reduced pressure and the crude material was chromatographed over silica gel eluting with a gradient (0-10% MeOH:CH2Cl2) to afford 2-phenyl-4-(piperidin-4-yl)thiazole (1 g, 96%) as an off white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11](I)=[CH:12][N:13]=[C:7]2[CH:6]=1)=[O:4].C([O-])([O-])=O.[Na+:19].[Na+].[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Na+:19].[Cl:21][C:22]1[CH:27]=[C:26]([C:11]2[N:8]3[CH:9]=[CH:10][C:5]([C:3]([O-:2])=[O:4])=[CH:6][C:7]3=[N:13][CH:12]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccn2c(I)cnc2c1
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C([O-])c1ccn2c(-c3cccc(Cl)c3)cnc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 44.7 %

Procedure:
A mixture of 3-iodo-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (230 mg, 0.76 mmol), Pd(PPh3)4 (44 mg, 0.038 mmol), Na2CO3 (161 mg, 1.52 mmol) and 3-chlorophenylboronic acid (131 mg, 0.84 mmol) was heated at reflux for 1 hour. The mixture was then allowed to cool and concentrated in vacuo. The residue was dissolved in MeOH (25 mL) and water (25 mL) and 50% NaOH (5 mL) was added. The mixture was allowed to stir at room temperature for 15 hours then concentrated in vacuo. The mixture was triturated with ethyl acetate (20 mL) and the resulting solid was filtered to afford 3-(3-chloro-phenyl)-imidazo[1,2-a]pyridine-7-carboxylic acid sodium salt (100 mg, 58%) The mixture was dissolved in DMF (2 mL) and EDC (100 mg, 0.52 mmol) and HOBt (70 mg, 0.52 mmol) were added. The mixture was allowed to stir for 10 minutes and 4-aminomethyltetrahydropyran (0.075 mL, 0.52 mmol) was added. The mixture was stirred for 2 hours then poured into water (15 mL) and the product extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-(3-chlorophenyl)-imidazo[1,2-a]pyridine-7-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide. 1H NMR (DMSO-d6) δ 8.75 (1H), 8.65 (1H), 8.25 (1H), 8.00 (1H), 7.80 (1H), 7.70 (1H), 7.60 (1H), 7.52 (1H), 7.41 (1H), 3.85 (2H), 3.32 (2H), 3.20 (2H), 1.83 (1H), 1.60 (2H), 1.22 (2H); m/z (M+H)=370.05.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)(=O)=O.O[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH:21]([C:20]1[CH:23]=[CH:24][C:17]([O:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:18][CH:19]=1)=[O:22]
Reactant: CS(=O)(=O)OCCc1ccc(C#N)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#Cc1ccc(CCOc2ccc(C=O)cc2)cc1
Yield: 16.8 %

Procedure:
8.55 g (38 mmole) 4-cyanophenethyl methanesulfonate, 4.64 g (38 mmole) p-hydroxybenzaldehyde and 18.7 g (57 mmole) cesium carbonate in 150 ml acetonitrile was refluxed over night. The salt was filtered off and the solvent evaporated in vacuo. The residue was treated with 2 M sodium hydroxide and dichloromethane. The organic phase was dried and evaporated in vacuo. Purification by chromatography on silica gel using dichloromethane as eluent gave 1.6 g (yield 17%) of 4-[2-(4-formylphenoxy)ethyl]benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:8])=[CH:5][C:6]=1C.[C:9](Cl)(=[O:11])[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:18](Cl)=O>>[Cl:8][C:4]1[S:3][C:2]([Cl:1])=[C:6]([CH3:5])[C:10]=1[C:9]([CH3:18])=[O:11]
Reactant: Cc1cc(Cl)sc1Cl
Reactant: O=C(Cl)Cl
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1c(Cl)sc(Cl)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 56.6 g. (0.315 mole) 2,5-dichloro-3-methylthiophene [prepared by the method of Campaigne and LeSeur, J. Am. Chem. Soc., 71, 333 (1949)] and 43.6 ml. (0.614 mole) of acetyl chloride in 165 ml. of petroleum ether under a nitrogen atmosphere was added 48 g. (0.36 mole) of anhydrous aluminum chloride. The mixture was stirred overnight at room temperature, then poured onto ice and extracted with ethyl ether. The combined organic layers were dried, evaporated to dryness and distilled at reduced pressure to yield 49 g. (74%) of the dichloroketone, boiling at 74°-78° C. (0.1 mm.); 1H--NMR (CDCl3), ppm. (δ): 2.6 (s, CH3), 2.25 (s, CH3CO).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:21])=[CH:5][C:6]([OH:20])=[C:7]2[C:12](=[O:13])[CH:11]=[C:10]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:9][C:8]=12.[CH2:22]=O.[OH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CO>[OH:20][C:6]1[C:5]([CH2:22][N:28]2[CH2:29][CH2:30][CH:25]([OH:24])[CH2:26][CH2:27]2)=[C:4]([OH:21])[C:3]([O:2][CH3:1])=[C:8]2[C:7]=1[C:12](=[O:13])[CH:11]=[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:9]2
Reactant: C=O
Reactant: COc1c(O)cc(O)c2c(=O)cc(-c3ccccc3)oc12
Reactant: OC1CCNCC1
Solvent: CO
Product: COc1c(O)c(CN2CCC(O)CC2)c(O)c2c(=O)cc(-c3ccccc3)oc12
Temperature: 50 °C
Reaction time: 4 h

Procedure:
The mixture of Wogonin (28.4 g), methanol (350 ml), 37% formaldehyde solution (8.04 ml), 4-hydroxy-piperidine (10.2 g) was stirred under for 4 hours at 50° C., then precipitates were removed by filtration and washed several times with methanol, after drying under reduced pressure at 65° C. to get the product as orange red solid 38.5 g of purity 99.4%. MS: (API-ES) m/z 398.5 [M+H]+420.5 [M+Na]+; 1H NMR (DMSO-d6, 400 MHz): δ 8.05˜8.06 (m, 2H, Ar-2′,6′-H), 7.60˜7.61 (m, 3H, Ar-3′,4′,5′-H), 6.90 (s, 1H, 3-H), 3.94 (s, 2H, CH2), 3.83 (s, 3H, 8-OCH3), 3.65-3.67 (m, 1H, CH), 2.62, 2.98 (m, 4H, CH2), 1.51, 1.83 (m, 4H, CH2).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([N:11]1[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([SH:19])[CH:13]=[N:12]1)([CH3:10])([CH3:9])[CH3:8].[F:20][C:21]([F:39])([O:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH:34]([CH2:37]Br)[CH2:33][CH2:32]1)[CH:22]([F:28])[O:23][C:24]([F:27])([F:26])[F:25]>CN(C)C=O.CCOCC>[C:7]([N:11]1[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([S:19][CH2:37][CH:34]2[CH2:35][CH2:36][CH:31]([CH2:30][O:29][C:21]([F:20])([F:39])[CH:22]([F:28])[O:23][C:24]([F:26])([F:27])[F:25])[CH2:32][CH2:33]2)[CH:13]=[N:12]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: FC(OC(F)(F)F)C(F)(F)OCC1CCC(CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)n1ncc(SCC2CCC(COC(F)(F)C(F)OC(F)(F)F)CC2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
To a suspension of 0.47 g of potassium carbonate in 10 ml of dimethylformamide, 0.75 g of 2-tert.butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 1.3 g of 4-(1,1,2-trifluoro-2-trifluoromethoxyethoxy)methyl-cyclohexylmethyl-bromide. Were added it was stirred for 2 hours at room temperature, it was diluted with ether, then it was washed with diluted HCl and brine; it was anhydrified, the solvent was evaporated and the obtained rough product was eluted by silica gel chromatography with hexane/ethyl acetate 98/2. 0.65 g of a mixture of CIS/trans (15/85) product was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Br[CH:8]1[CH2:11][O:10][CH2:9]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:8]2[CH2:11][O:10][CH2:9]2)[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: BrC1COC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1cnn(C2COC2)c1
Temperature: 130 °C

Procedure:
4-Bromo-1H-pyrazole (1.53 g, 10.7 mmol) is dissolved in anhydrous dimethylformamide (15 mL). 3-Bromooxetane (2.0 g, 14.6 mmol) and caesium carbonate (4.7 g, 14 mmol) are successively added thereto. The reaction mixture is heated for 8 hours at 130° C. in a sealed flask. At the end of the reaction, the solvent is evaporated off in vacuo and the residue is purified by chromatography over silica gel using dichloromethane containing diethylamine and methanol as eluants to yield the expected compound.
Reaction SMILES: ClC=C(Cl)Cl.[CH3:6][C:7]([CH2:9][CH2:10][C:11]([CH3:13])=[CH2:12])=[CH2:8].[Cl:14][C:15]([Cl:21])=[CH:16][CH2:17][C:18]([CH3:20])=[CH2:19]>>[CH3:6][C:7](=[CH:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH3:8].[Cl:14][C:15]([Cl:21])=[CH:16][CH:17]=[C:18]([CH3:20])[CH3:19]
Reactant: C=C(C)CC=C(Cl)Cl
Reactant: C=C(C)CCC(=C)C
Solvent: ClC=C(Cl)Cl
Product: CC(C)=CC=C(C)C
Product: CC(C)=CC=C(Cl)Cl

Procedure:
A portion of the effluent from Example 6 was taken, containing 800 m mole trichloroethylene, 35 m mole 2,5-dimethylhexa-1,5-diene and 91 m mole 1,1-dichloro-4-methylpenta-1,4-diene. This mixture was subjected to fractional distillation, and about 600 m mole of trichloroethylene were removed slowly at ≯ 87° C. The residue was treated with p-toluene sulphonic acid (1% by weight) in an autoclave at 150° for 4 hours under autogeneous pressure. Essentially complete isomerisation of the dienes to their conjugated isomers was effected by this treatment. The mixture was fractionally distilled to yield 2,5-dimethylhexa-2,4-diene (28 m mole) and 1,1-dichloro-4-methylpenta-1,3-diene (80 m mole).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[N:7]=[C:8]([C:13]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]2=O)=[O:14])[NH:9][C:10]=1[CH2:11][CH3:12].C([BH3-])#N.[Na+].C(O)(=O)C>O1CCCC1>[C:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][C@@H:16]([NH:15][C:13]([C:8]2[NH:9][C:10]([CH2:11][CH3:12])=[C:6]([Cl:5])[N:7]=2)=[O:14])[C@H:21]([NH:4][CH:1]2[CH2:3][CH2:2]2)[CH2:20]1)=[O:23])([CH3:28])([CH3:27])[CH3:26].[Cl:5][C:6]1[N:7]=[C:8]([C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:18][C@H:17]2[NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:14])[NH:9][C:10]=1[CH2:11][CH3:12]
Reactant: CCc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2=O)nc1Cl
Reactant: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC2CC2)nc1Cl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC2CC2)nc1Cl
Temperature: 50 °C
Reaction time: 15 h
Yield: 15 %

Procedure:
Cyclopropylamine (249 μL, 3.59 mmol) was added to a solution of tert-butyl 4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-oxopiperidine-1-carboxylate obtained in Example (201c) (190 mg, 0.512 mmol) in tetrahydrofuran (6 mL), and the mixture was heated under reflux at 50° C. for four hours. The reaction solution was concentrated under reduced pressure, and then tetrahydrofuran (3 mL) and methanol (3 mL) were added. Cyclopropylamine (71.0 μL, 0.102 mmol), sodium cyanoborohydride (97.0 mg, 1.54 mmol) and acetic acid (293 μL, 5.12 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with brine, and dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography and preparative TLC (eluent: chloroform:methanol=10:1 v/v) to obtain 34 mg of the cis isomer of the title compound (16%) as a pale yellow oily substance and 32 mg of the trans isomer of the title compound (15%) as a pale yellow oily substance.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[NH:6][C:7](=[O:19])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH:23]([CH2:27][OH:28])[CH2:22]1>>[CH2:13]([N:10]1[C:9]2[N:15]=[CH:16][CH:17]=[CH:18][C:8]=2[C:7](=[O:19])[NH:6][C:5]2[C:4]([CH3:20])=[CH:3][C:2]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([CH2:27][OH:28])[CH2:22]3)=[N:12][C:11]1=2)[CH3:14]
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(Cl)nc21
Reactant: OCC1CCCNC1
Product: CCN1c2ncccc2C(=O)Nc2c(C)cc(N3CCCC(CO)C3)nc21

Procedure:
The title compound, m.p. 194°-197° C., was synthesized from 2-chloro-5,11-dihydro-11l-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 3-piperidinemethanol using procedures analogous to those described above, except that the mixture was heated at 170°-180° C. for 2.5 hrs, and the product was crystallized from ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[Cl:22][C:23]1[CH:34]=[CH:33][C:26]([CH2:27][CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][CH:28]2[CH2:32][CH2:31][N:30]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[O:15])[CH2:29]2)=[CH:33][CH:34]=1
Reactant: Clc1ccc(CC2CCNC2)cc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: O=C(O)C(=O)O
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(Cc3ccc(Cl)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(4-chlorobenzyl)pyrrolidine oxalate (17.1 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (8.1 mg). Calcd for C22H21ClN2O2: 380.1292, found 380.1295.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19]3=[C:20]([CH2:22][O:23][CH2:24][CH2:25][N:18]3[C@H:17]3[CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C@@H:16]23)[CH:21]=1>>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:3]([CH2:4][NH:12][C:13]2[CH:14]=[C:15]3[C:19]4=[C:20]([CH2:22][O:23][CH2:24][CH2:25][N:18]4[C@H:17]4[CH2:26][CH2:27][NH:28][CH2:29][C@@H:16]34)[CH:21]=2)=[C:2]([CH3:1])[CH:9]=1
Reactant: COc1ccc(C=O)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Product: COc1ccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)c(C)c1

Procedure:
Using 2-methyl-4-methoxybenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 137. 1H NMR (CDCl3) δ: 7.21 (d, 1H, J=8.5 Hz), 6.75-6.68 (m, 2H), 6.59 (broad s, 1H), 6.43 (broad s, 1H), 4.58 (ABq, 2H), 4.23-4.16 (m, 1H), 4.16 (s, 2H), 3.78 (s, 3H), 3.68 (app t, 1H), 3.50-3.40 (m, 1H), 3.37-3.15 (m, 5H), 2.70-2.50 (m, 2H), 2.30 (s, 3H), 2.23-2.10 (m, 2H). LRMS (ES)+: 380.4 (M+)+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([I:30])[CH:22]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]2[CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[O:26])=[C:23]([I:30])[CH:22]=1
Reactant: O=C(O)c1ccc(F)cc1I
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2I)[C@@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (0.4 g, 1.549 mmol), 4-fluoro-2-iodobenzoic acid (0.374 g, 1.4 mmol), DIPEA (0.49 mL, 2.8 mmol) and HATU (0.53 g, 1.4 mmol) in DMF (10 mL) was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate and washed with satd. aq. NaHCO3 and brine successively. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/hex) to afford the title compound. MS (ESI) 507 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([O:19][C:20](=[O:22])[CH3:21])[CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:23]([O-])([OH:25])=[O:24]>CC(O)=O.OS(O)(=O)=O.O.[N+]([O-])([O-])=O.[Cu+2].O.O.O.O.[N+]([O-])([O-])=O.[Cu+2].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([O:19][C:20](=[O:22])[CH3:21])[CH2:16]2)=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)OC1CCc2ccc(OCc3ccccc3)cc2C1
Agent: [Cu+2]
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OC1CCc2cc([N+](=O)[O-])c(OCc3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of acetic acid 7-benzyloxy-1,2,3,4-tetrahydronaphthalen-2-yl ester (5.77 g, 19.5 mmol) in AcOH (30 mL) is added a solution of 90% HNO3 (3.0 mL, ca. 64 mmol) in AcOH (5 mL), copper(II) nitrate hemipentahydrate (3.71 g, 19.8 mmol) and conc. H2SO4 (3 drops) at room temperature. The mixture is stirred at room temperature for 1.5 h and partitioned between EtOAc and aq. KOH. The organic layer is dried over MgSO4, concentrated and chromatographed to afford acetic acid 7-benzyloxy-6-nitro-1,2,3,4-tetrahydronaphthalen-2-yl ester with some impurities. Crystallization from DCM-hexanes yields a precipitate, which is quickly rinsed with Et2O-hexanes to afford pure acetic acid 7-benzyloxy-6-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl ester: 1H NMR (CDCl3) δ 7.66 (s, 1H), 7.48-7.29 (m, 5H), 6.80 (s, 1H), 5.22-5.15 (m, 1H), 5.19 (s, 2H), 3.10 (dd, J=16.0, 8.0 Hz, 1H), 2.95-2.72 (m, 3H), 2.05 (s, 3H), 2.05-1.95 (m, 2H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C@H:11]2[C@@H:17]([CH2:18][NH:19][C:20](=[O:24])[CH2:21][O:22][CH3:23])[O:16][CH2:15][CH2:14][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10].[CH3:32]I.O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C@H:11]2[C@@H:17]([CH2:18][N:19]([C:20](=[O:24])[CH2:21][O:22][CH3:23])[CH3:32])[O:16][CH2:15][CH2:14][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CI
Reactant: COCC(=O)NC[C@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(=O)N(C)C[C@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.8 %

Procedure:
Sodium hydride (60% in oil, 16 mg) was added to a solution of tert-butyl (6R,7S)-6-(3,4-dichlorophenyl)-7-{[(methoxyacetyl)amino]methyl}-1,4-oxazepane-4-carboxylate (180 mg) in DMF (5 ml), and the mixture was stirred at room temperature for 20 min. Methyl iodide (57 mg) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (170 mg).
Reaction SMILES: [F:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:20].Br[CH2:22][CH:23]=[CH2:24].[H-].[Na+].[H][H]>C1COCC1.C(Cl)Cl.O>[F:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[N:4]([CH2:24][CH:23]=[CH2:22])[C:3]1=[O:20]
Reactant: [H][H]
Reactant: C=CCBr
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCN1C(=O)C(F)N=C(c2ccccc2)c2cc(Cl)ccc21
Yield: 43.2 %

Procedure:
To a well stirred solution of 3.0 g (0.01 mol) of 3-fluoro-1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one, 75 ml of dry THF and 21.78 g (0.18 mol) of 3-bromopropene, was added a suspension of 0.48 g (0.02 mol) of sodium hydride in 20 ml of THF. There was an immediate evolution of hydrogen. The contents of the flask were stirred under a nitrogen atmosphere for exactly two hours. The product mixture was poured into 100 ml of water and methylene chloride was added to extract the product. The organic layer was washed twice with 50 ml portions of water, and then allowed to dry over magnesium sulfate. Evaporation of the solvent under reduced pressure gave an orange gluey material which was recrystallized from 450 ml of hot heptane to give 1.42 g of 3-fluoro-1-(allyl)-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one as a very pale orange powder: mp 138°-140°, 1H nmr (CDCl3) δ 7.2-7.9 ppm (m, 8H), δ 5.6 ppm (d, J=57.5 Hz, 1H), δ 4.85-5.95 ppm (m, 3H, olefinic), δ 4.58 ppm (2H, N-CH2); 19F nmr (CDCl3) δ 161.97 ppm.
Reaction SMILES: [CH2:1]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH3:15])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:17]1([NH:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)(=O)C.C(O)C.O.C(O)(=O)C>[C:17]1([NH:23][N:24]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:9][CH:10]=2)[CH3:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCCCNc1ccc(C(C)=O)cc1
Reactant: NNc1ccccc1
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCCCNc1ccc(C(C)=NNc2ccccc2)cc1

Procedure:
p-Hexylaminoacetophenone dissolved in ethanol acetic acid is treated with a solution of phenylhydrazine in water-acetic acid. After a short time the phenylhydrazone separates out, and is collected and washed with water.
Reaction SMILES: [CH:1]1([C:4]#[C:5][CH2:6][OH:7])[CH2:3][CH2:2]1.[H-].[Na+].[NH2:10][C:11]1[O:12][C@H:13]2[C@@H:15]([C@:16]([C:21]3[CH:22]=[C:23]([NH:28][C:29]([C:31]4[CH:36]=[N:35][C:34](Cl)=[CH:33][N:32]=4)=[O:30])[CH:24]=[CH:25][C:26]=3[F:27])([CH:18]([F:20])[F:19])[N:17]=1)[CH2:14]2.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[NH2:10][C:11]1[O:12][C@H:13]2[C@@H:15]([C@:16]([C:21]3[CH:22]=[C:23]([NH:28][C:29]([C:31]4[CH:36]=[N:35][C:34]([O:7][CH2:6][C:5]#[C:4][CH:1]5[CH2:3][CH2:2]5)=[CH:33][N:32]=4)=[O:30])[CH:24]=[CH:25][C:26]=3[F:27])([CH:18]([F:20])[F:19])[N:17]=1)[CH2:14]2
Reactant: NC1=N[C@@](c2cc(NC(=O)c3cnc(Cl)cn3)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Reactant: OCC#CC1CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC1=N[C@@](c2cc(NC(=O)c3cnc(OCC#CC4CC4)cn3)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Temperature: 60 °C
Reaction time: 0.83 h
Yield: 57.5 %

Procedure:
To a solution of 3-cyclopropylprop-2-yn-1-ol (205 mg, 2.137 mmol) in DMF (1 mL) was added sodium hydride (60% dispersion in mineral oil; 8.6 mg, 0.214 mmol) at rt. After 15 min N-(3-((1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloropyrazine-2-carboxamide (Example 261, 88 mg, 0.214 mmol) was added and the reaction mixture was stirred at 60° C. for 50 min. Water (1.0 mL) and aqueous, saturated NaHCO3 solution (1 mL) were added. The resulting mixture was then extracted with EtOAc (2×10 mL). The combined organic extracts were washed with water and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (0%-20% MeOH/DCM) to give 58 mg of the title compound as an off-white solid. MS m/z=472 [M+H]+