Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[C:17]2[C:18]([NH:22][C:23](=[O:27])[C:24]([OH:26])=O)=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:28].[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[S:34]([NH2:37])(=[O:36])=[O:35].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(Cl)(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[C:17]2[C:18]([NH:22][C:23](=[O:27])[C:24](=[O:26])[NH:37][S:34]([C:30]3[S:29][CH:33]=[CH:32][CH:31]=3)(=[O:36])=[O:35])=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:28]
Reactant: O=C(O)C(=O)Nc1cccc2c1N(Cc1ccc3ccccc3c1)C(=O)CO2
Reactant: NS(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1cccc2c1N(Cc1ccc3ccccc3c1)C(=O)CO2)C(=O)NS(=O)(=O)c1cccs1

Procedure:
A mixture of N-(4-Naphthalen-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yl)-oxalamic acid, I-62 (52 mg, 0.14 mmol), thiophene sulfonamide (28 mg, 0.17 mmol), EDCI (33 mg, 0.17 mmol), DMAP (22 mg, 0.17 mmol) in methylene chloride was stirred at room temperature for 24 h. Reaction was diluted with chloroform (10 mL) and washed with 6.0 M HCl (3.0 mL×4), water (3.0 mL). Chloroform layer was concentrated and the residue was purified over silica gel with chloroform:methanol (90:10) as eluant to afford N-(4-Naphthalen-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yl)-2-oxo-2-(thiophen-2-sulfonylamino)-acetamide, P019 (7.0 mg). 1H NMR (500 MHz, DMSO-d6) 4.59 (s, 2H), 5.35 (s, 2H), 6.84 (dd, J=8.0, 1.5 Hz, 1H), 6.90 (dd, J=8.0, 8.0 Hz, 1H), 7.02 (m, 2H), 7.06 (dd, J=5.0, 3.5 Hz, 1H), 7.44 (m, 1H), 7.56 (s, 1H), 7.61 (dd, J=3.5, 1.5 Hz, 1H), 7.71-7.65 (m, 3H), 7.78 (m, 1H), 10.05 (s, 1H). MS (ESI−) Calcd. (M+) 521.6; Found: 520.7 (M−1).
Reaction SMILES: C([O:5][C:6]([C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([N:21]3[CH:26]=[CH:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)=O)CCC.[CH3:29][NH2:30]>CO>[CH3:29][NH:30][C:6]([C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]([F:28])[C:17]([N:21]3[CH:26]=[CH:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[C:18]([F:20])[CH:19]=2)[CH2:9]1)=[O:5]
Reactant: CCCCOC(=O)[C@H]1CN(c2cc(F)c(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2cc(F)c(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Yield: 85 %

Procedure:
To a stirred solution of (5R)-3-[3,5-Difluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid butyl ester (EXAMPLE 76, Step 5, 132 mg) in MeOH (1 mL) is added MeNH2 (2 mL, 4.0 mmol, 2.0 M solution in MeOH). The reaction mixture is then heated at 40–50° C. until all of the solid disappears. Solvent is removed and the residue is dissolved in 20% MeOH/CH2Cl2 and purified by silica gel chromatography (10% MeOH/CH2Cl2) to give the title compound as a yellow solid (100 mg, 76%), 1H NMR (300 MHz, DMSO) δ 8.40 (m, 1H), 7.52–7.38 (m, 3H), 5.08 (dd, 1H), 5.00 (d, 1H), 4.26 (t, 1H), 4.01 (dd, 1H), 3.78 (t, 2H), 2.65 (d, 3H); MS for C16H15F2N3O4 m/z 352.5 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[O:5][CH:6]=[CH:7][C:8]=1[S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21]Br)=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:3])[CH3:2].[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24].O.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31]>CS(C)=O>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[CH:1]([C:4]1[O:5][CH:6]=[CH:7][C:8]=1[S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][NH:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:3])[CH3:2]
Reactant: CC(C)c1occc1S(=O)(=O)c1ccc(OCCCBr)cc1
Reactant: CC(C)(C)N
Agent: O=C(O)C(=O)O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1occc1S(=O)(=O)c1ccc(OCCCNC(C)(C)C)cc1
Reaction time: 24 h

Procedure:
A mixture of 0.00282 mol of 2-isopropyl-3-[4-(3-bromopropyloxy)benzenesulphonyl]furan and 0.013 mol of tert-butylamine in 7 ml of dimethylsulphoxide was stirred at room-temperature for 24 hours. After that, the mixture was poured into water, distilled in the presence of ethyl acetate, dried on sodium sulphate, filtered and concentrated. The residue so obtained was purified on a silica column using a methanol/ethyl acetate 2/8 mixture as eluent. The oily base so provided was then treated with an ethereal solution of oxalic acid and the precipitate was recrystallized from ethanol.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[CH:6][CH:5]=1)([O-])=O.O.NN>[Pd].C(O)C>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]2[CH:25]=[CH:26][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccccc2Oc2ccc(N)cc2)cc1
Yield: 77.4 %

Procedure:
In a 3 l round-bottomed flask equipped with a magnetic stirrer bar, reflux condenser and dropping funnel was placed 64.20 g (0.182 mol) of 1,2-bis(4-nitrophenoxy)benzene (SI-319), 700 mL ethanol and 2 g 5% palladium on charcoal. The mixture was brought to boil when 200 mL of hydrazine hydrate was added dropwise during a period of 1.5 hours. The mixture was refluxed for a further 3 hours. The hot mixture was then filtered over a filter agent and left to 10 crystallize. The next day the crystals were separated and the liquid volume reduced to 400 mL, from which an additional crop of crystals was filtered off. The combined crystalline product was recrystallized twice from methanol/water (3:1) to yield 41.2 g of off-white crystals. By reducing the liquid volume a second crop of 5.7 g of crystals was obtained (overall yield 88.17% theoretical). Melting point 135-136° C. Elemental analysis: Calc: C, 73.95%, H, 5.51%, 9.59%; Found: C, 74.10%, H, 5.62%, 9.77%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][C:31](OC)=[O:32])[C:6]=2[CH:35]=1.CO[BH-](OC)OC.[Na+].Cl>COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][OH:32])[C:6]=2[CH:35]=1
Reactant: COC(=O)CC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)nc2)c2ccc(Cl)cc21
Agent: CO[BH-](OC)OC
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Nc1ccc(C(=O)N2CCCC(CCO)c3cc(Cl)ccc32)cn1)c1ccccc1Cl
Yield: 41 %

Procedure:
To a solution of 7-chloro-5-methoxycarbonylmethyl-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (8 g) in ethylene glycol dimethyl ether (50 ml)is added sodium trimethoxyborohydride (6 g), and the mixture is refluxed for 4 hours. To the mixture is added sodium trimethoxyborohydride (3 g), and the mixture is refluxed for two hours. The reaction solution is gradually poured into diluted aqueous hydrochloric acid solution, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and recrystallized from dichloromethane-diethyl ether to give 7-chloro-5-(2-hydroxyethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-l H-benzazepine (3.1 g) as white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[CH2:10][CH2:11][CH:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:13][C:7]=3[C:6]=2[CH:19]=1.[ClH:20].[C:21]([Cl:29])(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[ClH:29].[ClH:20].[CH2:15]([N:14]([CH2:17][CH3:18])[CH:12]1[CH2:11][CH2:10][C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:21](=[O:28])[C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)=[CH:19][C:6]=3[C:7]=2[CH2:13]1)[CH3:16]
Reactant: O=C(Cl)c1ccncc1
Reactant: CCN(CC)C1CCc2oc3ccc(N)cc3c2C1
Agent: Cl
Product: CCN(CC)C1CCc2oc3ccc(NC(=O)c4ccncc4)cc3c2C1
Yield: 51.9 %

Procedure:
Beginning with 0.100 gm (0.30 mMol) 8-amino-1,2,3,4-tetrahydro-2-diethylaminodibenzofuran and 0.059 gm (0.33 mMol) isonicotinoyl chloride hydrochloride, 0.068 gm (52%) of the title compound were recovered as a yellow solid by the procedure described in Example 17.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]([NH2:16])[C:8]([NH2:17])=[N:7][C:6]=1[CH3:18])[CH3:2].C(O)(=O)C.[N:24]([O-])=O.[Na+]>O>[CH2:1]([O:3][C:4]([C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]2[N:16]=[N:24][NH:17][C:8]2=[N:7][C:6]=1[CH3:18])=[O:19])[CH3:2]
Reactant: O=N[O-]
Reactant: CCCCNc1c(N)c(N)nc(C)c1C(=O)OCC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCNc1c(C(=O)OCC)c(C)nc2[nH]nnc12
Reaction time: 8 h

Procedure:
2.66 g. of 5,6-diamino-4-butylamino-2-methylnicotinic acid ethyl ester (0.01 mol.) are dissolved in 20 ml. of acetic acid and 5 ml. of water. The mixture is cooled to 5° with stirring. At this temperature, a solution of 0.9 g. of sodium nitrite in 5 ml. of water is showly added dropwise. Stirring is continued for an additional 8 hours. The solvent is distilled off and the residue treated with 20 ml. of water and extracted three times with 10 ml. portions of chloroform. The organic layers are dried with sodium sulfate, filtered and evaporated. The crystalline 7-butylamino-5-methyl-3H-[1,2,3]-triazolo-[4,5-b]pyridine-6-carboxylic acid ethyl ester remains and is recrystallized from methanol, yield 2.3 g. (83%), m.p. 188°-189°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([OH:26])=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2.C(=O)([O-])[O-].[K+].[K+].[CH:33]1(Br)[CH2:37][CH2:36][CH2:35][CH2:34]1.O>CN(C)C=O>[CH:33]1([O:26][C:17]2[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: BrC1CCCC1
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3OC3CCCC3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
6,7-Dimethoxy-4-(2-hydroxy-quinolin-3-yloxy)-quinoline (19 mg) was dissolved in N,N-dimethylformamide (4 ml) to prepare a solution. Potassium carbonate (180 mg) and cyclopentyl bromide (0.1 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography using acetone-chloroform to give the title compound (14 mg, yield 60%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@H:2]([C@@H:4]([C:6]([OH:8])=O)[OH:5])[OH:3].[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([OH:20])=O)=[CH:16][CH:17]=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:3][C@@H:2]2[C:1](=[O:9])[O:10][C:6](=[O:8])[C@H:4]2[O:5][C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][CH:14]=2)=[O:20])=[O:20])=[CH:14][CH:13]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=O)O[C@@H]2C(=O)OC(=O)[C@H]2OC(=O)c2ccc(C)cc2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a 300 ml reaction vessel equipped with a stirrer, thermometer, condenser and a dropping funnel, 30 g of D-tartaric acid, 70 g of toluene, 0.12 g of ferric chloride and 59.9 g of p-toluic acid were supplied, and the mixture was heated to 90° C. While keeping this temperature, 83.7 g of thionyl chloride was added from the dropping funnel for 6 hours and the resulting mixture was aged at 105°-110° C. for another 1 hour to carry out the reaction. The reaction mixture was then cooled to room temperature and the precipitated crystals were collected by filtration, followed by drying to obtain 67.2 g of O,O'-di-p-toluoyl-D-tartaric anhydride in the form of pale yellow crystals (purity: 100%, yield: 91.3%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][C:19]([Cl:25])=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:26]N1C(=O)CCC1=O>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([Br:26])=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][C:19]([Cl:25])=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnc(Cl)cc3c2)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnc(Cl)cc3c2Br)CC1
Temperature: 85 °C

Procedure:
200 mg of 4-(3-Chloro-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (178) were dissolved in 5 ml of CH3CN and heated to 85° C. Then a mixture of 148 mg of N-bromosuccinimide and 9 mg of AlBN was added as solid and the resulting mixture was heated to reflux for 1 h. The solvent was removed in vacuo and the residue subjected to flash column chromatography. The yield of the isolated product was 41% LCMS: detected mass: 441.03, Rt=2.41 min (Method #1)
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[C:9]([N:12]1[CH2:16][CH2:15][CH:14]([N:17]([CH3:39])[C:18]([C:20]2[O:21][C:22]3[C:28](F)=[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]([CH3:36])=[C:25]([C:37]#[N:38])[C:23]=3[N:24]=2)=[O:19])[CH2:13]1)(=[O:11])[CH3:10].C(N(CC)CC)C>CS(C)=O>[C:9]([N:12]1[CH2:16][CH2:15][CH:14]([N:17]([CH3:39])[C:18]([C:20]2[O:21][C:22]3[C:28]([N:5]4[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]4)=[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]([CH3:36])=[C:25]([C:37]#[N:38])[C:23]=3[N:24]=2)=[O:19])[CH2:13]1)(=[O:11])[CH3:10]
Reactant: CN(C)[C@H]1CCNC1
Reactant: CC(=O)N1CCC(N(C)C(=O)c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(N(C)C(=O)c2nc3c(C#N)c(C)c(-c4ccccc4)c(N4CC[C@H](N(C)C)C4)c3o2)C1
Reaction time: 0.75 h
Yield: 52.5 %

Procedure:
Under nitrogen atmosphere at 140 to 150° C., a dimethyl sulfoxide (1 ml) solution of (3S)-3-(dimethylamino)pyrrolidin (86 μl, 679 μmol) was added to a dimethyl sulfoxide (10 ml) solution of N-(1-acetylpyrrolidin-3-yl)-4-cyano-7-fluoro-N,5-dimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-206) (238 mg, 566 μmol) and triethylamine (103 μl, 736 μmol), followed by stirring at the same temperature for 45 minutes. After cooling, the solvent was evaporated away under reduced pressure, the residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine, then the aqueous layer was extracted with ethyl acetate. Next, saturated sodium hydrogencarbonate water was added to the aqueous layer, followed by extraction with chloroform. The combined organic layer was dried over anhydrous magnesium sulfate, then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with dichloromethane/methanol (10:1, v/v) gave the entitled compound (153 mg, 53%) as an amorphous substance.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([CH:19]=[CH:20][CH2:21]Cl)=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26].O>O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:21][CH:20]=[CH:19][C:18]2[CH:23]=[CH:24][C:15]([O:14][CH2:13][O:12][CH3:11])=[C:16]([N+:25]([O-:27])=[O:26])[CH:17]=2)=[CH:6][CH:5]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: COCOc1ccc(C=CCCl)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(C=CCSc2ccc(Cl)cc2)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
Under a current of argon, a solution having 251 mg of sodium hydride suspended in 10 ml of tetrahydrofuran and 906 mg of p-chlorothiophenol added thereto as kept cooled with ice were stirred for 30 minutes and the produced mixture and a solution of 1.62 g of 4-methoxymethoxy-3-nitrocinnamyl chloride in 5 ml tetrahydrofuran added thereto were stirred at normal room temperature for 14 hours. The resultant reaction mixture was combined with water and extracted from ethyl acetate. The consequently separated organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The residue from drying was concentrated under a vacuum. The concentrate was subjected to silica gel column chromatography. From the hexane-ethyl acetate (5:1 V/V) eluate, 1.77 g of 5-[3-(4-chlorophenylthio)-1-propenyl]-2-methoxymethoxy nitrobenzene was obtained in the form of a colorless oily substance. The yield was 77%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]([OH:15])[CH3:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[C:24]([CH3:26])([CH3:25])[O:23][C:22]([CH3:28])([CH3:27])[C:21](=[O:29])[CH:20]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH:13]([O:15][C:19]3[C:24]([CH3:25])([CH3:26])[O:23][C:22]([CH3:28])([CH3:27])[C:21](=[O:29])[CH:20]=3)[CH3:14])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(O)c1cnc(-c2ccc(Cl)cc2)s1
Reactant: CC1(C)OC(C)(C)C(Cl)=CC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(OC1=CC(=O)C(C)(C)OC1(C)C)c1cnc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a solution of 1-[2-(4-chlorophenyl)thiazol-5-yl]ethanol (335 mg, 1.4 mmol) in anhydrous tetrahydrofuran (5 ml) under nitrogen is added sodium hydride, 60% dispersion in mineral oil, (48 mg, 1.2 mmol) and the resulting yellow suspension is allowed to stir at room temperature for 1 hour. A solution of 5-chloro-2,2,6,6-tetramethyl-6H-pyran-3-one (189 mg, 1 mmol) in anhydrous tetrahydrofuran (2 ml) is then added and reaction is allowed to stir at room temperature for 17 hours. The crude reaction mixture is purified by flash chromatography on silica gel to give 5-{1-[2-(4-chlorophenyl)thiazol-5-yl]ethoxy}-2,2,6,6-tetramethyl-6H-pyran-3-one (288 mg).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:11])[N:3]=1.I[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:13]([O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:11])[N:3]=1)[CH3:14]
Reactant: COC(=O)c1cc(O)nn1C
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)n(C)n1
Yield: 93.7 %

Procedure:
Using methyl 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylate (2.34 g, 15.0 mmol), iodoethane (3.51 g, 22.5 mmol), potassium carbonate (4.15 g, 30.0 mmol) and N,N-dimethylformamide (15 mL), and in the same manner as in Reference Example 57, the title compound (2.59 g, yield 94%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:23]([NH2:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[C:20]([F:22])[CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([CH:23]([NH:30][C:9]([CH2:8][NH:7][C:6](=[O:12])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=2)=[O:11])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Reactant: NC(c1ccccc1)c1cc(F)cc(F)c1
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccccc1)c1cc(F)cc(F)c1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(3,5-difluoro-phenyl)-C-phenyl-methylamine (example 4.3).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[F:9])=[O:7].[CH:18]([C:20]1[S:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:28]([C:29]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[C:31]([CH:38]([CH3:40])[CH3:39])[C:30]=3[O:41][CH2:42][CH2:43][CH3:44])[C:22]=2[CH:21]=1)=O.O>CN(C=O)C>[CH2:4]([O:5][C:6](=[O:7])[C:8]([F:9])=[CH:18][C:20]1[S:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:28]([C:29]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[C:31]([CH:38]([CH3:39])[CH3:40])[C:30]=3[O:41][CH2:42][CH2:43][CH3:44])[C:22]=2[CH:21]=1)[CH3:3]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCCOc1c(-c2cccc3sc(C=O)cc23)cc(C(C)C)cc1C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1c(-c2cccc3sc(C=C(F)C(=O)OCC)cc23)cc(C(C)C)cc1C(C)C
Temperature: 40 °C

Procedure:
To a slurry of 74 mg (1.54 mmol) of NaH (50% in mineral oil) in 3 mL of dry DMF was added 285.6 mg (1.27 mmol, 2.5 equivalents) of triethyl phosphonofluoroacetate (diluted in 1 mL of dry DMF) at 0° C. After the gas evolution has ceased, 0.51 mmol of 2-formyl-4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thiophene diluted in 3 mL of dry DMF was added dropwise. The red mixture was slowly heated to 40° C. until complexion. After cooling, water was added and the solution was extracted 2 times with ethyl acetate. The organic layers were combined, washed with water and brine and dried over MgSO4. After evaporation of the solvents, the crude oil is purified over a short plug of silica gel (eluent: 95/5 hexane/ethyl acetate) to afford 2-fluoro-3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-prop-2-enoic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4]Br.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[C:21](=[C:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]=2[CH:28]=1.C(N(CC)CC)C>C1COCC1>[CH3:1][O:2][C:3](=[O:6])[CH2:4][N:25]1[CH2:24][CH2:23][C:22](=[C:21]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]3[CH:28]=[C:8]([Cl:7])[CH:9]=[CH:10][C:11]2=3)[CH2:27][CH2:26]1
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Reactant: COC(=O)CBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CN1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Reaction time: 18 h
Yield: 89.2 %

Procedure:
Methylbromoacetate (0.17 ml, 1.77 mmol) was added dropwise to a solution of 4-{8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene}-piperidine (0.50 g, 1.61 mmol) and triethylamine (0.45 ml, 3.22 mmol) in THF (15 ml) under an inert atmosphere. The reaction was left to stir for 18 hours. THF was removed under reduced pressure and the product purified by column chromatography on silica gel, eluting with 5% methanol/DCM. Product containing fractions were combined and solvent removed under reduced pressure to yield methyl-[4-{8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene}-piperidin-1-yl]acetate as an orange solid (550 mg, 90%).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14].N1C=CC=CC=1>ClCCl>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH:18][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 96.4 %

Procedure:
Tosyl chloride (14.75 g, 77.37 mmol) was added to a stirring mixture of glycine ethyl ester hydrochloride (9.0 g, 64.48 mmol) and pyridine (11.45 mL, 141.85 mmol) in 100 mL of dichloromethane. After stirring overnight, the mixture was washed with water and dilute NaOH. The combined organics were dried with Na2SO4, filtered, evaporated under reduced pressure to give 16.0 g (96%) of 81, which was used without purification in the next reaction. 1H-NMR (400 MHz, CDCl3): δ 1.18 (t, 3H), 2.42 (s, 3H), 3.76 (d, 2H), 4.08 (q, 2H), 5.22 (m, 1H), 7.30 (d, 2H), 7.75 (d, 2H) ppm. 13C-NMR (100 MHz, CDCl3): δ 13.99, 21.55, 44.19, 61.89, 127.28, 129.76, 136.20, 143.81, 168.87 ppm.□ DEPT (100 MHz, CDCl3): CH3 carbons: 13.99, 21.55; CH2 carbons: 44.19, 61.89; CH carbons: 127.28, 129.76 ppm. LC/MS: 95%, m/z=257.