Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([OH:7])[CH2:3][CH2:4][CH:5]=[CH2:6].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:7][CH:2]([CH2:3][CH2:4][CH:5]=[CH2:6])[CH3:1])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCCC(C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCC(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To a solution of Hex-5-en-2-ol (50 g crude, 500 mmole) in dichloromethane was added triethylamine (103 mL, 750 mmol) at room temperature. The reaction mass was cooled to 0° C. and to it was added a solution of methane sulfonyl chloride (50.4 mL, 650 mmol) in DCM over a period of 30 min. The reaction mass was allowed to come to room temperature and stirred for 2 h. The solution was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get crude compound Hex-5-en-2-yl methanesulfonate as light brown oily liquid (73 g, 82%). 1H NMR (400 MHz, CDCl3): δ ppm 5.84-5.80 (m, 1H), 5.10-5.0 (m, 2H), 4.99-4.98 (m, 1H), 3.15 (s, 3H), 2.52-2.09 (m, 2H), 1.75-1.66 (m, 2H), 1.36-1.34 (d, J=6.4 Hz, 3H).
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5](C)([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([Cl:22])[CH:19]=[N:18]2)=[C:13]([Cl:23])[CH:12]=1)[C:6](OCC)=O)C.[OH-].[K+].O>C(O)CCC>[Cl:23][C:13]1[CH:12]=[C:11]([CH:5]([CH3:6])[C:4]([OH:25])=[O:3])[CH:16]=[CH:15][C:14]=1[N:17]1[CH:21]=[C:20]([Cl:22])[CH:19]=[N:18]1
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: CC(C(=O)O)c1ccc(-n2cc(Cl)cn2)c(Cl)c1

Procedure:
3.83 g (10 mmoles) of methyl-[3-chloro-4-(4-chloropyrazol-1-yl) phenyl] malonic acid diethyl ester, 1.4 g of potassium hydroxide, 5 ml of water and 15 ml of n-butanol are heated to the boil for 3 hours, with stirring. The solvent is evaporated off, the residue is dissolved in water, the aqueous solution is extracted with ether, acidification is effected with hydrochloric acid and the precipitate is filtered off. 2-[3-chloro-4-(4-chloropyrazol-1-yl) phenyl] propionic acid is obtained; m.p. 102°-103° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[N:17]=[CH:18][C:19]([C:20]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:22])=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Reactant: C1COCCN1
Product: O=C(c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1)N1CCOCC1
Yield: 69 %

Procedure:
As described in example 43h, 6-(5-hydroxymethyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (881 mg, 2.7 mmol) was converted, using morpholine instead of thiomorpholine 1,1-dioxide, to the title compound (738 mg, 69%) which was obtained as a white foam. MS: m/e=397.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]3[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][NH:14]3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]([NH:24][C@@H:25]([CH:29]([CH3:31])[CH3:30])[C:26](O)=[O:27])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:20][O:21][C:22](=[O:23])[NH:24][C@H:25]([C:26]([N:14]1[CH2:15][C@@H:16]([CH3:19])[CH2:17][CH2:18][C@H:13]1[C:11]1[NH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:9][N:10]=1)=[O:27])[CH:29]([CH3:31])[CH3:30]
Reactant: CC1CCC(c2ncc(-c3ccc(Br)cc3)[nH]2)NC1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)CC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
A mixture of 2S,5S)-2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-5-methyl-piperidine (400 mg, 1.25 mmol) and (S)-2-methoxycarbonylamino-3-methyl-butyric acid (219 mg, 1.25 mmol), HATU (475 mg, 1.25 mmol), and DIPEA (485 mg, 3.75 mmol) in DCM (20 mL) was stirred at RT overnight. The reaction mixture was concentrated and purified by thin layer chromatography (1:1 petroleum ether:EtOAc) to provide the title intermediate (550 mg, 92% yield). (m/z): [M+H]+ calcd for C22H28BrN4O3 476.13, 478.13, found 478.7.
Reaction SMILES: S(=O)(=O)(O)O.[BrH:6].[CH:7]1([CH2:13][CH2:14]O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[Br:6][CH2:14][CH2:13][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Br
Reactant: OCCC1CCCCC1
Agent: O=S(=O)(O)O
Product: BrCCC1CCCCC1
Temperature: 25 °C
Yield: 840.2 %

Procedure:
In a 1 l-roundbottom flask equipped with a reflux condenser 164 g concentrated sulphuric acid and 200 g hydrobromic acid (48% in water) were added subsequently under cooling with an ice bath to 88.7 g (0.693 mole) 2-cyclohexyl-ethanol. The mixture was refluxed for 6 h and after cooling to room temperature it was poured onto 400 g of ice. The aqueous phase was extracted with 400 ml pentane. The organic layer was washed with a 2 M NaOH-solution and with water, dried over magnesium sulphate, and the solvent was removed in vacuo. The product was distilled in vacuo to yield 1112.7 g (85%) of (2-bromo-ethyl)-cyclohexane as a colourless oil 1H-NMR (4-MHz, CDCl3): δ=3.40 (2H, t, CH2Br), 1.73-1.61 (m, 7H), 1.44 (m, 1H), 1.26-1.11 (m, 3H), 0.92-0.84 (m, 2H) ppm.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][CH2:7][C:8]1[CH:9]=[C:10]([C:27]2[C:28]([CH3:33])=[N:29][O:30][C:31]=2[CH3:32])[C:11]2[O:16][CH2:15][C@H:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:13]3[C:23](=[O:26])[NH:24][C:25]=1[C:12]=23.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>O>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]([C:27]2[C:28]([CH3:33])=[N:29][O:30][C:31]=2[CH3:32])[C:11]2[O:16][CH2:15][C@H:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:13]3[C:23](=[O:26])[NH:24][C:25]=1[C:12]=23
Reactant: COc1ccc(CNCc2cc(-c3c(C)noc3C)c3c4c2[nH]c(=O)n4[C@@H](c2ccccn2)CO3)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1noc(C)c1-c1cc(CN)c2[nH]c(=O)n3c2c1OC[C@@H]3c1ccccn1
Yield: 82 %

Procedure:
A solution of (4S)-9-{[(2,4-dimethoxybenzyl)amino]methyl}-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (70.0 mg, 0.133 mmol) in trifluoroacetic acid (5 mL) and water (30 μL) was heated in the microwave at 120° C. for 10 min. The reaction mixture was concentrated to give a crude residue. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gave the desired product (66 mg, 82%) as a single enantiomer. 1H NMR (300 MHz, DMSO-d6) δ 11.28 (s, 1H), 8.48 (d, J=4.4 Hz, 1H), 8.18 (br s, 2H), 7.80 (ddd, J=7.7, 7.7, 1.7 Hz, 1H), 7.32 (dd, J=7.1, 5.0 Hz, 1H), 7.19 (d, J=7.9 Hz, 1H), 6.94 (s, 1H), 5.59 (s, 1H), 4.89-4.73 (m, 1H), 4.44 (dd, J=11.5, 3.0 Hz, 1H), 4.13 (d, J=5.5 Hz, 2H), 2.24 (s, 3H), 2.07 (s, 3H); LCMS calculated for C20H20N5O3 (M+H)+: m/z=378.2. found: 378.0.
Reaction SMILES: [Na].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]#[N:9].C([O:14][N:15]=O)CCC>C(O)C>[N:15](=[C:7]([C:3]1[S:2][CH:6]=[CH:5][CH:4]=1)[C:8]#[N:9])[OH:14]
Reactant: CCCCON=O
Reactant: N#CCc1cccs1
Agent: [Na]
Solvent: CCO
Product: N#CC(=NO)c1cccs1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2.3 g. (0.10 mole) of sodium metal dissolved in 50 ml. ethanol and cooled to 0° C. in an ice bath was added 12.3 g. (0.10 mole) of 2-thienylacetonitrile. After the addition was complete 10.3 g. (0.10 mole) of butylnitrite was added. The reaction was stirred 1 hour at 0° C. and 3 hours at room temperature before the mixture was concentrated to dryness in vacuo. The residue was washed with ether. The sodium salt of the product was dissolved in water and acidified with concentrated hydrochloric acid to a pH of 3. The solid was filtered, washed with water, dried and recrystallized from chloroform to give 6.6 g. of final product which melted at 135°-137° C.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=2)[CH2:3][CH2:2]1.[CH3:12][NH:13][CH2:14][CH2:15][CH:16]=[O:17]>C1C=CC=CC=1>[CH3:12][N:13]([CH2:14][CH2:15][CH:16]=[O:17])[C:10]([NH:9][C:7]1[S:8][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][N:6]=1)=[O:11]
Reactant: O=C=Nc1nnc(C2CC2)s1
Reactant: CNCCC=O
Solvent: c1ccccc1
Product: CN(CCC=O)C(=O)Nc1nnc(C2CC2)s1

Procedure:
A mixture of 5-cyclopropyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-methylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-methyl-3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: [CH2:1]([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:19][S:20](O)(=[O:22])=[O:21]>>[CH2:1]([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:20]([Cl:19])(=[O:22])=[O:21])=[CH:15][CH:14]=1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCCCCCNC(=O)Nc1ccccc1
Product: CCCCCCCCNC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 15.3 %

Procedure:
N-octyl-N′-phenylurea (10 g, 215 mmol) was dissolved in chlorosulfonic acid 925 g and stirred for 14 hours at ambient temperature. The reaction was poured into ice and extracted with ethyl acetate. The organic layer was washed with cold, dilute aqueous sodium bicarbonate, then dried (Na2SO4). The solvent was evaporated in vacuo to give the product as a white solid (11.46 g, 33 mmol).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[N:17]1CCOCC1.ClC(OCC(C)C)=O.[NH4+].[OH-]>C1COCC1>[C:1]([NH:8][C@@H:9]([C:13]([NH2:17])=[O:15])[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CN1CCOCC1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
To a stirred solution of Boc-D-Valine (25 g, 115 mMol) in THF (300 mL) at 0° C. was added N-Methylmorpholine (15 mL, 136 mMol) followed by the dropwise addition of isoButyl chloroformate (18 mL, 139 mMol) over 5 minutes. The reaction was stirred at 0° C. for 30 minutes after which a solution of 30 wt. % NH4OH (50 mL, 385 mMol) was quickly poured into the reaction. (Vigorous gas evolution was seen which subsided after a few minutes.) The reaction was allowed to warm to RT and stirred for 4 h. The reaction was concentrated under vacuum on the rotoevaporator to a volume which precipitated most of the product. The thick white slurry was diluted with an equal volume of water, filtered, rinsed with water, pressed dry then dried under vacuum to give the title compound (22.56 g, 91%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 6.17 (br s, 1H), 5.75 (br s, 1H), 5.12 (d, 1H), 4.00 (app. t, 1H), 2.13 (m, 1H), 1.44 (s, 9H), 0.99 (d, 3H), 0.94 (d, 3H).
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([NH:17][C:18]([NH:20][C:21](=[NH:23])[NH2:22])=[O:19])=[C:12]([CH3:24])[CH:11]=1)C1C=CC=CC=1.Cl.[H][H]>[Pd].C(O)C>[ClH:1].[OH:9][C:10]1[CH:11]=[C:12]([CH3:24])[C:13]([NH:17][C:18]([NH:20][C:21](=[NH:22])[NH2:23])=[O:19])=[C:14]([CH3:16])[CH:15]=1
Reactant: [H][H]
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1NC(=O)NC(=N)N
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1cc(O)cc(C)c1NC(=O)NC(=N)N

Procedure:
A mixture of 1-(4-benzyloxy-2,6-dimethylphenyl)-3-amidinourea hydrochloride (7.0 g), methanolic HCl (50 ml), 5% Pd/C (1.0 g) and 150 ml of absolute ethanol are shaken under an atmosphere of H2 (50 psi) until the uptake of hydrogen ceases. The mixture is filtered through a pad of Celite and the pad washed well with methanol. The filtrate is concentrated under vacuo and the residue crystallized from methanol/acetonitrile to give, after filtering and vacuum drying, 4.7 grams of an off-white solid, M.P. 204°-206° C. Recrystallization from methanol/acetonitrile gave, after filtering and vacuum drying, 2.3 grams, M.P. 208°-210° C. of the hydrochloride salt.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH:8]=O)[CH:6]=O)[CH3:2].Cl.[NH:12]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:17]([OH:19])=[O:18])[NH2:13]>CCO>[CH2:1]([O:3][C:4]([C:5]1[CH:8]=[N:13][N:12]([C:14]2[CH:15]=[C:16]([C:17]([OH:19])=[O:18])[CH:20]=[CH:21][C:22]=2[CH3:23])[CH:6]=1)=[O:10])[CH3:2]
Reactant: CCOC(=O)C(C=O)C=O
Reactant: Cc1ccc(C(=O)O)cc1NN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2cc(C(=O)O)ccc2C)c1
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A solution of 2-formyl-3-oxo-propionic acid ethyl ester (S. H. Bertz et al., J. Org. Chem., 1982, 47, 2216) (1.44 g, 10 mmol) in EtOH (10 mL) was cooled in an ice bath. A slurry of 3-hydrazino-4-methyl-benzoic acid hydrochloride (2.02 g, 10 mmol) in EtOH (50 mL) was added and the reaction was stirred overnight. The EtOH was removed under reduced pressure and the residue partitioned between water and CH2Cl2. The layers were separated and the organic layer washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Hexanes were added and the solution concentrated. The resulting solid was collected by vacuum filtration, washed with hexanes and dried under vacuum to provide 1-(5-carboxy-2-methyl-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (1.86 g, 68%) as a yellow solid: ESI MS m/z 275 [C14H14N2O4+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][N:5]([C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH:6]=1.[Cl-].[CH2:23]([O:25][C:26](=[O:38])[CH:27]([OH:37])[CH:28]([NH3+:36])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:24]>>[OH:37][CH:27]([CH:28]([NH:36][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[N:15][C:7]=1[N:5]1[CH:6]=[C:2]([CH3:1])[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4]1)[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:26]([O:25][CH2:23][CH3:24])=[O:38]
Reactant: Cc1cn(-c2ncccc2C(=O)O)nc1-c1ccccc1
Reactant: CCOC(=O)C(O)C([NH3+])Cc1ccccc1
Agent: [Cl-]
Product: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc(C)c(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.1 by reacting 2-(4-methyl-3-phenyl-1H-pyrazol-1-yl)nicotinic acid and 4-ethoxy-3-hydroxy-4-oxo-1-phenylbutan-2-aminium chloride. ESI-MS [M+H]+: 485.3
Reaction SMILES: [C:1]([C:4]1[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:6][N:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:8]=1)([OH:3])=[O:2].BrN1C(=O)C[CH2:23][C:22]1=O>CN(C=O)C.CCOC(C)=O>[CH2:22]([O:2][C:1]([C:4]1[C:5]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[N:6][N:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:8]=1)=[O:3])[CH3:23]
Reactant: CC(C)(C)n1cc(C(=O)O)c(-c2ccc(F)cc2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(C(C)(C)C)nc1-c1ccc(F)cc1
Yield: 75.2 %

Procedure:
Add a solution of NaOH (15%, 6 mL) to a solution of 4-ethoxycarbonyl-3-(4-fluorophenyl)-1-tert-butyl-1H-pyrazole (0.350 g, 1.2 mmol) in MeOH (3 mL) and then add acetonitrile (1 mL). Stir the mixture at 50° C. for 3 h, cool to RT and add HCl (10%) until the pH=3. Extract the mixture with EtOAc (3×100 mL). Combine the organic layers and wash with brine (100 mL), dry (MgSO4) and concentrate to provide 4-carboxy-3-(4-fluorophenyl)-1-tert-butyl-1H-pyrazole as a yellow solid (0.320 g), MS (ESi+): 229.1 (M+H)+. Next treat a solution of 4-carboxy-3-(4-fluorophenyl)-1-tert-butyl-1H-pyrazole (0.315 g, 1.2 mmol) in DMF (15 mL) previously degassed with N-bromosuccinimide (0.235 g, 1.32 mmol) at RT for about 18 h. Dilute the mixture with EtOAc (80 mL) and wash with cooled water (5×10 mL), dry (MgSO4), and concentrate to provide the desired compound as yellow solid (0.262 g, 73% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].N1C=CC=CC=1.[C:21](Cl)(=[O:25])[O:22][CH2:23][CH3:24]>C(OCC)(=O)C>[C:21](=[O:25])([O:22][CH2:23][CH3:24])[O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:14]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCOCCO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)OCCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 127.9 %

Procedure:
To a mixture of tert-butyl [2-(2-hydroxyethoxy)ethyl]carbamate (53.93 g) obtained above and ethyl acetate (350 mL) were added pyridine (53.78 mL) and ethyl chlorocarbonate (70.57 g) under ice-cooling, and stirred at room temperature for 96 hrs. To the reaction solution was added ethyl acetate (500 mL), and washed with water (500 mL), aqueous solution of copper sulfate (200 mL), water (300 mL) and saturated brine (300 mL), followed by drying over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to give 2-[2-[(tert-butoxycarbonyl)amino]ethoxy]ethyl ethyl carbonate as colorless oil (93.19 g).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][C:5]1([CH3:18])[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[O:6]1.[CH3:19][NH:20][CH3:21]>CO>[ClH:2].[CH3:19][N:20]([CH3:21])[CH2:3][CH2:4][C:5]1([CH3:18])[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[O:6]1
Reactant: CN1CC(C)(CCCl)Oc2ncccc2C1=O
Reactant: CNC
Agent: Cl
Solvent: CO
Product: CN(C)CCC1(C)CN(C)C(=O)c2cccnc2O1
Reaction time: 192 h
Yield: 67 %

Procedure:
To 4.5 g (0.015 mole) of 2-(2-chloroethyl)-2,3-dihydro-2,4-dimethylpyrido[3,2-f]-1,4-oxazepin-5(4H)-one hydrochloride in 15 ml of methanol was added 40 ml of dimethylamine. The flask was sealed tightly and left standing at room temperature for 8 days. The methanol and dimethylamine were removed by rotary evaporation (70° C.; 30 mm). The residue was taken up in 150 ml of chloroform, washed with 2×50 ml dil aqueous sodium hydroxide, dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation (70° C.; 30 mm). The syrupy residue was treated with hydrogen chloride in isopropyl alcohol, which afforded 3.5 g (67%) of white crystals, m.p. 188°-90° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[C:14](Cl)(=[O:16])[CH3:15]>>[C:14]([C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=2)[NH:1][CH:2]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Product: COC(=O)c1ccc2c(C(C)=O)c[nH]c2c1

Procedure:
Methyl 3-acetylindole-6-carboxylate (470 mg) was prepared from methyl indole-6-carboxylate (655 mg) and acetyl chloride (0.27 ml) in a similar manner to that of Preparation 1 (5).
Reaction SMILES: COCCOC[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]([CH2:24][C:25]3[CH:26]=[C:27]([C:31]4[CH:36]=[CH:35][C:34]([CH2:37][CH:38]5[S:42][C:41](=[O:43])[NH:40][C:39]5=[O:44])=[CH:33][CH:32]=4)[CH:28]=[CH:29][CH:30]=3)[CH3:23])=[O:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.S(=O)(=O)(O)O>CO>[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]([CH2:24][C:25]3[CH:26]=[C:27]([C:31]4[CH:36]=[CH:35][C:34]([CH2:37][CH:38]5[S:42][C:41](=[O:43])[NH:40][C:39]5=[O:44])=[CH:33][CH:32]=4)[CH:28]=[CH:29][CH:30]=3)[CH3:23])=[O:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1
Reactant: COCCOCOc1ccc(-c2ccc(C(=O)N(C)Cc3cccc(-c4ccc(CC5SC(=O)NC5=O)cc4)c3)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)c1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.9 %

Procedure:
1.6 g of 4′-(2-methoxyethoxymethoxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbiphenyl-4-carboxamide, 100 ml of methanol and 1 ml of 98% sulphuric acid are introduced, in order, into a 250 ml three-necked flask. The mixture is stirred at room temperature for 18 hours. The reaction medium is concentrated. It is taken up in ethyl acetate and it is washed twice with water. The organic phase is dried over magnesium sulphate. After filtration and evaporation, the product obtained is recrystallized from an acetone/dichloromethane mixture. After filtration and drying, 1.34 g (99%) of 4′-hydroxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbiphenyl-4-carboxamide are obtained in the form of a white powder having a melting point of 211–213° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3].[CH2:8]([O:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][N:18]([C@H:21]2[C:25]([F:27])([F:26])[C@H:24]([OH:28])[C@@H:23]([CH2:29][OH:30])[O:22]2)[C:17](=[O:31])[N:16]=1)=[O:13])[CH:9]=[CH2:10].C(N(CC)C(C)C)(C)C>CC#N>[CH2:8]([O:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][N:18]([C@H:21]2[C:25]([F:26])([F:27])[C@H:24]([O:28][C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3])[C@@H:23]([CH2:29][OH:30])[O:22]2)[C:17](=[O:31])[N:16]=1)=[O:13])[CH:9]=[CH2:10]
Reactant: C=CCOC(=O)Cl
Reactant: C=CCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](OC(=O)OCC=C)C2(F)F)c(=O)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
Allyl chloroformate (0.23 mL, 2.2 mmol) was added to a solution of 1 (694 mg, 2 mmol), N,N-diisopropylethylamine (0.7 mL, 4 mmol) in 20 mL MeCN at 0° C. The reaction mixture was stirred at 0° C. for 4 h and concentrated in vacuo. The crude residue was purified by flash column chromatography (2:1→4:1 EtOAc/Hexane) to give 2 (white solid, 65% yield): 1H NMR (400 MHz, DMSO-d6) δ11.05 (s, 1H), 8.19-8.22 (d, 1H), 7.16-7.18 (d, 1H), 6.32-6.37 (t, 1H), 5.93-6.05 (m, 2H), 5.43 (s, 1H), 5.27-5.39 (m, 5H), 4.74-4.75 (d, 2H), 4.67-4.69 (d, 2H), 4.31-4.33 (m, 1H), 3.82-3.84 (m, 1H), 3.73-3.76 (m, 1H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5]3=[C:6]([CH2:11][CH2:12][C:13](=[O:14])[N:4]3[CH2:3][CH2:2]1)[CH:7]=[CH:8][CH:9]=2.[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>>[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:8]1[CH:9]=[C:10]2[C:5]3=[C:6]([CH2:11][CH2:12][C:13](=[O:14])[N:4]3[CH2:3][CH2:2][CH2:1]2)[CH:7]=1)=[O:21]
Reactant: O=C1CCc2cccc3c2N1CCC3
Reactant: O=C(Cl)CCCCCl
Product: O=C(CCCCCl)c1cc2c3c(c1)CCC(=O)N3CCC2

Procedure:
Using 2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one and 5-chlorovaleryl chloride according to the same method as that of Reference Example 1, the title compound (3.53 g) was obtained as colorless crystals having a melting point of 83–84° C.