Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12]([CH2:14][C:15]([NH2:17])=[O:16])#[N:13]>N1CCCCC1.Cl.C(O)C>[C:12]([C:14](=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1)[C:15]([NH2:17])=[O:16])#[N:13]
Reactant: COc1cc(C=O)ccc1O
Reactant: N#CCC(N)=O
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(C=C(C#N)C(N)=O)ccc1O
Temperature: 25 °C

Procedure:
A reaction mixture of vanillin (1.52 g, 0.01 mol), α-cyanoacetamide (0.84 g, 0.01 mol), ethanol (25 mL) and piperidine (6 drops) is heated at reflux for 1 hour and then allowed to cool to room temperature. The reaction mixture is acidified to pH of about 3-4 by addition of a few drops of concentrated HCl. The product which is collected by filtration, washed with ethanol and dried in air has the following structure supported by mass spectrometry: ##STR23## The yield of product is 1.5 g (68.8%). In methylene chloride the product has an absorption maximum of 352 nm.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=[CH:4][CH:3]=1.[O:15]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][C:21]=2/[CH:26]=[CH:27]/[C:28](O)=[O:29])=[CH:16]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O>[O:15]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][C:21]=2/[CH:26]=[CH:27]/[C:28]([NH:1][C:2]2[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:8][CH3:9])[O:10][CH3:11])=[CH:4][CH:3]=2)=[O:29])=[CH:16]1
Reactant: Cn1ncc(/C=C/C(=O)O)c1-c1ccoc1
Reactant: COP(=O)(Cc1ccc(N)cc1)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COP(=O)(Cc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccoc2)cc1)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
A mixture of dimethyl 4-aminobenzylphosphonate (258 mg), (2E)-3-[5-(3-furyl)-1-methyl-1H-pyrazol-4-yl]acrylic acid (218 mg), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (184 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230 mg) and N,N-dimethylformamide (8 mL) was stirred overnight at room temperature. The reaction mixture was poured into a 0.5N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and then with saturated brine, dried (MgSO4) and concentrated. The obtained solid was recrystallized from ethyl acetate-hexane to give dimethyl 4-{[(2E)-3-[5-(3-furyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl]amino}benzylphosphonate (123 mg, yield 30%) as colorless prism crystals. melting point: 176-177° C.
Reaction SMILES: [Li]CCCC.Br[C:7]1[S:11][CH:10]=[N:9][C:8]=1[O:12][CH2:13][CH:14]1[CH2:16][O:15]1.[CH3:17][CH:18]([Si:20](Cl)([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH3:19]>C1COCC1>[CH:18]([Si:20]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[C:10]1[S:11][C:7]2[CH:14]([CH2:16][OH:15])[CH2:13][O:12][C:8]=2[N:9]=1)([CH3:19])[CH3:17]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Brc1scnc1OCC1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](c1nc2c(s1)C(CO)CO2)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
At −78° C., a soln. of n-BuLi in hexanes (2.18 M, 16.7 mL, 36.4 mmol) was added over 30 min to a soln. of 5-bromo-4-(oxiran-2-ylmethoxy)thiazole (7.17 g, 30.4 mmol) in THF (564 mL). The mixture was stirred at −78° C. for 2 h, then, TIPSCl (6.63 mL, 31.0 mmol) was added, the mixture was allowed to warm to RT and stirred at RT for 30 min. Subsequently, the mixture was cooled to −78° C. and treated with a soln. of n-BuLi in hexanes (2.18 M, 13.9 mL, 30.4 mmol). The mixture was stirred at 0° C. for 2 h, then, it was quenched with aq. sat. NaHCO3 and extracted with EtOAc. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo. The residue was purified by means of CC (100 g KP-Sil, EtOAc/Hept 5-50%), followed by CC (5-50% EtOAc/Hept) to provide a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[N:18]=[CH:17]3)[CH:10]([NH2:12])[CH3:11])[CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.[NH4+].[Cl-]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[N:18]=[CH:17]3)[CH:10]([NH:12][S:39]([CH:36]2[CH2:38][CH2:37]2)(=[O:41])=[O:40])[CH3:11])[CH:6]=[CH:5][N:4]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: COc1cc(C(Oc2ccc3c(cnn3-c3cccnc3)c2)C(C)N)ccn1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(Oc2ccc3c(cnn3-c3cccnc3)c2)C(C)NS(=O)(=O)C2CC2)ccn1
Reaction time: 20 h

Procedure:
To a stirred solution of 1-[2-methoxypyridin-4-yl]-1-[1-(pyridin-3-yl)indazol-5-yl]oxypropan-2-amine (41 mg, 110 μmol) in dichloromethane (4 ml) was added triethylamine (36 μl), followed by cyclopropanesulfonic acid chloride (23 mg, i 60 μmol) and DMAP (1.3 mg, 11 μmol).The stirring was continued for 20 h at room temp. The reaction mixture was poured into sat. NH4Cl solution and extracted with dichloromethane then the solvent was removed i.vac., and the product purified by chromatography on silica gel. Yield 4 mg (7.6%) as a racemic mixture of one diastereomer.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:11][C:10](=[O:12])[O:9][C:8]([CH3:14])([CH3:13])[C:7]=2[CH:15]=1.B(Br)(Br)Br.C(O)C>C(Cl)CCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:11][C:10](=[O:12])[O:9][C:8]([CH3:13])([CH3:14])[C:7]=2[CH:15]=1
Reactant: COc1ccc2c(c1)C(C)(C)OC(=O)N2
Agent: BrB(Br)Br
Solvent: ClCCCl
Solvent: CCO
Product: CC1(C)OC(=O)Nc2ccc(O)cc21
Reaction time: 8 h

Procedure:
An amount of 237.5 gm (1.146 mol) of 6-methoxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one is dissolved in 2.4 liters of dry ethylene chloride, and 125 ml (330.3 gm=1.3 mol) of boron tribromide are added thereto dropwise, under stirring, at -30° to -40° C. After the addition is complete, the mixture is allowed to return to ambient temperature and left overnight. Then, 1 liter of 50% ethanol is added dropwise, under cooling and stirring, and the mixture is evaporated down to about 500 ml and then diluted with 3 liters of water. The precipitate is subjected to suction filtration and dried.
Reaction SMILES: [C:1]([C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([O:32][CH2:33][CH3:34])[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:38][O:39][NH2:40].N1C=CC=CC=1>CO>[CH2:33]([O:32][CH:27]([CH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:18][CH2:17][N:13]2[C:12]3[CH:35]=[CH:36][C:9]([C:1](=[N:40][O:39][CH3:38])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11]=3[S:15][C:14]2=[O:16])=[CH:21][CH:22]=1)[C:28]([O:30][CH3:31])=[O:29])[CH3:34]
Reactant: CON
Reactant: CCOC(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)C(=O)OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CCOC(Cc1ccc(OCCn2c(=O)sc3cc(C(=NOC)c4ccccc4)ccc32)cc1)C(=O)OC

Procedure:
To 30 ml of methanol add the compound obtained in Step C (0.00198 mol), O-methyl-hydroxylamine hydrochloride (0.00594 mol) and pyridine (0.00594 mol). Heat at reflux for 3 hours. Evaporate to dryness. Add 100 ml of hydrochloric acid (1N) and then extract with 50 ml of dichloromethane twice. The organic phase is dried over MgSO4 and then evaporated to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])[CH3:24]
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 76.7 %

Procedure:
To a solution of 4-bromo-2-nitro-phenol (3.28 g, 15.0 mmol, 1 equiv) in dimethylformamide (40 mL) at 23° C. was added potassium carbonate (4.14 g, 30 mmol, 2 equiv) followed by ethyl bromoacetate (1.84 mL, 16.6 mmol, 1.1 equiv). The resulting mixture was warmed to 60° C. (oil bath) for 90 min then cooled to 23° C. The reaction mixture was partitioned between ethyl acetate:heptane (1:1) and water (100 mL each). The organic layer was separated and washed successively with water, saturated brine solution (100 ml, each) then dried (MgSO4), filtered and concentrated to give 4.50 g (11.5 mmol, 77%) of the product as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C)C=O>[C:23]([Si:20]([O:19][CH2:18][CH2:17][O:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=1)([CH3:22])[CH3:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1cc(C)cc(O)c1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(OCCO[Si](C)(C)C(C)(C)C)c1

Procedure:
To a solution of 3,5-dimethyl-phenol (3.000 g, 24.55 mmol) in N,N-dimethylformamide (120 mL) under nitrogen were added potassium carbonate (16.96 g, 122.7 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (7.90 mL, 36.8 mmol). The resulting slurry was heated at reflux for 20 hours; then, the solvent was removed under high vacuum. The residue was dissolved in ethyl acetate and the solution was backwashed with 0.2 N aqueous sodium hydroxide, water, and then brine, dried over sodium sulfate, and concentrated. The crude material (5.69 g) was purified by column chromatography (silica gel 230-400 mesh; methylene chloride as eluent) to give tert-butyl-[2-(3,5-dimethyl-phenoxy)-ethoxy]-dimethylsilane as light yellow oil. Yield: 3.72 g (47%).
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[H-].[Na+].[N+]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:18]=1[C:19]#[N:20])([O-])=O>CS(C)=O>[N+:25]([C:21]1[CH:22]=[CH:23][CH:24]=[C:17]([O:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:18]=1[C:19]#[N:20])([O-:27])=[O:26]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: OCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CS(C)=O
Product: N#Cc1c(OCCOc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99.7 %

Procedure:
2-Phenoxyethanol (4.15 ml, 0.033 mole) is added to dimethylsulfoxyl sodium prepared from 1.39 g of 57 per cent sodium hydride and 40 ml dimethylsulfoxide, giving a mixture of the solid salt of the alcohol after about 20 minutes. This mixture is added to a solution of 5.8 g (0.030 mole) 2,6-dinitrobenzonitrile in 20 ml of dimethylsulfoxide at 30°-40°C., and the resulting purple solution is stirred over night at room temperature. The solvent is removed at 70°C. on a rotary evaporator, and the residue is triturated with water. A solid is filtered off and it is dissolved in ethylacetate. The ethylacetate solution is washed twice with H2O, brine, and dried with calcium sulfate. Evaporation of the ethylacetate, gives 8.5 g of 2-nitro-6(2-phenoxyethoxy)-benzonitrile, which is crystallized from 200 ml ethyl alcohol, giving 6 g, m.p. 129°-137.5°C.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br.[K+].[Br-]>>[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][N:15]1[C:14]2[CH:18]=[C:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:20]=[CH:21][C:13]=2[O:12][CH:11]([CH2:10][CH2:9][OH:1])[C:16]1=[O:17]
Reactant: Clc1cccc(CBr)c1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccc(-c3ccccc3)cc2NC1=O
Agent: [Br-]
Agent: [K+]
Product: O=C1C(CCO)Oc2ccc(-c3ccccc3)cc2N1Cc1cccc(Cl)c1

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-6-phenyl-2H-1,4-benzoxazine by Methods F and G, alkylating with 3-chlorobenzyl bromide, to afford a white crystalline solid in 27% overall yield, mp 119°-121° C.; IR (KBr) 3517, 1659, 1487, 1435, 1387, 1282, 1260, 1060, 760 cm-1 ; 1H NMR (CDCl3) δ2.22-2.38 (m, 3H), 3.95 (v br s, 2H), 4.90 (dd, J=7.6, 5.5 Hz, 1H), 5.18 (ABq, JAB =17.1 Hz, 2H), 7.04 (d, J=1.9 Hz, 1H), 7.08 (d, J=8.3 Hz, 1H), 7.15-7.42 (m, 10H); MH+ at m/z=394; Anal. Calc'd for C23H20 ClNO3 : C, 70.14; H, 5.12; N, 3.56. Found: C, 70.10; H, 5.11; N, 3.51.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[N:23]1[S:24][N:25]=[C:26]2[CH:31]=[C:30]([N:32]=[C:33]=[S:34])[CH:29]=[CH:28][C:27]=12.C(N(CC)CC)C>>[CH3:1][CH2:2][N:3]1[C:9]2[C:8](=[CH:13][N:12]=[C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:33]([NH:32][C:30]4[CH:29]=[CH:28][C:27]5[C:26](=[N:25][S:24][N:23]=5)[CH:31]=4)=[S:34])[CH2:16][CH2:15]3)[N:10]=2)[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Reactant: S=C=Nc1ccc2nsnc2c1
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4ccc5nsnc5c4)CC3)nc21

Procedure:
Pipemidic acid (25 mg, 0.0824 mmol), 2,1,3-benzothiadiazol-5-yl isothiocyanate (15.8 mg, 0.0824 mmol) and triethylamine (23 μL, 0.165 mmol) were used. Purification on silica yielded compound 7 in Table 1, below (24 mg, 58%). 1H NMR (300 MHz, DMSO) δ 9.26 (s, 1H), 8.98 (s, 1H), 7.98-7.82 (m, 3H), 4.51-4.33 (m, 2H), 4.24-3.99 (m, 8H), 1.42-1.32 (m, 3H) ppm.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[Br:16][C:17]([CH2:19]Br)=[CH2:18].[H-].[Na+]>O1CCCC1.C(OCC)(=O)C>[Br:16][C:17](=[CH2:18])[CH2:19][CH2:2][C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:3]
Reactant: C=C(Br)CBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(Br)CCC(=O)NC(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To a stirred mixture of diethyl acetamidomalonate (217 g, 1.0 mol) and 2,3-dibromopropene (240 g, 1.2 mol) in anhydrous tetrahydrofuran (2.50 L), under nitrogen, was added sodium hydride (26.4 g, 1.1 mol) in several portions. The reaction mixture was stirred at ambient temperature for 30 minutes, then heated to reflux. After heating for 18 hours, the resultant slurry was cooled to ambient temperature and suction filtered through a short pad of silica gel. The solid residue was washed with tetrahydrofuran (2×50 mL), and the filtrates were combined and concentrated. The residue obtained was dissolved in ethyl acetate (2.0 L), washed with water and brine, and then was dried over magnesium sulfate. Filtration and concentration gave a yellow oil which solidified upon drying. The resultant solid was recrystallized from a mixture of hot ethyl acetate/hexane to give 301 g (89%) of the desired product: m.p. 85°-87° C. 1H NMR (300 MHz, CDCl3) δ 1.28 (t, J=7.4 Hz, 6H), 2.04 (s, 3H), 3.57 (s, 2H), 4.27 (m, 4H), 5.55 (bs, 1H), 5.61 (bs, 1H) , 6.82 (broad, 1H); IR (KBr) 1745, 1635 cm-1. Anal calcd for C12H18BrNO5 : C, 42.87; H, 5.40; Br, 23.77; N, 4.12. Found: C, 43.25; H, 5.56; Br, 22.97; N, 4.12.
Reaction SMILES: [CH:1]1([C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12]3[C:13]4[N:14]([CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:16][C:17]=3[C:18]([OH:20])=O)=[C:7]([F:24])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:55]([O:57][CH2:58][CH2:59][O:60][NH2:61])=[CH2:56]>C1COCC1>[CH:55]([O:57][CH2:58][CH2:59][O:60][NH:61][C:18]([C:17]1[CH:16]=[CH:15][N:14]2[CH:21]=[N:22][CH:23]=[C:13]2[C:12]=1[NH:11][C:8]1[CH:9]=[CH:10][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:6][C:7]=1[F:24])=[O:20])=[CH2:56]
Reactant: C=COCCON
Reactant: O=C(O)c1ccn2cncc2c1Nc1ccc(C2CCC2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1ccn2cncc2c1Nc1ccc(C2CCC2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.9 %

Procedure:
A suspension of 8-(4-cyclobutyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid (154 mg, 0.46 mmol), EDCI (105 mg, 0.55 mmol), HOBt (74 mg, 0.55 mmol), DIPEA (0.19 mL, 1.14 mmol) and O-(2-vinyloxy-ethyl)-hydroxylamine (52 mg, 0.50 mmol) in THF (2.5 mL) was stirred at room temperature for 18 hours. The reaction mixture was partitioned between DCM (20 mL) and saturated aqueous NaHCO3. The organic layer was isolated then washed with water (20 mL), followed by brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The resultant gum was subjected to flash chromatography (Si-PPC, gradient 0% to 100%, ethyl actetate in cyclohexane) to afford the title compound as a brown gum (149 mg, 80%). LCMS (method B): RT=3.49 min, [M+H]+=411.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[H-].[Na+].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CN(C=O)C>[CH2:10]([N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1NCCN1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 15.6 %

Procedure:
Step 1 A solution of imidazolidin-2-one (500 mg, 5.81 mmol) in DMF (30 mL) was stirred on ice and treated with sodium hydride, 60% oil dispersion (264 mg, 6.60 mmol). The mixture was stirred at rt for 50 min, then was treated with (bromomethyl)benzene (0.691 mL, 5.81 mmol). After 2 h, the mixture was poured into water and extracted three times with EtOAc. The combined organic layers were dried and concentrated, and the residue was purified by column chromatography (eluting with EtOAc) to provide 1-benzylimidazolidin-2-one as a white solid (160 mg, 16%). 1H NMR (400 MHz, chloroform-d) δ 7.22-7.39 (5 H, m), 4.53 (1 H, br. s.), 4.37 (2 H, s), 3.25-3.46 (4 H, m).
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]#[N:17])[C:10]([C:18]#[N:19])=[CH:9]2)[CH2:2][CH2:3][CH3:4].C[O-].[Na+].[Na].[NH3:24]>CO>[CH2:1]([S:5][C:6]1[CH:15]=[CH:14][C:13]2=[CH:12][C:11]3[C:16](=[NH:24])[NH:17][C:18](=[NH:19])[C:10]=3[CH:9]=[C:8]2[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSc1ccc2cc(C#N)c(C#N)cc2c1
Reactant: N
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCCCSc1ccc2cc3c(cc2c1)C(=N)NC3=N

Procedure:
In an atmosphere of nitrogen, 30.0 g (0.11 mole) of 6-n-butylthio-2,3-dicyanonaphthalene was added to a solution of sodium methoxide in methanol prepared by adding 1.46 g (64 mmoles) of metallic sodium in 5 portions to 350 ml of anhydrous methanol. While thoroughly stirring the mixture, anhydrous ammonia gas was slowly bubbled at room temperature over a period of about one hour. Then, the mixture was refluxed for about 3 hours, while bubbling anhydrous ammonia gas. After cooling, the yellow solid precipitated was filtered and the residue was thoroughly washed with methanol and dried under reduced pressure to obtain 30 g of 6-n-butylthio-1,3-diiminobenz[f]isoindoline as a yellow solid. FIG. 6 illustrates its IR spectrum. Without further purification, it was used in the subsequent reaction.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]([CH3:21])[NH:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:10][CH:9]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][CH2:2][CH2:3][C:4]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]([CH3:21])[NH:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:12][CH:13]=1)=[O:5]
Reactant: O=C(Cl)CCCl
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1NC(=O)NN=C1c1ccc(NC(=O)CCCl)cc1
Reaction time: 0.5 h

Procedure:
β-Chloropropionyl chloride (1.25 ml) was added dropwise to a stirred solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.04 g) and triethylamine (1.53 ml) in N,N-dimethylformamide (DMF) (10.5 ml) under ice cooling and the stirring was continued for 30 minutes. The solution was evaporated in vacuo and the residue as triturated with water under ice-cooling. The precipitates were collected by filtration, washed with water and dried to give 6-[4-(β-chloropropionylamino)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.55 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:21][CH2:20][CH:19]([C:22](OC)=[O:23])[CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[BH4-].[Na+].O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([S:13]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]2)(=[O:14])=[O:15])=[CH:11][CH:12]=1
Reactant: COC(=O)C1CCN(S(=O)(=O)c2ccc(-c3ccccn3)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=S(=O)(c1ccc(-c2ccccn2)cc1)N1CCC(CO)CC1

Procedure:
To a stirred solution of methyl 1-{[4-(pyridin-2-yl)phenyl]sulfonyl}piperidine-4-carboxylate (0.40 g, 1.11 mmol) in anhydrous methanol (8 mL) is added sodium borohydride (0.59 g, 15.5 mmol). After 18 h water (20 mL) is added. The resulting solid is filtered, washed with water and suspended in MeCN. The suspension is concentrated under reduced pressure to give 0.26 g (72%) of 1-{[4-(pyridin-2-yl)phenyl]sulfonyl}piperidin-4-yl)methanol. m/z=333 [M++H].
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16]Cl>>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][O:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(O)cc1
Reactant: COCCOCCl
Product: COCCOCOc1ccc(CC#N)cc1
Yield: 75.6 %

Procedure:
4-Hydroxybenzyl cyanide (4.3 g) and 2-methoxyethoxymethyl chloride (4.1 g) were subjected to reaction in accordance with (production process 1), to thereby produce 4-methoxyethoxymethoxybenzyl cyanide (5.4 g, yield: 75%). The thus-produced 4-methoxyethoxymethoxybenzyl cyanide (2.1 g) and 4-methoxyethoxymethoxybenzaldehyde (2.0 g) produced in the production process for compound 1 were subjected to condensation in accordance with process A of (production process 2), to thereby yield an MEM form of the target product. Subsequently, the protective group was removed from the MEM form in accordance with (production process 3), to thereby produce the target product (1.1 g, yield: 49%).
Reaction SMILES: [Na].Cl.[NH2:3]O.[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7]([CH2:14][C:15](Cl)=[N:16][OH:17])=[N:6]1>C(O)C>[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7]([CH2:14][C:15](=[N:16][OH:17])[NH2:3])=[N:6]1
Reactant: ON=C(Cl)Cc1noc2ccccc12
Reactant: NO
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: NC(Cc1noc2ccccc12)=NO
Yield: 45.4 %

Procedure:
In ethanol (10 ml) was dissolved metal sodium (0.4 g) and thereto was further added hydroxylamine hydrochloride (0.8 g). To the solution was added a solution of 1,2-benzisoxazole-3-acetohydroximic chloride (5.0 g) in ethanol (40 ml) under ice-cooling and the mixture was stirred for hour. The mixture was distilled under a reduced pressure to remove the solvent. To the residue was added chloroform and the insoluble substance was filtered off, and the filtrate was subjected to silica gel column chromatography and eluted with 5 % methanol-chloroform. The resulting precipitated crystallines were separated by filtration and recrystallized from ethanol to give the desired compound (1.0 g). m.p. 161° to 163°C.