Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[CH2:21]Cl.[NH:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[CH2:21][N:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(CCl)c3cc(Br)ccc32)cc1
Reactant: C1CNCCNC1
Product: Cc1ccc(S(=O)(=O)n2cc(CN3CCCNCC3)c3cc(Br)ccc32)cc1

Procedure:
Using essentially the same procedure as described in example 127, 5-Bromo-1-(4-methylbenzenesulfonyl)-3-chloromethyl-1H-indole was reacted with homopiperazine to obtain the above derivative.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]1[O:21][C:14]2([CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)[O:13][CH2:12]1>[OH-].[K+]>[CH2:11]1[O:21][C:14]2([CH2:19][CH2:18][C:17]([C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][CH:6]=3)=[CH:16][CH2:15]2)[O:13][CH2:12]1
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [K+]
Agent: [OH-]
Product: Fc1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Yield: 92.4 %

Procedure:
5-Fluoroindole (5.4 g, 0.04 mol), 1,4-cyclohexanedione monoethylene ketal (12.5 g, 0.08 mol) were placed in 60 ml of 2N potassium hydroxide methanolic solution. The reaction mixture were heated to reflux for 4 hours. The reaction was cooled and the product was isolated by filtration and washed with methanol to give 10.1 g (93%) of product as a white solid: mp 153-155° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH3:16])[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH3:16])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCON=C(C(=O)OCC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCON=C(C(=O)O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.6 %

Procedure:
I.R.νmaxNujol : 3450, 3275, 3125, 1715, 1620 cm-1. (3) Ethyl 2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetate (syn isomer, 5 g.) was added to a mixture of 1N sodium hydroxide (45.9 ml.) and ethanol (30 ml.) and stirred at room temperature for 5 hours. After removing ethanol from the resultant solution under reduced pressure, the residue was dissolved in water (60 ml.) and adjusted to pH 2.0 with 10% hydrochloric acid. The solution was subjected to salting-out, and the precipitates were collected by filtration and dried to give 2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetic acid (syn isomer, 2.9 g.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:9]([O:13][C:14](ON=C(C1C=CC=CC=1)C#N)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C(Cl)(Cl)Cl>[C:9]([O:13][C:14]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCCCCCCO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCCCCCO
Yield: 106.7 %

Procedure:
Four grams of 6-amino-1-hexanol (34.1 mmols) was dissolved in 30 ml of chloroform and ice-cooled. Seven grams of 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-ON) dissolved in 20 ml of chloroform was added, and the mixture was ice-cooled and reacted for 16 hours. Chloroform was evaporated, and the residue was separated and purified by silica gel column chromatography to obtain 6.59 g of the captioned compound. Yield: 89 %.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2([CH3:12])[CH3:11])=[CH:4][CH:3]=1.CCCCCC.C[CH2:20][O:21]C(C)=O>>[CH3:11][C:8]1([CH3:12])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([CH:20]=[O:21])[CH:10]=2)[CH2:6][O:7]1
Reactant: CCOC(C)=O
Reactant: CC1(C)OCc2ccc(Br)cc21
Solvent: CCCCCC
Product: CC1(C)OCc2ccc(C=O)cc21

Procedure:
The title compound is prepared in analogous manner as described for example 47a from 6-bromo-1,1-dimethyl-1,3-dihydro-isobenzofuran to yield a light yellow oil: TLC (hexane-EtOAc 1:1) Rf=0.50; HPLC RtA=1.43 min; 1H NMR (400 MHz, CDCl3): δ10.02 (s, 1H), 7.78 (d, 1H), 7.65 (s, 1H), 7.36 (d, 1H), 5.11 (s, 2H), 1.53 (s, 9H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])(=[O:25])=[O:24])=[CH:19][CH:18]=1)CC.[OH-].[Na+].Cl>CO>[OH:4][CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:7]=1[C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])(=[O:24])=[O:25])=[CH:19][CH:18]=1
Reactant: CCCOCc1onc(-c2ccccc2)c1-c1ccc(S(=O)(=O)NC(=O)CC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(=O)NS(=O)(=O)c1ccc(-c2c(-c3ccccc3)noc2CO)cc1
Reaction time: 12 h
Yield: 83 %

Procedure:
The N-[[4-(5-propoxymethyl-3-phenylisoxazol-4-yl]phenyl]sulfonyl]propanamide (Step 1) was dissolved in methanol and NaOH solution (0.89 mL of 2.5 N, 2.24 mmol) added with stirring. After 12 hours, the reaction was acidified with 1 N HCl solution and extracted with a mixture of dichloromethane and ethyl acetate. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo yielding N-[[4-(5-hydroxymethyl-3-phenylisoxazol-4-yl]phenyl]sulfonyl]propanamide (0.238 g, 83%) of sufficient purity to use in the next step.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([NH:16][C:17](=[O:25])OC3C=CC=CC=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH2:39][CH2:40][O:41][CH3:42])[N:34]=[CH:33][N:32]=[C:31]2[O:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH2:47]>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH2:39][CH2:40][O:41][CH3:42])[N:34]=[CH:33][N:32]=[C:31]2[O:43][C:44]1[CH:45]=[C:46]([NH:47][C:17]([NH:16][C:9]2[CH:10]=[C:11]([C:12]([F:13])([F:14])[F:15])[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[O:25])[CH:48]=[CH:49][CH:50]=1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C(F)(F)F)n(-c2ccccc2)n1)Oc1ccccc1
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)n(-c5ccccc5)n4)c3)c2cc1OC
Yield: 58 %

Procedure:
The title compound was prepared as described in Example 169C using phenyl 1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamate described in Example 169B (0.115 g, 0.33 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (0.112 g, 0.33 mmol), to afford 1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]urea as solid (0.114 g, 58%). 1H NMR (300 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.99 (s, 1H), 8.56 (s, 1H), 7.58 (m, 7H), 7.42 (m, 2H), 7.27 (d, 1H), 7.13 (s, 1H), 6.97 (d, 1H), 4.35 (m, 2H), 4.00 (s, 3H), 3.78 (m, 2H), 3.35 (s, 3H); LC-MS (ESI) m/z 595 (M+H)+.
Reaction SMILES: I[CH2:2][CH3:3].[OH:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[Cl:21])[CH:13]=2)=[O:11])[CH2:6]1>>[Cl:21][C:18]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:13]=[C:12]([C:10]([N:7]3[CH2:8][CH2:9][C@H:5]([O:4][CH2:2][CH3:3])[CH2:6]3)=[O:11])[S:20][C:19]=12
Reactant: CCI
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@H](O)C1
Product: CCO[C@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1

Procedure:
The title compound was prepared from iodoethane and (3S)-(3-hydroxy-pyrrolidin-1-yl)-[7-chloro-thieno[3,2-b]pyridin-2-yl]-methanone by a procedure analogous to Example 67B. MS: 311.2/313.2 (MH+); HPLC Rf: 4.692 min.; HPLC purity: 96%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH:9]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: C1CNCCNC1
Reactant: Fc1ccc(Br)cn1
Solvent: CC#N
Product: Brc1ccc(N2CCCNCC2)nc1
Yield: 50.3 %

Procedure:
A solution of 5-Bromo-2-fluoro-pyridine (2.0 g, 11.4 mmol), [1,4]Diazepane (2.2 g, 22.8 mmol) in CH3CN (5.0 mL) was stirred at 50° C. for 3 hrs. Filter of the solid and the mother solution was brine, and concentrated in vacuo to give the title product (1.47 g, 51%) as a brown solid. ESI MS m/z 256 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J=7.0 Hz, 1H), 7.45 (dd, J=22.0, 6 Hz, 1H), 6.38 (d, J=22.0 Hz, 1H), 3.66 (m, 4H), 2.81 (t, J=15.0 Hz, 2H), 1.86 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Oc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-Chloro-3-nitrophenol (2.0 g, 0.012 mol), phenylboronic acid (3.5 g, 0.029 mol), TEA (9.6 mL, 0.069 mol), cupric acetate (3.3 g, 0.018 mol) and DCM (100 mL, 2 mol) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 48 h. The solvent was then removed under reduced pressure and the resulting residue was purified by flash chromatography (5% EtOAc in Hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9](OS(C)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br-:19].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([Br:19])[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: [Br-]
Reactant: COC(=O)C(OS(C)(=O)=O)c1cc(Cl)cc(Cl)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(Br)c1cc(Cl)cc(Cl)c1
Yield: 102.5 %

Procedure:
A solution of methyl 2-(3,5-dichlorophenyl)-2-mesyloxyacetate (8.2 g) in dimethylformamide (30 ml) was treated with potassium bromide (4.0 g) at 50° C. for 1.5 hours. The reaction mixture was partitioned between water (200 ml) and ethyl acetate (300 ml). The organic phase was separated and washed twice with water (2×200 ml) and finally with saturated brine solution (200 ml). The ethyl acetate solution was dried and concentrated to dryness giving crude methyl 2-(3,5-dichlorophenyl)-2-bromoacetate (8 g). Filtration through a column of silica gel using dichloromethane as eluent gave the pure substance as an oil (7.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][C:11]2([CH3:21])[CH3:20])[CH:8]=[N:7][CH:6]=1)=[O:4].[OH-:22].[Na+]>O>[CH3:1][O:2][C:3]([C:5]1[N:9]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:22])[CH2:12][C:11]2([CH3:21])[CH3:20])[CH:8]=[N:7][CH:6]=1)=[O:4]
Reactant: [OH-]
Reactant: COC(=O)c1cncn1C1c2ccccc2CCC1(C)C
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cncn1C1c2ccccc2C(=O)CC1(C)C
Yield: 28.2 %

Procedure:
142 g of 1-(2,2-dimethyl-tetralin-1-yl)-5-imidazolecarboxylic acid methyl ester are dispersed in 1 liter of deionisized water. The suspension is heated to +87° C., and within a period of 1.5 hours a total of 335 g of ammoniaperoxodisulfate is added portionwise in such a manner, that the temperature does not exceed +90° C. After cooling the reaction mixture to +15° C., the pH-value is adjusted to pH 4 by addition of 335 g of a sodium hydroxide solution 30%. The mixture is extracted with 500 ml of methylene chloride. The organic phase is separated, dried with sodium sulfate, treated with activated carbon and concentrated. Crystallisation of the residue from diethyl ether yields 42 g of 1-(2,2-dimethyl-4-oxo-tetralin-1-yl)-5-imidazolecarboxylic acid methyl ester, having a melting point of 93°-95° C.
Reaction SMILES: [CH:1](=[N:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([Li])C=CC=CC=1.[Cl:25][C:26]([Cl:33])([Cl:32])[CH2:27][O:28][C:29](Cl)=[O:30].C(=O)=O>O1CCCC1.C1C=CC=CC=1.C(OCC)C>[CH:1](=[N:8][CH:9]([P:10]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])=[O:17])[C:29]([O:28][CH2:27][C:26]([Cl:33])([Cl:32])[Cl:25])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(CN=Cc1ccccc1)OCC
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C=O
Agent: [Li]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCOP(=O)(OCC)C(N=Cc1ccccc1)C(=O)OCC(Cl)(Cl)Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A solution of diethyl N-benzylidene-aminomethylphosphonate (12.738 g., 50 mmole) in dry tetrahydrofuran (250 ml.) is stirred in a dry ice-acetone bath and under a nitrogen atmosphere. Phenyllithium (25 ml. of a 2.0 M solution in 7:3 benzene-ethyl ether) is added via syringe. The resulting burgundy solution is stirred for 30 minutes at -78°C., then treated dropwise over 45 minutes with a solution of 2,2,2-trichloroethyoxycarbonyl chloride (5.30 g., 25 mmole) in dry tetrahydrofuran (50 ml.). After stirring the mixture for an additional 2 hours at -78°C., the dry ice bath is replaced by an ice water bath and stirring is continued for 1 hour. Evaporation of the solvent in vacuo leaves a yellow foam which is partitioned between ethyl ether (250 ml.) and aqueous phosphate (50 ml. of 1M pH 3 phosphate + 50 ml. water). The aqueous portion is separated and extracted with ethyl ether (2 × 50 ml.). The combined ethereal solution is washed with saturated brine (100 ml.), dried over magnesium sulfate, and evaporated in vacuo to yield a cloudy, yellow oil (17.1 g.). The crude product is purified by chromatography on silica gel (430 g., packed under ethyl ether). Elution with ethyl ether affords trichloroethyl N-benzylidene-α-amino-diethylphosphonoacetate (7.058 g.) as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:18][CH3:19])[C:15]([OH:17])=O)=[CH:8][CH:7]=2)#[CH:2].[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21].Cl.CN(C)CCCN=C=NCC.C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>[C:20]([NH:24][C:15](=[O:17])[CH:14]([O:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:1]#[CH:2])=[CH:12]2)[S:18][CH3:19])([CH3:23])([CH3:22])[CH3:21]
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)O)cc2c1
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(C)C)cc2c1

Procedure:
(3-Ethynyl-quinolin-6-yloxy)-methylsulfanyl-acetic acid (1.1 g), N-tert-Butyl amine (0.467 ml), 1-hydroxy-7-azabenzotriazole (HOAT) (0.602 mg), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCl) (849 mg) and triethylamine (0.84 ml) in dry N,N-dimethylformamide (20 ml) were stirred at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and poured on 60 ml aq. sat. sodium hydrogen carbonate. The water phase was extracted with 3×150 ml ethyl acetate. All organic layers were combined, dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (heptane/ethyl acetate 13:7) to give N-tert-Butyl-2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamide (1.11 g) as yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26](OC)=O)[CH:21]=3)[C:10](=[O:30])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Li+].[Cl:35]C(OCC)=O.[BH4-].[Na+].CS(Cl)(=O)=O>C1COCC1.ClCCl.C(OCC)(=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][Cl:35])[CH:21]=3)[C:10](=[O:30])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: COC(=O)c1cccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)c1
Agent: CS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)N1CC(=O)N(Cc2cccc(CCl)c2)c2ccccc2C1
Reaction time: 8 h

Procedure:
145 mg (0.32 mmol) of 4-(4-chlorobenzoyl)-1-(3-methoxycarbonylbenzyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on obtained in step 1 was dissolved in 3 ml of THF. 1.6 ml of 1 M aqueous lithium hydroxide solution was added to the obtained solution, and they were stirred overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was dissolved in 5 ml of THF. 0.1 ml (0.7 mmol) of triethylamine and 0.05 ml (0.5 mmol) of ethyl chloroformate were added to the obtained solution under cooling with ice, and they were stirred for 30 minutes. A piece of ice and 50 mg (1.4 mmol) of sodium borohydride were added to the obtained mixture. The temperature was elevated to room temperature, and the obtained mixture was stirred overnight. The solvent was evaporated, and the obtained crude product was dissolved in 8 ml of dichloromethane. 0.03 ml (0.22 mmol)) of triethylamine and 0.01 ml (0.13 mmol) of methanesulfonyl chloride were added to the obtained solution under cooling with ice, and they were stirred overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the crude product was obtained. After the purification by the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[NH2:9][C:10]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>O1CCOCC1>[F:19][C:16]1[CH:17]=[CH:18][C:10]2[NH:9][C:2](=[O:3])[O:13][C:12](=[O:14])[C:11]=2[CH:15]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(F)cc1C(=O)O
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(F)cc2c(=O)o1
Yield: 95.1 %

Procedure:
Trichloromethyl chloroformate (7.01 mL, 58.13 mmol) was added to a stirred solution of Compound 34 (8.2 g, 52.85 mmol) in dry dioxane at room temperature and the solution was refluxed for 4 h. The solution was cooled in an ice bath and the solids formed were filtered. The solids were washed by ether and dried under vacuum at room temperature to yield 9.1 g (96%) of white solids. M.P. 240° C. 1H NMR (DMSO-d6): δ 7.19 (dd, J=4.2, 8.9 Hz, 1H), 7.63–7.71 (m, 1H), 11.77 (s, 1H). EIMS (neg. mode) m/z 180 (M−1). Anal. (C8H4FNO3) C, H, N.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[OH:6][CH:7]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=1)=[O:9].CN1CCOCC1>ClCCl>[Br:1][CH2:2][C:3]([O:9][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=1)[C:7]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=1)=[O:6])=[O:4]
Reactant: CCc1ccc(C(=O)C(O)c2ccc(CC)cc2)cc1
Reactant: O=C(Cl)CBr
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCc1ccc(C(=O)C(OC(=O)CBr)c2ccc(CC)cc2)cc1
Reaction time: 1 h
Yield: 64.8 %

Procedure:
A solution of bromoacetyl chloride (2.00 mL, 24.2 mmol) in anhydrous dichloromethane (20 mL) was added dropwise to a cold (0° C.) mixture of 2-hydroxy-1,2-di-(4-ethylphenyl)ethanone (IX; 6.5 g, 24.2 mmol) and N-methylmorpholine (NMM; 2.7 mL, 24.2 mmol) in anhydrous dichloromethane (180 mL). The mixture was stirred at 0° C. for 1 hour and at ambient temperature for 2 hours before additional 2-hydroxy-1,2-di-(4-ethylphenyl)ethanone (0.5 mL) and NMM (0.6 mL) were added to aid in completeion. After 1 hour, the mixture was washed with saturated sodium bicarbonate solution, 1N HCl and brine. Following drying and solvent evaporation, the residue was purified by flash chromatography on silica gel (gradient elution with 10% ethyl acetate in hexanes followed by 25% ethyl acetate in hexanes) and furnished 6.10 g (65%) of bromoacetoxy-1,2-di(4-ethylphenyl)ethanone as a pal-yellow oil which was used in subsequent reactions without further purification.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH2:11][C:12]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][CH2:13]1.[CH2:20]([N:27]=[C:28]=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH2:20]([NH:27][C:28](=[O:29])[NH:10][CH2:11][C:12]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][CH2:13]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C1(CN)CC1
Reactant: O=C=NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1(CNC(=O)NCc2ccccc2)CC1
Yield: 95.7 %

Procedure:
According to the procedure described in the synthesis method of Compound V-1 with the modification that the reaction solvent was changed to CH2Cl2 and DIPEA (1.6 ml, 9.3 mmol) was added, ethyl 1-(aminomethyl)cyclopropanecarboxylate (880 mg, 6.2 mmol) was reacted with benzyl isocyanate (1.15 ml, 8.0 mmol) to obtain the title compound (1.64 g, 106%).
Reaction SMILES: C(=O)=O.[CH3:4][C:5]([CH3:7])=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[C:16]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1.[H-].[Na+].IC(C)C>CN(C)C=O>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[C:16]([C:22]2[N:23]=[N:24][N:25]([CH:5]([CH3:7])[CH3:4])[N:26]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn[nH]1
Reactant: CC(C)=O
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)I
Solvent: CN(C)C=O
Product: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(C(C)C)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a chilled (-78° C., dry ice-acetone) solution of ethyl 3,3-bis(4-fluorophenyl)-2-(1-H-tetrazol-5-yl)-2-propenoate (2.6 g, 7.3 mmoles) [prepared in Example 2] in 20 mL of dried N,N-dimethylformamide under argon was added NaH (0.44 g, 11.0 mmoles; 60% in mineral oil) followed by reagent grade 2-iodopropane (2.0 mL, 20.0 mmoles) in one single portion. The thick reaction mixture was stirred under argon at -78° C. for 30 minutes and the mixture was allowed to warm to room temperature slowly over a period of 16 hours. Analytical TLC eluted once with 50% ethyl acetate in hexanes showed only one spot at Rf =0.86. The white suspension was diluted with 40 mL of half saturated brine followed by 20 mL of ethyl acetate. The aqueous layer was washed with ethyl acetate (2×20 mL). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure. Analytical TLC eluted four times with 8% (v/v) ethyl acetate in hexanes showed two spots at Rf =0.38(21) and Rf =0.49 (21a). The desired products were purified by silica gel column chromatography eluted with 8% EtOAc in hexanes. The fast moving product was collected to give 1.64 g (56.5%) of the title compound. MS (CI): m/e=399 for (M+H)+ ;
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[CH2:12][CH2:13][NH:14][CH2:15][CH:4]2[C:3]1=[O:16].Cl.[N:18]1[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.CC(C)=O.C(N(CC)CC)C>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[CH2:12][CH2:13][N:14]([CH2:24][C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[CH2:15][CH:4]2[C:3]1=[O:16]
Reactant: ClCc1ccncc1
Reactant: CN1C(=O)C2CNCCN2c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1C(=O)C2CN(Cc3ccncc3)CCN2c2ccccc21

Procedure:
A solution of 6 g. (0.03 mole) of 2,3,4,4a-tetrahydro-6-methyl-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one, 5 g. (0.03 mole) of 4-picolyl chloride hydrochloride, 10 g. of potassium carbonate and 0.5 ml. of triethylamine was stirred and refluxed in 200 ml. of acetone overnight, cooled and filtered. The solvent was removed and the residue was dissolved in methylene chloride. This solution was washed with water and brine, dried over magnesium sulfate and filtered. The solvent was removed and the residue was chromatographed on 460 g. of Silicar, CC-7. Fractions eluted with 10% methanol in ethyl acetate afforded the product as a free base. This free base was dissolved in ethanol and treated with dry hydrogen chloride saturated ether. The product hydrochloride was filtered and recrystallized from methanol to yield 5.2 g. of the title compound as the dihydrochloride salt, m.p. 252°-254.5° C.