Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](OS(C(F)(F)F)(=O)=O)=[CH:8][CH:7]=1.[CH2:29]([Sn](CCCC)(CCCC)CCCC)[CH:30]=[CH2:31].[Cl-].[Li+]>CN(C)C=O.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:31][CH:30]=[CH2:29])=[CH:8][CH:7]=1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Yield: 92.2 %

Procedure:
Argon was passed through a solution of 7.0 g (0.0164 mol) of (S)-4-[[(trifluoromethyl)sulfonyl]oxy]-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]benzenepropanoic acid methyl ester, 5.7 g (0.0165 mol) of allyltributyl tin, and 1.42 g (0.04 mol) of lithium chloride in 50 mL of dimethylformamide for 10 minutes and 210 mg (0.0003 mol) of bis(triphenylphosphine)palladium dichloride was added. The bath temperature was raised to 90°-95° C. for 40 minutes and the mixture was allowed to cool. The mixture was diluted with ether and washed with water and saturated sodium chloride solution and dried over magnesium sulfate. The residue obtained after filtration and evaporation was purified by preparative liquid chromatography using silica gel cartridges on a Waters Prep 500 chromatograph, eluting with 10% ethyl acetate-hexane to give 4.83 g (92%) of (S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]-4-(2-propenyl)benzenepropanoic acid methyl ester, mp 56°-59° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:5])[CH2:4][O:3]1.[Br:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([OH:14])=[CH:9][C:8]=1[CH3:15].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([O:14][CH2:1][C:2]([CH3:5])([OH:3])[CH3:4])=[CH:9][C:8]=1[CH3:15]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC(C)(C)O)cc(C)c1Br
Temperature: 25 °C

Procedure:
In a microwave vial 2,2-dimethyloxirane (2.2 g) is added to a suspension of 4-bromo-3,5-dimethylphenol and K2CO3 (11 g) in N,N-dimethylformamide (6 mL). The vial is sealed and the mixture is heated for 48 hours to 120° C. After cooling to room temperature the mixture is partitioned between saturated aqueous Na2CO3 solution and ethyl acetate. The aqueous phase is extracted twice with ethyl acetate and the combined organic phases are dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 100:0→50:50) to give the title compound. Yield: 2.9 g; LC (method 4): tR=1.76 min; Mass spectrum (ESI+): m/z=273 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]3[C@@H:16]([CH3:17])[CH2:15][N:14]([CH2:18][CH3:19])[C:13](=[O:20])[C:9]3=[C:10]([O:11]C)[C:6]=2[C:5](=[O:21])[N:4]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)[N:3]=1.B(Br)(Br)Br.CO>ClCCl>[NH2:1][C:2]1[C:7]2[N:8]3[C@@H:16]([CH3:17])[CH2:15][N:14]([CH2:18][CH3:19])[C:13](=[O:20])[C:9]3=[C:10]([OH:11])[C:6]=2[C:5](=[O:21])[N:4]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)[N:3]=1
Reactant: CCN1C[C@H](C)n2c(c(OC)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(N)c32)C1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CCN1C[C@H](C)n2c(c(O)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(N)c32)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (6S)-4-amino-2-(3-chloro-4-fluorobenzyl)-10-methoxy-8-ethyl-6-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (62 mg, 0.14 mmol) in anhydrous dichloromethane (2 mL), a solution of boron tribromide in dichloromethane (0.43 mL, 0.43 mmol; 1 M) was added. After stirring at room temperature for 30 minutes, the reaction mixture was treated with anhydrous methanol, stirred for 30 minutes, and concentrated under vacuum. The procedure was repeated twice. The residue was subjected to purification on preparative reverse phase high pressure column chromatography. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:14]=1.[C:26]([C:28]1[CH:29]=[C:30]([CH:34]=[N:35][S@:36]([C:38]([CH3:41])([CH3:40])[CH3:39])=[O:37])[CH:31]=[CH:32][CH:33]=1)#[N:27]>C1COCC1>[C:26]([C:28]1[CH:29]=[C:30]([CH:34]([NH:35][S:36]([C:38]([CH3:41])([CH3:40])[CH3:39])=[O:37])[CH:19]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[CH:31]=[CH:32][CH:33]=1)#[N:27]
Reactant: c1cncc(Cc2cccnc2)c1
Reactant: CC(C)(C)[S@](=O)N=Cc1cccc(C#N)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC(c1cccc(C#N)c1)C(c1cccnc1)c1cccnc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a flame dried flask under N2, diisopropylamine (1.647 mL, 11.75 mmol) was dissolved in anhydrous THF (5 mL) and the solution was cooled to 0° C. nBuLi (2.5 M solution in hexanes, 4.406 mL, 11.02 mmol) was added and the reaction was stirred at 0° C. for 15 min. A solution of 3-(pyridin-3-ylmethyl)pyridine (1.250 g, 7.34 mmol) in anhydrous THF (15 mL) was slowly added and the reaction became dark red. After 15 min, a solution of (S)—N-[(3-cyanophenyl)methylidene]-2-methylpropane-2-sulfinamide (1.893 g, 8.08 mmol) in anhydrous THF (10 mL) was added. The reaction was stirred at 0° C. for 2.5 h and was quenched with saturated aqueous NH4Cl (150 mL). The product was extracted with ethyl acetate (4×100 mL). The combined organics were dried over Na2SO4, filtered, concentrated in vacuo and purified by reverse phase HPLC (DeltaPak C18, 47 mm×300 mm, 15 □, 0% CH3OH/100% H2O to 100% CH3OH/0% H2O). The fractions containing each diastereomer were separately combined and concentrated in vacuo to afford N-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]-2-methylpropane-2-sulfinamide as two diastereomers;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[I:12]N1C(=O)CCC1=O>CC#N>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[I:12])[C:7](=[O:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(O)ccc21
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: O=C1CCc2cc(O)c(I)cc21

Procedure:
5-Hydroxy-1-indanone (1.48 g), N-iodosuccinimide (2.25 g) and CH3CN (20 ml) were stirred at room temperature overnight. The solution was evaporated to dryness, slurried with EtOAc, then filtered. The filtrate was evaporated to dryness and the solid recrystallized from CH3CN affording the desired compound (0.92 g), m.p. 114°-15° C.
Reaction SMILES: [CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17]([CH:19]=C)[CH:16]=[C:15]([Cl:21])[C:14]=2[Cl:22])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.[O:23]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17]([CH:19]=[O:23])[CH:16]=[C:15]([Cl:21])[C:14]=2[Cl:22])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1
Reactant: C=Cc1cc(Cl)c(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1cc(C=O)cc(Cl)c1Cl)C1CC1

Procedure:
To a dichloromethane (0.03 M) solution of 1,1-dimethylethyl cyclopropyl[(2,3-dichloro-5-ethenylphenyl)methyl]carbamate (1 eq.) from Step 2, Amine 6 was bubbled at −78° C. freshly generated ozone until a persistent blue color was obtained. To this was then added triphenylphosphine (1.2 eq.) in one rapid portion and the resulting mixture was slowly warmed to RT over 3 h. The volatiles were removed in vacuo and the remaining residue was triturated with 2:1 (v/v) Hex:Et2O. The insolubles were removed via filtration and the filtrate was concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[CH:24](OCC)(OCC)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:24]=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc2oc(-c3ccc4c(c3)ncn4C3CCOCC3)nc2c1
Temperature: 100 °C
Yield: 31.5 %

Procedure:
To 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (0.20 g, 0.646 mmol), triethyl orthoformate (5 mL) was added a catalytic amount of p-toluenesulfonic acid monohydrate, and this was heated to 100° C. for 1.5 hours. The reaction mixture was cooled, ethyl acetate and water added, and this was extracted. This was washed with water, dried over magnesium sulfate, and after concentration the precipitated crystals were filtered off. These were washed with a hexane/ethyl acetate mixture solution, and dried to yield the title compound (65 mg, 31.5% yield) as light reddish-brown crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[OH:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][O:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCOC(=O)c1cccc(O)c1
Product: CCOC(=O)c1cccc(OCc2ccc3ccccc3c2)c1
Yield: 85 %

Procedure:
In an analogous procedure to that described in Example 1, 2-bromomethylnaphthalene was reacted with ethyl 3-hydroxybenzoate to give ethyl 3-(naphth-2-ylmethoxy)benzoate in 85% yield, m.p. 45°-46.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:21])([F:20])[CH:17]([F:19])[F:18])=[CH:10][CH:9]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32]>ClCCl>[Cl:29][CH2:30][C:31]([N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:20])([F:21])[CH:17]([F:18])[F:19])=[CH:10][CH:9]=1)=[O:32]
Reactant: CCOC(=O)CNc1ccc(OCC(F)(F)C(F)F)cc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)CCl)c1ccc(OCC(F)(F)C(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 2.1 g of the resulting N-ethoxycarbonylmethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline, 1.1 ml of triethylamine and 50 ml of dichloromethane was added dropwise a solution of 0.6 ml of chloroacetyl chloride in 6 ml of dichloromethane with ice cooling and the resulting mixture was stirred at room temperature for five hours. To the reaction solution was added 50 ml of dichloromethane and 100 ml of ice water to factionate. The dichloromethane layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane [1:2 v/v]) to give 2.4 g of N-chloroacetyl-N-ethoxycarbonylmethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline as a yellow oily substance.
Reaction SMILES: B(F)(F)F.CCOCC.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1>C1(C)C=CC=CC=1>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(Br)cc1
Reactant: C1=CCCCC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Brc1ccc(OC2CCCCC2)cc1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
Boron trifluoride etherate (5.83 mL) was added to a mixture of 4-bromophenol (39.8 g) and cyclohexene (187 mL) in toluene (160 mL) to form bright orange-red solution. The mixture was stirred at 40° C. under nitrogen for 5 hr. The mixture was quenched with 2N NaOH aq. (40 mL) and water at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with hexane) to give the title compound (46.3 g) as pale yellow oil.
Reaction SMILES: [Na+].[C:2]1([S:8]([O-:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][C:12]1[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH:17]=1.Cl>O>[CH3:11][CH:12]1[CH:17]([S:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:10])=[O:9])[CH2:16][CH2:15][CH2:14][C:13]1=[O:18]
Reactant: CC1=CCCCC1=O
Reactant: O=S([O-])c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1C(=O)CCCC1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
Benzenesulfinic acid sodium salt (2.9 g) was added to a solution containing 1.5 g of 2-methyl-2-cyclohexen-1-one and 8 ml of water. Then 16 ml of 1N hydrochloric acid was added dropwise to the resulting mixture. The reaction mixture was stirred at room temperature for 24 hours. The crystals so precipitated were filtered and then, washed with water, isopropanol and cold ethyl ether. After recrystallization from isopropanol, 2-methyl-3-(phenylsulfonyl)-cyclohexan-1-one was obtained in the form of white crystals. Yield: 93%
Reaction SMILES: [ClH:1].F[C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][C:6]1[N:11]=[CH:10][C:9]2[C:12]([CH3:16])([CH3:15])[CH2:13][NH:14][C:8]=2[CH:7]=1.[Br-].[C:22](C1C=C(C=CC=1)C[Zn+])#[N:23]>>[ClH:1].[C:22]([C:20]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[N:11]=[CH:10][C:9]2[C:12]([CH3:16])([CH3:15])[CH2:13][NH:14][C:8]=2[CH:7]=1)#[N:23]
Reactant: CC1(C)CNc2cc(Cc3ccccc3F)ncc21
Reactant: N#Cc1cccc(C[Zn+])c1
Agent: Cl
Agent: [Br-]
Product: CC1(C)CNc2cc(Cc3cccc(C#N)c3)ncc21

Procedure:
Prepared in an analogous manner to 6-(2-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine hydrochloride (Preparation 119) using 3-cyanobenzylzinc bromide instead of 2-fluorobenzylzinc chloride. MS: [M+H]+=264.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][N:10]1[C:14]2[C:15]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[CH:24]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33])O)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Cl:33][C:27]1[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:26]=1[CH:24]1[C:11]2=[N:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[C:14]=3[N:10]2[CH2:9][CH2:8][N:7]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34]
Reactant: CCN(CC)c1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCNC(=O)OC(C)(C)C)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCN(CC)c1cccc2nc3n(c12)CCN(C(=O)OC(C)(C)C)C3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
To a stirred solution of tert-butyl(2-{2-[(2,4-dichlorophenyl)(hydroxy)methyl]-7-(diethylamino)-1H-benzimidazol-1-yl}ethyl)carbamate (Reference example 223, 100 mg, 0.197 mmol) and triphenylphosphine (77.5 mg, 0.295 mmol) in tetrahydrofuran (2 mL) was added a solution of diethyl azodicarboxylate in toluene (40%, 0.135 mL, 0.296 mmol) at room temperature. The mixture was stirred at room temperature for 30 min, concentrated in vacuo, and purified by column chromatography on silica gel eluting with a 15-30% ethyl acetate/n-hexane gradient mixture to give a yellow oil (54.8 mg, 0.119 mmol, 60%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:22]=[CH:21][C:20]2[C:19]3[CH2:18][CH2:17][C@@:15]4([CH3:16])[C@@H:11]([CH2:12][CH2:13][C:14]4=[O:23])[C:10]=3[CH2:9][CH2:8][C:7]=2[CH:6]=1.C(O)(=O)C.O>C(O)C>[CH3:3][O:4][C:5]1[CH:22]=[CH:21][C:20]2[C:19]3[CH2:18][CH2:17][C@@:15]4([CH3:16])[C@@H:11]([CH2:12][CH2:13][C@@H:14]4[OH:23])[C:10]=3[CH2:9][CH2:8][C:7]=2[CH:6]=1
Reactant: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Yield: 93.1 %

Procedure:
Add sodium borohydride (8.5 g) to 3-methoxyestra-1,3,5(10),8-tetraen-17-one (40 g) in ethanol (500 ml) and reflux the mixture for 90 minutes. Acidify the cooled solution with acetic acid, add water and extract with benzene. Wash, dry and evaporate the organic extract to obtain dl-3-methoxyestra-1,3,5(10),8-tetraen-17β-ol (37.5 g), m.p. 130°-133°; ultraviolet absorption peak at 280 mμ(ε16,100); infrared maxima at 3.1 μ, 3.58 μ, 6.25 μ, 6.4 μ, 6.7 μ.
Reaction SMILES: [CH:1]([S:4]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)=[O:5])([CH3:3])[CH3:2].[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15](Cl)=[O:16])[CH:12]=[CH2:13].O1CCCC1>C(N(CC)CC)C>[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:4]([CH:1]([CH3:3])[CH3:2])=[O:5])=[N:7]1)=[O:16])[CH:12]=[CH2:13]
Reactant: CC(C)S(=O)c1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)C(C)C)n1

Procedure:
A mixture of 6.4 g. 3-isopropylsulphinyl-1,2,4-triazole, 8.0 ml. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 10 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The cooled reaction mixture was filtered and the filtrate was distilled under reduced pressure to give an oily residue which subsequently solidified. This solid residue was recrystallized from petroleum ether (b.p. 60° - 80°C.) to give 1-diallylcarbamoyl-3-isopropylsulphinyl-1,2,4-triazole, m.p. 32° - 34°C. Elemental analysis satisfactory. EXAMPLE 19
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]3)=[C:15]([O:25][CH3:26])[CH:14]=2)[N:7]=1)=[O:5])C.[CH:27]1([Mg]Br)[CH2:29][CH2:28]1.C(=O)([O-])[O-].[Na+].[Na+].O1[CH2:42][CH2:41][CH2:40]C1>>[CH:27]1([C:4]([CH:40]2[CH2:41][CH2:42]2)([C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]4)=[C:15]([O:25][CH3:26])[CH:14]=3)[N:7]=2)[OH:5])[CH2:29][CH2:28]1
Reactant: CCOC(=O)c1ccnc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: C1CCOC1
Reactant: Br[Mg]C1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cc(Nc2nccc(C(O)(C3CC3)C3CC3)n2)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a solution of 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-pyrimidine-4-carboxylic acid ethyl ester (46 mg, 0.13 mmol) in tetrahydrofurane (2.5 mL) was added at 0° C. over 1 min a 0.5 M solution of cyclopropylmagnesiumbromide in tetrahydrofurane (1.02 mL, 0.51 mmol). The reaction mixture was stirred at 0° C. for 15 min followed by 1.5 h at 20° C. The mixture was poured on saturated sodium carbonate solution (5 mL) and the mixture was extracted with ethyl acetate (40 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using dichloromethane/0-10% methanol as eluent to give the title compound as light yellow foam (44 mg, 88%). MS ISP (m/e): 392.3 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.45 (d, 1H), 7.64 (s, 1H), 7.56 (d, 1H), 7.23 (s, 1H), 7.19 (d, 1H), 7.08 (dd, 1H), 7.00 (d, 1H), 6.88 (s, 1H), 4.15 (s, 1H), 3.87 (s, 3H), 2.30 (s, 3H), 1.14 (m, 2H), 0.70, 0.50, 0.35, 0.25 (4 m, 4×2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([O-:3])=[O:2].[H-].[Na+].[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.CN(C=O)C>C1COCC1>[ClH:16].[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH2:30][CH2:31][O:32][CH3:33])[N:20]=[CH:19][N:18]=[C:17]2[CH:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][C:8]1=[O:13]
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2N1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(C3C(=O)Nc4ccc([N+](=O)[O-])cc43)c2cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
A solution of 5-nitrooxindole (400 mg, 2.2 mmol) in THF (4 ml) was added to sodium hydride (89 mg, 3.7 mmol, prewashed with THF) in THF (4 ml). The mixture was stirred for 30 minutes at ambient temperature and a solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (200 mg, 0.75 mmol), (prepared as described for the starting material in Example 2), in THF (3 ml) and DMF (1 ml) was added dropwise. The mixture was stirred for 1 hour at ambient temperature, followed by 1.5 hours at 70° C. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and water. The aqueous layer was adjusted to pH7 with 2M hydrochloric acid. The precipitated product was collected by filtration, washed with ether and dried under vacuum at 60° C. The solid was dissolved in methanol (10 ml) and 7.5M hydrogen chloride in methanol (2 ml) was added. The volatiles were removed by evaporation, the solid residue was triturated with ether, collected by filtration and dried under vacuum to give 6-methoxy-7-(2-methoxyethoxy)-4-(5-nitrooxindol-3-yl)quinazoline hydrochloride (173 mg, 57%).
Reaction SMILES: [H-].[Na+].C[C:4]([CH3:7])([OH:6])C.[NH2:8][CH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][N:18]=[C:17]2[NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)=[C:27]([Cl:40])[CH:26]=1)=[O:12]>C1COCC1>[Cl:40][C:27]1[CH:26]=[C:25]([NH:24][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:11](=[O:12])[CH2:10][CH2:9][NH:8][C:11](=[O:12])[CH2:10][O:6][CH2:4][CH2:7][N:18]([CH3:19])[CH3:17])[CH:15]=3)[N:20]=[CH:19][N:18]=2)[CH:30]=[CH:29][C:28]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1
Reactant: CC(C)(C)O
Reactant: NCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCOCC(=O)NCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1

Procedure:
44 mg of sodium hydride (60%, oil suspension) dissolved in 2 ml of THF was reacted with 0.03 ml of dimethylethanol for 30 mins, 100 mg of the compound obtained (20-1) of Example 20 dissolved in 5 ml of THF was added thereto at 0° C., and the resulting solution was reacted for 3 hours while heating to room temperature. The reacted solution was diluted with saturated sodium bicarbonate solution, extracted with chloroform, dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-chloroform:methanol=15:1) to obtain the title compound (70 mg, 64%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=C2C(=CC=1OC)NC(=O)N=C2.CS(O)(=O)=O.N[C@H](C(O)=O)CCSC.[OH:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[NH:37][C:36](=O)[N:35]=[CH:34]2.O=S(Cl)[Cl:46]>>[Cl:46][C:34]1[C:33]2[C:38](=[CH:39][C:40]([O:41][CH3:42])=[C:31]([O:30][C:3](=[O:2])[CH3:4])[CH:32]=2)[N:37]=[CH:36][N:35]=1
Reactant: COc1cc2[nH]c(=O)ncc2cc1O
Reactant: COc1cc2cnc(=O)[nH]c2cc1OC
Reactant: O=S(Cl)Cl
Agent: CS(=O)(=O)O
Agent: CSCC[C@H](N)C(=O)O
Product: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Temperature: 0 °C

Procedure:
6,7-dimethoxy-quinazolone was reacted with methanesulfonic acid and L-methionine under reflux for 2 h, and then the mixture was poured into ice water to deposit a solid, which is 6-hydroxy-7-methoxy-quinazolone intermediate. After the hydroxyl group therein was protected by acylation, the intermediate was treated with SOCl2 to obtain 4-chloro-6-acetoxy-7-methoxy-quinazoline.