Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][O:13][CH2:14][CH2:15][CH2:16][OH:17])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:21][C:22]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:23]=1[C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25].O>CN1C(=O)N(C)CCC1.C1COCC1>[CH3:21][C:22]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][O:17][CH2:16][CH2:15][CH2:14][O:13][CH2:12][C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][CH:9]=2)[C:23]=1[C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25]
Reactant: Cc1cccc(CBr)c1C(=O)OCC(C)C
Reactant: OCCCOCc1coc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: Cc1cccc(COCCCOCc2coc(-c3ccccc3)n2)c1C(=O)OCC(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
3-(2-Phenyl-oxazol-4-ylmethoxy)-propan-1-ol (1.26 g, 5.4 mmol) is dissolved in 10% DMPU in THF (20 mL) and cooled to 0° C. Sodium hydride (60%, 237 mg, 5.9 mmol) is added portionwise. The contents are stirred for 10 min.at 0° C., warmed to r.t. and stirred for another 10 min. isobutyl 2-bromomethyl-6-methyl-benzoate (2.69 g, 5.4 mmol, EXAMPLE 2b) is added, allowed to come to r.t and stirred overnight. The reaction is poured into water (200 mL) and extracted with ethyl acetate (2×200 mL). The organic fractions were pooled and washed with brine (2×200 mL), dried over MgSO4, filtered and reduced under vacuum to an oil. The crude material was purified by flash chromatography (silica, 15-20% ethyl acetate in hexane) to give the title compound (1.06 g). MS (ESI) 438 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[CH:29]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([OH:40])=[O:39])=[CH:33][CH:32]=1)=O>>[C:38]([CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:29][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:32][CH:33]=1)([OH:40])=[O:39]
Reactant: CCNc1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=Cc1ccc(CC(=O)O)cc1
Product: COc1ccc([C@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Yield: 94 %

Procedure:
Synthesized from pivalic acid (S)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (59 mg) and (4-formylphenyl)acetic acid (126 mg) according to an analogous synthetic method to Example 212,the title compound (77 mg) was obtained.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:7]=[C:8]([C:17]([OH:19])=[O:18])[C:9]2[O:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:10]=2[CH:16]=1.[CH3:20]O>>[Br:5][C:6]1[CH:7]=[C:8]([C:17]([O:19][CH3:20])=[O:18])[C:9]2[O:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:10]=2[CH:16]=1
Reactant: CC1(C)Cc2cc(Br)cc(C(=O)O)c2O1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)cc2c1OC(C)(C)C2

Procedure:
Thionyl chloride (0.6 mL, 8.12 mmol) was added slowly to a solution of 5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid (667) (1.1 g, 4.06 mmol) in methanol (41 mL). After refluxing for 3 hours the solvent was removed in vacuo to obtain methyl 5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate (668).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH:14]([NH:17][C:18](=[O:22])[CH2:19][C:20]#[N:21])([CH3:16])[CH3:15]>>[CH:14]([NH:17][C:18](=[O:22])[C:19]([C:20]#[N:21])=[CH:5][C:4]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]([OH:10])=[C:2]([OH:1])[CH:3]=1)([CH3:16])[CH3:15]
Reactant: CC(C)NC(=O)CC#N
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Product: CC(C)NC(=O)C(C#N)=Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
The procedure described in Example 99 was repeated using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.3 g of N-isopropylcyanoacetamide. Yield 1.46 g (50%), m.p. 243°-245° C.
Reaction SMILES: [CH2:1]([O:3][S:4]([CH2:7]P(OCC)(OCC)=O)(=[O:6])=[O:5])[CH3:2].C([Li])CCC.[Cl:21][C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2[CH:31]1[CH:35]2[O:36][C:37]([CH3:40])([CH3:39])[O:38][CH:34]2[CH:33]([CH:41]=O)[O:32]1>C1COCC1.CCCCCC>[Cl:21][C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2[C@H:31]1[C@@H:35]2[O:36][C:37]([CH3:40])([CH3:39])[O:38][C@@H:34]2[C@@H:33]([CH:41]=[CH:7][S:4]([O:3][CH2:1][CH3:2])(=[O:5])=[O:6])[O:32]1
Reactant: CC1(C)OC2C(C=O)OC(n3cnc4c(Cl)ncnc43)C2O1
Reactant: CCOP(=O)(CS(=O)(=O)OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOS(=O)(=O)C=C[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a solution of (diethoxy-phosphoryl)-methanesulfonic acid ethyl ester (7.991 g, 0.03070 mol) in THF (100 mL), at −78° C. under an atmosphere of nitrogen, was added dropwise 2.5M n-butyllithium in hexane (13 mL), and the solution was stirred for 30 minutes. Freshly prepared 6-(6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]-dioxole-4-carbaldehyde (13.10 g, 0.03026 mol) in THF (100 mL) was added over 15 min at −78° C. The reaction was allowed to slowly warm to −10° C. over 4 hours with stirring. The reaction was quenched with water (400 mL) and 5M ammonium chloride in water (100 mL) and extracted with methylene chloride (600 mL). The organic phase was concentrated in vacuo and the residue was purified by flash chromatography (30 to 100% EtOAc:hexanes) to yield the product as a foam (10.5 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:45])[NH:24][C@H:25]([CH2:33][N:34]([CH3:44])[C:35]([O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])=[O:36])[CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:18]2)([O:10][CH2:11][C:12]([O:14]CC)=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:46][NH2:47]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]([NH:24][C@@H:25]([CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:33][N:34]([CH3:44])[C:35](=[O:36])[O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:42])[CH3:43])=[O:45])[CH2:18]2)([O:10][CH2:11][C:12]([NH:47][CH3:46])=[O:14])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: CCOC(=O)CO[C@@](C)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Solvent: CCO
Product: CNC(=O)CO[C@@](C)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of ethyl 2-((R)-1-(3-chlorophenyl)-1-((R)-1-((S)-1-cyclohexyl-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)propan-2-ylcarbamoyl)piperidin-3-yl)ethoxy)acetate (0.0185 g) and 33% wt. methylamine in ethyl alcohol (10 mL) was stirred at rt for 3 d. After the reaction mixture was evaporated under reduced pressure, the crude product was purified by reversed-phase HPLC to afford 0.0035 g of 2-(trimethylsilyl)ethyl (S)-2-((R)-3-((R)-1-(3-chlorophenyl)-1-(2-(methylamino)-2-oxoethoxy)ethyl)piperidine-1-carboxamido)-3-cyclohexylpropyl(methyl)carbamate. MS ESI +ve m/z 653 (M+H).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11]C[C@H:9]2[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:27]1COCC1>>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C@H:9]2[CH2:14][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:27]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCOC1
Reactant: O=C([C@@H]1CCCCN1Cc1ccccc1)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: c1ccc(CN2CCC[C@H]2CN2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
(2S)-1-(Phenylmethyl)-2-(1-pyrrolidinylcarbonyl)piperidine (901 mg, 3.307 mmol) was dissolved in 20 mL of THF, cooled to 0° C., and then LiAlH4 (251 mg, 6.615 mmol) was added portion wise. The mixture was heated to 80° C. for 2 h, then allowed to cool to RT. The reaction was quenched in succession with H2O (0.300 mL), 15% aq. NaOH (0.300 mL) and H2O (0.900 mL) and was stirred at room temperature overnight. The contents were filtered, and the filtrate was concentrated in vacuo to provide 1-{[(2S)-1-(phenylmethyl)-2-pyrrolidinyl]methyl}piperidine (710 mg, 83%).
Reaction SMILES: ClC1C=CC([N+](=NC2C=CC(Cl)=CC=2)[O-:9])=CC=1.Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.C(OC1C=CC(N=NC2C=CC(OCC)=CC=2)=CC=1)C>>[CH:21]1[C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=[C:19]([OH:9])[CH:20]=1
Reactant: [O-][N+](=Nc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: CCOc1ccc(N=Nc2ccc(OCC)cc2)cc1
Product: O=[N+]([O-])c1ccc(O)cc1
Yield: 95 %

Procedure:
It has now been found that p-nitrophenetole is obtained with excellent purity and high yields by reaction of p-chloronitrobenzene with ethanol and alkali metal hydroxide in the presence of a phase transfer catalyst, when the reaction is carried out at a temperature in the range of from 60° to 80° C. Thus, a product having a melting point of 58°-59.5° C. and being free from 4,4'-dichloroazoxybenzene, p-chloronitrobenzene, 4,4'-diethoxyazobenzene and p-nitrophenol is obtained with a yield of about 95%.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10]O)[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5].P(Br)(Br)[Br:14]>C(Cl)Cl>[F:1][C:2]1[CH:9]=[C:8]([CH2:10][Br:14])[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(F)c(CO)cc1F
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: N#Cc1cc(F)c(CBr)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2,5-difluoro-4-(hydroxymethyl)benzonitrile (Preparation 21, 390 mg, 2.30 mmol) in DCM (12 mL) was added phosphorus tribromide (0.238 mL, 2.53 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with DCM to 30 mL and washed with saturated aqueous sodium bicarbonate (30 mL). The organic layer was dried over sodium sulphate, and evaporated to afford the title compound as a yellow oil, which was used in the next step without further purification (530 mg, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[C:18](Cl)=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2].[NH3:26]>CCO>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[C:18]([NH2:26])=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2]
Reactant: N
Reactant: CCOC(=O)Cc1csc2cc(OCc3cnc(C)nc3Cl)ccc12
Solvent: CCO
Product: CCOC(=O)Cc1csc2cc(OCc3cnc(C)nc3N)ccc12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of ethyl(6-((4-chloro-2-methylpyrimidin-5-yl)methoxy)-1-benzothiophen-3-yl)acetate (100 mg) and 2M ammonia in EtOH (10 mL) was stirred at 100° C. for 5 h under microwave irradiation. The mixture was concentrated in vacuo. The residual solid was recrystallized from EtOAc-IPE to give the title compound (92 mg).
Reaction SMILES: [C:1]([O:4][Si:5]([CH:12]([CH3:14])[CH3:13])([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7])(=[O:3])[CH3:2].[C:15](O)(=O)C=C>C1(C)C=CC=CC=1.CN(C)C=O>[C:1]([O:4][Si:5]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[CH:12]([CH3:14])[CH3:13])(=[O:3])[CH:2]=[CH2:15]
Reactant: C=CC(=O)O
Reactant: CC(=O)O[Si](C(C)C)(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=CC(=O)O[Si](C(C)C)(C(C)C)C(C)C

Procedure:
4 g of acetoxy-triisopropylsilane and 1.6 g of acrylic acid (ATOFINA Norsocryl AA®) in 100 ml of toluene and 1 mL of N,N-dimethylformamide are mixed and heated. Azeotropic distillation of acetic acid affords triisopropylsilyl acrylate.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([CH2:16][S:17][C:18]2[N:19]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:20]([C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([O:33][CH3:34])[CH:27]=3)([CH3:25])[CH3:24])=[CH:21][N:22]=2)=[C:11]([F:42])[CH:10]=1)(=O)=O.[CH3:43][NH:44][CH3:45].C(NC(C)C)(C)C.CN(C=O)C>CCOC(C)=O>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]([C:20]2[N:19]([C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[C:18]([S:17][CH2:16][C:12]3[C:13]([F:15])=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:44]([CH3:45])[CH3:43])=[CH:10][C:11]=3[F:42])=[N:22][CH:21]=2)([CH3:25])[CH3:24])=[CH:27][C:28]=1[O:33][CH3:34]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCOS(C)(=O)=O)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reactant: CNC
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCN(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 110 °C
Yield: 88 %

Procedure:
A mixture of 2-(4-((5-(2-(4-Chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethyl methanesulfonate (230 mg, 0.36 mmol, 1.0 eq), dimethylamine (7.2 mL, 14.4 mmol, 40.0 eq, 2.0 M in THF) and diisopropylamine (0.2 mL, 1.1 mmol, 3.0 eq) in anhyd DMF (3.5 mL) was heated at 110° C. for 16 h. The mixture was diluted with EtOAc, washed sequentially with brine, satd NaHCO3 and brine, dried over MgSO4 and concentrated to provide 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)-N,N-dimethylethanamine (187 mg). 1H NMR (400 MHz, CDCl3) δ 7.13 (s, 1H), 7.07 (d, J=8.2 Hz, 1H), 6.72-6.65 (m, 2H), 6.48-6.40 (m, 2H), 6.34-6.25 (m, 4H), 3.98-3.92 (m, 4H), 3.68 (s, 3H), 2.68 (t, J=5.5 Hz, 2H), 2.28 (s, 3H), 1.41 (s, 6H); MS (EI) m/z 590 (MH+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][C:8](Cl)=[O:9].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[NH:19][C:18](=[O:20])[NH:17][C:16]=2[CH:21]=1>CN(C=O)C>[Cl:5][CH2:6][CH2:7][C:8]([C:13]1[C:12]([Cl:11])=[CH:21][C:16]2[NH:17][C:18](=[O:20])[NH:19][C:15]=2[CH:14]=1)=[O:9]
Reactant: O=C(Cl)CCCl
Reactant: O=c1[nH]c2ccc(Cl)cc2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C(CCCl)c1cc2[nH]c(=O)[nH]c2cc1Cl
Temperature: 0 °C

Procedure:
44.68 g of aluminium chloride (0.335 mol) are initially introduced into a reaction flask. 4.9 ml of DMF are slowly added dropwise with stirring, the temperature rising to approximately 56° C. 6.9 ml of 3-chloropropionyl chloride (0.072 mol) are added to this mixture. 8.07 g of 6-chloro-2,3-dihydrobenzimidazol-2-one (0.048 mol) are then slowly added in portions and the mixture is stirred at 80° C. for one hour. After completion of the reaction the reaction mixture obtained is stirred into 400 g of ice, and the precipitate is filtered off with suction and washed with plenty of water and small amounts of acetone. The reaction leads to a slightly more non-polar product which can be separated by thin-layer chromatography using an eluent consisting of-chloroform and methanol in the mixture ratio 9:1. Yield: 9.72 g of 5-(3-chloro-1-oxopropyl)-6-chloro-2,3-dihydrobenzimidazol-2-one (78.2% of theory); m.p.: 201°-204° C.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CC[CH2:3][CH2:2]1.[O:23]1C=CC(N)=[N:24]1>>[CH3:13][C:12]1[C:7]([NH:6][C:1]2[CH:2]=[CH:3][O:23][N:24]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Nc1ccon1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccon2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using isoxazol-3-amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.08 (s, 3H), 2.35 (s, 3H), 4.74 (d, J=2.8 Hz, 2H), 5.97 (bs, 1H), 6.98 (s, 1H), 7.17 (t, J=6.4 Hz, 1H), 7.31-7.44 (m, 2H), 7.63 (t, J=6.5 Hz, 1H), 8.17 (s, 1H), 8.56 (d, J=4.6 Hz, 1H); MS (ESI) m/z 297.8 (M+1)+.
Reaction SMILES: CS(O[CH:6]([CH2:16][CH2:17][O:18][Si:19]([CH3:25])([CH3:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:7][O:8][Si:9]([CH3:15])([CH3:14])[C:10]([CH3:13])([CH3:12])[CH3:11])(=O)=O.[C-:26]#[N:27].[Na+].O>CS(C)=O>[CH3:23][C:20]([Si:19]([CH3:24])([CH3:25])[O:18][CH2:17][CH2:16][CH:6]([CH2:7][O:8][Si:9]([C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:14])[CH3:15])[C:26]#[N:27])([CH3:21])[CH3:22]
Reactant: [C-]#N
Reactant: CC(C)(C)[Si](C)(C)OCCC(CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OCCC(C#N)CO[Si](C)(C)C(C)(C)C
Temperature: 90 °C

Procedure:
A mixture of 6-methylsulfonyloxy-2,2,3,3,10,10,11,11-octamethyl-4,9-dioxa-3,10-disiladodecane (i.e. the product of Step B) (59.29 g, 0.144 mol) and sodium cyanide (15.55 g, 0.317 mol) in DMSO was heated at 90° C. (using an oil bath) for 2 h. The reaction mixture was cooled to room temperature, water (500 mL) was added and the mixture was extracted with diethyl ether (4×250 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (300 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to a dark-yellow oil (48.86 g). The oil was purified by silica gel chromatography (eluting with petroleum ether, followed 1-4% gradient of ethyl acetate in petroleum ether) to provide the title compound (150 mg), a compound of the present invention, as a dark foam. Mixed fractions were combined with mixtures from a previous experiment (total weight 19 g) and purified by silica gel chromatography to provide the title compound (about 11 g).
Reaction SMILES: C([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])C1C=CC=CC=1.C([Li])CCC.[C:18]1(=[O:22])[CH2:21][CH2:20][CH2:19]1.C(O)(=O)C>C1COCC1.CCCCCC>[OH:22][C:18]1([CH2:12][S:9]([NH2:8])(=[O:10])=[O:11])[CH2:21][CH2:20][CH2:19]1
Reactant: CS(=O)(=O)NCc1ccccc1
Reactant: O=C1CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: NS(=O)(=O)CC1(O)CCC1
Reaction time: 0.08 h

Procedure:
Under inert gas, 2.00 g of N-benzylmethanesulfonamide were initially charged in 20 ml of THF, then, at a temperature of −78° C., 13.50 ml of a 1.6 N solution of butyllithium in hexane were added dropwise and the mixture was stirred at constant temperature for 5 minutes. The reaction solution was admixed with 3.23 ml of cyclobutanone and allowed to come to room temperature while stirring. After the addition of 1.24 ml of acetic acid, the volatile constituents were removed under reduced pressure. The residue was taken up in a mixture of 50 ml of ethyl acetate and 50 ml of aqueous sodium hydrogencarbonate solution, and the aqueous phase was extracted again with 50 ml of ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by rotary evaporation. The crude product thus obtained was recrystallized from ethyl acetate/n-heptane, then dissolved in 20 ml of methanol and, with addition of 0.36 g of 20% Pd(OH)2/C, stirred under a hydrogen atmosphere at 60° C. for 3 hours. After filtration to remove the solid residues, the filtrate was freed of the solvent under reduced pressure. This gave the product (1.07 g) with a molecular weight of 165.2 g/mol (C5H11NO2S).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13]N(C)C)[C:9]2=[O:12])=[CH:4][CH:3]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][C:18]3[NH:17][CH:21]=[CH:20][N:19]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CN(C)CC1CCc2ccc(Br)cc2C1=O
Reactant: c1c[nH]cn1
Solvent: Cc1ccccc1C
Product: O=C1c2cc(Br)ccc2CCC1Cc1ncc[nH]1

Procedure:
A solution of 7-bromo-2-dimethylaminomethyl-1-tetralone free base (6.0 g) and imidazole (2.5 g) in xylene (30 ml) was heated under reflux for 1.5 hours and then evaporated. The residue was dissolved in ether and the solution was washed with water followed by dilute hydrochloric acid. The acid extract was made just alkaline with dilute sodium hydroxide solution. The mixture was extracted with chloroform and the combined chloroform extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave a solid which was crystallised from ethyl acetate to give 7-bromo-2-(1-imidazolylmethyl)-1-tetralone, m.p. 129°-131°.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Br:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[Cl:14]>S(=O)(=O)(O)O>[Br:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([N+:1]([O-:4])=[O:2])=[CH:9][C:8]=1[Cl:14]
Reactant: Fc1ccc(Cl)c(Br)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc(Cl)c(Br)cc1F
Reaction time: 10 h
Yield: 77 %

Procedure:
Potassium nitrate (2.91 g, 28.8 mmol) was gradually added to a stirred solution of 1-bromo-2-chloro-5-fluorobenzene (5 g, 24 mmol) in concentrated sulphuric acid (50 mL) at −5° C. The reaction was stirred for 10 hours then slowly poured in to crushed ice with stirring. The formed precipitate was collected by filtration and dried under reduced pressure to give the title compound (4.7 g, 77%) as a solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:15])[N:3]=1.[CH:16]([O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH3:27])=[CH:22][CH:21]=1)([CH3:18])[CH3:17]>>[CH:16]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:27])[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[C:4]([CH3:15])[N:3]=2)=[CH:22][CH:21]=1)([CH3:18])[CH3:17]
Reactant: CNc1ccc(OC(C)C)cc1
Reactant: Cc1nc(Cl)c2cc([N+](=O)[O-])ccc2n1
Product: Cc1nc(N(C)c2ccc(OC(C)C)cc2)c2cc([N+](=O)[O-])ccc2n1

Procedure:
The title compound was synthesized from 4-chloro-2-methyl-6-nitro-quinazoline and (4-isopropoxy-phenyl)-methyl-amine by a procedure similar to Example 1b. 1H NMR (DMSO-d6) δ 8.5-7.1 (7H), 4.73 (m, 1H), 3.7 (s, 3H), 2.7 (s, 3H), 1.32 (d, 6H); LC-MS (ESI+; 353 ([M+H]+)).
Reaction SMILES: [C:1]([CH:4]1[CH:9]([C:10]#[N:11])[CH2:8][CH:7]2[CH2:12][CH:5]1[C:6]2([CH3:14])[CH3:13])([CH3:3])=[CH2:2].C(C1C(CN2C(=O)C(CC3C=CN=CC=3)(CC3C=CN=CC=3)NC2=CC(C2C=CC(C#N)=CC=2)=O)CC2CC1C2(C)C)(C)=C.[N-]=[C:60]=[S:61]>>[C:1]([CH:4]1[CH:9]([CH2:10][N:11]=[C:60]=[S:61])[CH2:8][CH:7]2[CH2:12][CH:5]1[C:6]2([CH3:14])[CH3:13])([CH3:3])=[CH2:2]
Reactant: C=C(C)C1C(C#N)CC2CC1C2(C)C
Reactant: [N-]=C=S
Agent: C=C(C)C1C(CN2C(=O)C(Cc3ccncc3)(Cc3ccncc3)NC2=CC(=O)c2ccc(C#N)cc2)CC2CC1C2(C)C
Product: C=C(C)C1C(CN=C=S)CC2CC1C2(C)C

Procedure:
The same procedure that was used in example 1 was followed except that 2-isopropenyl-3-isothiocyanatomethyl-6,6-dimethyl-bicyclo[3.1.1]heptane was used in the place of (+)-3-pinanemethyl isothiocyanate in step D to give the titled compound as a tan solid. 2-Isopropenyl-3-isothiocyanatomethyl-6,6-dimethyl-bicyclo[3.1.1]heptane was prepared by reducing 2-isopropenyl-6,6-dimethyl-bicyclo[3.1.1]heptane-3-carbonitrile to the requisite amine following the procedure in step C of example 42 and subsequently converted to the isothiocyanate using step A of example 15: C.I. m/z 586 [M+1]; 1H NMR (CDCl3)δ 10.47 (br s, 1H), 8.43-8.49 (m, 4H), 7.82 (d, J=8.7 Hz, 2H), 7.69 (d, J=8.7 Hz, 2H), 7.13 (m, 2H), 7.08 (m, 2H), 5.27 (s, 1H), 4.74 (m, 2H), 3.33 (dd, J=11.2, 13.9 Hz, 1H), 3.23 (d, J=13.5 Hz, 2H), 3.03-3.15 (m, 2H), 2.84 (dd, J=3.2, 13.9 Hz, 1H), 1.99-2.15 (m, 2H), 1.70 (m, 3H), 1.63 (s, 3H), 1.20 (m, 2H), 1.15 (s, 3H), 0.77(s, 3H), 0.66 (m, 1H).