Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][S:8][C:9]1[N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1)(=O)=O.[CH2:18]([N:20](CC)CC)C.CN.CO>C(Cl)(Cl)Cl>[CH3:18][NH:20][CH2:6][CH2:7][S:8][C:9]1[N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)OCCSc1cccc2nccn12
Reactant: CCN(CC)CC
Agent: CN
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNCCSc1cccc2nccn12
Yield: 47.1 %

Procedure:
A solution of 5-[2-(methylsulfonyloxy)ethylthio]imidazo[1,2-a]pyridine (2.18 g, 8 mmoles), triethylamine (2.24 ml, 16 mmoles) and a 40% methylamine-methanol solution (20 ml) in chloroform (20 ml) was heated at reflux for 3 hours. The reaction solution was washed with an aqueous 3N-sodium hydroxide solution and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent: methanol/chloroform=1:10) to obtain 781 mg of the desired product (47.1%, light brown oily product).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:9]=1[NH:10][C:11]1[C:12]([CH3:20])=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:7]#[N:8].C([Sn](CCCC)(CCCC)[C:26]1[O:27][C:28]2[CH:34]=[CH:33][C:32]([CH:35]=[O:36])=[CH:31][C:29]=2[CH:30]=1)CCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:35]([C:32]1[CH:33]=[CH:34][C:28]2[O:27][C:26]([C:2]3[CH:3]=[N:4][CH:5]=[C:6]([C:9]=3[NH:10][C:11]3[C:12]([CH3:20])=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][CH:15]=[CH:14]4)[C:7]#[N:8])=[CH:30][C:29]=2[CH:31]=1)=[O:36]
Reactant: Cc1c(Nc2c(I)cncc2C#N)ccc2[nH]ccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2cc(C=O)ccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(C=O)ccc3o2)ccc2[nH]ccc12
Temperature: 120 °C
Yield: 76.1 %

Procedure:
A mixture of 5-iodo-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile (2.5 g, 6.7 mmol), 2-(tributylstannyl)-1-benzofuran-5-carbaldehyde (4.35 g, 10 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.34 mmol) in DMF (25 mL) was heated at 120° C. for 1 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water, resulting in a suspension. The insoluble material was removed by filtration and the residue was washed thoroughly with ethyl acetate. The organic layer (from filtrate) was washed with water twice and brine, dried over sodium sulfate, and concentrated and the residue was purified by column chromatography (ethyl acetate/hexane, 1:1) to give 2.0 g (76%) of 5-(5-formyl-1-benzofuran-2-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile as a yellow solid. HPLC retention time: 10.7 min.(h); MS: 393.2 (M+H); melting point: 235-237° C.; and HRMS: 393.13484.
Reaction SMILES: [C:1]1([C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.O>CS(C)=O>[C:1]1([C:7]2([O:13][C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cnccn1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(C2(Oc3cnccn3)CCNCC2)cc1
Temperature: 25 °C
Yield: 3.9 %

Procedure:
A mixture of 4-phenyl-4-piperidinol (7.1 g, 40 mM), DMSO (50 ml) and sodium hydride (2 g of a 50% dispersion in oil) was heated at 80° until homogenous, cooled to room temperature and treated with chloropyrazine (4.6 g, 40 mM) in DMSO (10 ml). After 24 hours the reaction mixture was poured on to water (250 ml) and extracted with toluene (2×250 ml). The combined organic phases were washed with brine, dried and the solvents removed under reduced pressure. Sublimation of the residue at 0.1 mm Hg (bath temp. 100°) gave the title compound (400 mg) m.p. 107°-8°.
Reaction SMILES: [H-].[Na+].[H][H].Br[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=1.[CH2:13]([OH:17])[CH2:14][CH2:15][CH3:16]>>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([O:17][CH2:13][CH2:14][CH2:15][CH3:16])=[N:7][CH:8]=1
Reactant: [H][H]
Reactant: CCCCO
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Product: CCCCOc1ccc(Br)cn1

Procedure:
Sodium hydride (60% w/v dispersion in mineral oil; 1.8 g) was added in portions over 20 minutes to n-butanol (100 ml) with stirring. The mixture was then stirred until no further hydrogen evolution was noted. 2,5-Dibromopyridine (7.1 g) was added and the resulting mixture stirred at reflux for 6 hours. After cooling, the n-butanal was removed by evaporation and the residue was treated with water (50 ml) and extracted with dichloromethane (2×20 ml). The organic extracts were combined, washed with water (20 ml), dried (MgSO4) and evaporated to give 5-bromo-2-n-butoxypyridine (6.3) as a pale yellow oil, NMR (DHSOd6): 0.9-0.96(3H, t), 1.32-1.5(2H, m), 1.62-1.76(2H, m), 4.2-4.28(2H, t), 6.79-6.82(1H, d), 7.85-7.9(1H, d of d) and 8.26(1H, d).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=O.[NH2:14][C:15]1[N:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]([NH2:32])[C:24]([NH:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:25][CH:26]=2)=[CH:17][N:16]=1.O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:28]([N:27]1[C:24]2[CH:25]=[CH:26][C:21]([C:18]3[CH:17]=[N:16][C:15]([NH2:14])=[N:20][CH:19]=3)=[CH:22][C:23]=2[N:32]=[C:8]1[C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[C:2]1[S:1][CH:5]=[CH:4][N:3]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Reactant: O=Cc1ccccc1-c1nccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)n1c(-c2ccccc2-c2nccs2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 25 °C
Reaction time: 60 h
Yield: 15.6 %

Procedure:
A solution of 2-thiazol-2-yl-benzaldehyde (100 mg, 0.53 mmol) and 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (120 mg, 0.45 mmol) in acetic acid (5 mL) is warmed to 50° C. for 12 hours and then at 80° C. for 60 hours. After this time the reaction is cooled to room temperature and pour into water and NaHCO3 (sat.). The product is extracted into EtOAc (3×) and the combined organics are dried (MgSO4), filtered and concentrated. Purification via flash chromatography (12 g silica gel, 0-5% MeOH/CH2Cl2) affords the title compound (30 mg, 16%). LCMS (ESMS): m/z 427.20 (M++1)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].[H-].[Na+].[H][H].Br[CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21]>CN(C=O)C.O>[CH3:21][CH:20]([CH3:22])[CH2:19][CH2:18][N:7]1[C:6]2[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1
Reactant: CC(C)CCBr
Reactant: [H][H]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCn1cnc2c1c(=O)[nH]c(=O)n2C
Temperature: 60 °C
Reaction time: 12 h

Procedure:
100 g (0.602 mol) of 3-methylxanthine, dissolved in 1200 ml of DMF, were slowly treated with 16 g (0.66 mol) of sodium hydride. The solution was heated to 60° C. and, when the evolution of hydrogen was at an end, treated with 109 g (0.66 mol) of 1-bromo-3-methylbutane. The reaction mixture was stirred at 100° C. for 12 hours and introduced into 2000 ml of water. The precipitate was filtered off with suction, washed with water and dried to constant weight.
Reaction SMILES: [F:1][CH:2]([F:27])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:22][C:21]([CH2:23]O)=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:26])[CH3:25])=[O:4].[N:28]1C=CC=C[CH:29]=1.C(N(C(C)C)CC)(C)C.Cl>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:1][CH:2]([F:27])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:22][C:21]([CH2:23][NH:28][CH3:29])=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:25])[CH3:26])=[O:4]
Reactant: c1ccncc1
Reactant: CC1(C)O[C@H](c2ccc(-c3cnc(CO)s3)cc2)[C@@H](CF)N1C(=O)C(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNCc1ncc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
Mesyl anhydride (860 mg, 4.9 mmol) is added to 2,2-difluoro-1-((4S,5R)-4-(fluoromethyl)-5-(4-(2-(hydroxymethyl)thiazol-5-yl)phenyl)-2,2-dimethyl-oxazolidin-3-yl)ethanone (1.4 g, 3.5 mmol) in CH2Cl2 (35 mL). Pyridine (0.5 mL, 5.9 mmol) is added and stirred at room temperature for 1 hour. The reaction is diluted with CH2Cl2 (35 mL) and washed with water and brine. The organic phase is dried (Na2SO4) and concentrated under vacuum. The crude mesylate is dissolved in acetonitrile (10 mL) and transferred to a scintillation vial. Diisopropylethylamine (0.65 mL, 3.7 mmol) and metyhlamine HCl (130 mg, 1.9 mmol) are added and the reaction mixture is heated to 55° C. for 18 hours. The reaction mixture is cooled and diluted with saturated NaHCO3 (75 mL). The reaction mixture is extracted with CH2Cl2 (2×75 mL) and the combined organic phase is dried (Na2SO4) and concentrated under vacuum to afford the title compound (475 mg): m/z (Cl) M+H 414.
Reaction SMILES: [C:1]([O:5][NH:6][C:7](=[O:24])[C@H:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C@H:9]([OH:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Cl)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]([O:5][NH:6][C:7](=[O:24])[C@H:8]([N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:32][C:28]1[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=1)[C@H:9]([O:11][CH2:32][C:28]1[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=1)[CH3:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(S(=O)(=O)N[C@@H](C(=O)NOC(C)(C)C)[C@@H](C)O)cc1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)NOC(C)(C)C)[C@@H](C)OCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(t-butyloxy)-2(R)-[[4-methoxybenzenesulfonyl]amino]-3(R)-hydroxybutanamide (3.04 g, 8.44 mmol) in dimethylformamide (150 mL) is added 3-picolyl chloride hydrochloride (1.45 g, 8.87 mmol) followed by potassium carbonate (11.65 g, 84.4 mmol). The reaction mixture is stirred at room temperature overnight, then heated to 45° C. for 5 hours. An additional amount of 3-picolyl chloride hydrochloride (692.0 mg, 4.23 mmol) is added at this point. The reaction mixture is stirred at 45° C. for 10 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude product is purified by silica gel chromatography (ethyl acetate, then 5% methanol/methylene chloride) to give N-(t-butyloxy)-2(R)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-3(R)-(3-picolyloxy)butanamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:9]=O)=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.[CH2:11]([NH:18][CH2:19][C@@H:20]([OH:22])[CH3:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C.C(O)(=O)C>[CH2:11]([N:18]([CH2:9][C:3]1[C:2]([Cl:1])=[N:7][C:6]([Cl:8])=[CH:5][N:4]=1)[CH2:19][C@@H:20]([OH:22])[CH3:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ncc(Cl)nc1Cl
Reactant: C[C@H](O)CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[C@H](O)CN(Cc1ccccc1)Cc1ncc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a solution of 3,5-dichloropyrazine-2-carbaldehyde (3.0 g), (2S)-1-(benzylamino)propan-2-ol (3.36 g) and acetic acid (4.9 mL) in THF (50 mL) was added sodium triacetoxyborohydride (7.18 g), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, and basified with saturated aqueous sodium hydrogen carbonate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (solvent gradient: 5→25% ethyl acetate/hexane) to give the title compound (3.48 g, 63%) as a pale-yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][OH:24])[C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:34][O:35][C:36]1[CH:37]=[N:38][C:39](S(C)(=O)=O)=[N:40][CH:41]=1>O1CCCC1.CC(N(C)C)=O.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][C:39]3[N:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][N:38]=3)[C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cnc(S(C)(=O)=O)nc1
Reactant: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1cnc(OCCOc2nn(C)c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)c2-c2ccc(C)cc2)nc1
Reaction time: 0.08 h
Yield: 61.1 %

Procedure:
To 4-(tert-butyl)-N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]benzenesulfonamide (Example 2) (250 mg) in tetrahydrofuran (20 ml) at room temperature under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 47 mg) and the mixture was stirred for 5 minutes. To the mixture was added a solution of 5-methoxy-2-methylsulphonylpyrimidine (Aktual. Probl. Razvit. Nauchn. Issled. Molodykh Uch. Spets. Vil'nyus. Gosuniv. im. V. Kapsukasa, Mater. Konf. Molodykh Uch. Spets. Estestv. Khim. Fak. (1980), 87-90. Editor(s): Grigonis, I. Publisher: Vil'nyus. Gos. Univ. im. V. Kapsukasa, Vilnius, USSR.) (160 mg) in dimethylacetamide (2 ml) and the reaction was stirred for a further 16 hrs. The reaction was diluted with water (100 ml) and extracted with ethyl acetate (100 ml). The organic fraction was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with dichloromethane: ether:hexane (10:2.5:1) to yield the title compound as a white solid (190 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[Br:14][N:15]1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[OH:13][N:11]1[C:10]2[C:2](=[CH:3][C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=2)[CH:1]=[N:15]1.[Br:14][CH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6]
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: O=C(O)c1ccc([N+](=O)[O-])c(CBr)c1
Product: O=C(O)c1ccc2c(cnn2O)c1
Temperature: 25 °C
Yield: 142.7 %

Procedure:
A solution of 3-methyl-4-nitrobenzoic acid (539 mg, 2.98 mmol) in benzene (20 mL) was heated to reflux in a sealed tube after which N-bromosuccinimide (679 mg, 3.43 mol) and AIBN (49 mg, 0.298 mol) were carefully added in a portion wise manner over 5 min. After 12 h the mixture was cooled to room temperature, and the succinimide was filtered off and washed with benzene (5 mL×3). The solvent was removed under reduced pressure and purified by column chromatography to give the desired product 3-(bromomethyl)-4-nitrobenzoic acid (553 mg, 68% yield) as a viscous yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:16])=[C:13]([OH:15])[CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27]>CC(C)=O>[CH3:16][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)=[CH:14][C:13]=1[O:15][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27]
Reactant: CC(C)=CCBr
Reactant: Cc1ccc(Nc2ccnc(N)n2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)=CCOc1cc(Nc2ccnc(N)n2)ccc1C
Yield: 22 %

Procedure:
Following the general procedure for O-alkylation of 2-R-5-(heteroaryl-2-ylamino)phenol, 5-(2-aminopyrimidin-4-ylamino)-2-methylphenol (89 mg, 0.41 mmol) and Cs2CO3 (134 mg, 0.41 mmol) in acetone (4.1 mL) was treated with 4-bromo-2-methyl-2-butene (50 μL, 0.41 mmol) at room temperature. The title compound was obtained after purification by flash chromatography on silica gel (CH2Cl2:MeOH 6/4) in 22% yield (26 mg).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH:8]=[CH:9][C:10]4[C@:15]3([CH3:16])[CH:14]=[CH:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[CH3:22][Al](C)C.O>O1CCOCC1.C1(C)C=CC=CC=1.[Cu]Br>[CH3:22][C@@H:14]1[C@@:15]2([CH3:16])[C:10]([CH:9]=[CH:8][C@@H:7]3[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]3[CH2:5][CH2:4][C:3]2=[O:21])=[CH:11][C:12](=[O:20])[CH2:13]1
Reactant: C[Al](C)C
Reactant: C[C@]12C=CC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Cu]Br
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1CC(=O)C=C2C=C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
2.82 g (10 mmol) of androsta-1,4,6-triene-3,17-dione is dissolved in 20 ml of dioxane at 20° C. and mixed with 143.3 mg (1 mmol) of copper(I) bromide. 9.4 ml (11 mmol) of a 10% solution of trimethyl aluminum in toluene is added to the reaction at room temperature under nitrogen atmosphere and stirred for 10 minutes at 20° C. For hydrolysis, 1 ml of water dissolved in 5 ml of dioxane is carefully added to the reaction. It is stirred for 10 minutes more and the inorganic precipitate filtered off with dioxane is washed again. The dioxane solution is concentrated by evaporation on a rotary evaporator and the residue is chromatographed on silica gel with ethyl acetate/hexane as eluent. After concentration by evaporation of the fractions, 2.97 g of 1α-methyl-androsta-4,6-diene-3,17-dione (99% of theory) of a melting point of 171° C. is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[Cl:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
To a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 0.0025 mole) in dry 1,2-dichloroethane (5 mL) (under an atmosphere of nitrogen for 10 minutes) was added, 2-chloroaniline (0.352 g, 0.0027 mole), acetic acid (0.125 g, 0.00209 mole) and sodium triacetoxyborohydride (0.442 g, 0.00209 mole). The resulting mixture was stirred at ambient temperature for 16 hours. The reaction mixture was quenched in cold aqueous 1N NaOH solution and the product was extracted with dichloromethane. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was stirred with hexane. The hexane was then decanted and the residue was dried to afford 0.615 g (79%) of 4-(2-chloro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a solid. 1H NMR (DMSO-d6): δ 7.6 (dd, 1H), 7.1 (t, 1H), 6.8 (d, 1H), 6.54 (t, 1H), 4.8 (d, 1H), 3.9 (d, 3H), 3.5 (m, 1H), 2.9 (bs, 2H), 1.8 (d, 2H), 1.4 (s, 9H), 1.3 (d, 1H). To a stirred, cooled (0° C.) solution of 4-(2-chloro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.150 g, 0.00048 mole) in dioxane (0.5 mL) was added dioxane.HCl (1.5 mL). The stirring was continued at the same temperature for 10 minutes, then the mixture was gradually brought to ambient temperature with continued stirring for a further 15 minutes. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with dry ether and dried to afford 0.118 g (99%) of (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7](F)=[C:8]([F:13])[CH:9]=2)[N:4]([CH:15]2[CH2:17][CH2:16]2)[C:3]1=[O:18].C(N(CC)CC)C.[C:26]([O:30][C:31](=[O:38])[NH:32][C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27]>C(#N)C>[NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([N:35]3[CH2:36][CH2:37][C@H:33]([NH:32][C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:38])[CH2:34]3)=[C:8]([F:13])[CH:9]=2)[N:4]([CH:15]2[CH2:17][CH2:16]2)[C:3]1=[O:18]
Reactant: Nn1c(=O)c2cc(F)c(F)cc2n(C2CC2)c1=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2cc3c(cc2F)c(=O)n(N)c(=O)n3C2CC2)C1
Yield: 88.2 %

Procedure:
To a solution of 3-amino-1-cyclopropyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example 24a) (50.0 mg, 0.20 mmol) and triethylamine (74 mg, 0.74 mmol) in acetonitrile (3 mL) is added (S)-pyrrolidin-3-yl carbamic acid tert-butyl ester (74 mg, 0.40 mmol). The solution is refluxed for 18 hours, the solvent is removed under reduced pressure, and the residue triturated with water. The solid is collected by filtration and air dried to afford 74 mg of the title compound. MS CI: m/z 420 (MH+).
Reaction SMILES: ClC1C=C(Cl)C=C(OC)C=1[S:11]([Cl:14])(=[O:13])=[O:12].Cl[C:16]1C=C(Cl)C=CC=1OC.ClC1C(C)=CC(Cl)=C(C)C=1S(Cl)(=O)=O.Cl[C:40]1[CH:45]=[C:44](C)[C:43]([Cl:47])=[CH:42][C:41]=1[CH3:48]>>[CH3:16][C:45]1[CH:44]=[C:43]([Cl:47])[CH:42]=[C:41]([CH3:48])[C:40]=1[S:11]([Cl:14])(=[O:13])=[O:12]
Reactant: COc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: Cc1cc(Cl)c(C)cc1Cl
Reactant: COc1ccc(Cl)cc1Cl
Agent: Cc1cc(Cl)c(C)c(S(=O)(=O)Cl)c1Cl
Product: Cc1cc(Cl)cc(C)c1S(=O)(=O)Cl

Procedure:
2,4-dichloro-6-methoxybenzenesulfonyl chloride from 2,4-dichloroanisole and 2,5-dichloro-3,6-dimethylbenzenesulfonyl chloride from 2,5-dichloro-p-xylene.
Reaction SMILES: COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:10]2)=CC=1.[CH2:23]([NH:27][C:28](=O)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C@@H:39]1[CH2:56][C:55]2[CH:54]=[C:53]([O:57][CH3:58])[CH:52]=[CH:51][C:50]=2[C@@H:49]2[C@@H:40]1[C@H:41]1[C@@:45]([CH2:47][CH2:48]2)([CH3:46])[C@@H:44]([O:59]C2CCCCO2)[CH2:43][CH2:42]1)[CH2:24][CH2:25][CH3:26]>C1(C)C(C)=CC=CC=1>[CH2:23]([NH:27][C:28](=[S:10])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C@@H:39]1[CH2:56][C:55]2[CH:54]=[C:53]([O:57][CH3:58])[CH:52]=[CH:51][C:50]=2[C@@H:49]2[C@@H:40]1[C@H:41]1[C@@:45]([CH2:47][CH2:48]2)([CH3:46])[C@@H:44]([OH:59])[CH2:43][CH2:42]1)[CH2:24][CH2:25][CH3:26]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCNC(=O)CCCCCCCCCC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)[C@@H](OC4CCCCO4)CC[C@H]3[C@H]12
Solvent: Cc1ccccc1C
Product: CCCCNC(=S)CCCCCCCCCC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: 130 °C

Procedure:
2,4-Bis-(p-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (Lawesson's Reagent; 0.375 g.) was added to a stirred solution of N-n-butyl-11-(3-methoxy-17β-tetrahydropyranyloxyoestra-1,3,5(10)-trien-7α-yl)undecanamide (0.25 g.) in xylene (14 ml.) and the mixture was stirred and heated at 130° C. for 5 hours and then evaporated to dryness under reduced pressure. The residue was dissolved in a mixture of tetrahydrofuran (2 ml.), water (2 ml.) and acetic acid (4 ml.) and the solution was stirred at laboratory temperature for 16 hours and then evaporated to dryness under reduced pressure. The residue was purified by chromatography on a silica gel column using a 4:1 v/v mixture of toluene and ethyl acetate as eluant, and there was thus obtained as an oil N-n-butyl-11-(17β-hydroxy-3-methoxyoestra-1,3,5(10)-trien-7α-yl)thioundecanamide.