Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](OS(C(F)(F)F)(=O)=O)=[C:10]2[N+:13]([O-:15])=[O:14])=[CH:5][CH:4]=1.C[Sn](C)(C)[C:26]1[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][C:29]2[O:35][CH2:36][O:37][C:28]=2[CH:27]=1.C1C[O:43][CH2:42]C1>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>[CH2:36]1[O:37][C:28]2[C:29](=[CH:30][C:31]([N+:32]([O-:34])=[O:33])=[C:26]([C:9]3[C:10]([N+:13]([O-:15])=[O:14])=[C:11]4[C:6](=[CH:7][CH:8]=3)[CH:5]=[C:4]([O:43][CH3:42])[C:3]([O:2][CH3:1])=[CH:12]4)[CH:27]=2)[O:35]1
Reactant: C[Sn](C)(C)c1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c2c1
Reactant: C1CCOC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COc1cc2ccc(-c3cc4c(cc3[N+](=O)[O-])OCO4)c([N+](=O)[O-])c2cc1OC
Reaction time: 0.5 h
Yield: 42 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (100 mg) and cuprous bromide (20 mg) was added to a solution of 7-Methoxy-1-nitro-2-trifluoromethanesulfonyloxy-naphthalene 53 (366 mg, 1.04 mmol) and trimethylnitroarylstannane 62 (500 mg, 1.52 mmol) in THF (30 mL) at room temperature and stirred for 0.5 h. The mixture was then refluxed under N2 overnight. After cooling, THF was evaporated and ethyl acetate (30 mL) was added to the residue. The solution was washed with water. The organic layer was separated and passed through a Celite bed to remove suspended particles. The organic layer was then washed with brine, dried (anhydrous Na2SO4), and evaporated in vacuo. The residue was chromatographed using a 70:30 mixture of hexanes:ethyl acetate to give 54 (160 mg) in 42% yield; mp 187-189° C.; IR (KBr) 2925, 1628, 1526, 1487, 1364, 1332, 1265, 1230 cm−1; 1H NMR (CDCl3) δ3.92 (3H, s), 6.19 (2H, d), 6.76 (1H, s), 7.12 (1H, d, J=2.5), 7.18 (1H, d, J=8.3), 7.28 (1H, dd, J1=9.0, J2=2.3), 7.70 (1H, s), 7.85 (1H, d, J=9.2), 7.93 (1H, d, J=8.4), 13C NMR δ56.08, 100.59, 103.93, 106.31, 110.70, 121.54, 124.07, 126.47, 128.71, 129.55, 130.33, 130.99, 131.23, 142.83, 148.92, 152.07, 160.68.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[C:5]#[N:6].[NH3:14]>>[NH2:14][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[C:5]#[N:6]
Reactant: N
Reactant: N#Cc1ccc(C(F)(F)F)c(F)c1
Product: N#Cc1ccc(C(F)(F)F)c(N)c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A closed pressure tube charged with 3-fluoro-4-trifluoromethyl-benzonitrile (10.0 g; 52.9 mmol) and liquid NH3 (60 mL) was heated for 6 days at 90° C. The tube was cooled to −60° C. and opened. The mixture was allowed to stir for 1 h at rt, washed with brine, extracted with EtOAc, dried over Na2SO4, filtered and concentrated.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:33](=[O:34])[C:12]2=[CH:13][N:14]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)=[CH:24][CH:23]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]2=[N:10]1.C(N(C(C)C)CC)(C)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl>[CH3:44][S:45]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:33](=[O:34])[C:12]2=[CH:13][N:14]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)=[CH:24][CH:23]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]2=[N:10]1)(=[O:47])=[O:46]
Reactant: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1-c1ccccc1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-[2-(Hydroxymethyl)phenyl]-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 654, 0.23 g, 0.51 mmol) was suspended in dichloromethane (5 mL), treated with diisopropylethylamine (0.20 mL, 1.1 mmol, 2.2 equiv) and cooled to −78° C. Methanesulfonyl chloride (60 μL, 0.77 mmol, 1.5 equiv) was added and the mixture was stirred at −78° C. for 30 minutes. The dry ice/acetone bath was removed, the mixture was warmed to ambient temperature and stirred for an additional 45 minutes. The mixture was poured into ammonium chloride (20 mL, aqueous saturated) and extracted with dichloromethane (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.O.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>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)=[CH:26][CH:25]=1
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2ccccc2-c2ccc(F)cc2)CCN(C)C1
Temperature: 95 °C
Yield: 18.4 %

Procedure:
To a de-aerated solution of 5-(2-bromo-phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.282 mmol), 4-fluorophenylboronic acid (59 mg, 0.423 mmol) and K3PO4 (149 mg, 0.706 mmol) in DMF-water (4:1 mL) was added PdCl2(PPh3)2 (10 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield crude, which was purified by reverse phase HPLC to yield 5-(4′-fluorobiphenyl-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as semisolid (19.23 mg). 1H NMR (Oxalate salt, CD3OD) d (ppm): 7.65-7.59 (m, 3H), 7.41 (d, 1H), 7.25 (s, 1H), 7.15 (m, 1H), 7.05-6.85 (m, 5H), 4.5-3.39 (m, 2H), 3.6-3.5 (m, 1H), 3.2-3.19 (m, 1H), 2.95 (s, 3H), 2.85-2.8 (m, 1H), 2.59-2.50 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([CH:20]=[O:21])=[CH:5][N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.[NH:33]1[CH2:39][CH2:38][CH2:37][C@H:34]1[CH2:35][OH:36].C(N(CC)CC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[OH:36][CH2:35][C@@H:34]1[CH2:37][CH2:38][CH2:39][N:33]1[C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([CH:20]=[O:21])=[CH:5][N:4]=1
Reactant: OC[C@@H]1CCCN1
Reactant: COc1ccc(CNc2nc(SC)ncc2C=O)cc1Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2nc(N3CCC[C@H]3CO)ncc2C=O)cc1Cl
Temperature: 25 °C
Yield: 83.5 %

Procedure:
A solution of 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-formylpyrimidine (2.057 g) in chloroform (20 ml) is treated with m-chloroperbenzoic acid (80%, 1.468 g) at 0° C. for 30 minutes. To the reaction mixture are is added L-prolinol (0.901 g), and then triethylamine (1.33 ml), and the mixture is reacted at 0° C. for one hour. The reaction mixture is warmed to room temperature, and diluted with ethyl acetate. The mixture is washed successively with a saturated aqueous sodium hydrogen carbonate solution, water and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The precipitates are removed by filtration through a silica plug. The filtrate is concentrated under reduced pressure to give (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino) -5-formylpyrimidine (1.9990 g) as colorless amorphous, MS (m/z): 377 (MH+).
Reaction SMILES: [C:1]([C:9]1([CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:19])[CH2:14]CCC[C:10]1=[O:15])(=O)[C:2]1C=CC=C[CH:3]=1.[OH:30]O>C(O)(C)(C)C.S(=O)(=O)(O)O>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:18]([CH2:17][CH2:16][C:9]2([C:10]([OH:30])=[O:15])[CH2:14][CH2:3][CH2:2][CH2:1]2)=[O:19])=[CH:23][CH:24]=1
Reactant: OO
Reactant: COc1ccc(COC(=O)CCC2(C(=O)c3ccccc3)CCCCC2=O)cc1
Agent: O=S(=O)(O)O
Solvent: CC(C)(C)O
Product: COc1ccc(COC(=O)CCC2(C(=O)O)CCCC2)cc1
Reaction time: 48 h
Yield: 44.5 %

Procedure:
To a solution of 2-benzoyl-2-[2-(4-methoxybenzyloxycarbonyl)-ethyl]cyclohexanone (see Preparation 9) (2.16 g, 5.47 mmol) in tert-butanol (4.3 ml) was added, dropwise, a 30% aqueous solution of hydrogen peroxide (0.74 ml, 6.56 mmol) and concentrated sulphuric acid (98% w/w, one drop) at room temperature. The mixture was stirred for 48 hours, partitioned between toluene (25 ml) and 5% aqueous sodium sulphite solution and the layers separated. The toluene layer was washed with dilute aqueous ammonia solution (25 ml of 0.880 ammonia in 200 ml of distilled water, 4×25 ml). The combined aqueous extracts were washed with toluene (25 ml), acidified to pH 2-3 with 5.ON aqueous hydrochloric acid solution and extracted with toluene (3×25 ml). The combined toluene extracts were dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound as an oil, (0.746 g, 44.6%). RF. 0.16 silica, hexane/ethyl acetate 2:1). 1H-NMR (300 MHz, CDCl3):=1.45-1.59 (m, 2H), 1.65-1.78 (m, 4H), 1.98-2.06 (m, 2H), 2.12-2.22 (m, 2H), 2.34-2.46 (m, 2H), 3.84 (s, 3H), 5.06 (s, 2H), 6.91 (d, 2H), 7.31 (d, 2H) ppm. Analysis %: Found: C, 67.05; H, 7.18; C17H22O5 requires: C, 66.65; H, 7.24.
Reaction SMILES: CO[C:3]1[CH:8]=[N:7][N:6]([CH3:9])[C:5](=[O:10])[CH:4]=1.P(Cl)(Cl)([Cl:13])=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.O>[Cl:13][C:3]1[CH:8]=[N:7][N:6]([CH3:9])[C:5](=[O:10])[CH:4]=1
Reactant: COc1cnn(C)c(=O)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cn1ncc(Cl)cc1=O
Temperature: 110 °C
Yield: 58.4 %

Procedure:
A mixture of 1.50 g (10.70 mmol) of 5-methoxy-2-methyl-2H-pyridazin-3-one and 7.8 ml (13.1 g, 85.6 mmol) of phosphorus oxychloride was heated at 110° C. for 2 h. After allowing to cool to room temperature, the mixture was poured into 100 ml of ice/water with vigourous stirring. After neutralization by addition of saturated sodium carbonate solution, the compound was worked up with methylene chloride/water, dried over magnesium sulfate and concentrated in vaccuo. The crude material was purified by flash chromatography on silicagel using a 80:20 mixture of ethyl acetate and heptane as eluant to yield 904 mg (6.25 mmol, 58%) of the title compound as a crystalline white solid, MS: 141.2 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1([CH3:25])[CH3:24])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C.[Cl:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39](Cl)=[O:40]>CCOC(C)=O>[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:39](=[O:40])[C:38]2[CH:42]=[CH:43][CH:44]=[C:36]([Cl:35])[CH:37]=2)[CH2:20][C:19]1([CH3:25])[CH3:24])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CC1(C)CNCCN1C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC1(C)CN(C(=O)c2cccc(Cl)c2)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.00 g (8.28 mmol) 2,2-dimethyl-piperazine-1-carboxylic acid benzyl ester trifluoroacetate in 50 mL EtOAc was added 3.50 mL (20.3 mmol) DIPEA followed by 1.07 mL (8.28 mmol) 3-chloro-benzoyl chloride dropwise at RT. The reaction mixture was stirred at RT for 1 h. Then the suspension was washed with water. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@@H:2]1[CH2:11][C:12]([OH:14])=O.[CH3:15][O:16][C:17](=[O:23])[C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1.C1(CC(O)=O)C2C(=CC=CC=2)CC1.C(OC(=O)[C@@H]1CSCN1)C>>[CH3:15][O:16][C:17](=[O:23])[C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:12](=[O:14])[CH2:11][C@H:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(O)C[C@H]1CCc2ccccc2C1
Agent: CCOC(=O)[C@@H]1CSCN1
Agent: O=C(O)CC1CCc2ccccc21
Product: COC(=O)[C@@H]1CCCN1C(=O)C[C@H]1CCc2ccccc2C1
Yield: 72 %

Procedure:
Colorless crystals of 1-[(S)-(-)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl]-L-proline methyl ester were prepared in the same manner as in Reference Example 1, except that (S)-(-)-1,2,3,4-tetrahydronaphthalen-2-ylacetic acid and L-proline methyl ester were used instead of 2-indanyl acetic acid and L-thioproline ethyl ester, respectively yield: 72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18].S1C=CC=C1C(Cl)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([O:13][CH3:12])[CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: COc1cccc(C(=O)Cl)c1
Agent: O=C(Cl)c1cccs1
Product: COc1cccc(C(=O)Nc2ccc(F)c([N+](=O)[O-])c2)c1

Procedure:
4-Fluoro-3-nitro-phenylamine was reacted with 3-methoxybenzoyl chloride according to the procedure of Example 256a substituting 3-methoxybenzoyl chloride for thiophene-2-carbonyl chloride to provide N-(4-Fluoro-3-nitro-phenyl)-3-methoxy-benzamide which was then reacted according to the procedures of Examples 256b and 256c to provide the title product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18]2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:38]([O:42][C:43]([N:45]1[C:53]2[C:48](=[CH:49][C:50]([NH:54][C:55](OC3C=CC=CC=3)=[O:56])=[CH:51][CH:52]=2)[CH:47]=[N:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>C(#N)C.C(OCC)(=O)C>[C:38]([O:42][C:43]([N:45]1[C:53]2[C:48](=[CH:49][C:50]([NH:54][C:55]([NH:14][C@@H:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C@H:10]3[C:15]([N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[CH2:18]3)=[O:16])=[O:56])=[CH:51][CH:52]=2)[CH:47]=[N:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(NC(=O)Oc3ccccc3)ccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)Nc2ccc3c(cnn3C(=O)OC(C)(C)C)c2)[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Temperature: 60 °C
Reaction time: 64 h
Yield: 61.2 %

Procedure:
In a dry flask (3R,4R)-4-Amino-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester (72 mg, 0.171 mmol) was dissolved in acetonitrile (2 mL) and triethylamine (25 μL, 0.179 mmol) and 5-(phenoxycarbonylamino)-1-indazolecarboxylic acid 1-tert-butyl ester (72 mg, 0.204 mmol) were added. The reaction mixture was stirred for 64 hours while heating to 60° C. The reaction mixture was cooled, diluted with ethyl acetate, washed twice with water and once with brine. The organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative reverse-phase HPLC (10-80% acetonitrile in water with 0.05% trifluoroacetic acid) to give a white amorphous solid (71 mg, 61%). 1H NMR (300 MHz, CDCl3), δ: 8.09 (m, 2H), 7.90 (2s, 1H), 7.44 (m, 1H), 7.10 (m, 1H), 6.99 (m, 1H), 6.83 (m, 2H), 4.90 (bs, 1H), 4.43 (bd, 1H, J=11), 4.22 (bs, 2H), 3.98 (bm, 2H), 3.14 (t, 1H, J=13), 2.75 (bm, 4H), 2.45 (bm, 3H), 1.94 (bm, 3H), 1.73 (2s, 9H), 1.48 (m, 9H), 1.45 (bm, 3H), 1.22 (bm, 1H). HRMS (ESI), C36H48FN6O6 m+/z: calc.=679.3619, found=679.3621.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:25]([CH2:26][CH2:27][C@:6]12[CH3:7])[C@:19]1([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C:14](=[CH:15][C@@H:16]([OH:28])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2].[CH3:29][Si:30]([CH3:33])([CH3:32])Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:25]([CH2:26][CH2:27][C@:6]12[CH3:7])[C@:19]1([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C:14](=[CH:15][C@@H:16]([O:28][Si:30]([CH3:33])([CH3:32])[CH3:29])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@]12CC[C@H](O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Reactant: C[Si](C)(C)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC[C@]12CC[C@H](O[Si](C)(C)C)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12

Procedure:
A solution of 4-androstene-3β,17β,19-triol 17,19-diacetate, trimethylchlorosilane and pyridine in toluene is refluxed for 24 hours. The solid is removed by filtration and the filtrate reduced to dryness under vacuum. The oil is crystallized from hexane to yield 3β-trimethylsiloxy-4-androstene-17β,19-diol 17,19-diacetate. This produce is refluxed one hour with 1 equivalent of sodium bicarbonate in 10% aqueous methanol. The solution is poured onto water. The solid which forms is filtered, dried, and crystallized from ether-hexane to yield 3β-trimethylsiloxy-4-androstene-17β,19-diol 17-acetate.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:15][C:14]4[N:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl-].[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH2:36][NH:37][CH:38]=[S:39])=[CH:35][C:30]=2[O:29][CH2:28]1.CO>ClCCl>[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH2:36][NH:37][C:38]([N:4]3[CH2:3][CH2:2][N:1]([C:7]4[N:12]=[CH:11][N:10]=[C:9]5[C:8]=4[S:15][C:14]4[N:16]=[CH:17][CH:18]=[CH:19][C:13]5=4)[CH2:6][CH2:5]3)=[S:39])=[CH:35][C:30]=2[O:29][CH2:28]1
Reactant: c1cnc2sc3c(N4CCNCC4)ncnc3c2c1
Reactant: S=CNCc1ccc2c(c1)OCO2
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: S=C(NCc1ccc2c(c1)OCO2)N1CCN(c2ncnc3c2sc2ncccc23)CC1
Reaction time: 8 h

Procedure:
To a solution of 4-piperazinopyrido[3′,2′;4,5]thieno[3,2-d]pyrimidine (200 mg, 0.74 mmol) and pyridine (0.5 mL, 7.9 mmol) in dichloromethane (20 mL) was added a solution of product 1c in dichloromethane (20 mL) and this was stirred overnight. Methanol was added to quench excess thiophosgene, and the residue after removal of solvent was purified by silica gel column chromatography eluting with 5% methanol/dichloromethane and further recrystallized from dichloromethane/hexane to give 110 mg (32%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:12](F)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.ClC1N=C(Cl)C([C:32]([F:35])([F:34])[F:33])=CN=1.NC1C=C(O)C=CC=1>>[OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:12]([C:32]([F:35])([F:34])[F:33])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Agent: Nc1cccc(O)c1
Product: Oc1cccc(Nc2ncc(C(F)(F)F)c(Nc3cccc(O)c3)n2)c1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-trifluoromethylpyrimidine and 3-aminophenol were reacted to yield N2,N4-bis(3-hydroxyphenyl)-5-trifluoromethyl-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.82 (bs, 1H), 8.88 (bs, 1H), 8.36 (s, 1H), 7.18-7.11 (m, 2H), 6.96 (m, 4H), 6.63 (dd, 1H, J=2.4 and 8.1 Hz), 6.38 (d, 1H, J=8.1 Hz); 19F NMR (DMSO-d6): −16979; LCMS: ret. time: 19.04 min.; purity: 95%; MS (m/e): 363 (MH+).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[N:6]1[C:15]2[CH:14]=[CH:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1>C(OCC)(=O)C>[NH2:5][CH:13]1[CH2:14][C:15]2[N:6]=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:11][CH2:12]1
Reactant: C1=Cc2ncccc2CC1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: NC1CCc2cccnc2C1

Procedure:
This compound was prepared from ammonium acetate (1 54 g, 20 mmol) and 5,6-dihydroquinoline (2.31 g, 10 mmol) using the method described in Example 36 and ethyl acetate instead of ether as the extracting solvent.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:40][CH2:41][CH3:42])[C:34]=1[C:35]1[CH:36]=[N:37][NH:38][CH:39]=1)[C:29]([OH:31])=O)[CH3:24].Cl.[NH:44]1[C:48]([C:49]2[CH:50]=[C:51]3[C:61](=[CH:62][CH:63]=2)[O:60][C:54]2([CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:53][C:52]3=[O:64])=[N:47][N:46]=[N:45]1>O.CN(C=O)C.CCN(CC)CC>[CH2:41]([O:40][C:33]1[CH:32]=[C:28]([C:29]([N:57]2[CH2:58][CH2:59][C:54]3([CH2:53][C:52](=[O:64])[C:51]4[C:61](=[CH:62][CH:63]=[C:49]([C:48]5[NH:47][N:46]=[N:45][N:44]=5)[CH:50]=4)[O:60]3)[CH2:55][CH2:56]2)=[O:31])[CH:27]=[C:26]([O:25][CH2:23][CH3:24])[C:34]=1[C:35]1[CH:36]=[N:37][NH:38][CH:39]=1)[CH3:42]
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1cn[nH]c1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)cc(OCC)c1-c1cn[nH]c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Et3N (83 μL), HOBT (46 mg) and WSC hydrochloride (58 mg) were added to a DMF (4 mL) solution of 3,5-diethoxy-4-(1H-pyrazol-4-yl)benzoic acid (97 mg) and 6-(tetrazol-5-yl)spiro [chroman-2,4′-piperidin]-4-one hydrochloride (70 mg), stirred overnight at room temperature. Water was added to the reaction liquid, the formed solid was taken out through filtration, and the solid was washed with water and ether. The solid was dried under reduced pressure to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 8.41 (1H, d, J=4.0 Hz), 8.23 (1H, dd, J=8.0, 4.0 Hz), 8.04 (2H, s), 7.32 (1H, d, J=8.0 Hz), 6.68 (2H, s), 4.32-4.18 (1H, m), 4.08 (4H, q, J=8.0 Hz), 3.64-3.20 (3H, m), 2.97 (2H, s), 2.10-1.75 (4H, m), 1.37 (6H, t, J=8.0 Hz). MS [M+H]+=544.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([CH:22]=[C:23]2[S:27][C:26](SC)=[N:25][C:24]2=[O:30])[CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[C:14]([F:17])([F:16])[F:15].[C:31]([O:35][C:36](=[O:41])[NH:37][CH2:38][CH2:39][NH2:40])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36](=[O:41])[NH:37][CH2:38][CH2:39][NH:40][C:26]1[S:27][C:23](=[CH:22][C:20]2[CH:19]=[CH:18][C:4]([O:5][C:6]3[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=3[C:14]([F:15])([F:17])[F:16])=[C:3]([O:2][CH3:1])[CH:21]=2)[C:24](=[O:30])[N:25]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: COc1cc(C=C2SC(SC)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCN
Product: COc1cc(C=C2SC(NCCNC(=O)OC(C)(C)C)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F

Procedure:
(2-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-ethyl)-carbamic acid tert-butyl ester was prepared using 4-[2-Methoxy-4-(2-methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile and (2-Amino-ethyl)-carbamic acid tert-butyl ester as described in Example 5C.
Reaction SMILES: [CH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][N:2]=1.[C:14](#[N:17])[CH:15]=[CH2:16].[OH-].[CH2:19]([N+](C)(C)C)C1C=CC=CC=1>C1C=CC=CC=1>[CH3:19][N:2]1[CH2:3][CH2:4][C:5]2[N:6]([CH2:16][CH2:15][C:14]#[N:17])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[CH2:1]1
Reactant: c1ccc2c(c1)[nH]c1ccncc12
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: C=CC#N
Agent: [OH-]
Solvent: c1ccccc1
Product: CN1CCc2c(c3ccccc3n2CCC#N)C1
Yield: 80 %

Procedure:
To a solution of Pyrido[4,3-b]indole G3-a (R19=H) (2.108 g, 11.3 mmol) in mixture benzene (30 ml) and acrylonitrile (10 mL) was added benzyltrimethylammonium hydroxide solution (40% wt. % in methanol, 0.7 mL). The mixture was heated under reflux for 1 h, cooled, washed with water, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (benzene/Et3N, 9:1) gave 2.174 g (80%) of the title compound, mp 108-110° C. (acetone, −12° C.). 1H NMR (Acetone-d6): 2.46 (3H, s), 2.73-3.01 (6H, m), 3.56 (2H, s), 4.48 (2H, t), 6.97-7.16 (2-H, m), 7.38 (1H, d), 7.45 (1H, d).