Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[CH2:11]=O>O.[Pd]>[CH3:11][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1
Reactant: C=O
Reactant: O=C(O)CC1CCNCC1
Agent: [Pd]
Solvent: O
Product: CN1CCC(CC(=O)O)CC1

Procedure:
4-Piperidinylacetic acid (4 grams) (28.0 mmoles) from Preparative Example 17A was dissolved in water (50 ml) and 37% formalin (2.72 ml) (33.6 mmoles) was added. The mixture was hydrogenated over 10% Pd—C at 55 psi at 25° C. for 68 hours. The catalyst was filtered off and washed with water. The combined filtrates were evaporated to dryness to give the title compound (MH+158).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:14]([CH3:15])[C:13](=[O:16])[CH2:12][C@@H:11]3[N:7]([CH2:8][CH2:9][CH2:10]3)[C:6]=2[N:17]=1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[O:28][CH3:29]>C(O)C.O.Cl>[CH3:29][O:28][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:19]=1[NH:18][C:2]1[N:3]=[CH:4][C:5]2[N:14]([CH3:15])[C:13](=[O:16])[CH2:12][C@@H:11]3[N:7]([CH2:8][CH2:9][CH2:10]3)[C:6]=2[N:17]=1)[C:23]([OH:25])=[O:24]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C[C@H]2CCCN2c2nc(Cl)ncc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N1CCC[C@@H]1CC(=O)N2C

Procedure:
A mixture of 0.15 g (0.0006 mole) of (R)-9-chloro-6-methyl-2,3,3a,4-tetrahydro-1H,6H-6,8,10,10b-tetraaza-benzo[e]azulen-5-one (VII-102) and 0.11 g (0.00066 mole) of 4-amino-3-methoxy-benzoic acid (Aldrich) in 15 mL of ethanol-water-hydrochloric acid (20:80:1) was heated by microwave at 160 degrees for 40 minutes, and then concentrated under reduced pressure. The residue was lyophilized to give crude 3-methoxy-4-((R)-6-methyl-5-oxo-2,3,3a,4,5,6-hexahydro-1H-6,8,10,10b-tetraaza-benzo[e]azulen-9-ylamino)-benzoic acid (I-102a) as a light yellow solid which was used without further purification in subsequent steps.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:17])[C:8]([CH:10]1[CH2:14][CH2:13][CH:12]([CH3:15])[C:11]1=O)=O)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[C:10]2[CH2:14][CH2:13][CH:12]([CH3:15])[C:11]=2[NH:3][N:2]=1)=[O:17])[CH3:5]
Reactant: CCOC(=O)C(=O)C1CCC(C)C1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1n[nH]c2c1CCC2C
Yield: 50.3 %

Procedure:
Hydrazine hydrate (0.101 mL, 2.05 mmol) was added to a stirring room temperature solution of 4 (0.4055 g, 2.05 mmol) in EtOH (2.0 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by TLC. The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 96:4 Hexanes:2N NH3 in EtOH): Only pure fractions were combined and concentrated to obtain 0.2003 g (50.4%) of 5. 1H (CDCl3, 400 MHz): δ 9.55 (1H, broad s), 4.35 (2H, q, J=7.1 Hz), 3.26-3.16 (1H, m), 2.89-2.63 (3H, m), 2.09-1.98 (1H, m), 1.37 (3H, t, J=7.2 Hz), 1.30 (3H, d, J=6.9 Hz) ppm. Partial 13C (CDCl3, 100 MHz): δ 128.67, 61.32, 39.73, 32.64, 22.94, 19.62, 14.52 ppm. HPLC: 8.901 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:20][N:11]([C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1])[C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=O)c1ccccc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc([N+](=O)[O-])ccc1N(C)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of N-(2-methyl-4-nitrophenyl)benzamide (Example 1099A) (0.38 g, 1.48 mmol) in DMF (2 mL) was added cesium carbonate (1.2 g, 3.68 mmol) followed by methyl iodide (0.12 mL, 1.9 mmol). The reaction mixture was stirred at room temp for 2 hr, extracted with EtOAc, washed with water and brine, dried and concentrated in vacuo to give N-methyl-N-(2-methyl-4-nitrophenyl)-benzamide (0.38 g, 95%). ES-MS (M+H)+=271.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(N(CC)CC)C>C(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Oc1ccc(Nc2cc(Cl)ncn2)cc1
Yield: 76 %

Procedure:
A mixture of 4,6-dichloropyrimidine (3.0 g), 4-aminophenol (2.2 g) and triethylamine (6 ml) in ethanol.(50 ml) was refluxed for 2 hours. The product so obtained was recrystallised from a mixture of ethyl acetate and hexane to give 6-chloro-4-(4'-hydroxyanilino)pyrimidine in 76% yield, m.p. 241-244° C.;
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=4)[N:13]([CH2:22][CH3:23])[CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:24](Br)CC>>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=4)[N:13]([CH2:22][CH2:23][CH3:24])[CH:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CCn1cc(C2CCC3(CC2)OCCO3)c2cc(C#N)ccc21
Reactant: CCCBr
Product: CCCn1cc(C2CCC3(CC2)OCCO3)c2cc(C#N)ccc21
Yield: 75 %

Procedure:
This compound was prepared in the manner described above for intermediate 5b by replacing ethylbromide with n-propylbromide (13.1 g, 11 mmol) to afford 4.33 g (75%) of the title compound as a oil: MS EI m/e 324 (M+)
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][CH:9]([C:12](OCC)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[BH4-].[Li+].B(OC)(OC)OC>O1CCCC1.O>[CH:1]1([C:4]([N:6]2[CH2:7][CH2:8][CH:9]([CH2:12][OH:13])[CH2:10][CH2:11]2)=[O:5])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1CCN(C(=O)C2CC2)CC1
Agent: COB(OC)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(C1CC1)N1CCC(CO)CC1
Reaction time: 48 h
Yield: 63.7 %

Procedure:
A solution of 1-(cyclopropylcarbonyl)-4-carboethoxy piperidine (35 g, 156 mmol) in anhydrous tetrahydrofuran (350 mi) was stirred at ambient temperature under a nitrogen atmosphere. A solution of lithium borohydride in tetrahydrofuran (2 M, 78 ML, 156 mmol) was added dropwise. Trimethyl borate (1.77 mL, 15.7 mmol) was added, then the reduction mixture was stirred for about 48 hours. Water was added dropwise with vigorous stirring until the vigorous gas evolution ceased. The mixture was diluted twofold with water and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Vacuum distillation (bp 165° C., 0.5 mm Hg) gave a clear, colorless liquid (18.2 g):IR (neat): 3410 (br s), 3094 (w), 3008 (s), 2918 (s), 2858 (s), 1738 (m), 1613 (s), 1448 (s), 1375 (s), 1316 (s); 1H-NMR: 4.7-4.5 (m, 1H), 4.4-4.1 (m, 1H), 3.6-3.4 (m, 2H), 3.2-2.5 (m, 3H), 2.0-1.7 (m, 4H), 1.4-1.1 (m, 1H), 1.0-0.8 (m, 2H), 0.8-0.65 (m, 2H); HRMS:Calcd for C10H17NO2 :183.1259; Found: 183.1250; Anal.:Calcd for C10H17NO2 : C, 65.54, H, 9.35, N, 7.64; Found: C, 65.83, H, 9.43, N, 7.50.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:13][NH2:14])=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:11])=[N:7][C:6]=2[CH:12]=1.CCN(C(C)C)C(C)C.Cl[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=1>>[F:1][C:2]1[C:3]([CH2:13][NH:14][C:25]2[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:11])=[N:7][C:6]=2[CH:12]=1
Reactant: CSc1nc2cc(F)c(CN)cc2s1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc2cc(F)c(CNc3ncccc3[N+](=O)[O-])cc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.5 %

Procedure:
To a stirred mixture of (5-fluoro-2-(methylthio)benzo[d]thiazol-6-yl)methanamine (128 mg, 0.6 mmol) and DIEA (195 μL, 1.2 mmol) at 0° C. under argon was added 2-chloro-3-nitropyridine (98 mg, 0.7 mmol) in one portion. The mixture was stirred at rt for 18 h and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% hexanes to 50% EtOAc in hexanes to afford N-((5-fluoro-2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-amine (165 mg, 84%) as a yellow oil. LCMS (ESI) m/z 351 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].C(N(CC)CC)C.[C:26]([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)(=[O:28])[CH3:27]>C(#N)C>[C:26]([NH:29][CH:30]1[CH2:34][CH2:33][N:32]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:18])[CH2:31]1)(=[O:28])[CH3:27]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: CC(=O)NC1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(NC(C)=O)C3)nc21
Yield: 88.5 %

Procedure:
A mixture containing 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (2.7 g), triethylamine (1.01 g), 3-acetylaminopyrrolidine (2.56 g), and acetonitrile (100 ml) was heated under reflux for 2 hours. The mixture was concentrated to dryness under reduced pressure. The residue was mixed with water, neutralized with acetic acid, and cooled. The precipitate was collected, washed successively with water and ethanol, and dried to give 3.2 g of 7-(3-acetylamino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 283°-284° C., on recrystallization from dimethylformamide-ethanol.
Reaction SMILES: Br[C:2]1[C:3]([N:7]2[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]3[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]2=3)=[CH:4][S:5][CH:6]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.O>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[C:2]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)=[CH:6][S:5][CH:4]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: OB(O)c1cccnc1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cscc2Br)CCN(C)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2-c2cscc2-c2cccnc2)CCN(C)C1
Temperature: 95 °C
Yield: 25.3 %

Procedure:
To a de-aerated solution of 5-(4-bromo-thiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (160 mg, 0.44 mmol), 3-pyridinylboronic acid (81.9 mg, 0.66 mmol) and K3PO4 (235 mg, 1.11 mmol) in DMF-water (4.5:0.5 mL) was added dichlorobis(triphenylphosphine) palladium (II) (15.5 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 afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(4-pyridin-3-yl-thiophen-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (40 mg). 1H NMR (Oxalate salt, CD3OD) d (ppm): 8.35 (bs, 1H), 8.10 (bs, 1H), 7.95 (s, 1H), 7.8 (s, 1H), 7.45 (bs, 1H), 7.3-7.2 (m, 2H), 6.95 (d, 1H), 6.9 (d, 1H), 4.5 (bs, 2H), 3.6-3.45 (m, 2H), 3.15-3.05 (m, 1H), 3.0 (s, 3H), 2.65-2.59 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: [Cl:1][C:2]([O:5]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][C@H:22]([CH2:26][CH3:27])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].N1C=CC=CC=1>ClCCl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]([Cl:1])=[O:5])[C@H:22]([CH2:26][CH3:27])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 262.3 %

Procedure:
Bis-(trichloromethyl)-carbonate (13.9 g, 47 mM) was dissolved in dichloromethane (500 mL) and cooled to 0° C. A mixture of (R)-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester (26.5 g; 0.124 M) and pyridine (10.9 mL, 0.136 M) in dichloromethane (150 mL) was added dropwise with stirring (0–3° C.). Stirring was continued for another ½ h at room temperature. The mixture was washed with water and brine, the water phases were extracted with dichloromethane, organic phases were pooled, dried with Na2SO4 and evaporated to yield a brown oil (34 g, 99%) which crystallized upon standing; MS (EI): 276.2 (M)+.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=1>CN(C=O)C.[Cl-].[Na+].O>[CH3:19][C:20]1[CH:25]=[CH:24][N:23]2[CH:2]=[C:3]([CH2:4][C@@H:5]3[CH2:10][CH2:9][CH2:8][CH2:7][N:6]3[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:26]=[C:22]2[N:21]=1
Reactant: Cc1ccnc(N)n1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CC(=O)CBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccn2cc(C[C@@H]3CCCCN3C(=O)OC(C)(C)C)nc2n1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1,1-dimethylethyl (2S)-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate D2 (0.300 g, 0.94 mmol) in DMF (2 ml) was added 4-methyl-2-pyrimidinamine (0.153 g, 1.41 mmol) and the mixture was stirred at 80° C. for 1.5 h. To the reaction mixture was added brine and a saturated NaHCO3 aqueous solution and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash cromatography on silica gel (Biotage 25+M, DCM/MeOH from 100/0 to 90/10). Collected fractions gave the title compound (0.350 g slightly contaminated with residual 4-methyl-2-pyrimidinamine). UPLC: rt=0.53, peak observed: 331 (M+1). C18H26N4O2 requires 330.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[OH:15])[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH2:18](Br)[C:19]#[CH:20].C([O-])([O-])=O.[K+].[K+].CC(C)=O>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH2:20][C:19]#[CH:18])[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: Nc1ccc2c(c1)ncn2-c1ccccc1O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: C#CCOc1ccccc1-n1cnc2cc(N)ccc21
Temperature: 70 °C
Reaction time: 18.5 h
Yield: 36.6 %

Procedure:
A suspension of 5-amino-1-(2-hydroxyphenyl)benzimidazole (4) (499 mg, 2.21 mmol), 80% propargyl bromide (2.43 mmol) in toluene (271 μL), K2CO3 (398 mg, 2.88 mmol), and acetone (15 mL) is stirred at 70° C. under argon for 18.5 h and then cooled to room temperature. The mixture is concentrated, diluted with H2O (35 mL), and extracted with ethyl acetate (100 mL and 50 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (2% to 7% methanol/ethyl acetate) to give 213 mg (39%) of 5 as a light-brown solid, mp 40-42° C. IR 3379, 2966, 1512, 1239 cm−1; 1H NMR (CDCl3) δ 2.51 (t, J=2.4 Hz, 1H, C≡CH), 3.09 (bs, 2H, NH2), 4.68 (d, J=2.4 Hz, 2H, CH2C≡CH), 6.74 (dd, J=8.4 Hz, 2.1 Hz, 1H, 6-BenzimidH), 7.14 (d, J=8.4 Hz, 1H, 7-BenzimidH), 7.16 (d, J=2.1 Hz, 1H, 4-BenzimidH), 7.19 (m, 1H, 3-PhH), 7.29 (m, 1H, 5-PhH), 7.42-7.49 (m, 2H, 4,6-PhH), 8.01 ppm (s, 1H, 2-BenzimidH). HRMS calcd C16H13N3O [M+H]+ 264.1137. found 264.1129.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C@@:8]2([CH3:23])[CH2:9][CH2:10][C@@H:11]3[C@@:16]4([CH3:22])[CH2:17][CH2:18][C@H:19]([OH:21])[CH2:20][C:15]4=[CH:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH:5]=1)=[O:3].[Br:24]C1(Br)C(=O)NC(=O)NC1=O.Br>O1CCCC1.C(Cl)Cl>[Br:24][CH2:1][C:2](=[O:3])[C:4]1[C@:8]2([CH3:23])[C@H:7]([C@H:12]3[C@H:11]([CH2:10][CH2:9]2)[C@:16]2([CH3:22])[C:15]([CH2:20][C@@H:19]([OH:21])[CH2:18][CH2:17]2)=[CH:14][CH2:13]3)[CH2:6][CH:5]=1
Reactant: O=C1NC(=O)C(Br)(Br)C(=O)N1
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Br
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(C(=O)CBr)=CC[C@@H]12
Yield: 104.4 %

Procedure:
Dissolve 16-dehydropregnenolone (5.00 g, 15.90 mmol) and 5,5-dibromobarbituric acid (4.55 g, 15.90 mmol) in tetrahydrofuran (60 mL). Add concentrated aqueous hydrogen bromide (100 μL of a 48% solution) to the stirring solution and heat the reaction at reflux for 1 hour. Cool slightly and then concentrate under vacuum to produce a brown oily foam. Dissolve the residue in methylene chloride (350 mL), rinse with 50% saturated sodium bicarbonate (2×200 mL, brine (125 mL), dry over anhydrous magnesium sulfate, filter and concentrate under vacuum to provide 21-bromo-3β-hydroxypregna-5,16-dien-20-one (6.53 g) as an orange-brown solid, slightly contaminated with starting material.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH:6]=1)C.[C:36]1([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][NH2:50])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:36]1([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][NH:50][C:4](=[O:3])[C:5]2[CH:6]=[C:7]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=3)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[CH:10]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NCCCCCCCCc1ccccc1
Reactant: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
N-(8-phenyl-octyl)-3,5-bis(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)benzamide was prepared as a white solid (0.331 g, 74%) from 3,5-bis-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)benzoic acid ethyl ester and phenyloctyl amine using a procedure similar to step 2 of Example 1. 1H NMR (CDCl3) δ 7.96–7.50 (m, 10H); 7.35–7.10 (m, 5H); 6.28 (m, 1H); 3.45 (m, 2H); 3.31 (m, 4H); 2.60 (m, 2H); 1.60 (m, 4H); 1.33 (m, 8H).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]([CH2:8][O:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH:5]([CH3:29])[C:4]1=[O:30])[CH3:2].[CH:31]([N-]C(C)C)(C)C.[Li+].IC>O1CCCC1>[CH2:1]([N:3]1[CH:7]([CH2:8][O:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:5]([CH3:31])([CH3:29])[C:4]1=[O:30])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CCN1C(=O)C(C)CC1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCN1C(=O)C(C)(C)CC1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 2M solution of lithium diisopropylamide in tetrahydrofuran (1.912 ml, 3.82 mmol) at −78° C. was added, drop-wise, a solution of 1-ethyl-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone (1.34 g, 3.48 mmol) in tetrahydrofuran (10 ml) and the resulting mixture was stirred for 1 hr at −78° C. Iodomethane (0.239 ml, 3.82 mmol) was then added and after stirring for a further 1 hr at −78° C. the mixture was allowed to warm to room temperature over 3 hrs. The mixture was then re-cooled to −78° C. and treated, drop-wise, with a further aliquot of a 2M solution of lithium diisopropylamide in tetrahydrofuran (1.912 ml, 3.82 mmol). After stirring for an additional 1 hr at −78° C. the mixture was again treated with iodomethane (0.239 ml, 3.82 mmol) and then the mixture was allowed to warm to room temperature and stirred overnight. The mixture was quenched with saturated aqueous ammonium chloride and then extracted with ethyl acetate (2×). The combined organic extracts were then washed with water (3×) and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated to a crude oily solid (1.7 g). The crude solid was purified by automated flash silica-gel column chromatography (Biotage SP4), eluting with a 0-100% gradient of ethyl acetate in hexane, to give pure product fractions (i.e. 1-ethyl-3,3-dimethyl-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone (0.468 g)) as well as pure monoalkyated material (i.e. 1-ethyl-3-methyl-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone (0.524 g)) and a mixture of these two (0.240 g). The desired product was set aside while the 1-ethyl-3-methyl-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone and the mixed material were combined and dissolved in tetrahydrofuran (20 ml). This solution was then added drop wise to a 2M solution of lithium diisopropylamide in tetrahydrofuran (1.912 ml, 3.82 mmol) at −78° C. and stirring at this temperature was continued for 1 hr. Iodomethane (0.239 ml, 3.82 mmol) was then added to the mixture and the mixture was allowed to warm to room temperature over 4 hrs. Workup as described above gave an additional batch of 1-ethyl-3,3-dimethyl-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone (0.846 g) as an oil which was combined with the material set aside earlier (total mass=1.08 g) and used in the next step without further purification.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:38]=[CH:37][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([C:33]([F:36])([F:35])[F:34])[CH:22]=2)=[O:19])=[CH:16][C:15]=1I>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([C:33]([F:35])([F:34])[F:36])[CH:22]=2)=[O:19])=[CH:37][C:38]=1[C:12]#[C:11][C:8]1[N:7]=[N:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=1
Reactant: Cc1cn(-c2ccc(NC(=O)c3ccc(Cl)c(I)c3)cc2C(F)(F)F)cn1
Reactant: C#Cc1ccc(NC(C)C)nn1
Product: Cc1cn(-c2ccc(NC(=O)c3ccc(Cl)c(C#Cc4ccc(NC(C)C)nn4)c3)cc2C(F)(F)F)cn1

Procedure:
The title compound was synthesized from N-isopropyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp:133-135° C.; 1H NMR (300 MHz, CDCl3) δ: 10.46 (1 H, s), 8.40 (1 H, s), 8.28-8.31 (1 H, d, J=8.1 Hz), 8.04 (1 H, s), 7.82-7.84 (1 H, d, J=8.1 Hz), 7.53 (1 H, s), 7.41-7.43 (1 H, d, J=8.4 Hz), 7.34-7.36 (2 H, m), 6.81 (1 H, s), 6.66-6.69 (1 H, d, J=9.3 Hz), 5.13-5.15 (1 H, d, J=6.3 Hz), 4.08 (1 H, m), 2.29 (3 H, s), 1.30-1.32 (6 H, d, J=6.0 Hz). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C27H23ClF3N6O: 539.1568. found: 539.1592.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1.C(N(CC)CC)C.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl>[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([O:1][CH2:2][CH2:3][CH:4]([NH:14][C:15]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:21])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)NC(CCO)c1cccc([N+](=O)[O-])c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC(NC(=O)OC(C)(C)C)c2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.4 %

Procedure:
To a solution of tert-butyl [3-hydroxy-1-(3-nitrophenyl)propyl]carbamate (4.00 g; 13.50 mmol; 1.00 eq.) in anhydrous DCM (15 mL) and N,N-diethylethanamine (2.82 ml; 20.25 mmol; 1.50 eq.) at 0° C. was added dropwise 4-methylbenzenesulfonyl chloride (3.09 g; 16.20 mmol; 1.20 eq.). The mixture was stirred at room temperature for 15 h. After workup, the crude product was purified by flash chromatography on silica gel (EtOAc:Hex from 10:90 to 20:80) to provide 5.5 g of the 3-[(tert-butoxycarbonyl)amino]-3-(3-nitrophenyl)propyl 4-methylbenzenesulfonate.