Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:8][C:9]3[C:14]([C:15](=O)[CH:16]=2)=[CH:13][CH:12]=[CH:11][C:10]=3[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:3][CH2:2]1.COC(Cl)[Cl:27]>>[Cl-:27].[Cl:27][C:15]1[C:14]2[C:9](=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]=[CH:12][CH:13]=2)[O+:8]=[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:16]=1
Reactant: O=c1cc(N2CCOCC2)oc2c(-c3ccccc3)cccc12
Reactant: COC(Cl)Cl
Product: Clc1cc(N2CCOCC2)[o+]c2c(-c3ccccc3)cccc12
Product: [Cl-]
Temperature: 80 °C

Procedure:
A solution of 2-morpholino-8-phenyl-4H-chromen-4-one (LY294002) (1.50 g, 4.93 mmol) and dichloromethyl methyl ether (15 mL) was stirred and heated to 80° C. for 2 hours under argon. The mixture was cooled to room temperature, and then concentrated in vacuo to give 4-chloro-2-morpholino-8-phenylchromenylium chloride (78) (2.06 g, 5.73 mmol).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([OH:14])[C:12]#[CH:13].N1C=CC=CC=1.[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1.O>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([O:14][C:24]([CH:21]1[CH2:23][CH2:22]1)=[O:25])[C:12]#[CH:13]
Reactant: O=C(Cl)C1CC1
Reactant: C#CC(O)c1ccc2ccccc2c1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#CC(OC(=O)C1CC1)c1ccc2ccccc2c1
Reaction time: 2 h

Procedure:
3.6 g of 1-(2-naphthyl)-2-propyn-1-ol and 1.6 g of pyridine are dissolved in 30 ml of methylene chloride, the solution is cooled to 0°-5° C. and a solution of 2.3 g of cyclopropane carboxylic acid chloride in 10 ml of methylene chloride is added with stirring. The mixture is left at room temperature for 2 hours, then poured into water and diluted with 50 ml of methylene chloride. The methylene chloride solution is separated and washed, in sequence, with 2 N hydrochloric acid solution, 10% potassium bicarbonate solution and a semi-saturated sodium chloride solution. The solution is then dried over sodium sulfate and evaporated. The crude product is purified by crystallization or by adsorption chromatography on silica gel to yield pure cyclopropane carboxylic acid 1-(2-naphthyl)-2-propynyl ester, m.p. 94°-96° C. (from cyclohexane).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=[C:7]([Cl:15])[CH:6]=1>C1COCC1>[Cl:15][C:7]1[CH:6]=[C:5]([O:2][CH3:1])[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=1
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(Cl)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.7 %

Procedure:
Sodium methoxide powder (0.136 g, 2.52 mmol) was added slowly to a stirred solution of methyl 4,6-dichloronicotinate (0.40 g, 1.94 mmol) in THF (4 mL) at room temperature. The reaction mixture was stirred at room temperature for 18 hours, then concentrated in vacuo onto silica gel. Gradient chromatography, eluting with 5% EtOAc:c-Hex over 5 column volume and 5-50% over 15 column volume, gave methyl 6-chloro-4-methoxynicotinate (218 mg, 1.08 mmol, 56% yield) as a white crystalline solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[C:19]([C:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=3)[CH:18]=[CH:17][C:16]=2[F:27])[CH2:13][C:12]([C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[N:11]1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[C:19]([C:21]3[CH2:22][CH2:23][N:24]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:25][CH:26]=3)[CH:18]=[CH:17][C:16]=2[F:27])[CH2:13][C:12]([C:28]([F:33])([F:34])[C:29]([F:30])([F:32])[F:31])=[N:11]1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(C3=CCNCC3)ccc2F)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC=C(c2ccc(F)c(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[2-fluoro-5-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 148, triethylamine (41.0 uL, 0.30 mmol) and methanesulfonyl chloride (8.1 mg, 0.07 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 3 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 15 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][CH:19]1[CH:26]2[CH2:27][C:22]3([OH:29])[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:18][CH:19]1[CH:20]2[CH2:28][CH:24]3[CH2:23][C:22]([OH:29])([CH2:27][CH:26]1[CH2:25]3)[CH2:21]2)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1cccc(OCc2ccccc2)c1

Procedure:
Prepared from 3-(benzyloxy)benzoic acid and 4-amino-1-hydroxyadamantane to give the title compound as a mixture of two isomers. 1H NMR (300 MHz, CDCl3): δ 7.69-7.74 (m, 1H), 7.29-7.48 (m, 7H), 7.20-7.24 (m, 0.5H), 7.09-7.13 (m, 0.5; H), 6.27 (d, 1H), 5.12 (s, 2H), 4.18-4.23 (m, 1H), 2.16-2.27 (m, 3H), 1.91-1.98 (m, 2H), 1.71-1.84 (m, 6H), 1.54-1.61 (m, 2H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([CH:20]=1)[O:7][C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].[CH3:24][N:25]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][C:27]([OH:34])=[N:26]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH3:24][N:25]1[C:29]([C:30]([F:31])([F:32])[F:33])=[CH:28][C:27]([O:34][C:2]2[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([CH:20]=2)[O:7][C:8]2[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=2[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:26]1
Reactant: Cn1nc(O)cc1C(F)(F)F
Reactant: COC(=O)COc1ccccc1Oc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccccc1Oc1cc(Oc2cc(C(F)(F)F)n(C)n2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 18 h
Yield: 31.5 %

Procedure:
A mixture of methyl [o-(5-fluoro-2-nitrophenoxy)phenoxy]acetate (1.1 g, 3.4 mmol), 1-methyl-5-(trifluoromethyl)pyrazol-3-ol (0.63 g, 3.8 mmol) and potassium carbonate (0.53 g, 3.8 mmol) in N,N-dimethylformamide is stirred at 100° C. for 18 hours, cooled to room temperature, poured into water and extracted with ethyl acetate. The organic extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an orange oil. Column chromatography of the oil using silica gel and a 30% ethyl acetate in hexanes solution gives the title product as a yellow oil (0.5 g) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9]2)=[CH:3][CH:2]=1.[CH2:20]([N:26]=[C:27]=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:20]([NH:26][C:27](=[O:28])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[CH2:9][C:10]2([CH3:19])[CH3:18])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCN=C=O
Reactant: CC1(C)CN(Cc2ccncc2)c2ccc(O)cc21
Product: CCCCCCNC(=O)Oc1ccc2c(c1)C(C)(C)CN2Cc1ccncc1

Procedure:
The title compound was synthesized from 1-(4-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with n-hexylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (10.4 mg, 35%) having the following characteristics.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:19][C:20]1[CH:27]=[C:26]([CH2:28][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:25]=[C:22]([CH3:23])[CH:21]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: Cc1cc(C)cc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cc(C)cc(C)c2)CCCC1=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 66.5 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (850 mg, 3.5 mM), 3,5-dimethylbenzyl bromide (765 mg, 3.8 mM), and potassium carbonate (500 mg, 3.61 mM) in 25 mL DMF was stirred at room temperature for 19 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 0.84 g (67%) of the 9-[(3,5-dimethylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a foam. 1H NMR (DMSO-d6) δ 7.7 (dd, 1H, J=1 and 8 Hz), 7.3-7.2 (m, 2H), 6.9 (s, 1H), 6.75 (s, 2H), 5.45 (s, 2H), 3.8 (s, 3H), 3.0 (m, 2H), 2.45 (m, 2H), 2.2 (s, 6H), and 2.1 (m, 2H). IR (KBr, cm−1) 1726, 1653, 1602, 1465, 1442, 1282, 1172, and 1116. MS (ES) m/e 362.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([O-])=[O:15])[S:13][C:6]=12.[Li+]>>[CH2:1]([NH:3][C:14]([C:12]1[S:13][C:6]2[C:7](=[N:8][CH:9]=[CH:10][C:5]=2[Cl:4])[CH:11]=1)=[O:15])[CH3:2]
Reactant: CCN
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: CCNC(=O)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from ethylamine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: n.d.; HPLC Rf: 4.18 min; HPLC purity: 98%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:19])[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:19][CH2:26][CH:28]3[CH2:29][O:30]3)=[CH:8][C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(=O)cc(-c3ccccc3)[nH]c2c1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2c(OCC3CO3)cc(-c3ccccc3)nc2c1
Temperature: 65 °C
Reaction time: 3 h
Yield: 56.9 %

Procedure:
To a solution of 7-methoxy-2-phenyl-1H-quinolin-4-one (1.5 g, 6 mmol) in DMF (11 ml) were added successively K2CO3 (1.66 g, 12 mmol) and (RS)-epichlorohydrin (1.9 ml, 24 mmol). The reaction mixture was stirred at 65° C. for 3 hours, then cooled to room temperature and diluted with CH2Cl2 (25 ml). Solid was filtrated, and filtrate was concentrated. The residue was chromatographed over silica gel (hexane-ethyl acetate, 4:1) to provide (RS)-7-methoxy-4-oxiranylmethoxy-2-phenyl-quinoline (1.05 g, 57%) as a colorless oil, MS: m/e=307 (M+).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].C(N(CC)CC)C.Cl.Cl.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29]([C@@H:31]3[CH:36]4[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]4)[CH2:32]3)=[O:30])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.O>CN(C=O)C>[CH2:1]([NH:3][C:4]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:29]([C@@H:31]3[CH:36]4[CH2:35][CH2:34][N:33]([CH2:38][CH2:37]4)[CH2:32]3)=[O:30])=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)=[O:5])[CH3:2]
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reactant: CCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reaction time: 18 h

Procedure:
21.6 mg (0.30 mmol) of ethyl isocyanate and 84.8 μl (0.61 mmol) of triethylamine are added to a solution of 60 mg (0.15 mmol) of ((3R)-N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) in 0.5 ml of DMF. After 18 h at room temperature, 5 ml of water are added to the reaction mixture. The resulting precipitate is filtered off with suction, washed with water and dried under high vacuum. 57 mg (88.0% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][N:2]1[C@H:6]([CH2:7][O:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][C:3]1=O.[CH:29]([NH2:31])=O>CN(C=O)C.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[C:9]([O:8][CH2:7][C@H:6]1[N:2]2[N:1]=[CH:29][N:31]=[C:3]2[CH2:4][CH2:5]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NC=O
Reactant: NN1C(=O)CC[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(C(OC[C@@H]2CCc3ncnn32)(c2ccccc2)c2ccccc2)cc1
Temperature: 160 °C
Yield: 48.8 %

Procedure:
To a stirred solution of 0.540 g (1.45 mmol) of (5S)-1-amino-5-[(trityloxy)methyl]pyrrolidin-2-one from step A in 5 mL of anhydrous DMF was added 0.327 g (7.25 mmol) of formamide followed by 0.050 g (036 mmol) of zinc(II)chloride. The resulting mixture was heated to 160° C. for 48 h, cooled to ambient temperature and diluted with 25 mL of ethyl acetate. The solution was washed sequentially with an aqueous sodium bicarbonate solution, water and then brine and the organic layer dried over magnesium sulfate. The mixture was then filtered, evaporated to dryness in vacuo and purified by silica gel chromatography eluting with a 0-100% ethyl acetatae in hexanes gradient to afford the title compound (0.27 g, 49%). LC-MS: m/z (ES) 382 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([CH3:12])[CH3:11])=[CH:4][C:3]=1C.ClC1N=NC(Cl)=CC=1[C:28]([NH2:30])=[O:29].FC1C=CC(C(C)(C)CN)=CC=1.C(N(C(C)C)CC)(C)C>CC#N>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)([CH3:11])[CH3:12])=[C:4]([C:28]([NH2:30])=[O:29])[CH:3]=1
Reactant: NC(=O)c1cc(Cl)nnc1Cl
Reactant: Cc1cc(NCC(C)(C)c2ccc(F)cc2)nnc1Cl
Agent: CC(C)(CN)c1ccc(F)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CNc1nnc(Cl)cc1C(N)=O)c1ccc(F)cc1
Yield: 78 %

Procedure:
Using a similar procedure as was used for 6-chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)-5-methylpyridazin-3-amine in example 14, 3,6-dichloropyridazine-4-carboxamide (2.6 g, 13 mmol, 1.0 equiv), (2-(4-fluorophenyl)-2-methylpropan-1-amine (2.5 g, 15 mmol, 1.1 equiv), and diisopropylethylamine (2.8 mL, 16 mmol, 1.2 equiv) in CH3CN (54 mL) was heated at 60-90° C. for 48 hours. The product was purified over silica gel with 100% EtOAc to give the desired product (3.4 g, 78%) as a yellow foamy solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]2[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=2)[CH:29]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:19][CH:20]=2)[CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[C:30]([C:34]3[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=3)[CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(OC(F)(F)F)cc2)CC1
Product: COc1cc(-c2cc(CN(c3ccc(OC(F)(F)F)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)ccn2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[[4-(trifluoromethoxy)phenyl]amino]piperidine (721 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[CH:17][C:18]([C:21](O)=[O:22])=[N:19][CH:20]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:21](=[O:22])[C:18]3[CH:17]=[CH:16][C:15]([C:14]([F:24])([F:13])[F:25])=[CH:20][N:19]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
TEA (0.61 mL, 4.35 mmol) was added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.87 mmol, Example 1, Step H), 5-(trifluoromethyl)picolinic acid (200 mg, 1.04 mmol) and BOP-Cl (330 mg, 1.30 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 1 hour, and then a LiOH solution (3 mL, 2N) was added. The mixture was stirred for 30 minutes, and water (10 mL) was added. The solid formed was collected by filtration, washed with DCM (10 mL) and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)picolinamide (195 mg, 55% yield) as a solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[NH:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26]>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26])=[CH:22][C:11]=3[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1
Reactant: OCCNCCO
Product: OCCN(CCO)CCCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1

Procedure:
According to the method in example 29, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene and diethanolamine were converted to yield 2-[{4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-(2-hydroxy-ethyl)-amino]-ethanol as light yellow oil, MS: 464 (MH+, 1Br).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[H][H]>CCOC(C)=O.CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: [H][H]
Reactant: CCOC(=O)CC/C=C/c1ccccc1OC
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCc1ccccc1OC
Yield: 99.2 %

Procedure:
To a solution of ethyl (4E)-5-(2-methoxyphenyl)-4-pentenoate (3.40 g, 14.5 mmol) in a mixture of EtOAc and MeOH (40.0/10.0 mL), Pd/C (palladium on carbon 10%, 0.700 g) was added in small portions to avoid fire. The reaction mixture was then stirred for overnight at room temperature under 300 psi of hydrogen. After the pressure was released, the mixture was filtered through Celite and the Celite was washed with EtOAc (3×50 mL). The filtrate was concentrated in vacuo to afford crude product as a light yellow oil (3.40 g 100%), which was used without further purification.
Reaction SMILES: N1C=CC=CC=1C[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1.OC1(CC2C=CC=CN=2)C2C(=CC=CC=2)NC1=O.CO>O1CCCC1>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc(Cc2c[nH]c3ccccc23)nc1
Agent: O=C1Nc2ccccc2C1(O)Cc1ccccn1
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Pyridin-2-ylmethyl-1H-indole (Ind-49) A 2 M solution of borane-dimethyl sulfide complex (20 ml, 40 mmol) was added to a solution of 3-hydroxy-3-pyridin-2-ylmethyl-1,3-dihydroindol-2-one (4.80 g, 20 mmol) in anhydrous tetrahydrofuran (250 ml) and the mixture was stirred at room temperature overnight. Methanol (10 ml) was cautiously added to the reaction mixture and the mixture was concentrated i. vac. Methanol was repeatedly added to the residue, the mixture was in each case concentrated again i. vac., and the residue was taken up in 1N hydrochloric acid. The aqueous suspension was extracted with ethyl acetate (2×40 ml). The aqueous phase was adjusted to pH 10 with saturated potassium carbonate solution and extracted with ethyl acetate (3×30 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product (4.0 g) was purified by flash chromatography (400 g, 20×7.6 cm) first with ethyl acetate/cyclohexane (2:1) and then chloroform.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:13]CC(C1C=CC(O)=CC=1O)=O>>[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=[O:11])[CH2:10][CH3:13])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCC(=O)c1ccc(O)cc1O
Reactant: CC(=O)c1ccc(O)c(Cl)c1O
Product: CCC(=O)c1ccc(O)c(Cl)c1O

Procedure:
The title compound is prepared in a similar manner to 1-(3-chloro-2,4-dihydroxy-phenyl)-ethanone (Preparation 11) employing 2,4-dihydroxypropiophenone to give 4.5 g, 37% of an off-white solid. LCMS 1 201 m+.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].CCO[C:8]([CH2:10][C:11]#[N:12])=[O:9]>>[C:11]([CH2:10][C:8]([NH:4][CH2:1][C:2]#[CH:3])=[O:9])#[N:12]
Reactant: CCOC(=O)CC#N
Reactant: C#CCN
Product: C#CCNC(=O)CC#N
Yield: 94.2 %

Procedure:
A mixture of 15.4 ml (240 mmol) of propargyl amine and 17.1 ml (160 mmol) of ethyl cyano acetate was heated for 7 hours to 40° C. in a reaction flask. The crystalline material formed was heated for another 17 hours to 70° C. Then, the cooled reddish product was dried at high vacuum to yield 18.4 g (94%) of a red powder, m.p. 100-103° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH2:10])[S:9][C:5]=2[CH:4]=1.[C:13](N1C=CN=C1)([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[S:14]>C(#N)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH:10][C:13]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[S:14])[S:9][C:5]=2[CH:4]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc2nc(N)sc2c1
Solvent: CC#N
Product: COc1ccc2nc(NC(=S)n3ccnc3)sc2c1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
To 6-methoxybenzo[d]thiazol-2-amine (0.53 g, 2.94 mmol) in acetonitrile (20 mL) was added 1,1′-thiocarbonyldiimidazole (0.681 g, 3.82 mmol). The reaction mixture was stirred at 65° C. for 24 hours. The precipitate was filtered and washed with acetonitrile (2×20 mL) to yield the product. The product was taken directly to the next step without any further purification or characterization.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N:11]2[CH:15]([CH3:16])[C:14](=[O:17])[C:13]([CH3:19])([CH3:18])[C:12]2=[O:20])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH3:21][Mg]Br.C1COCC1>>[OH:17][C@:14]1([CH3:21])[C:13]([CH3:19])([CH3:18])[C:12](=[O:20])[N:11]([C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=2)[C@@H:15]1[CH3:16]
Reactant: C[Mg]Br
Reactant: COc1cc(N2C(=O)C(C)(C)C(=O)C2C)ccc1C#N
Solvent: C1CCOC1
Product: COc1cc(N2C(=O)C(C)(C)[C@@](C)(O)[C@H]2C)ccc1C#N

Procedure:
Using 2-methoxy-4-(3,3,5-trimethyl-2,4-dioxopyrrolidin-1-yl)benzonitrile (100 mg) and methylmagnesium bromide-THF solution (3.67 mL, 1.0 mol/L), and in the same manner as in Example 2, the title compound was obtained as a colorless, solid (yield: 96 mg, 90%).
Reaction SMILES: [NH2:1][C:2](=[C:5]([Cl:7])[Cl:6])[C:3]#[N:4].[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)([O-:10])=[O:9]>C1(C)C=CC=CC=1>[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[N:1][C:2](=[C:5]([Cl:7])[Cl:6])[C:3]#[N:4])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: N#CC(N)=C(Cl)Cl
Solvent: Cc1ccccc1
Product: N#CC(N=Cc1ccc([N+](=O)[O-])cc1)=C(Cl)Cl
Reaction time: 8 h

Procedure:
A solution of 2-amino-3,3-dichloropropenonitrile (15.0 g, 0.11 mole) and 4-nitrobenzaldehyde (15.1 g, 0.10 mmol) in toluene (200 ml) was refluxed for 23 hours. The mixture was evaporated, methanol (100 ml) was added and the mixture was allowed to stand overnight. After filtration, the title compound was isolated as a brown-yellow solid.