Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[C:24]([F:23])([F:33])[F:34]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: FC(F)(F)c1ccccc1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1ccccc1C(F)(F)F
Temperature: 100 °C
Yield: 34.1 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 100 mg, 0.33 mmol), tetrabutylammonium iodide (120 mg, 0.32 mmol) and 2-(trifluoromethyl)benzyl bromide (200 μL, 1.3 mmol) in dimethylformamide (2 mL) was heated at 100° C. overnight. Dichloromethane (50 mL) was added and the solution was washed with 1:1 water/brine (20 mL), aqueous sodium thiosulfate, water, and brine. The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 50-70% ethyl acetate/petroleum ether, to give (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1-(2-trifluoromethyl-benzyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (52 mg, 34%) as a white solid. APCI(+)-MS (M+H) 463.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[NH:18][C:19]1[NH:20][CH2:21][CH2:22][N:23]=1>O1CCCC1.CS(C)=O>[CH3:1][C:2]1[S:3][C:4]([C:7]([N:23]2[CH2:22][CH2:21][N:20]=[C:19]2[NH:18][C:12]2[C:13]([Cl:17])=[CH:14][CH:15]=[CH:16][C:11]=2[Cl:10])=[O:9])=[CH:5][N:6]=1
Reactant: Cc1ncc(C(=O)O)s1
Reactant: Clc1cccc(Cl)c1NC1=NCCN1
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ncc(C(=O)N2CCN=C2Nc2c(Cl)cccc2Cl)s1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 72.6 %

Procedure:
3.15 g (22.0 millimoles) of 2-methyl-thiazole-5-carboxylic acid are dissolved in 500 ml of absolute tetrahydrofuran and 50 ml of absolute dimethylsulfoxide, 3.6 g (22.2 millimoles) of N,N'-carbonyldiimidazole are added and the mixture is stirred for 45 minutes at room temperature. A solution of 5.0 g (21.7 millimoles) of 2-(2',6'-dichlorophenylamino)-2-imidazoline in 100 ml of absolute tetrahydrofuran is then added dropwise and the mixture is stirred overnight at room temperature. The solvents are stripped off under reduced pressure on a rotary evaporator and the residue is stirred thoroughly with 100 ml of 0.5 percent strength sodium bicarbonate solution, whereupon crystallization occurs. The crystals are filtered off, washed with water and dried under reduced pressure, over a phosphorus pentoxide desiccant. 5.6 g of crude 1-(2-methylthiazol-5-oyl)-2-(2',6'-dichlorophenylamino)-2-imidazoline are obtained and are recrystallized from isopropanol, giving 2.7 g of pure product, of melting point 183°-185° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]([NH:12][C:13]1[NH:14][C:15]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=[CH:16][C:17]=1[C:18]([NH2:20])=[O:19])=[O:11].O>CN(C)C=O>[NH2:9][C:10]([NH:12][C:13]1[NH:14][C:15]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=[C:16]([Cl:1])[C:17]=1[C:18]([NH2:20])=[O:19])=[O:11]
Reactant: NC(=O)Nc1[nH]c(-c2ccc(Br)cc2)cc1C(N)=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)Nc1[nH]c(-c2ccc(Br)cc2)c(Cl)c1C(N)=O
Yield: 51 %

Procedure:
N-Chlorosuccinimide (48 mg, 0.36 mmol) was added to a solution of 2-aminocarbonylamino-5-(4-bromophenyl)pyrrole-3-carboxamide (Compound No. 1-1, 97 mg, 0.30 mmol) in anhydrous N,N-dimethylformamide (2 mL), and the mixture was stirred overnight at 50° C. After cooling, water (4 mL) was added thereto, the precipitated solid was filtered off, and washed with water (5 mL). The obtained solid was dried under reduced pressure to give the target compound (54 mg) as a pale brown solid (Yield 51%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:14]([F:27])[CH:13]=1.N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[C:14]([F:27])[CH:13]=1)[C:34](=[O:36])[CH3:35]
Reactant: COc1ccc(Br)c(NCc2ccc(OCCN3CCCCC3)c(F)c2)c1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1ccc(Br)c(N(Cc2ccc(OCCN3CCCCC3)c(F)c2)C(C)=O)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of (2-bromo-5-methoxyphenyl)[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amine (690 mg), pyridine (2 ml) and acetic anhydride (2 ml) was stirred for 4 hours at 80° C. The reaction mixture was diluted with an aqueous solution of 1N sodium hydroxide, extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (530 mg).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[CH:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[OH:32]>C(Cl)Cl.CCOC(C)=O>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[C:31]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:32]
Reactant: OC(c1ccccc1)c1cc(F)ccc1Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1cc(F)ccc1Br
Yield: 92.4 %

Procedure:
A mixture of Dess-Martin periodinane (0.931 g, 2.20 mmol) and the product of example 35A (0.561 g, 2.00 mmol) was stirred in CH2Cl2 (10 mL) for 1 hour, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated. The residue was chromatographed on SiO2 (eluted with 4% Et2O/hexanes) to give 515.6 mg of the title compound as a clear gum. 1H NMR (300 MHz, DMSO) δ 7.81 (dd, 1H), 7.69-7.76 (m, 3H), 7.54-7.61 (m, 2H), 7.50 (dd, 1H), 7.39 (ddd, 1H).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:19][CH2:18][N:17](C(=O)C(F)(F)F)[CH2:16][CH2:15]2)[C@H:10]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:9]1)=[O:7].O.C(=O)([O-])[O-].[K+].[K+]>CO>[F:39][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C:6]([N:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C@H:10]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:9]2)=[O:7])[CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(C(=O)C(F)(F)F)CC2)[C@H](c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.1 %

Procedure:
Rac-cis-1-{4-[1-(3,5-Bis-trifluoromethyl-benzoyl)-3-phenyl-piperidin-4-yl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone (4.15 g, 7.14 mmol) was dissolved in methanol (25 mL). Water (1 mL) and potassium carbonate (2.96 g, 21.4 mmol) were added and the reaction mixture was stirred at room temperature for 4 h. Water (100 mL) was added and the mixture was extracted twice with 200 mL methylene chloride. Organic phases were pooled and dried with magnesium sulfate. Evaporation of the solvent gave the title compound (3.4 g, 98%) as a white foam which was used without any further purification, MS: m/e=486.3 (M+H+).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:21].[K+].[K+].CC#N.O>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[C:18](=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: c1cc2c(cc1OCC1CCCCC1)CCCCC2
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1CCCCc2cc(OCC3CCCCC3)ccc21

Procedure:
A mixture of 2-cyclohexylmethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene (0.50 g, 1.94 mmol), potassium persulfate (1.57 g, 5.82 mmol), copper(II) sulfate pentahydrate (0.48 g, 1.94 mmol) and CH3CN/H2O (1:1, 13 mL) were heated at reflux for 45 min. After cooling the mixture was diluted with water and extracted with EtOAc. The combined extracts were washed with water, dried over magnesium sulfate, concentrated, and chomatographed over silica gel (20% EtOAc/hexane) to a white solid (0.46 g, 87%). MS [M+H]+ 273, m.p. 86-88° C.
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: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: NCCCCCCCCc1ccccc1
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: [OH:1][C:2]([CH3:10])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].N1C=CN=C1.CN(C)C=O.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23]>CCCCCC>[CH3:10][C:2]([O:1][Si:22]([CH3:25])([CH3:24])[CH3:23])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCC(C)(O)CCCC
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C#CCC(C)(CCCC)O[Si](C)(C)C
Reaction time: 8 h

Procedure:
To a stirred solution of 75.4 g (0.537 moles) of 4-hydroxy-4-methyl-1-octyne (Example 122), 104.9 g (1.54 moles) of imidazole, and 325 ml of dimethylformamide is added 65.2 g (0.60 moles) of chlorotrimethylsilane. After standing overnight the mixture is poured into 800 ml of hexane. The mixture is washed thoroughly with water followed by sodium bicarbonate solution and brine. The solution is dried over magnesium sulfate, filtrated, and evaporated to give a liquid, p.m.r. spectrum, δ 1.26 (singlet, 3, CH3), 1.92 (triplet, 1, HC), 2.30 (doublet, 2, CH2).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:19]([N:21]3C(=O)C4C(=CC=CC=4)C3=O)[CH3:20])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.NN>CCO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:19]([NH2:21])[CH3:20])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1cc2ccc(F)cc2nc1-c1cccc(F)c1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: C[C@H](N)c1cc2ccc(F)cc2nc1-c1cccc(F)c1
Temperature: 80 °C

Procedure:
To a solution of 2-((S)-1-(7-fluoro-2-(3-fluorophenyl)quinolin-3-yl)ethyl)-isoindoline-1,3-dione (60.0 mg, 145 μmol) in EtOH (2 mL) was added NH2NH2 (1.0 mL, 1.45 mmol, 10 eq) and the resulting solution was heated to 80° C. for 2 h. A precipitate was filtered away and the filtrate was removed under reduce pressure to afford (1S)-1-(7-fluoro-2-(3-fluorophenyl)quinolin-3-yl)ethanamine To the crude residue of (1S)-1-(7-fluoro-2-(3-fluorophenyl)quinolin-3-yl)-ethanamine in DMF (2 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (22 mg, 145 μmol) and DIEA (0.06 mL, 319 μmol). The resulting mixture was heated to 100° C. overnight. Solvent was removed under reduce pressure and purified via preparatory HPLC using 15-60% MeCN/H2O w/0.01% TFA to afford a white solid of 4-amino-6-((S)-1-(7-fluoro-2-(3-fluorophenyl)-quinolin-3-yl)ethylamino)pyrimidine-5-carbonitrile (9.3 mg, 16%). 1H NMR (500 MHz, CD3OD) δ ppm 1.63 (d, J=6.85 Hz, 3H) 5.70 (q, J=7.01 Hz, 1H) 7.25-7.34 (m, 1H) 7.44-7.54 (m, 2H) 7.55-7.63 (m, 2H) 7.74 (dd, J=9.78, 2.45 Hz, 1H) 8.05 (s, 1H) 8.18 (dd, J=9.05, 5.87 Hz, 1H) 8.72 (s, 1H). Mass Spectrum (ESI) m/e=403 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[OH:17].[C:18](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[O:17][CH3:18]
Reactant: O=C([O-])[O-]
Reactant: CCNC(=O)Nc1nc2ccc(Br)c(O)c2s1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2ccc(Br)c(OC)c2s1
Yield: 2 %

Procedure:
A mixture of 1-(6-bromo-7-hydroxy-2-benzothiazolyl)-3-ethyl-urea 6, potassium carbonate and iodomethane in DMF was reacted to give 0.0034 g (2%) of the desired compound 10. 1H NMR (DMSO) δ 10.88 (br s, 1H, NH), 7.55 (d, 1H, J=8.5 Hz, ArH), 7.33 (d, 1H, J=8.5 Hz, ArH), 6.82 (br s, 1H, NH), 3.93 (s, 3H, CH3), 3.18 (m, 2H, CH2), 1.09 (t, 3H, J=7.2 Hz, CH3); LC/MS 330 (MH+); RP-HPLC RT 3.04 minutes.
Reaction SMILES: N1C2C(=CC=CC=2)C([CH:11]=[C:12]2[CH:24]=[C:23]3[C:15](=[CH:16][C:17]4[C:22]3=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:14]([O:25][CH3:26])=[C:13]2[O:27][CH3:28])=CC=1>CC(C)=O.C1CCCCC1>[C:12]1([CH:24]=[C:23]2[C:15]3[C:14]([O:25][CH3:26])=[C:13]([O:27][CH3:28])[CH:12]=[CH:11][C:16]=3[C:17]3[C:22]2=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:24]=[CH:23][CH:15]=[CH:14][CH:13]=1
Reactant: COc1c(OC)c2c(cc1=Cc1ccnc3ccccc13)-c1ccccc1C=2
Solvent: CC(C)=O
Solvent: C1CCCCC1
Product: COc1ccc2c(c1OC)C(=Cc1ccccc1)c1ccccc1-2

Procedure:
9-((4-Quinolyl)methylene-1,2-dimethoxyfluorene; m.p. 210° C. (acetone/cyclohexane). Anal. Calcd. for C25H19NO2: C, 82.17; H, 5.24; N, 3.83. Found: C, 82.23; H, 5.00; N, 3.88.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:9]C=O)[CH:5]=[CH:6][CH:7]=1.[ClH:18]>>[ClH:18].[NH2:9][CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1
Reactant: O=CNC(c1ccccc1)c1cccc(O)c1
Agent: Cl
Product: NC(c1ccccc1)c1cccc(O)c1
Yield: 97.9 %

Procedure:
Methanol (125 mL), was cooled to 0° C. and acetyl chloride (17.8 mL) added dropwise to give a 2M solution of methanolic hydrogen chloride. N-((3-hydroxyphenyl)(phenyl)methyl)formamide was stirred at 40° C. for 1.5 hours with the 2M methanolic hydrogen chloride. The solvent was removed under reduced pressure and the residue re-dissolved in methanol and the solvent removed under reduced pressure. This process was repeated three times to give the title compound as a brown solid (29.09 g, 97.9%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2=[N:9][C:10]3[C:15]([C:14](=O)[NH:13][CH2:12][N:11]=3)=[C:5]2[CH:4]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:14]1[C:15]2[C:5]3[C:6](=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:9][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: COc1ccc2c(c1)=C1C(=O)NCN=C1N=2
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2[nH]c3ncnc(Cl)c3c2c1
Temperature: 90 °C
Yield: 81 %

Procedure:
A suspension of 6-methoxy-3H-indolo[2,3-d]pyrimidine-4-one (800 mg, 3.08 mmol, ~83% pure) and POCl3 (7 mL) is heated at 90° C. for 6 h. The suspension is concentrated to a solid that is evacuated at 1 mm for 1 h. The solids are cooled in a -78° C. bath then treated dropwise with cold H2O. The bath is removed and the frozen solids are allowed to gradually melt. The solids are filtered, washed well with cold H2O, and dried to leave 4-chloro-6-methoxyindolo[2,3-d]pyrimidine (733 mg, 81%) that is about 80% pure. 1H NMR (DMSO): δ12.64 (1H, br s, exchanges with D2O), 8.74 (1H, s), 7.74 (1H, d, J=2.4 Hz), 7.57 (1H, d, J=8.9 Hz), 7.28 (1H, dd, J=8.9, 2.4 Hz), 3.88 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:18][C:19]([N:21]3[CH2:25][CH2:24][C@@H:23]([F:26])[CH2:22]3)=[O:20])[N:15]=[C:16](I)[C:3]=12.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:18][C:19]([N:21]3[CH2:25][CH2:24][C@@H:23]([F:26])[CH2:22]3)=[O:20])[N:15]=[C:16]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)[C:3]=12
Reactant: O=C(Cn1nc(I)c2c(Cl)c(-c3ccccc3)nnc21)N1CC[C@@H](F)C1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1nc(-c2ccc(F)cc2)c2c(Cl)c(-c3ccccc3)nnc21)N1CC[C@@H](F)C1
Yield: 30.6 %

Procedure:
Nitrogen was bubbled through a suspension of 2-(4-chloro-3-iodo-5-phenyl-pyrazolo[3,4-c]pyridazin-1-yl)-1-[(3R)-3-fluoropyrrolidin-1-yl]ethanone (70 mg, 0.144 mmol), 4-fluorophenylboronic acid (22 mg, 0.158 mmol) and K3PO4 (92 mg, 0.43 mmol) in DMF (1.1 mL) and water (0.4 mL) for 20 min. 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (12 mg, 0.014 mmol) was added and the tube sealed and heated using microwave irradiation to 60° C. for 30 min. The crude reaction mixture was filtered and partially purified by preparative HPLC. The residue was purified by chromatography (silica gel, isohexane/ethyl acetate 1:0 to 7:3) to provide Compound 1 (20 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[N:11][C:10]=2[CH3:18])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1nc(N)ccc1Oc1ccnc(Cl)c1
Temperature: 80 °C
Yield: 72.8 %

Procedure:
A solution of Example A6 (1 g, 3.76 mmol) in EtOH (38 mL) was treated with tin(II) chloride dihydrate (4.25 g, 18.8 mmol), heated at 80° C. for 30 h, then cooled to RT and treated slowly with satd. NaHCO3. The mixture was stirred for several minutes, the solids removed via filtration through diatomaceous earth and the filtrate was dried over Na2SO4 and concentrated to dryness to afford crude 5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-amine (645 mg, 73%) which was used without further purification. MS (ESI) m/z: 236.1 (M+H+).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39][CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][CH:42]=5)=[C:35]([CH3:49])[CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39]([CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][CH:42]=5)=[O:59])=[C:35]([CH3:49])[CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CCC)c(C)c2)CCCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)c(C)c2)CCCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[[[1-propylimidazol-5-yl]methyl]sulfanyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (370 mg) in dichloromethane (10 ml) was added dropwise a 70% solution of 3-chloro-per-benzoic acid (144 mg) in dichloromethane (10 ml) at −78° C. After stirring as such for 1 hour, the dry ice-acetone bath was removed, and an aqueous sodium thiosulfate solution was added with vigorous stirring. The mixture was returned to room temperature and stirred for 30 minutes, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium bicarbonate solution and saturated brine, and was dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated and purified with basic silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:40) and recrystallized from hexane-ethyl acetate to give 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (289 mg) as yellow crystals (Compound 39).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(COC)OC.[Zn].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>[C:18]1([C:17]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[O:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Zn]
Solvent: COCCOC
Solvent: O
Product: COC=C(C(=O)OC)c1ccccc1CC(=O)c1ccccc1
Temperature: 50 °C
Yield: 29 %

Procedure:
A solution of 5 g (17.5 mmol) of methyl α-(2-bromomethylphenyl)-β-methoxyacrylate and 2.5 g (17.8 mmol) of benzoyl chloride in 50 ml of dimethoxyethane is added dropwise to 2.3 g (0.035 mol) of zinc powder and 600 mg (0.9 mmol) of Pd(Ph3P)2Cl2 under nitrogen and the mixture is then heated at 50° C. for 30 minutes. Water is added, the mixture is extracted with ethyl acetate and the organic phase is dried and evaporated down. The residue is chromatographed over silica gel using hexane/ethyl acetate. 1.6 g of compound No. 1 (Table 1) are obtained as a pale yellow solid of melting point 97°-99° C. Yield: 29%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)#[CH:2].Br[C:11]1[CH:25]=[CH:24][C:14]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:16])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:11]2[CH:12]=[CH:13][C:14]([C:15](=[O:16])[C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[CH:24][CH:25]=2)=[CH:4][CH:5]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: O=C(c1ccc(F)cc1)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
Into a 250 mL, 3-neck, round-bottom flask equipped with a magnetic stirrer, a thermocouple, and a condenser were placed 12.00 g (100.0 mMol) of 1-ethynyl-4-fluorobenzene, 27.93 g (100.0 mMol) of 4-bromo-4′-fluorobenzophenone (Rieke Metals, Inc.), 1.5 g of tetrakis(triphenylphosphine)palladium[0], and 150 mL of de-aerated triethylamine. The reaction mixture was heated to 80° C. with stirring under argon for 3 hr and then cooled to ambient overnight (16 hr) with stirring. The reaction mixture was filtered to remove a white precipitate of triethylamine hydrobromide. The triethylamine solvent was evaporated and the solids obtained were dissolved in dichloromethane. The resulting solution was washed with water (2×50 mL), 2% HCl (2×50 mL), brine, and then dried over sodium sulfate. After removal of the solvent, the crude 4-fluoro-4′-(4-fluorobenzoyl)tolane was purified by silica gel column chromatography using hexanes as the elutant. White crystals having a melting point of 190-191° C. were obtained in a yield of 81%.