Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]3[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[CH:11][C:12]=3[S:13][CH2:14][C:5]=2[C:4]([C:18]([OH:20])=O)=[N:3]1.C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCOC(C)=O.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>C1COCC1>[CH3:1][N:2]1[C:6]2[C:7]3[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[CH:11][C:12]=3[S:13][CH2:14][C:5]=2[C:4]([C:18]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[O:20])=[N:3]1
Reactant: C1COCCN1
Reactant: Cn1nc(C(=O)O)c2c1-c1cc([N+](=O)[O-])ccc1SC2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1nc(C(=O)N2CCOCC2)c2c1-c1cc([N+](=O)[O-])ccc1SC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To 1-methyl-8-nitro-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid (0.088 g, 0.30 mmol) in THF is added triethylamine (0.13 mL, 0.9 mmol, 3 Eq) followed by 50% T3P (propane phosphonic acid anhydride) in EtOAc (0.50 mL, 0.81 mmol, 2.7 Eq). The reaction mixture is cooled to 0° C. and then morpholine (0.38 mL, 0.60 mmol, 2Eq) is added and the reaction is stirred overnight at rt. Then the solvent is removed under vacuo and the residue is diluted with EtOAc. The organic layer is washed with 10% NaHCO3 followed by brine. The organic layer is dried over MgS)4and concentrated in vacuo to afford 0.084 g (77%) of the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.55 (d, J=2.4 Hz, 1H), 8.10 (dd, J=8.5 Hz, J=2.4 Hz, 1H), 7.76 (d, J=8.7 Hz, 1H), 4.20 (s, 3H), 4.19 (s, 2H), 3.95 (brs, 2H), 3.63 (brs, 6H). MS (ESI+): 359.0. HPLC (max plot) 96.9%; Rt 3.78 min.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]([NH:19][S@@](C(C)(C)C)=O)([CH2:12][C@H:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[CH2:10][F:11].Cl.O1CCOCC1>ClCCl.CO>[NH2:19][C@@:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])([CH2:10][F:11])[CH2:12][C@H:13]([OH:18])[C:14]([F:16])([F:17])[F:15]
Reactant: CC(C)(C)[S@@](=O)N[C@@](CF)(C[C@H](O)C(F)(F)F)c1cccc(F)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: N[C@@](CF)(C[C@H](O)C(F)(F)F)c1cccc(F)c1F
Reaction time: 0.17 h

Procedure:
(R)-N-((2S,4S)-2-(2,3-difluorophenyl)-1,5,5,5-tetrafluoro-4-hydroxypentan-2-yl)-2-methylpropane-2-sulfinamide (2.48 g, 6.34 mmol) was dissolved in dichloromethane (12.0 mL) and MeOH (4.0 mL). To this solution was added hydrogen chloride, 4M in 1,4-dioxane (12.0 mL, 48.0 mmol). After stirred for 10 min, the mixture was concentrated, diluted with dichloromethane and washed with 1N NaOH followed by brine. The organic layer was dried over Na2SO4 and then filtered. The filtrate was concentrated and dried to afford (2S,4S)-4-amino-4-(2,3-difluorophenyl)-1,1,1,5-tetrafluoropentan-2-ol as colorless oil. This crude product was dissolved in THF (60 ml) and then treated with benzoyl isothiocyanate (0.938 mL, 6.97 mmol). After stirred for 1.5 h, triethylamine (1.058 mL, 7.60 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hcl (1.336 g, 6.97 mmol) were added, and the resulted reaction mixture was brought to 70° C. for 2 h. Reaction mixture was partitioned between EtOAc and water. The separated organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column (0-20% EtOAc/hexane) to afford N-((4S,6S)-4-(2,3-difluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (2.22 g, 5.33 mmol, 84% yield) as white solid. MS m/z=417.1 [M+H]+. Calculated for C19H14F6N2O2: 416.3
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7](COC(=O)C(C)(C)C)[C:8]([CH3:12])=[N:9]2)=[CH:4][C:3]=1[CH2:22][N:23]([C:27]1[CH:46]=[CH:45][C:30]([C:31](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:32])=[CH:29][CH:28]=1)[CH2:24][C:25]#[CH:26].[NH2:47][CH:48]([C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([N+:57]([O-:59])=[O:58])[CH:52]=1)[CH2:49][OH:50]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[NH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][C:3]=1[CH2:22][N:23]([C:27]1[CH:28]=[CH:29][C:30]([C:31]([NH:47][CH:48]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([N+:57]([O-:59])=[O:58])[CH:52]=2)[CH2:49][OH:50])=[O:32])=[CH:45][CH:46]=1)[CH2:24][C:25]#[CH:26]
Reactant: C#CCN(Cc1cc2c(=O)n(COC(=O)C(C)(C)C)c(C)nc2cc1Br)c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Reactant: NC(CO)c1cccc([N+](=O)[O-])c1
Product: C#CCN(Cc1cc2c(=O)[nH]c(C)nc2cc1Br)c1ccc(C(=O)NC(CO)c2cccc([N+](=O)[O-])c2)cc1
Yield: 61 %

Procedure:
Using an analogous procedure to that described in Example 19, pentafluorophenyl p-[N-(7-bromo-2-methyl-4-oxo-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzoate was reacted with 2-amino-2-(3-nitrophenyl)ethanol and the pivaloyloxymethyl protecting group was removed from the resultant product to give p-[N-(7-bromo-2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]-N-[2-hydroxy-1-(3-nitrophenyl)ethyl]benzamide (containing 0.25 equivalents of water) in 61% yield, m.p. 221°-232° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[O:28]=[C:29]1[NH:34][CH:33]=[C:32](B(O)O)[CH:31]=[CH:30]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:31]=[CH:30][C:29](=[O:28])[NH:34][CH:33]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=c1ccc(B(O)O)c[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 90 °C
Yield: 18.7 %

Procedure:
To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (112 mg, 0.259 mmol) in 1,4-dioxane (3 mL) was added 6-oxo-1,6-dihydropyridin-3-ylboronic acid (55 mg, 0.40 mmol), followed by Pd(dppf)Cl2 (11 mg, 0.015 mmol), and an aq solution of Cs2CO3 (0.48 mL, 2M in H2O). A reflux condenser was attached and the apparatus was degassed and flushed with N2 three times. The reaction was heated to 90° C. for 24 h. After cooling to rt the mixture was diluted with water and extracted three times with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by prep HPLC to afford the title compounds (21.6 mg) as an oil. LC-MS Method 1 tR=1.25 min, m/z=447, 389; 1H NMR (CD3OD) 0.96 (s, 3H), 1.28 (s, 3H), 1.57 (d, 3H), 2.16 (s, 2H), 2.21 (m, 1H), 2.46 (m, 2H), 3.03 (m, 1H), 5.57 (q, 1H), 6.66 (d, 1H), 7.02 (d, 2H), 7.25-7.40 (7H), 7.66 (s, 1H), 7.90 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[C:18]2[Cl:21])=[N:13]1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:18]1[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=1)=[N:13][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH:20]=2
Reactant: C#CCCn1cc2c(Cl)cccc2n1
Reactant: Brc1ccccn1
Product: Clc1cccc2nn(CCC#Cc3ccccn3)cc12
Yield: 17.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (42 mg, 0.27 mmol) and 2-but-3-ynyl-4-chloro-2H-indazole (50 mg, 0.24 mmol). Reaction time: 8 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 1:1) to yield 12 mg (43 μmol, 17%) of 4-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-indazole as a brown solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:6])=[CH2:5].[CH3:8][O:9][C:10](=[O:13])[CH2:11][SH:12].N1CCCCC1.C[O-].[Na+]>CO>[CH3:8][O:9][C:10]([CH:11]1[C:3](=[O:2])[CH:4]([CH3:6])[CH2:5][S:12]1)=[O:13]
Reactant: COC(=O)CS
Reactant: C=C(C)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CO
Product: COC(=O)C1SCC(C)C1=O

Procedure:
100 g (1 mole) of methacrylic acid methyl ester are added dropwise to 106 g of thioglycolic acid methyl ester and 1 ml of piperidine. The reaction mixture is added dropwise to a solution of 40 g of sodium methylate in 200 ml of methanol. The mixture is stirred for a further half an hour, poured onto water, acidified and extracted with methylene chloride and the organic phase is washed with water and dried with sodium sulfate. After distillation, 4-methyl-3-oxotetrahydro-2-thiophencarboxylic acid methyl ester is obtained (bp. 110° to 115°/14 Pascal).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:19])[C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[N:8]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[CH:7]=[C:6]([C:27]([OH:29])=[O:28])[C:5]2=[O:30].[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:19])[C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[N:8]([C:20]1[CH:21]=[CH:22][C:23]([O:26][C:31](=[O:33])[CH3:32])=[CH:24][CH:25]=1)[CH:7]=[C:6]([C:27]([OH:29])=[O:28])[C:5]2=[O:30]
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(O)cc4)c3c2F)CC1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CCN(C)CC4)c(F)c32)cc1
Reaction time: 16 h

Procedure:
6,8-Difluoro-7-(4-methyl-1-piperazinyl)-1-(4-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.14 g) is dissolved in dry pyridine (5 ml) and acetic anhydride (5 ml), and the mixture is allowed to stand at room temperature for 16 hours. Excess acetic anhydride and pyridine are distilled off under reduced pressure, and the resulting residue is dissolved in dichloromethane. The dichloromethane solution is washed with diluted hydrochloric acid, saturated aqueous sodium chloride, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride in this order, and dried over sodium sulfate. The solvent is distilled off, and the residue is recrystallized from ethanol-chloroform to give 6,8-difluoro-7-(4-methyl-1-piperazinyl)-1-(4-acetyloxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.12 g) as pale yellowish white crystals, m.p. 247°-251° C.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]C(=O)N(C)C)=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OCC)(=O)C>O.O.CO.C1COCC1.CCCCCCC>[SH:22][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[C:12]([NH:11][C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[N:13][CH:14]=[CH:15]2
Reactant: CN(C)C(=O)Sc1ccc2c(NC(=O)c3ccccc3)nccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1nccc2cc(S)ccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of NaOH (92 mg) in water H2O (1 ml) was added to a solution of dimethylthiocarbamic acid S-(1-benzoylaminoisoquinolin-6-yl)ester (70 mg) in MeOH (1 ml) and THF (1 ml). The mixture was stirred for 1 h at ambient temperature then for a further 1 h at 56° C. The organics were removed in vacuo then the mixture was diluted with water and acidified with dilute hydrochloric acid (pH ˜3.5). The mixture was extracted with ethyl acetate (X3), dried (sodium sulphate) and concentrated in vacuo to give a residue. Flash chromatography of the residue (eluent: 1-5% ethyl acetate in heptane) gave N-(6-mercaptoisoquinolin-1-yl)-benzamide as a yellow residue (30 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[N:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:8]=1[OH:20])=O.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:24]=[N:23][CH:22]=[CH:21][C:3]=1[C:4]1[O:20][C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:19])([F:18])[C:14]([F:16])([F:17])[F:15])=[CH:12][C:7]=2[N:6]=1
Reactant: O=C(Nc1cc(C(F)(F)C(F)(F)F)ccc1O)c1ccncc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: FC(F)(F)C(F)(F)c1ccc2oc(-c3ccncc3Cl)nc2c1
Reaction time: 1.8 h
Yield: 83.3 %

Procedure:
To a mixture of 0.24 g of 3-chloro-N-[2-hydroxy-5-(pentafluoroethyl)phenyl]isonicotinamide, 4 ml of tetrahydrofuran and 0.21 g of triphenylphosphine, 0.34 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred for 1.8 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.19 g of 2-(3-chloropyridin-4-yl)-5-(pentafluoroethyl)benzoxazole (hereinafter, referred to as “active compound 66”).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:22]([O:24]C)=[O:23].[I-].[Li+]>N1C=CC=CC=1>[O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:22]([OH:24])=[O:23]
Reactant: COC(=O)c1cnc2c3cc(NC(=O)C(C)C)ccc3ncn2c1=O
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1ccc2ncn3c(=O)c(C(=O)O)cnc3c2c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
A mixture of methyl 4-oxo-10-(2-methylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (5.42 g) and anhydrous lithium iodide (13.55 g) in dry pyridine (54 ml) was stirred at 100° C. for 1.5 hours. The reaction mixture was cooled to give crystals which were collected by filtration and washed with pyridine. The crystals were suspended in water (200 ml). The suspension was adjusted to pH 2.5-3.0 with conc. hydrochloric acid to give yellow crystals, which were separated by filtration, washed with water and dried. The crude crystals were washed with a mixture of chloroform and methanol (1:1) two times and dried. There was obtained crystalline 4-oxo-10-(2-methylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylic acid (3.80 g).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:15]=[CH:14][N:13]=[N:12][CH:11]=1>[Cl-].[Zn+2].[Cl-]>[C:2]1([CH:1]=[CH:9][C:10]2[CH:15]=[CH:14][N:13]=[N:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnnc1
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Product: C(=Cc1ccnnc1)c1ccccc1
Temperature: 150 °C
Yield: 66.8 %

Procedure:
Zinc chloride (820 mg, 6 mmol) was added to a stirred mixture of benzaldehyde (6.11 ml, 60 mmol) and 4-methylpyridazine (2.83 g, 30 mmol) and the resulting mixture heated for 20 hours at 150° C. The cool reaction mixture was partitioned between dichloromethane (40 ml) and 2M aqueous sodium hydroxide solution (20 ml), then the organic phase separated, combined with a dichloromethane extract (80 ml) of the aqueous phase, dried (Na2SO4) and evaporated under reduced pressure. The residual pale brown oil was purified by column chromatography on silica gel, using dichloromethane:methanol (99:1) as eluant, to give the title compound (3.65 g) as a pale brown solid. Found: C, 78.95; H, . 5.52; N, 15.39. C12H10N2 requires C, 79.10; H, 5.53; N, 15.37%. δ (CDCl3): 6.96 (1H, d), 7.45 (5H, m), 7.55 (2H, m), 9.12 (1H, d), 9.30 (1H, s). LRMS: m/z 183 (M+1)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.Cl.Cl.[F:28][C:29]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:30]=1[CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:28][C:29]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:30]=1[CH2:31][N:32]1[CH2:33][CH2:34][N:35]([CH2:6][CH2:7][N:8]2[C:16]3[N:15]=[C:14]([NH2:17])[N:13]4[N:18]=[C:19]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)[N:20]=[C:12]4[C:11]=3[CH:10]=[CH:9]2)[CH2:36][CH2:37]1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Reactant: Fc1ccc(CN2CCNCC2)c(F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(ccn2CCN2CCN(Cc3ccc(F)cc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title B compound, 4-(2,4-difluorobenzyl)piperazine dihydrochloride (0.33 mmol) and 0.06 mL of DIEA are added and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 7-(2-(4-(2,4-difluorobenzyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=478.2). 1H NMR (DMSO-d6, 400 MHz) δ 2.30 (m, 4H), 2.36 (m, 4H), 2.67 (t, 2H, J=6.8 Hz), 3.47 (s, 2H), 4.22 (t, 2H, J=6.8 Hz), 6.58 (d, 1H, J=3.6 Hz), 6.72 (m, 1H), 7.06 (dt, 1H, J=8.4 Hz and 2.0 Hz), 7.14 (d, 1H, J=3.2 Hz), 7.20 (m, 2H), 7.42 (dd, 1H, J=15.2 Hz and 8.0 Hz), 754 (br s, NH2), 7.93 (s, 1H). Anal. calculated for (C24H24F2N80+0.5 H2O): C, 59.13; H, 5.17; F, 7.79; N, 22.98; O, 4.92. Found C, 58.84; H, 4.97; N, 22.63.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[N:21]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:22]([Br:26])=[C:23]([Br:25])[N:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:35](Br)[CH:36]=[CH2:37].C(Cl)Cl>CN(C=O)C>[CH2:37]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:8]1[C:20]1[N:21]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:22]([Br:26])=[C:23]([Br:25])[N:24]=1)[CH:36]=[CH2:35]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3nc(Br)c(Br)n3COCC[Si](C)(C)C)[nH]c2c1
Reactant: C=CCBr
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCn1c(-c2nc(Br)c(Br)n2COCC[Si](C)(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 3-cyclohexyl-2-(4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1H-indole-6-carboxylate (428 mg, 0.7 mmol) in dry DMF (5 mL) was added KH (30% in oil, 0.8 mmol, 109 mg) proportion-wise at RT. The mixture was stirred at RT for 10 min until no further effervescence was observed. Allyl bromide (420 mg, 3.5 mmol) was added and the resulting mixture was stirred at RT for 15 min. Methylene chloride (10 mL) was added and the solution was washed with 1N HCl (3×10 mL), dried (Na2SO4), filtered and evaporated to give the title compound in a form pure enough for use in the following step (100%). 1H NMR (300 MHz, CDCl3) δ 0.04 (s, 9H), 0.80 (m, 2H), 1.00–2.00(m, 10H), 2.45 (m, 1H), 3.43 (dd, 2H, J=7.5, 9.6 Hz), 3.91 (s, 3H), 4.50 (dd, 1H, J=4.8, 15.0), 4.60 (dd, 1H, J=6.0, 15.0), 4.88 (dd, 1H, J=1.2, 17.1 Hz), 5.03 (s, 2H), 5.04 (dd, 1H, J=0.9, 9.0 Hz), 5.78 (m, 1H), 7.75 (dd, 1H, J=1.5, 8.5 Hz), 7.82 (d, 1H, J=8.5 Hz), 8.02 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C=O.[CH2:18](N(CC)CC)C>[Ni].CO>[CH3:18][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:15])=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: [Ni]
Agent: C=O
Solvent: CO
Product: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 127 °C
Reaction time: 0.25 h
Yield: 91.8 %

Procedure:
A 2.5 liter shaker reactor was charged with 2,6-di-t-butylphenol (52 g, 0.25 m), formaldehyde (21 g of 37% aq. solution, 0.25 m), triethylamine (30 g, 0.3 m) and methyl alcohol (200 ml). The mixture was heated at 127° C. for 2 hrs. under a nitrogen blanket with agitation. The mixture was hydrogenated at 160° C. in the presence of nickel catalyst (5 g) and 300 psig of H2. Absorption of hydrogen ceased after 15 minutes. The product, after filtering to remove the catalyst, was distilled to recover methyl alcohol, triethylamine and crude DBPC which was distilled at 128° C./6-8 mm Hg to give 51 g (93 mole % yield) of DBPC. Analysis of DBPC by GC was 97% DBPC and 2.8% 2,6-di-t-butylphenol.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][O:5][C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CNC1(NC)CCCCC1>C1(C)C=CC=CC=1.[Cu]I.CCCCCC.C(OCC)(=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:8]2[CH:9]=[CH:10][C:6]([O:5][CH2:4][C:3]3[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=3[Br:1])=[N:7]2)=[CH:18][CH:17]=1
Reactant: Brc1ccccc1COc1cc[nH]n1
Reactant: Clc1ccc(I)cc1
Agent: [Cu]I
Agent: CNC1(NC)CCCCC1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Clc1ccc(-n2ccc(OCc3ccccc3Br)n2)cc1
Temperature: 100 °C
Yield: 19.2 %

Procedure:
A suspension consisting of 3-(2-bromobenzyloxy)-1H-pyrazole (0.20 g, 0.91 mmol), 4-chloroiodobenzene (0.17 g, 0.73 mmol), CuI (9 mg, 0.05 mmol), K2CO3 (0.05 mg, 0.38 mmol) and N,N′-dimethylcyclohexanediamine (72 μL, 0.46 mmol) in 2 mL of toluene was heated to 100° C. for 20 h. The mixture was then cooled to room temperature and directly subjected to column chromatography (SiO2, hexane/ethyl acetate=100:0 to 80:20). The product was obtained as a colorless solid (140 mg, 0.14 mmol, 53% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([C:13](B(O)O)=[CH2:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:18]1[CH2:23][CH2:22][CH2:21][O:20][CH:19]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:31][C:32]3[CH:38]=[C:37](Br)[CH:36]=[CH:35][C:33]=3[N:34]=2)=[C:26]([F:40])[CH:25]=1>O1CCOCC1.CO>[O:18]1[CH2:23][CH2:22][CH2:21][O:20][CH:19]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:31][C:32]3[CH:38]=[C:37]([C:13]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[CH2:14])[CH:36]=[CH:35][C:33]=3[N:34]=2)=[C:26]([F:40])[CH:25]=1
Reactant: C=C(B(O)O)c1ccccc1
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(Br)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: C=C(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1
Temperature: 90 °C

Procedure:
A slurry of (amphos)2PdCl2 (0.114 g, 0.161 mmol), potassium carbonate (2.85 g, 20.6 mmol), 1-phenylvinylboronic acid (2.10 g, 14.2 mmol), 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-bromobenzo[d]thiazole (2.54 g, 6.44 mmol) in 20 mL dioxane/4 mL water was flushed with argon and sealed, and heated at 90° C. overnight. In the morning the reaction mixture was cooled and judged complete by LCMS. The reaction mixture was partitioned between EA/H2O and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give a solid. The material was suspended in MeOH, and filtered. The resulting solid was dried in vacuo to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-(1-phenylvinyl)benzo[d]thiazole as a dull yellow solid. MS (ESI) m/z: Calculated: 417.1; Observed: 418.0 (M++1).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]1)[NH:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][NH:31][CH3:32]>>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]1)[N:12]=[C:11]2[N:31]([CH3:32])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(Cc4ccccc4)cc3c(=O)[nH]2)c1
Product: CN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(F)c(Cc3ccccc3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-benzyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E. MS (ESI): predicted mass calcd. for C21H18FN5O2, 391.1