Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([O:10][CH3:11])=[N:8][C:7]([Br:12])=[CH:6][N:5]=1.[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([S:29](OC3C=CC([N+]([O-])=O)=CC=3)(=[O:31])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)[CH:14]([CH3:16])[CH3:15].Cl>C(COC)OC.O>[Br:12][C:7]1[N:8]=[C:9]([O:10][CH3:11])[C:4]([NH:3][S:29]([C:24]2[C:23]([C:20]3[CH:19]=[CH:18][C:17]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:22][CH:21]=3)=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:31])=[O:30])=[N:5][CH:6]=1
Reactant: COc1nc(Br)cnc1N
Reactant: CC(C)Cc1ccc(-c2ccccc2S(=O)(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccccc1-c1ccc(CC(C)C)cc1
Reaction time: 0.17 h
Yield: 24.2 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.094 g) was added to a solution of 2-amino-5-bromo-3-methoxypyrazine (0.159 g) in dimethoxyethane (4 ml). The solution was stirred for 10 minutes and then 4-nitrophenyl 4'-isobutyl-2-biphenylsulphonate (0.321 g) was added. The solution was allowed to stand for 5 hours and then water (20 ml) was added. 2M Hydrochloric acid (2 ml) was added and the mixture was extracted with ethyl acetate (2×30 ml). The extracts were dried (MgSO4) and volatile material was removed by evaporation. The residue was purified by elution with ethyl acetate/hexane (1:3 v/v) through a silica gel Mega Bond Elut column. The resulting solid was recrystallised from a mixture of ether and hexane to give N-(5-bromo-3-methoxy-2-pyrazinyl)-4'-isobutyl-2-biphenylsulphonamide (0.09 g), m.p. 154°-156° C.; 1H NMR (d6 -DMSO): 0.9 (d,6H), 1.8-2.0 (m,1H), 2.5 (d,2H), 3.85 (s,3H), 7.1 (s,4H), 7.3 (d,1H), 7.5-7.7 (m,2H), 7.8 (br s,1H), 8.05 (d,1H), 10.2-10.3 (br, 1H); mass spectrum (+ve FAB, methanol/NBA): 478 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:12]=[CH:11][C:10]=1[CH:25]=[CH:26][C:27]1[S:31][C:30]([CH:32]=O)=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([C:36]1[C:37](=[C:44]([C:47]#[N:48])[C:45]#[N:46])[O:38][C:39]([CH3:43])([CH3:42])[C:40]=1[CH3:41])#[N:35].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:12]=[CH:11][C:10]=1[CH:25]=[CH:26][C:27]1[S:31][C:30]([CH:32]=[CH:41][C:40]2[C:39]([CH3:42])([CH3:43])[O:38][C:37](=[C:44]([C:45]#[N:46])[C:47]#[N:48])[C:36]=2[C:34]#[N:35])=[CH:29][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: CCCCN(CCCCO)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCCO)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)s2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.4 %

Procedure:
In 7 ml of ethanol and 2 ml of tetrahydrofuran were dissolved 218 mg (0.47 mmol) of 5-[2-[2-benzyloxy-4-[butyl(4-hydroxybutyl)amino]phenyl]vinyl]thiophene-2-carboaldehyde and 103 mg (0.52 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene)propanedinitrile. To this mixture was added 40 mg (0.52 mmol) of ammonium acetate, and the mixture was stirred at room temperature for 90 minutes. The precipitate was separated by filtration, purified by silica gel column chromatography and washed with methanol to give 171 mg of a dark brown crystal having a mp of 216-217° C. (yield: 56.4%).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16](Br)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>CN(C=O)C.C(OCC)(=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([S:3][C:1](=[O:4])[CH3:2])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 82.9 %

Procedure:
2.2 g (19.3 mmol) Potassium thioacetate and 2.65 g (10 mmol) 4-Bromo-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 50 ml of DMF and stirred at 100° C. for 4 h. The mixture was taken up in ethyl acetate and washed with brine. The organic phases were dried over Sodium sulfate and evaporated. Purification over silica gel (10% to 20% ethyl acetate in heptane) gave 2.15 g of the expected compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH:11]([CH2:15][OH:16])[O:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:16][CH2:15][CH:11]2[CH2:10][CH2:9][C:8]3[C:13](=[CH:14][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[O:12]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CO)CC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Preparation according to Preparation 22 using [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methanol (0.4 g, 1.65 mmol), DCM (25 ml), p-toluenesulfonyl chloride (0.47 g, 2.5 mmol), TEA (0.28 ml, 2.0 mmol) and 4-DMAP (0.24 g, 2.0 mmol) stirred for overnight at room temperature. Yield: 0.59 g. MS m/z (rel. intensity, 70 eV) 419 (62), 416 (14), 415 (25), 414 (bp), 397 (M+1, 39).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[N:3]=1.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[C:4]([N:16]3[CH2:17][CH2:18][N:19]([C:22]4[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:20][CH2:21]3)[N:3]=[C:2]([N:34]([CH2:35][CH3:36])[CH2:32][CH3:33])[N:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: Fc1ccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(Cl)n2)cc1Cl
Reactant: CCNCC
Product: CCN(CC)c1nc(-c2ccc(F)c(Cl)c2)cc(N2CCN(c3ncccc3C(F)(F)F)CC2)n1
Temperature: 60 °C

Procedure:
Combine a mixture of 2-chloro-4-(3-chloro-4-fluoro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine (47 mg, 1 mmol) and diethylamine (2 mL). Heat the mixture in a sealed tube at 60° C. for 16 hours. Cool to room temperature and evaporate. Add 1 M NaOH (1 mL) and extract 2× with EtOAc (2 mL each). Combine the organic layers, dry (Na2SO4), and purify using preparative TLC (9:1 hexanes/EtOAc) to obtain {4-(3-Chloro-4-fluoro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-diethyl-amine as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:24]1[CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:24]1([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]2[C:11]([O:21][CH3:22])=[N:10][C:9]3[C:13]2=[N:14][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[N:7][C:8]=3[NH2:23])[CH2:27][CH2:26][CH2:25]1
Reactant: C1CNC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCN3CCC3)c2n1
Temperature: 50 °C
Yield: 6.4 %

Procedure:
2-(Butyloxy)-9-(5-chloropentyl)-8-(methyloxy)-9H-purin-6-amine (100 mg, 0.293 mmol), azetidine (0.020 ml, 0.293 mmol) and N,N-diisopropylethylamine (0.102 ml, 0.585 mmol) were dissolved in DMF (2 ml) and heated at 50° C. for 72 hours. The solvent was removed in vacuo and the residue partitioned between DCM (5 ml) and water (5 ml) and the layers separated using a hydrophobic frit. The aqueous phase was re-extracted with DCM (5 ml) and the combined organic extracts concentrated and the residue dissolved in 1:1 MeOH:DMSO (1 ml) and purified by MDAP (Method A). The product-containing fractions were evaporated under a stream of nitrogen to give the title compound as a clear gum (6.8 mg).
Reaction SMILES: P(O)(O)(O)=O.O=[C:7]([CH2:9][N:10]([C:12](=N)N)C)O.O=C(CN(C(=N)N)C)O.[Mg+2].[Cl-].[Cl-].P(OC[C@H]1[O:45][C@@H:44]([N:46]2C3N=CN=C(N)C=3N=C2)[C@H:43](O)[C@@H:42]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O>O>[C:44]([NH2:46])(=[O:45])[C:43]1[CH:42]=[CH:7][CH:9]=[N:10][CH:12]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Reactant: CN(CC(=O)O)C(=N)N
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Product: NC(=O)c1cccnc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Creatine phosphate (14.5 mg) and creatine kinase (0.1 mg) were dissolved in a mixture of TRIS buffer (pH 7.5, 15 mM MgCl2, 960 μl) and ATP (100 mM/l in H2O, 40 μl). A solution of the riboside (compound 14, or analogue thereof, as given above) (100 mg/ml in H2O, 100 μl) was added, followed by the addition of ribosyl kinase (0.7 U/ml, 230 μl). The reaction mixture was incubated for 16 hrs. at 37° C. Next, the reaction mixture was warmed up to 80° C., filtered and analyzed by high performance liquid chromatography (“HPLC”).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[N:8]=[C:9]([S:13][CH3:14])[NH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:14][S:13][C:9]1[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([CH3:12])[N:10]=1
Reactant: CCOC(=O)C1=C(C)NC(SC)=NC1c1cccc(OC)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1c(C)nc(SC)nc1-c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl-2-methylthio-4-(3-methoxyphenyl)-6-methyl-1,4-dihydro-pyrimidine-5-carboxylate (example 24a, 7.65 g) was dissolved in a mixture of toluene (200 ml) and CH2Cl2 (100 ml). 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (5.45 g) was added and the reaction mixture was stirred at room temperature for 15 min. 0.2M aq. NaOH (250 ml) was added. The organic layer was separated, washed with H2O (2*250 ml) and sat. aq. NaCl (2*250 ml), dried (MgSO4) and concentrated under reduced pressure. The title compound was purified by chromatography on silica gel with hept/EtOAc=4/1 (v/v) as eluent.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]O.S(=O)(=O)(O)O.O.C1(N)C=CC=CC=1.C1(N)C=CC=CC=1>C(O)(=O)C>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:14][C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=1[NH2:11]
Reactant: Nc1ccccc1CO
Reactant: Sc1nc2ccccc2[nH]1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Solvent: Nc1ccccc1
Product: Nc1ccccc1CSc1nc2ccccc2[nH]1

Procedure:
A mixture of 9.0 g (60 mmole) of 2-mercaptobenzimidazole and 4.9 g (40 mmole) of 2-aminobenzyl alcohol were heated at 84° C. in a mixture of 45 ml of glacial acetic acid and 12.0 g (120 mmole) of sulfuric acid. After two hours an additional 1 g (8 mmole) of 2-aminobenzyl alcohol and 1 g of sulfuric acid were added. After one hour the reaction mixture was cooled and poured into cold benzenamine hemihydrate.
Reaction SMILES: N1C=CC=CC=1.[Br:7][C:8]1[CH:9]=[C:10]([C:14](Cl)=[O:15])[CH:11]=[N:12][CH:13]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.CN(C=O)C.O1CCCC1>[Br:7][C:8]1[CH:9]=[C:10]([C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH:11]=[N:12][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1cncc(Br)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1cncc(Br)c1
Reaction time: 3 h

Procedure:
Under argon and at RT, 32.4 ml (400 mmol, 2 eq.) of pyridine, 2.4 g (20 mmol, 0.1 eq.) of 4-dimethylaminopyridine and, dropwise, a solution of 44.1 g (200 mmol, 1.0 eq.) of 5-bromopyridine-3-carbonyl chloride in 200 ml of DMF were added to a solution of 18.6 g (200 mmol) of aniline in 500 ml of tetrahydrofuran. After 3 h, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water/dichloromethane and the solid was stirred well, washed repeatedly with water and dichloromethane and dried under reduced pressure. Yield: 35.7 g (52% of theory) After phase separation of the mother liquor, the organic phase was extracted twice with dichloromethane. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, dichloromethane/methanol 100:1), which gave 11.7 g (18% of theory) of Example 14A.
Reaction SMILES: C(#N)C.[C:4]([C:8]1[CH:9]=[C:10]([S:19][CH2:20][C@H:21]2[O:26][C:25](=[O:27])[CH2:24][C@H:23]([OH:28])[CH2:22]2)[CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])([CH3:7])([CH3:6])[CH3:5].[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:34]>>[C:15]([C:12]1[CH:11]=[C:10]([S:19][CH2:20][C@@H:21]([OH:34])[CH2:22][C@@H:23]([OH:28])[CH2:24][C:25]([OH:26])=[O:27])[CH:9]=[C:8]([C:4]([CH3:7])([CH3:5])[CH3:6])[C:13]=1[OH:14])([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1cc(SC[C@@H]2C[C@@H](O)CC(=O)O2)cc(C(C)(C)C)c1O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)(C)c1cc(SC[C@@H](O)C[C@@H](O)CC(=O)O)cc(C(C)(C)C)c1O
Temperature: -20 °C

Procedure:
To 1.6 ml of a solution of acetonitrile containing 150 mg (0.409 mmol) of (4R,6S)-6-[[(3,5-di-tert-butyl-4-hydroxyphenyl)thio]methyl]-4-hydroxytetrahydropyrane-2-one was added 0.98 ml of 1N lithium hydroxide with stirring in an atmosphere of argon at -20° C. After 30 minutes thereto was added 3.9 ml of 0.1 M solution of citric acid, and an organic solvent was distilled away under reduced pressure at a temperature not more than 25° C. In ether was dissolved the residue and the mixture was washed with saturated brine solution, dried and distilled away under reduced pressure to give 157 mg of (3R,5S)-6-[(3,5-di-tert-butyl-4-hydroxyphenyl)thio]-3,5-dihydroxyhexanoic acid. Thereto was added 3.9 ml (0.389 mmol) of 0.1 N sodium hydroxide which was ice-cooled, washed with ether and freeze-dried to give 151 mg of the desired compound (yield: 89%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][C:13]([Cl:17])=[N:14][CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[C:25](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][C:13]([Cl:17])=[N:14][CH:15]=3)[N:10]([C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncc2c(-c3cccc(Br)c3)n[nH]c2n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Clc1ncc2c(-c3cccc(Br)c3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-(3-bromo-phenyl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidine (from Example 38 supra) (4.0 g, 12.9 mmol) and Et3N (2.6 g, 25.8 mmol) in DMF (40 mL) was added the solution of trityl chloride (4.3 g, 15.5 mmol) in DMF (40 mL) at room temperature. This mixture was stirred at room temperature for 2 hours. The reaction solution was then poured into water (400 mL), and the yellow precipitate was collected by filtration. This crude product was purified by chromatography (silica gel, dichloromethane:petroleum ether, 1:1) to give 3-(3-bromo-phenyl)-6-chloro-1-trityl-1H-pyrazolo[3,4-d]pyrimidine as a light yellow solid. (Yield 3.5 g, 30%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1Br)=[O:4].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>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.C1COCC1>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3]([O:2][CH3:1])=[O:4])[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COC(=O)c1sccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1sccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 34.4 %

Procedure:
3-Bromothiophene-2-carboxylic acid methyl ester (1.0 g, 4.5 mmol, 1.0 eq.), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (1.4 g, 4.5 mmol, 1.0 eq.), THF (50 mL) and Na2CO3 (9 mL, 18 mmol, 4.0 eq.) were combined. The mixture was degassed and purged with nitrogen (3×). PdCl2(PPh3)2 (10.1 g, 0.14 mmol, 0.03 eq.) was added, and the mixture was again degassed and purged with nitrogen (3×), then heated at 80° C. overnight. The mixture was then cooled and the layers were separated. The THF layer was diluted with EtOAc (50 mL), washed with saturated aqueous NaCl (20 mL) and dried over Na2SO4. The material was filtered and applied onto a silica gel column and purified by chromatography with PE/EtOAc (20:1˜10:1) to yield 4-(2-methoxycarbonylthiophen-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (0.5 g) as an oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:31]([N:33]2C=N[CH:35]=[CH:34]2)=[O:32])C=1.[CH3:38][O:39][C:40]1[CH:46]=CC(N)=[CH:42][C:41]=1[C:47]([F:50])([F:49])[F:48]>ClCCCl.C(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:31]([NH:33][C:34]2[CH:35]=[CH:46][C:40]([O:39][CH3:38])=[C:41]([C:47]([F:50])([F:49])[F:48])[CH:42]=2)=[O:32])[CH:21]=[CH:20]3)[CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: c1ccc(COCc2cc(Oc3ccc4[nH]ccc4c3)ncn2)cc1
Reactant: COc1ccc(N)cc1C(F)(F)F
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(NC(=O)n2ccc3cc(Oc4cc(COCc5ccccc5)ncn4)ccc32)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(6-(benzyloxymethyl)pyrimidin-4-yloxy)-1H-indole (0.8 g, 2.41 mmol) in 35 mL of DCE, CDI (1.17 g, 7.24 mmol) is added followed by TEA (1 mL, 7.24 mmol). Mixture is stirred at rt overnight and then 4-methoxy-3-(trifluoromethyl)aniline (1.38 g, 7.24 mmol) is added followed by stirring for 4 days. The reaction is diluted with DCM, washed with saturated aqueous NaHCO3 (×2), brine, and the organic layer is dried over Na2SO4. After concentration, the residue is purified by FCC (5-60% EtOAc/heptane) to give the title compound. MS (ESI) m/z 549.1 (M+1).
Reaction SMILES: C(C[CH:5]1[C:13](=O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:11]=2)[N:6]1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)(O)=O.[Mg+2].[Cl-:27].[Cl-].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>CN(P(N(C)C)(N(C)C)=O)C>[ClH:27].[ClH:27].[F:25][C:22]1[CH:23]=[CH:24][C:19]([N:6]2[C:7]3[C:12](=[CH:11][C:10]([C:15]([F:18])([F:16])[F:17])=[CH:9][CH:8]=3)[C:13]([NH+:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[CH:5]2)=[CH:20][CH:21]=1
Reactant: [Cl-]
Reactant: O=C(O)CC1C(=O)c2cc(C(F)(F)F)ccc2N1c1ccc(F)cc1
Reactant: CN1CCNCC1
Agent: [Mg+2]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CN1CC[NH+](c2cn(-c3ccc(F)cc3)c3ccc(C(F)(F)F)cc23)CC1
Product: Cl
Temperature: 200 °C

Procedure:
2-Carboxymethyl-1-(4'-fluorophenyl)-5-trifluoromethylindolin-3-on (15 g) and MgCl2. 6H2O (30 g) in HMPA (100 ml) were heated under N2 at 120°-140° C. for 1 h and finally at 150° C. for another 1/2 h. 1-Methylpiperazin (25 ml) was added and the mixture was refluxed under N2 at an oil bath temperature of 200° C. for 16 h. The mixture was cooled and poured into 1 ltr. of H2O and extracted with ether (3×200 ml). The combined ether extracts were washed with 0.5 M HCl (3×300 ml). The acidic H2O phase was made alkaline and reextracted with ether (2×200 ml). The combined organic phase was dried (MgSO4) and the ether evaporated. The remaining oil was dissolved in acetone and the title compound precipitated as a dihydrochloride. Yield: 6.7 g (35%). M.p. 245°- 247° C.
Reaction SMILES: [SH2:1].[C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])[CH:19]=[CH:18]3)=[N:8][CH:9]=1)#[N:3].C(NCC)C>CN(C=O)C>[NH2:3][C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])[CH:19]=[CH:18]3)=[N:8][CH:9]=1)=[S:1]
Reactant: S
Reactant: COC(=O)C(C)n1ccc2cc(OCCCOc3ccc(C#N)cn3)ccc21
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COC(=O)C(C)n1ccc2cc(OCCCOc3ccc(C(N)=S)cn3)ccc21
Temperature: 60 °C
Yield: 90 %

Procedure:
H2S gas was passed slowly through a solution of methyl 2-(5-{3-[5-cyano-2-pyridinyl)oxy]propoxy}-1H-indol-1-yl)propanoate (Example 67, 0.50 g, 1.32 mmol) in DMF (7.80 mL) for 20 minutes at rt. Diethylamine (0.21 mL, 2.37 mmol) was added in one portion, and the resultant light green solution was heated at 60° C. for 3 h. The reaction mixture was purged with a stream of argon, and then concentrated under reduced pressure. The desired compound (0.49 g, 90%) was isolated by column chromatography (50% hexanes in EtOAc) as a bright yellow solid. 1H NMR (400 MHz, CD2Cl2) δ 8.63 (dd, 1H), 8.16 (dd, 1H), 7.25-7.08 (m, 3H), 6.86-6.74 (m, 2H), 6.46 (d, 1H), 5.16 (qt, 1H), 4.59 (t, 2H), 4.17 (t, 2H), 3.71 (s, 3H), 2.35-2.25 (m, 2H), 1.82 (d, 3H).
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[CH3:6][O:7][C:8](=[O:14])[C:9]([CH3:13])([CH3:12])[CH2:10][OH:11].C(N(CC)CC)C>ClCCl.C(OCC)C>[CH3:6][O:7][C:8](=[O:14])[C:9]([CH3:13])([CH3:12])[CH2:10][O:11][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: COC(=O)C(C)(C)CO
Reactant: C[Si](C)(C)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)CO[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
TMSCl (2.30 mL, 0.018 mol) was added dropwise to a solution of 3-hydroxy-2,2-dimethyl-propionic acid methyl ester (2.0 g, 0.015 mot) and triethylamine (3.16 mL, 0.023 mol) in dichloromethane at 0° C. After stirring for 1 h, the reaction was warmed to room temperature and stirred for an additional 1.5 h. Volatiles were removed under reduced pressure to provide a solid that was slurried in a mixture of ethyl ether and hexanes. The solid was removed by filtration and the filtrate was concentrated to provide a yellow liquid that was purified by bulb to bulb distillation under reduced pressure to provide 2,2-dimethyl-3-trimethylsilanyloxy-propionic acid methyl ester (2.8 g, 91%) as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=O.[NH2:12]C(N)=O>ClCCl.CO>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]#[N:12]
Reactant: O=C(O)c1ccc(Cl)cc1Br
Reactant: NC(N)=O
Solvent: ClCCl
Solvent: CO
Product: N#Cc1ccc(Cl)cc1Br

Procedure:
588 mg (2.5 mmol) of 2-bromo-4-chlorobenzoic acid and 300 mg of urea are dissolved in dichloromethane/methanol and concentrated onto 364 mg of alumina (neutral) on a rotary evaporator. The residue is microwaved at 150° C. for a total of 60 min. After cooling, the residue is stirred with ethyl acetate and water, filtered, and the aqueous phase is separated. The organic phase is washed with a sodium hydrogen carbonate solution, dried over sodium sulfate, concentrated on a rotary evaporator and then dried under high vacuum. The product (383 mg, 80% pure, 57% of theory.) is reacted further without additional purification.