Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[ClH:36]>O.C(#N)C>[ClH:36].[N:29]1([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][N:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]2=3)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Reactant: BrCCCCCCN1CCCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC#N
Solvent: O
Product: O=C1Nc2ccccc2N(CCCCCCN2CCCCCC2)c2ccccc21
Yield: 15 %

Procedure:
Prepared analogously to Example 6 from 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, n-butyl-lithium and 1-bromo-6-(hexahydro-1H-1-azepinyl)hexane in a yield of 15% of theory. The monohydrochloride, which is sparingly soluble in water, melted at 103°-105° C. (from acetonitrile using activated charcoal).
Reaction SMILES: [Na+].[N+:2]([C:5]1[CH:11]=[C:10]([S:12]([O-:15])(=O)=[O:13])[CH:9]=[CH:8][C:6]=1[NH2:7])([O-:4])=[O:3].P(Cl)(Cl)([Cl:18])=O>>[N+:2]([C:5]1[CH:11]=[C:10]([S:12]([Cl:18])(=[O:15])=[O:13])[CH:9]=[CH:8][C:6]=1[NH2:7])([O-:4])=[O:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1ccc(S(=O)(=O)[O-])cc1[N+](=O)[O-]
Agent: [Na+]
Product: Nc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
A mixure of o-nitroaniline-p-sulfonic acid sodium salt (25.00 g, 104 mmol) and phosphoryl chloride (75 mL, 804 mmol) under Argon was heated to reflux and vigorously stirred for 4 hours. After cooling to ambient temperature, the reaction mixture was carefully added to a large excess of ice. The resulting slurry was stirred for 15 min., filtered and dried under vacuum to provide o-nitroaniline-p-sulfonyl chloride (21.43 g, 87%) as a yellow solid. H1-NMR (dimethylsulfoxide-D6): 5.8 (b, 2H), 6.97 (d, 1H, J 8.8), 7.57 (m, 1H), 8.18 (d, 1H, J=2.0).
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[N:9]=[C:10](Cl)[C:5]=2[S:4][CH:3]=1.[BH4-].[Na+].O>O1CCCC1CCO>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[NH:9][CH2:10][C:5]=2[S:4][CH:3]=1
Reactant: Clc1nc(Cl)c2scc(Br)c2n1
Agent: OCCC1CCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: ClC1=Nc2c(Br)csc2CN1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
7-Bromo-2,4-dichlorothieno[3,2-d]pyrimidine (1000 mg, 3.54 mmol) was dissolved in tetrahydrofuran-ethanol (1/1, 30 mL) and sodium borohydride (670 mg, 17.74 mmol) was added in several aliquots. The reaction mixture solution was cooled to room temperature and stirred for an hour. After adding water to terminate the reaction, the mixture solution was extracted with dichloromethane. The organic layer was washed with brine, dried with magnesium sulfate, and then concentrated. The yielded 7-bromo-2-chloro-3,4-dihydrothieno[3,2-d]pyrimidine (720 mg, 81% yield) was used without purification.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:5]=2[N:4]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1O.CCN=C=NCCCN(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O.CN(C=O)C>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]2[N:21]=[C:18]([C:16]3[CH:15]=[CH:14][C:6]4[N:7]([CH:8]5[CH2:9][CH2:10][O:11][CH2:12][CH2:13]5)[C:3]([CH3:2])=[N:4][C:5]=4[CH:17]=3)[O:20][C:23]=2[CH:24]=1
Reactant: Cc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Reactant: Cc1ccc(N)c(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1ccc2nc(-c3ccc4c(c3)nc(C)n4C3CCOCC3)oc2c1
Yield: 4.8 %

Procedure:
2-methyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid HCl salt (see Working Example 4-3) (0.25 g, 0.96 mmol), 2-amino-5-methylphenol (0.13 g, 1.05 mmol), anhydrous DMF (10 mL) and WSC (0.22 g, 1.14 mmol) were stirred overnight at room temperature. After the reaction was complete, water (50 mL) was added, the precipitated crystals were filtered off, and the filter residue was extracted with water/chloroform. After the organic layer was dried over anhydrous sodium sulfate, filtration and concentration gave crystals that were dissolved in toluene (5 mL), to which p-toluenesulfonic acid hydrate (0.45 g, 2.37 mmol) was added and this was stirred at reflux for 2 hours. After the solvent was concentrated at reduced pressure, water (5 mL) was added and the solid obtained was filtered off, and after washing with water, drying at reduced pressure at 50° C. yielded the title compound (16 mg, 4.8% yield) as an orange solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:8][S:9](=[O:23])(=[O:22])[C:10]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:11]=2[C:12]=1[OH:13])=[O:6].[CH3:24]I>O.CO>[CH3:3][O:4][C:5]([C:7]1[N:8]([CH3:24])[S:9](=[O:23])(=[O:22])[C:10]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:11]=2[C:12]=1[OH:13])=[O:6]
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Temperature: 40 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
A solution of 8.2 gm (0.205 mol) of sodium hydroxide in 200 ml of water wasadded dropwise over a period of 40 minutes at a reaction temperature of 20°-25° C to a suspension of 61.0 gm (0.2 mol) of 4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide and 85.1 gm (0.6 mol) of methyl iodide in 500 ml of methanol. After stirring it for 4 hours, the mixture was cooled to +5° C, and the precipitate (= 50 gm of crude product) was suction-filtered off and washed with ice-cold methanol. The combined methanolic solutions were heated at 40° C for 15 minutes and then evaporated in vacuo until onset of crystallization. An additional 9 gm of crude product were obtained by suctionfiltration and washing with ice-coldmethanol. Recrystallization of the combined crude products from ethylene chloride yielded 53.3 gm (85% of theory) of 4 -hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide, m.p. 229°-230° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:14])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:15]1[CH:23]2[N:18]([CH2:19][CH2:20][C:21]([CH2:24]O)=[CH:22]2)[CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(O)C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:14][CH2:24][C:21]3[CH2:20][CH2:19][N:18]4[CH:23]([CH:22]=3)[CH2:15][CH2:16][CH2:17]4)=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(O)c(Br)cc21
Reactant: OCC1=CC2CCCN2CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2cc(OCC3=CC4CCCN4CC3)c(Br)cc21
Reaction time: 1 h
Yield: 13.3 %

Procedure:
1-Acetyl-6-bromo-5-hydroxyindoline (Tetrahedron, 1973, 29(8), 1115) (1.24 g, 4.8 mmol), 1,2,3,5,6,8a-hexahydroindolizine-7-methanol (D2, 0.74 g, 4.8 mmol) and triphenylphosphine (1.27 g, 4.8 mmol) were stirred under Ar in dry THF (50 ml) as diethyl azodicarboxylate (0.76 ml, 4.8 mmol) was added dropwise. The mixture was stirred for 1 h, diluted with ethyl acetate, and extracted with dil. HCl. The extract was basified with potassium carbonate, and extracted with chloroform. This extract was dried (Na2SO4) and evaporated to give a dark oil. Further treatment of this oil as above with the phenol, triphenylphosphine and diethyl azodicarboxylate caused reaction to proceed further. Chromatography on silica, eluting with 0-20% methanol/dichloromethane, gave the title compound (0.25 g, 13%) as a brown gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4C3CCCCO3)=[CH:16][C:13]([CH:14]=O)=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[C:34]([NH2:38])([CH3:37])([CH3:36])[CH3:35].[BH4-].[Na+].Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(O)C.CO.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[C:34]([NH:38][CH2:14][C:13]1[CH:16]=[C:17]([C:18]2[N:26]=[C:25]([CH3:27])[N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)[C:10]([NH:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:11][CH:12]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: COc1ccc(Nc2ncc(C=O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Reactant: CC(C)(C)N
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(CNC(C)(C)C)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54.8 %

Procedure:
6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (99.5 mg, 0.223 mmol) was suspended in CH2Cl2 (1.5 mL) and ethanol (1.5 mL), and tert-butylamine (0.075 mL, 0.71 mmol) and tetraisopropoxytitanium (0.20 mL, 0.68 mmol) were added. The reaction was stirred under nitrogen at room temperature for 20 min, and then was fitted with a reflux condenser and put in a preheated oil bath (about 50° C.) and stirred for 90 min. Then, the reaction was cooled to room temperature and sodium borohydride (28.7 mg, 0.759 mmol) and MeOH (1.0 mL) were added. The reaction was stirred at room temperature for 45 minutes, and then more MeOH and 5 N HCl (0.50 mL) were added, and stirring was continued overnight at room temperature. Then, the reaction was diluted with DCM and MeOH and filtered through a Celite® (diatomaceous earth) pad, which was washed with DCM, MeOH, and a 1:1 mixture of these 2 solvents. The filtrate was concentrated and diluted with DCM and MeOH and filtered through another Celite® (diatomaceous earth) pad, which was washed with DCM and MeOH. The filtrate was concentrated and purified by prep HPLC to give 5-((tert-butylamino)methyl)-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)pyridin-2-amine (51.1 mg, 98.3% purity, 43% yield) as a TFA salt. 1H NMR (d6-DMSO, 400 MHz) δ 12.74 (br s, 1H), 9.81 (br s, 1H), 8.70 (s, 1H), 8.65 (br s, 2H), 8.59 (d, J=2.74 Hz, 1H), 8.42 (d, J=2.35 Hz, 1H), 8.14 (dd, J=8.80 Hz, 2.74 Hz, 1H), 6.89 (d, J=8.80 Hz, 1H), 4.18 (br s, 2H), 3.86 (s, 3H), 2.87 (s, 3H), 1.39 (s, 9H). m/z (ESI, +ve ion) 419 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[C:9]2[C:4]=1[C:5](=O)[N:6]=[CH:7][NH:8]2.O=P(Cl)(Cl)[Cl:20]>CN(C=O)C>[Cl:20][C:5]1[C:4]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:3]=2[O:2][CH3:1])[N:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2[nH]cnc(=O)c2c(OC)c1OC
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2c(OC)c1OC
Temperature: 100 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
5,6,7-tris(methyloxy)-4(1H)-quinazolinone (0.8 g, 3.39 mmol) was treated with POCl3 (10 ml, 107 mmol) and one drop of DMF, and stirred at 100° C. for 1 hour before being concentrated. The residue was treated with saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic extracts were dried (sodium sulfate) and concentrated to give 4-chloro-5,6,7-tris(methyloxy)quinazoline (770 mg, 89%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.88 (s, 1 H), 7.37 (s, 1 H), 4.04 (s, 3 H), 3.94 (s, 3 H), 3.91 (s, 3 H). MS (m/z) 255.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: C1CCNC1
Solvent: c1ccccc1
Product: O=C(Nc1ccc(Cl)cc1Cl)N1CCCC1
Yield: 100.1 %

Procedure:
3.76 g of 2,4-dichlorophenyl isocyanate was dissolved in 100 ml of benzene and 1.44 g of pyrrolidine was added to this resulting solution and reacted for 8 hours at room temperature. After completing the reaction, benzene was evaporated under reduced pressure to obtain 5.19 g of N-(2,4-dichlorophenyl)pyrrolidine-1-carboxamide. 0.50 g of the obtained N-(2,4-dichlorophenyl)pyrrolidine-1-carboxamide was dissolved in the mixed solvent composed of 10 ml of acetonitrile and 0.4 ml of carbon tetrachloride and 0.69 g of triphenylphosphine was then added to this resulting solution and the entire mixture was stirred for 1 hour at room temperature. 0.55 g of cuprous cyanide was added to this reaction solution and the entire mixture was refluxed for 2.5 hours. After cooling the reaction solution, insolubles were removed by filtration and the concentrate obtained by evaporating the filtrate under reduced pressure was purified by silica gel column chromatography to obtain 0.39 g of N′-(2,4-dichlorophenyl)-N,N-(butane-1,4-di-yl)cyanoformamidine (1-1) (yield: 72%).
Reaction SMILES: C[O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[C:26](=[O:27])[CH2:25][C:24]([CH3:29])([CH3:28])[CH2:23][C:22]3=[O:30])[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[C:22](=[O:30])[CH2:23][C:24]([CH3:28])([CH3:29])[CH2:25][C:26]3=[O:27])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCCN1C(=O)CC(C)(C)CC1=O
Agent: Cl
Solvent: c1ccncc1
Product: CC1(C)CC(=O)N(CCCCCN2CC[C@@H]3c4cccc(O)c4CC[C@@H]32)C(=O)C1
Yield: 91.8 %

Procedure:
In an analogous manner to that described in Example 20b), from 9.2 g (21.6 mmol) of rac-cis-1-[5-(6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-3-yl)pentyl]-4,4-dimethylpiperidine-2,6-dione using pyridine hydrochloride there were obtained 7.9 g of rac-cis-1-[5-(6-hydroxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-3-yl)pentyl]-4,4-dimethylpiperidine-2,6-dione; yellowish crystals of m.p. 133°-134° after crystallization from t-butyl methyl ether/hexane.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[N:12]=[C:11]([O:13]C)[C:10]([N+:15]([O-:17])=[O:16])=[C:9]([O:18]C)[N:8]=2)=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>O>[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[N:8]=[C:9]([OH:18])[C:10]([N+:15]([O-:17])=[O:16])=[C:11]([OH:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COc1nc(Cc2ccc(F)cc2)nc(OC)c1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1c(O)nc(Cc2ccc(F)cc2)nc1O
Temperature: 25 °C
Yield: 62 %

Procedure:
(27) A mixture of compound (26) (1.0 g, 3.4 mmol) and pyridine hydrochloride (3.9 g, 34 mmol) was heated to 140 C for 1 hour. After it cooled to room temperature, the resultant was diluted with water. The product was collected on a filter and dried in vacuo. 2-(4-Fluoro-benzyl)-5-nitro-pyrimidine-4,6-diol (27) was obtained in a yield of 62% (1.1 g). 1H NMR (DMSO-d6)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1([CH:13]([N:17]2[CH:21]=[C:20](B3OC(C)(C)C(C)(C)O3)[CH:19]=[N:18]2)[CH2:14][C:15]#[N:16])[CH2:12][CH2:11][CH2:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:20]2[CH:19]=[N:18][N:17]([CH:13]([CH:9]3[CH2:12][CH2:11][CH2:10]3)[CH2:14][C:15]#[N:16])[CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC1(C)OB(c2cnn(C(CC#N)C3CCC3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: N#CCC(C1CCC1)n1cc(-c2ccnc(Cl)n2)cn1
Temperature: 100 °C
Yield: 71.2 %

Procedure:
A mixture of 2,4-dichloropyrimidine (4.8 g, 0.032 mol), 3-cyclobutyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile (8.10 g, 0.0269 mol), tetrakis(triphenylphosphine)palladium (2.0 g, 0.002 mol), and potassium phosphate (17 g, 0.081 mol) in 1,4-dioxane (80 mL) and water (8 mL) was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified on silica gel, eluting with 0 to 80%, to give the desired product (5.51 g, 71.2%). LCMS (M+H) 288.3.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH:10]=1)=[O:8])C>O1CCCC1.O.Cl>[C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH:10]=1)([OH:8])=[O:6]
Reactant: CCOC(=O)c1cn(-c2ccnc3ccccc23)c(C)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)cn(-c2ccnc3ccccc23)c1C

Procedure:
1.89 g (45 mmol) of lithium hydroxide monohydrate are added at a temperature in the region of 20° C. to 1.3 g (4.42 mmol) of 3-ethoxycarbonyl-4,5-dimethyl-1-(quinol-4-yl)-1H-pyrrole dissolved in 50 mL of tetrahydrofuran and 50 mL of water. After stirring at reflux for 42 hours, the reaction mixture is concentrated virtually to dryness under reduced pressure (2.7 kPa) to give a residue that is taken up in 41 mL of 1N hydrochloric acid. After filtering off and drying the solid residue at ambient pressure at a temperature in the region of 50° C., 1.1 g of 3-carboxy-4,5-dimethyl-1-(quinol-4-yl)-1H-pyrrole are obtained in the form of a whitish solid melting at approximately 238° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13](O)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.P(Br)(Br)[Br:19]>C1(C)C=CC=CC=1.O>[Br:19][CH:13]([C:5]1[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[CH3:14]
Reactant: BrP(Br)Br
Reactant: CC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
To a solution of 1-[3,5-bis(trifluoromethyl)phenyl]ethanol (500 mg, 1.94 mmol) in toluene (5 mL) was added phosphorus tribromide (550 mg, 2.03 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane (258 mg, 41%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:32][CH2:33][CH3:34])=[C:16]([CH:22]([CH2:28][N+:29]([O-])=O)[CH2:23][C:24](OC)=[O:25])[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.[BH4-].[Na+]>CO.C(=O)(O)[O-].[Na+].ClCCl.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:32][CH2:33][CH3:34])=[C:16]([CH:22]4[CH2:28][NH:29][C:24](=[O:25])[CH2:23]4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C(CC(=O)OC)C[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC(=O)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of methyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-4-nitrobutanoate (0.089 g, 0.18 mmol) in methanol (1.3 mL) was treated with nickel chloride hexahydrate (0.087 g, 0.36 mmol) was and stirred for 5 min. The reaction mixture was cooled to 0° C., treated with sodium tetrahydroborate (0.073 g, 1.9 mmol) in four portions, and stirred at room temperature for 30 min. The reaction mixture was heated at 60° C. for 1.5 h, cooled to room temperature, diluted with saturated sodium bicarbonate solution (10 mL) and dichloromethane (25 mL), and filtered through Celite. The Celite was washed with dichloromethane and the filtrate was transferred to a separatory funnel. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated to residue. The crude residue was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired peak 1 diastereoisomer (16 mg, 21%) and peak 2 diastereoisomer (19 mg, 24%). Peak 1 (compound 310): 1H NMR (300 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.89 (s, 1H), 7.34 (s, 1H), 6.21 (q, J=7.1 Hz, 1H), 4.38-4.22 (m, 1H), 3.93-3.80 (m, 1H), 3.79-3.67 (m, 1H), 3.65-3.55 (m, 1H), 3.28-3.20 (m, 1H), 2.54 (s, 3H), 2.29 (dd, J=17.5, 8.3 Hz, 1H), 2.21 (s, 3H), 1.70 (d, J=7.0 Hz, 3H), 1.40 (t, J=6.9 Hz, 3H). LCMS for C21H26ClN6O2 (M+H)+: m/z=429.2; Found: 429.2. Peak 2 (compound 311): 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.89 (s, 1H), 7.33 (s, 1H), 6.20 (q, J=7.1 Hz, 1H), 4.38-4.22 (m, 1H), 3.90-3.68 (m, 2H), 3.65-3.56 (m, 1H), 3.28-3.17 (m, 1H), 2.54 (s, 3H), 2.32 (dd, J=17.3, 8.5 Hz, 1H), 2.21 (s, 3H), 1.69 (d, J=7.0 Hz, 3H), 1.39 (t, J=6.9 Hz, 3H). LCMS for C21H26ClN6O2 (M+H)+: m/z=429.2; Found: 429.2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([OH:13])=O)[N:8]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:7]=1.[CH3:19][N:20](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:21].F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.CNC.C(O)C>CN(C)C=O.C(OCC)(=O)C>[CH3:19][N:20]([CH3:21])[C:11]([C:9]1[N:8]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc2cnc(Cl)nc2n1C1CCCC1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (1.07 g, 4.03 mmol), HBTU (1.53 g, 4.03 mmol) and diisopropylethylamine (2 mL, 12.1 mmol) are dissolves in dimethylformamide (20 mL). 2 M solution of dimethylamine in ethanol (2.4 mL, 4.8 mmol) is added and the mixture is stirred for 30 minutes to achieve complete conversion. The reaction mixture is diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate, water, then brine. The organic phase is dried (Na2SO4), filtered and concentrated. Purification by chromatography on silicagel (ethyl acetate:heptane) provides 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (927 mg, 79% yield) MS (ESI) m/z 293.1 (M+H)+
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[P:13](OCC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[P:13]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=1)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(OCC)OCc1ccc(C(=O)OC)cc1

Procedure:
contacting the methyl p-(hydroxymethyl)benzoate of step (1) with triethyl phosphite to obtain diethyl p-(methoxycarbonyl)benzyl phosphite;
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:22])(=[O:21])[NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1.CO>>[CH2:14]([NH:13][S:12]([C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:23])=[O:2])[CH:11]=[CH:10][CH:9]=1)(=[O:22])=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)NCc2ccccc2)c1
Solvent: CO
Product: O=C(O)C=Cc1cccc(S(=O)(=O)NCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To a suspension of 3-(3-benzylsulfamoyl-phenyl)-acrylic acid methyl ester (4g) (0.29 g, 0.87 mmol) in methanol (4.5 ml) 1N NaOH solution (2.60 ml, 2.60 mmol) was added and the resultant mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 2N HCl solution and stirred for 30 min. The precipitated solid was filtered, washed with water and dried in desiccator over P2O5 to give the title compound as a white solid (0.22 g, 81%). 1H NMR (DMSO-d6, HMDSO), δ: 4.05 (2H, d, J=6.4 Hz); 6.60 (1H, d, J=16.0 Hz); 7.27 (4H, s), 7.52–8.09 (6H, m); 8.20 (1H, t, J=6.4 Hz); 12.58 (1H, br s).