Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[N:4]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:6]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=1.CO.Cl>O1CCCC1>[CH3:9][C:7]1[NH:8][C:3](=[O:2])[N:4]([C:25]([NH:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26])[CH:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:6]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11]
Reactant: COC1=NC(C)=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)N1C(=O)NCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)N(C(=O)NCc2ccccc2)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A solution of 1,6-dihydro-2-methoxy-4-methyl-6-(3-nitrophenyl)-1-[[(phenylmethyl)amino]carbonyl]-5-pyrimidinecarboxylic acid, 1-methylethyl ester (3.00 g, 6.45 mmol) in tetrahydrofuran (50 ml)/methanol (25 ml) was treated with 1 N hydrochloric acid (6.0 ml, pH 1) and stirred at room temperature for 1 hour. The reaction was quenched with saturated sodium bicarbonate and partially evaporated. The residue was partitioned between chloroform and water. The organic phase was washed with saturated sodium chloride, dried (magnesium sulfate) and evaporated. The residue was crystallized from dichloromethane/isopropyl ether. The solids which precipitated were recrystallized to give the title compound as a colorless electrostatic solid (1.84 g), melting point 184°-185° C. TLC (5% ethyl acetate/dichloromethane) single spot, Rf =0.39.
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[C:7]([N+:14]([O-])=O)[CH:6]=1.C>CO.[Fe](Cl)(Cl)Cl>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[C:7]([CH:6]=1)[NH2:14]
Reactant: CC(C)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Solvent: CO
Product: CC(C)c1ccc(Cl)cc1N
Yield: 93.8 %

Procedure:
A solution of hydrazine hydrate (1.7 mL, 35.1 mmol) in methanol (12 mL) was added drop wise to a solution of 4-chloro-2-nitro-1-(propan-2-yl)benzene (1.75 g, 8.8 mmol) in methanol (40 mL), in the presence of iron (III) chloride (146 mg, 0.9 mmol) and activated charcoal (146 mg) and the reaction mixture was stirred under reflux for 7 h. The solid was filtered over celite, the filtrate concentrated and purified by flash chromatography (hexane/EtOAc 9/1) to obtain the title compound as a light-pink oil (1.4 g, 94%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:25])[CH2:22][CH2:23][OH:24])=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[OH:27][CH2:28][CH2:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1>>[OH:27][CH2:28][CH2:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]2[NH:10][C:9]3[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:26])[C:15]4[CH:20]=[CH:19][C:18]([N:21]([CH2:22][CH2:23][OH:24])[CH3:25])=[CH:17][CH:16]=4)=[CH:5][C:4]=3[N:1]=2)=[CH:33][CH:32]=1
Reactant: CN(CCO)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Reactant: O=Cc1ccc(OCCO)cc1
Product: CN(CCO)c1ccc(C(=O)Nc2ccc3[nH]c(-c4ccc(OCCO)cc4)nc3c2)cc1

Procedure:
Compound 223 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-(N-methyl-N-2-hydroxyethylamino)benzamide and 4-(2-hydroxyethyloxy)benzaldehyde. [M+H]+ calcd for C25H26N4O4: 447.21; found: 446.89.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]([NH:11][C:12]([CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:38]=[CH:39][CH:40]=1)[C:19]([C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[C:24]([C:35]([OH:37])=[O:36])=[CH:23][N:22]=1)=[O:20])=[O:13])([CH3:10])C.[C:41]1([N:47]2CCN[CH2:49][CH2:48]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:34][O:33][C:27]1[CH:26]=[C:25]2[C:30](=[CH:29][C:28]=1[O:31][CH3:32])[C:21]([C:19](=[O:20])[C:18]1[CH:38]=[CH:39][CH:40]=[C:16]([O:15][CH2:14][C:12](=[O:13])[N:11]3[CH2:49][CH2:48][N:47]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH2:10][CH2:8]3)[CH:17]=1)=[N:22][CH:23]=[C:24]2[C:35]([OH:37])=[O:36]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)NC(C)C)c3)c2cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)N4CCN(c5ccccc5)CC4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The resin bound activated ester (intermediate in the preparation of 1-[3-(Isopropylcarbamoyl-methoxy)-benzoyl]-6,7-dimethoxy-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 37)) (225 mg, 0.19 mmol) was combined with 3 ml of methylene chloride and 0.060 ml of N-phenylpiperazine (0.388 mmol). The mixture was shaken for 15 minutes under argon at room temperature. The mixture was filtered and the filter cake was washed with methylene chloride. The filtrate was evaporated to dryness. The residue was saponified by dissolving in 1 ml of methanol containing 0.5 ml of 1N sodium hydroxide solution and several drops of tetrahydrofuran. The mixture was stirred at room temperature for 4 hrs and then evaporated to dryness. The residue was purified through a reverse phase preparative HPLC to give 6,7-Dimethoxy-1-{3-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethoxy]-benzoyl}-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid, as a fluffy solid (30 mg).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:20])=[CH:17]/[CH:18]=[O:19].CC(=CC)C.Cl([O-])=[O:28].[Na+].P(=O)(O)(O)O>O1CCOCC1>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:20])=[CH:17]/[C:18]([OH:28])=[O:19]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=O)C(C)(C)CCC1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Temperature: 5 °C
Reaction time: 0.67 h
Yield: 46 %

Procedure:
A 200-ml three-necked flask was charged under an atmosphere of nitrogen with 8.86 g of vitamin A aldehyde (80.1% purity, 25 mmoles, ratio of 13-cis form: 92%), 50 g of 2-methyl-2-butene, 20 ml of dioxane and 10 g of a 25% aqueous sodium chlorite solution, and the mixture was mechanically stirred vigorously. Then, 32 g of an aqueous phosphoric acid solution was added dropwise thereto, while the internal temperature was maintained at 5° C., over 15 minutes. Vigorous stirring was continued at 5° C. for further 40 minutes. Confirmation of completion of the reaction and after-treatment were conducted in the same manner as in Example 1, to obtain 3.46 g of vitamin A acid with a purity of at least 99%. The yield was 46%. The vitamin A acid thus obtained had a 13-cis form ratio of 95%.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]([C:14]2[CH:36]=[CH:35][C:17]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]([C:29]([O:31]CC)=[O:30])[CH2:24][CH2:25][O:26]4)=[CH:21][C:20]=3[Cl:34])=[CH:16][CH:15]=2)=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]([C:14]2[CH:36]=[CH:35][C:17]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][O:26]4)=[CH:21][C:20]=3[Cl:34])=[CH:16][CH:15]=2)=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCC(C(C)(C)C)CC4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C1CCC(NC(=O)c2ccc(Oc3cc4c(cc3Cl)C(C(=O)O)CCO4)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.4 %

Procedure:
To a solution of ethyl 7-(4-(4-tert-butylcyclohexylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (0.037 g, 0.072 mmol) in 3:1 THF/methanol (1 ml) was added 1M sodium hydroxide (0.15 ml, 0.15 mmol), and the reaction was stirred for 16 hours at ambient temperature. The reaction was concentrated and the residue was diluted with dilute hydrochloric acid and extracted twice with EtOAc. The combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 32 mg of the title compound (91% yield). MS (apci) m/z=486.1 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:6][O:7][C:8](=[O:21])[C@H:9]([CH:18]([CH3:20])[CH3:19])[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:3]([OH:5])=[O:4].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:41][CH2:42]I>O1CCOCC1>[Cl:41][CH2:42][O:4][C:3](=[O:5])[C:2]([CH3:1])([CH3:22])[CH2:6][O:7][C:8](=[O:21])[C@H:9]([CH:18]([CH3:19])[CH3:20])[NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(C)(C)C(=O)O
Reactant: ClCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(C)(C)C(=O)OCCl
Reaction time: 18 h

Procedure:
2,2-dimethyl-3-(N-Boc-L-valyloxy)propionic acid (3.9 g, 12.3 mmole) was dissolved in dioxane (60 ml). To the solution was added tetrabutylammonium hydroxide aqueous solution (40%, 7.78 ml, 12 mmole). The solution was dried in vacuo, and it was coevaporated with toluene for several times. The residue was dissolved in methylene chloride and then chloroiodomethane (18.9 ml, 260 mmole) was added to the solution. After 18 hr, the reaction solution was evaporated and the product was isolated with silica gel column chromatography to yield 3.7 g.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:27][CH3:28])=[C:10]([CH2:19][NH:20][C:21](=[O:26])[CH2:22][C:23](O)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:29][C:30]1[CH:31]=[C:32]([CH2:37][NH2:38])[CH:33]=[CH:34][C:35]=1[F:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Br:29][C:30]1[CH:31]=[C:32]([CH2:37][NH:38][C:23](=[O:24])[CH2:22][C:21]([NH:20][CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:27][CH3:28])=[O:26])[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: NCc1ccc(F)c(Br)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(F)c(Br)c1
Yield: 106.3 %

Procedure:
A solution of 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3-oxopropanoic acid (0.600 g, 1.541 mmol), 1-(3-bromo-4-fluorophenyl)methanamine (0.432 g, 1.796 mmol), HATU (0.760 g, 1.999 mmol) and triethylamine (0.600 mL, 4.30 mmol) in dichloromethane (35 mL) was stirred overnight at room temperature. The solution was diluted with DCM, washed with saturated NaHCO3, water followed by saturated NaCl, and dried over Na2SO4. The organic layer was evaporated to a pale amber residue. This was purified on 80 g. Combi-Flash column with DCM [0-8% MeOH] to give N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}propanediamide (942.9 mg, 106%, containing 12% impurities). LC-MS m/z 575.3 (M+H)+, 0.84 min (ret time).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:19][N:18]=2)=[CH:11][CH:10]=1)(=O)=O.[CH:30]1([CH2:33][NH2:34])[CH2:32][CH2:31]1>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:16]#[C:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][NH:34][CH2:33][CH:30]4[CH2:32][CH2:31]4)=[CH:10][CH:11]=3)=[N:18][CH:19]=2)=[CH:24][CH:25]=1
Reactant: CS(=O)(=O)OCCOc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Reactant: NCC1CC1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCNCC4CC4)cc3)nc2)cc1

Procedure:
The product was obtained analogously to Example 4.1f starting from 2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethyl methanesulfonate (Example 4.1e) and C-cyclopropylmethylamine. Yield: 700 mg (43% of theoretical); C25H23ClN2O (M=402.916); calc.: molpeak (M+H)+: 403/405 (Cl); found: molpeak (M+H)+: 403/405 (Cl); HPLC-MS: 5.08 minutes (method B).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]1([CH:15](O)[CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[CH:4][CH:3]=1
Reactant: OC(CCN1CCN(c2ccccc2)CC1)c1ccccc1
Reactant: Oc1ccc(F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(OC(CCN2CCN(c3ccccc3)CC2)c2ccccc2)cc1
Reaction time: 48 h
Yield: 28.9 %

Procedure:
In a stirring solution of THF (10 mL) under N2, 2 equivalents of 4-fluorophenol (1.40 g, 12.4 mmol) was added to a solution of 1-Phenyl-3-(4-phenyl-piperazin-1-yl)-propan-1-ol (20) (1.84 g, 6.22 mmol) and allowed to dissolve. 1.5 equivalents of triphenylphosphine, PPh3, (2.49 g, 9.32 mmol) was then added and dissolved. After the reaction was allowed to equilibrate at a temperature between 10-15° C., 1.5 equivalents of diisopropyl azodicarboxylate, DLAD, (1.85 mL, 9.32 mmol) was added dropwise. The reaction was then allowed to return to room temperature and continued stirring for 48 hours. The solvent was then evaporated under reduced pressure and aspirated under vacuum for an extended period. Purification was performed by Flash Column Chromatography on silica gel by first washing with 500 mL of 10% EtOAc/hexanes and then extracting with 20% EtOAc/hexanes. Analytical thin-layer chromatography showed that the desired product had an Rf value of approximately 0.56 when developed in 30% EtOAc/hexanes. The fractions containing the desired product were combined, and the solvent was removed under reduced pressure. 0.70 g of the product 1a (1.795 mmol, 29%) was obtained as a yellow, clear oil. 1H-NMR (CDCl3): δ 7.29 (7H, m), 6.93 (2H, d, J=7.93 Hz), 6.86 (5H, m), 5.16 (1H, dd, J=5.00, 4.96 Hz), 3.21 (4H, t, J=4.85, 5.10 Hz), 2.60 (6H, m), 2.23 (1H, sextuplet, J=7.26, 6.75, 7.44, 6.91, 7.72 Hz), 2.02 (1H, m). 13C-NMR (CDCl3): δ 155.62, 154.34, 151.28, 141.61, 129.11, 128.63, 127.69, 126.02, 119.72, 117.15, 117.04, 116.09, 115.80, 115.50, 79.34, 54.62, 53.26, 49.15, 35.96. 19F-NMR(CDCl3): δ −123.77.
Reaction SMILES: C(Cl)(=O)C.[CH3:5][O:6][CH2:7][C@@H:8]1[CH2:13][C:12]([C:14]([O:16][C:17](C)(C)C)=[O:15])=[CH:11][CH2:10][N:9]1[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22]>CO>[CH3:5][O:6][CH2:7][C@@H:8]1[CH2:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH2:10][N:9]1[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22]
Reactant: C=CCOC(=O)N1CC=C(C(=O)OC(C)(C)C)C[C@H]1COC
Solvent: CC(=O)Cl
Solvent: CO
Product: C=CCOC(=O)N1CC=C(C(=O)OC)C[C@H]1COC
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
To methanol (19 ml, 470 mmol) was added at 0° C. acetyl chloride (12 ml, 169 mmol) and the mixture was stirred at the same temperature for 30 minutes. This solution was added to a solution of 1-allyl 4-tert-butyl (2S)-2-(methoxymethyl)-3,6-dihydro-1,4(2 H)-pyridinedicarboxylate (744 mg, 2.4 mmol) in methanol (3 ml) and the mixture was stirred at room temperature for 2 hours. The solvent was removed and the residue was dissolved in ethyl acetate. The solution was washed with a saturated sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed in vacuo to give 1-allyl 4-methyl (2S)-2-(methoxymethyl)-3,6-dihydro-1,4(2 H)-pyridinedicarboxylate (600 mg, 93%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[C:5]2=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)(=[O:28])=[O:27].O>CN(C=O)C>[F:17][C:15]1[CH:14]=[CH:13][C:12]([O:18][CH3:19])=[C:11]([C:10]2[C:5]3[C:6](=[N:7][C:2]([NH:35][CH:32]4[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]4)=[N:3][CH:4]=3)[NH:8][N:9]=2)[CH:16]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: COc1ccc(F)cc1-c1n[nH]c2nc(Cl)ncc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)cc1-c1n[nH]c2nc(NC3CCN(S(C)(=O)=O)CC3)ncc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 35.3 %

Procedure:
To a stirred solution of 6-chloro-3-(5-fluoro-2-methoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 24, 97 mg, 0.35 mmol) in DMF (4 mL), sodium bicarbonate (60 mg) and 1-methanesulfonyl-piperidin-4-ylamine (93 mg, 0.52 mmol) were added and the mixture was stirred at 100° C. for 4 hours. The reaction was cooled and the mixture was poured into water (60 mL). The solid was filtered and dried to give a yellow solid, which was purified by reverse phase HPLC to give 52 mg pale yellow solid. Yield, 35%. MS (M+H)+, 421.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].C(N(CC)CC)C.[C:20](Cl)(Cl)=[S:21]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[O:10][CH3:11])[CH2:5][N:6]=[C:20]=[S:21]
Reactant: COc1c(F)cc(CN)cc1F
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1c(F)cc(CN=C=S)cc1F
Temperature: -10 °C
Reaction time: 2.75 h
Yield: 85.5 %

Procedure:
A solution of 3,5-difluoro-4-methoxybenzylamine (8.7 g, 0.05 mole) and triethylamine (15.5 ml, 0.11 mole) in 50 ml of tetrahydrofuran was added dropwise to a solution of thiophosgene (4.2 ml, 0.055 mole) in 50 ml of tetrahydrofuran with cooling to -10° C. over a period of twenty minutes. The mixture was stirred at 25° C. for 2.75 hours and then filtered. The filtrate was treated with charcoal, filtered, and evaporated to an oil. The oil was diluted with hexane:ethyl acetate (90:10) and purified on a flash silica column using hexane:ethyl acetate (90:10) as the eluant to yield 9.2 g (79%) of 3,5-difluoro-4-methoxybenzyl isothiocyanate.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:59][N:60]1[C:64]([CH3:65])=[CH:63][C:62]([CH2:66]O)=[N:61]1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:66][C:62]2[CH:63]=[C:64]([CH3:65])[N:60]([CH3:59])[N:61]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Cc1cc(CO)nn1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(Cc2cc(C)n(C)n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.4 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), (1,5-dimethyl-1H-pyrazol-3-yl)methanol (0.53 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.80 g, 61%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>CC(C)=O>[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(-c2ccc(OCCCCCCBr)cc2)cc1
Yield: 67 %

Procedure:
A mixture of 4'-hydroxy-4-cyanobiphenyl (7.8 g, 40 mmol), potassium carbonate (8.3 g, 60 mmol), 1,6-dibromohexane (29.8 g, 120 mmol), and acetone (80 milliliters ("mL")) was heated to reflux for 6 hours ("h") under a nitrogen atmosphere. The acetone was concentrated and the residue dissolved in ether-dichloromethane (4:1, 400 mL). The solution was filtered through glass fiber. The filtrate was washed with water and brine, dried over magnesium sulfate, and concentrated. Excess 1,6-dibromohexane was removed by Kugelrohr distillation up to 75° C. at 0.1 mm Hg. The material remaining in the pot was recrystallized from ethanol (100 mL), filtered while hot, and cooled in the freezer to give crystals of the 4'-(6-bromohexyloxy)-4-cyanobiphenyl (9.6 g, 67%): melting point ("mp") 65.5-66° C., nematic mesophase at 63° C. in cooling; NMR (CDCl3) 7.55(s, 4H), 7.49(d, 2H), 6.82(d, 2H), 3.91(t, 2H), 2.0-1.3(m, 8H); IR (CH2Cl2) 2222, 1602 cm-1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.CON(C)[C:16](=[O:23])[CH2:17][C:18]1[CH:22]=[CH:21][S:20][CH:19]=1.[NH4+].[Cl-]>C1COCC1>[C:2]1([C:16](=[O:23])[CH2:17][C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: CON(C)C(=O)Cc1ccsc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(Cc1ccsc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 54.9 %

Procedure:
To the solution of bromo-benzene (1.0 g, 6.36 mmol) in anhydrous THF (30 mL) was added n-BuLi (5.9 mmol, 2.4 mL) at −78° C. under nitrogen, and the mixture was stirred at −78° C. for further 20 min., a solution of N-methoxy-N-methyl-2-(thiophen-3-yl)acetamide (1 g, 5.4 mmol) in anhydrous THF (10 mL) was added. The resulting mixture was stirred at −78° C. under nitrogen for about 30 min., poured into NH4Cl aqueous solution, and extracted with EtOAc. The organic layers were washed with brine, dried over sodium sulfate, concentrated, and purified by column chromatography (PE:EtOAc=20:1) to afford Intermediate 6 (600 mg, yield 55.0%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:27][OH:28])=[C:24]([CH:29]=[CH2:30])[N:23]=[C:22]3[O:31][CH2:32][CH3:33])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.C>[OH-].[OH-].[Pd+2].O>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:27][OH:28])=[C:24]([CH2:29][CH3:30])[N:23]=[C:22]3[O:31][CH2:32][CH3:33])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1C=NO
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1nc(CC)c(C=NO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
Intermediate (17c) (3.5 g, 7.7 mmol) was dissolved in ethanol (100 mL, 2 mol). Pearlman's Catalyst, wet (0.1:0.4:0.5, palladium hydroxide:carbon black:water, 660 mg) was added. The mixture was degassed and stirred at room temperature under hydrogen for 3 hours. The palladium was filtered off and the solute was concentrated to yield intermediate (17d) (3.3 g). MS m/z: [M+H+] calcd for C26H3N3O4, 450.2; found 450.3.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:7]=1[CH2:8][OH:9].C(O)(=O)C>O>[CH3:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:6]([NH:5][C:2]([NH2:3])=[O:1])[C:7]=1[CH2:8][OH:9]
Reactant: Cc1cccc(N)c1CO
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc(NC(N)=O)c1CO
Reaction time: 2.5 h
Yield: 73.9 %

Procedure:
A solution of potassium cyanate (1.62 g) in water (5 ml) was added dropwise to a mixture of 2-amino-6-methylbenzyl alcohol (1.37 g), water (5 ml), and acetic acid (6 ml) at room temperature. After being stirred for 2.5 hours, the resulting precipitates were collected by filtration, washed with water, and dried to give 2-methyl-6-ureidobenzyl alcohol (1.33 g).