Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[S:39](Cl)(=[O:41])=[O:40]>N1C=CC=CC=1>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[S:39]([NH:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1)(=[O:41])=[O:40]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4c(Cl)cccc4Cl)ccc3N2)c(O)c2cccnc21
Temperature: 120 °C
Yield: 15.7 %

Procedure:
To the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was added 2,6-dichlorobenzenesulfonyl chloride (49, 0.2 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 120 minutes. The reaction was cooled to 25° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered, and washed with 1:1 hexane:ethyl acetat. The crude product was chromatographed on silica gel eluting with 399:1 dichloromethane:methanol to give the title compound (5 mg, 16%). 1H NMR (300 MHz, DMSO-d6) δ 0.97 (d, J=6.62 Hz, 6 H) 1.54 (m, 2 H) 1.67 (m, 1 H) 4.46 (m, 2 H) 7.47 (m, 2 H) 7.58 (m, 2 H) 7.68 (m, 3 H) 8.54 (dd, J=7.72, 1.84 Hz, 1 H) 8.88 (dd, J=4.78, 1.84 Hz, 1 H) 11.43 (s, 1 H) 14.02 (s, 1 H). MS (ESI−) m/z 634 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][OH:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14](=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1>[OH:13][CH2:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([CH3:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)cc(CO)c1
Agent: CB1OB(C)OB(C)O1
Agent: [Cs+]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(C)cc(CO)c1
Temperature: 25 °C

Procedure:
To a stirred solution of methyl 3-bromo-5-(hydroxymethyl)benzoate (4.53 g, 18.5 mmol) in dioxane (74 mL) is added cesium carbonate (6.0 g, 18.5 mmol), potassium carbonate (5.1 g, 37 mmol), and palladium(0)tetrakis(triphenylphosphine) (2.1 g, 1.85 mmol), followed by trimethyl boroxine (5.1 mL, 37 mmol). The reaction mixture is refluxed for 12 h, cooled to room temperature, and then partitioned between water and ethyl acetate. The organic layer is washed with water and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The black oil is adsorbed onto silica gel followed by purification by flash column chromatography (silica, 25% ethyl acetate/hexanes) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 7.75 (s, 1H), 7.65 (s, 1H), 7.39 (s, 1H), 5.31 (br s, 1H), 4.53 (s, 1H), 3.84 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[CH2:9][C@H:8]2[O:10][C@@:7]2([CH3:11])[CH2:6][CH2:5]1)=[CH2:3].[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.Cl.[K+].[Br-]>C(OCC)C.C(Cl)(Cl)Cl.O>[N:12]1([C@H:8]2[CH2:9][C@H:4]([C:2]([CH3:1])=[CH2:3])[CH2:5][CH2:6][C@:7]2([CH3:11])[OH:10])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: C=C(C)[C@@H]1CC[C@]2(C)O[C@@H]2C1
Reactant: c1c[nH]cn1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: C=C(C)[C@@H]1CC[C@](C)(O)[C@@H](n2ccnc2)C1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To (R)-(+)-limonene oxide (6.88 mmol, 1.047 g, 1.13 mL) were added 6 mL of deionized water and imidazole (21 mmol, 1.43 g) at 25° C. A reflux condenser was attached and the flask was set in an oil bath that was heated to 100° C. After 5.0 h at 100° C., the reaction mixture was cooled to 25° C., acidified with 12M hydrochloric acid, and extracted with diethyl ether (7×30 mL). The aqueous layer was cooled to 0° C. and treated with solid sodium hydroxide until the solution was strongly basic to litmus (pH 10). The solution was extracted with methylene chloride (10×30 mL) and the combined extracts were dried. The solvent was removed in vacuo leaving a semi-solid material that was taken up in hot diethyl ether. The solution was cooled to give a white, crystalline solid, mp 126-128° C.; [α]25D=+11.4 (c=3.5 in CHCl3); IR (KBr) 3210.0, 2850.0 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22](O)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34].N.C[N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:32])[CH3:33])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([NH2:37])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34]
Reactant: CN(C)CCNc1nc(-c2cccc(C(=O)O)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNc1nc(-c2cccc(C(N)=O)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 25.7 %

Procedure:
To the solution of 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoic acid (23 mg, 0.05 mmol) in CH2Cl2 (3 mL) were added ammonia (2.0 M soln. in isopropanol, 0.0275 mL, 0.055 mmol), HATU (20 mg, 0.052 mmol) and diisopropyl ethyl amine (0.05 mL, 0.3 mmol). The reaction mixture was stirred over night. The reaction mixture was diluted with CH2Cl2 (5 mL) and water (5 mL) and shaked. The layers were separated and the organic layer was washed with brine (8 mL), dried over Na2SO4, filtered and concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) then provided the title compound as a white solid (6 mg, 26%). LC-MS m/z 468 (M+H)+; 1H-NMR (MeOD) δ 2.16 (s, 6H), 2.36 (m, 2H), 3.20 (m, 2H), 4.46 (s, 2H), 7.14 (m, 2H), 7.49 (m, 1H), 7.61 (m, 1H), 7.75 (m, 1H), 8.00 (d, 1H), 8.07 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12](=[O:24])[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]([CH3:17])[C:15]=2[CH3:16])=[O:10])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH2:40])=[O:39])[CH:33]=1>CN(C=O)C.O>[CH3:17][N:14]1[C:15]([CH3:16])=[C:11]([C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][C:32]3[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH2:40])=[O:39])[CH:33]=3)=[CH:3][CH:4]=2)=[O:10])[C:12](=[O:24])[N:13]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Cc1c(C(=O)Nc2ccc(O)cc2)c(=O)n(-c2ccccc2)n1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.9 %

Procedure:
To a solution of N-(4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1.80 g, 5.57 mmol) in DMF (35 mL) was added potassium tert-butoxide (1.87 g, 16.7 mmol). The solution was stirred at rt for 20 minutes, followed by the addition of 4-chloropicolinamide (1.046 g, 6.68 mmol). The reaction was heated at 120° C. for 3 hours, then cocentrated to 2 mL in vacuo, and diluted with water (60 mL). The precipitate was obtained by filtration, washed with water (5 mL) and dried. The crude product was washed with DCM (20 mL) to give the title compound as a brown solid (1.8 g, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]#[CH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[CH:14](NC(C)C)(C)C.O1CCOCC1>CCOCC>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]=[C:11]=[CH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: C=O
Solvent: CCOCC
Solvent: C1COCCO1
Product: C=C=CCNC(=O)OC(C)(C)C

Procedure:
Reflux a mixture containing N-(t-butoxycarbonyl)-propargylamine (70 gm), 93.5 ml of 32% formaldehyde, 76.4 ml of diisopropylamine, 19.66 gm of cuprous bromide and 860 ml of p-dioxane for 12 hours. Cool and dilute the resulting mixture with 3000 ml of Et2O, wash with 500 ml of water, 1000 ml acetic acid, 500 ml of water (2×), 200 ml sat'd. sodium chloride, dry (MgSO4) and evaporate in vacuo. Flash chromatograph the residue eluting from silica gel with 10% Et2O/hexane to yield 40.8 g of the desired compound. Rf is 0.31 (eluted from silica gel with 10% EtOAc/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[C:32]1([CH:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:39][NH2:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:40][CH2:39][CH:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:23])=[CH:17][C:9]1=2
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(NCC(c1ccccc1)c1ccccc1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2,2-diphenylethylamine as in General Procedure 10 to give the title compound. LCMS: m/z=626.96 (M+H+); retention time=1.06 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[NH:13][C:14]([CH:19]([CH3:21])[CH3:20])([CH3:18])[C:15](=[O:17])[N:16]=1)=[O:5])[CH3:2].Cl[C:23]([O:25][CH3:26])=[O:24]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:13]([C:23]([O:25][CH3:26])=[O:24])[C:14]([CH:19]([CH3:20])[CH3:21])([CH3:18])[C:15](=[O:17])[N:16]=1)=[O:5])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)c1ccccc1C1=NC(=O)C(C)(C(C)C)N1
Solvent: c1ccncc1
Product: CCOC(=O)c1ccccc1C1=NC(=O)C(C)(C(C)C)N1C(=O)OC
Reaction time: 1 h
Yield: 89.7 %

Procedure:
8 g (0.028 mole) of 2-(2-ethoxycarbonylphenyl)-5-isopropyl-5-methyl-4-oxo-2-imidazoline are dissolved in 30 ml of absolute pyridine, and 5.3 g (0.056 mole) of methyl chloroformate are added at room temperature. After 1 hour, the mixture is poured onto ice and extracted twice with 100 ml of toluene each time and the organic phase is washed twice with water, dried and evaporated. 8.7 g (90% of theory) of 2-(2-ethoxycarbonylphenyl)-5-isopropyl-1-methoxycarbonyl-5-methyl-4-oxo-2-imidazoline are obtained as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]=[O:15])[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][Mg]Br>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@H:14]([OH:15])[CH3:18])[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC=O)COC1(C)C
Solvent: CCOCC
Product: C[C@@H](O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a stirred solution of (S)-2,2-dimethyl-4-(2-oxo-ethyl)-oxazolidine-3-carboxylic acid tert-butyl ester (12.0 g; CAS 147959-19-1) in dry diethyl ether (200 ml) under an argon atmosphere at room temperature was added dropwise a solution of methylmagnesium bromide in diethyl ether (49.3 ml, 3 M solution) and stirring continued overnight. The reaction mixture was then quenched by careful addition of water and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo. The reside was purified by column chromatography (SiO2; gradient: heptane/EtOAc 100:0→50:50) to give (S)-4-((R)-2-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (5.89 g) from fractions eluting first and (S)-4-((S)-2-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (4.07 g) from fractions eluting later, both compounds as light yellow oils. (S)-4-((R)-2-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester: 1H NMR δ (CDCl3, 300 MHz): 4.60 (1H, br. D, J=3.3 Hz), 4.23 (1H, m), 4.00 (1H, dd, J=8.7 & 5.4 Hz), 3.71 (1H, m), 3.65 (1H, d, J=8.7 Hz), 1.76 (1H, td, J=11.4 & 2.1 Hz), 1.61-1.46 (16H, m), 1.20 (3H, d, J=6.3 Hz). (S)-4-((S)-2-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester: 1H NMR δ (CDCl3, 300 MHz): 4.13 (1H, m), 3.98 (1H, m), 3.85-3.60 (2H, m), 2.50 (1H, br. s), 1.80 (1H, m), 1.60-1.49 (16H, m), 1.22 (3H, d, J=6.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[S:19][C:5]2[NH:6][C:7](=S)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[CH3:20][O:21][C:22]1[CH:34]=[CH:33][C:25]([CH2:26][O:27][CH2:28][C:29]([NH:31][NH2:32])=O)=[CH:24][CH:23]=1>C(O)CCC>[Cl:1][C:2]1[S:19][C:5]2[N:6]3[C:29]([CH2:28][O:27][CH2:26][C:25]4[CH:33]=[CH:34][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)=[N:31][N:32]=[C:7]3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: COc1ccc(COCC(=O)NN)cc1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)sc2N1
Solvent: CCCCO
Product: COc1ccc(COCc2nnc3n2-c2sc(Cl)cc2C(c2ccccc2Cl)=NC3)cc1

Procedure:
1.5 g of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-thione are refluxed for 4 hours with 4 g of 2-(p-methoxybenzyloxy)acetic acid hydrazide in 100 ml of absolute butanol, a nitrogen stream being conducted through the solution. The mixture is evaporated, taken up in methylene chloride, washed with water and saturated sodium chloride solution, dried and evaporated. By recrystallization of the residue from ethyl acetate containing active carbon, there is obtained 2-chloro-4-(o-chlorophenyl)-9-[(p-methoxybenzyloxy)methyl]-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([OH:30])=O)[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]3[CH2:37][CH2:36]3)[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1.[CH:38]1([NH2:41])[CH2:40][CH2:39]1.C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([NH:41][CH:38]3[CH2:40][CH2:39]3)=[O:30])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]3[CH2:36][CH2:37]3)[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1
Reactant: Cn1cc(C(=O)O)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Reactant: NC1CC1
Agent: CCOP(=O)(C#N)OCC
Product: Cn1cc(C(=O)NC2CC2)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12

Procedure:
This compound was synthesized by the reaction of 5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carboxylic acid and cyclopropylamine using diethyl cyanophosphonate as a coupling reagent. Mass: 558.15 (M+H).
Reaction SMILES: NO.CC1[N:5]([C:10]2[S:11][C:12]([C:19]3[C:20]([CH3:34])=[N:21][N:22]4[C:27]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:26][C:25]([CH3:33])=[N:24][C:23]=34)=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)C(C)=CC=1.C(OCC)C>C(O)(=O)C>[CH2:29]([CH:28]([C:27]1[N:22]2[N:21]=[C:20]([CH3:34])[C:19]([C:12]3[S:11][C:10]([NH2:5])=[N:14][C:13]=3[C:15]([F:16])([F:18])[F:17])=[C:23]2[N:24]=[C:25]([CH3:33])[CH:26]=1)[CH2:31][CH3:32])[CH3:30]
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(-n4c(C)ccc4C)nc3C(F)(F)F)c(C)nn12
Agent: NO
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCC(CC)c1cc(C)nc2c(-c3sc(N)nc3C(F)(F)F)c(C)nn12
Temperature: 25 °C
Yield: 86.2 %

Procedure:
Add hydroxylamine (2 mL, 50% in water) to a solution of 3-[2-(2,5-dimethyl-pyrrol-1-yl)-4-trifluoromethyl-thiazol-5-yl]-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (1.1 g, 2.3 mmol) in acetic acid (10 mL). Heat the reaction to 80° C. for 6 h. Cool to room temperature. Pour into diethyl ether and wash with 2 M NaOH (2×) and then once with water. Dry the organic portion over sodium sulfate, filter, and concentrate to dryness under vacuum. Purify the resulting residue by silica gel chromatography (40% ethyl acetate in hexanes) to give the title compound (0.76 g, 87%). ES/MS m/z 384 (M+1)+.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][N:6]=[C:5]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:4]=1)[CH3:2].[NH4+].[Cl-]>O.[Fe]>[CH2:1]([C:3]1[CH:4]=[C:5]([S:12]([CH3:15])(=[O:14])=[O:13])[N:6]=[CH:7][C:8]=1[NH2:9])[CH3:2]
Reactant: CCc1cc(S(C)(=O)=O)ncc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CCc1cc(S(C)(=O)=O)ncc1N
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 4-ethyl-2-methylsulfonyl-5-nitro-pyridine (4.1 mmol), NH4Cl (26.65 mmol) and iron powder (33 mmol) in H2O (10 mL) was stirred at 90° C. for 1 h. The reaction was stopped, filtered and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated to yield the desired product.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[N:12]=[C:13]([C:16]#[N:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:47]>C(Cl)Cl>[Br:47][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:8]2[N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:11]3[N:12]=[C:13]([C:16]#[N:17])[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:20][CH:21]=1
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1ncc2cc(Cc3ccc(CO)cc3)n(C3CCCCC3)c2n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ncc2cc(Cc3ccc(CBr)cc3)n(C3CCCCC3)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a solution of 7-cyclohexyl-6-(4-hydroxymethyl-benzyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.43 mmol) in CH2Cl2 (5 ml), triphenylphosphine (0.47 mmol) and carbontetrabromide (0.47 mmol) are added at 0° C. under nitrogen. The reaction mixture is stirred at 0° C. for 1 h and at room temperature for 1 h. The crude product is applied to a column of silica gel, which is eluted with following solvents: n-hexane:AcOEt=10:1 (v/v), n-hexane:AcOEt=8:1 (v/v) and n-hexane:AcOEt=5:1 (v/v). The solvent of the latter effluent is removed by evaporation and dried in vacuo to afford the title compound. yield 73.9%, Rf=0.72 (n-hexane:AcOEt=1:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]([CH3:18])=[N:14][NH:15][C:16]=2[NH2:17])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[Cl:19][C:20]1[C:21]([OH:29])=[CH:22][C:23]([F:28])=[C:24]([CH:27]=1)[CH:25]=O>FC(F)(F)C(O)=O>[Cl:19][C:20]1[CH:27]=[C:24]([C:25]2[C:3]3[C:4](=[C:5]4[O:10][CH2:9][CH2:8][O:7][C:6]4=[CH:11][C:2]=3[F:1])[C:12]3[C:13]([CH3:18])=[N:14][NH:15][C:16]=3[N:17]=2)[C:23]([F:28])=[CH:22][C:21]=1[OH:29]
Reactant: O=Cc1cc(Cl)c(O)cc1F
Reactant: Cc1n[nH]c(N)c1-c1cc(F)cc2c1OCCO2
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2nc(-c3cc(Cl)c(O)cc3F)c3c(F)cc4c(c3c12)OCCO4
Reaction time: 12 h
Yield: 4.2 %

Procedure:
A solution of 4-(7-fluoro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-methyl-1H-pyrazol-5-amine (109 mg, 0.338 mmol) and 5-chloro-2-fluoro-4-hydroxybenzaldehyde (60 mg, 0.338 mmol) in trifluoroacetic acid (2.0 mL) was heated to 75° C. and allowed to stir for 12 h. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC to afford 5.8 mg (4.2%) of 2-Chloro-5-fluoro-4-(6-fluoro-11-methyl-2,3-dihydro-9H-[1,4]dioxino[2,3-f]pyrazolo[3,4-c]isoquinolin-7-yl)phenol as a white powder: 1H NMR (400 MHz, d4-MeOH): 7.67 (d, J=7.6 Hz, 1H), 7.07 (d, J=13.2 Hz, 1H), 6.85 (d, J=10.8 Hz, 1H) 4.59-4.56 (m, 4H), 2.99 (s, 3H); MS (EI) for C19H12ClF2N3O3: 404 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:9])([F:21])[F:22])=[CH:17][CH:16]=2)=[N:6][CH:7]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Brc1cnc(I)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)Oc1ccc(-c2ncc(Br)cn2)cc1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
5-bromo-2-iodopyrimidine (0.320 g), 4-(trifluoromethyloxy)phenylboronic acid (FRONTIER SCIEN., 0.231 g), tetrakis(triphenylphosphine)palladium(0) (ALDRICH, 0.026 g) and sodium carbonate (1.6 ml, 2M in H2O) in dry toluene (2.8 ml) was refluxed for 24 hours under argon atmosphere. After cooling to room temperature, H2O (5 ml) was added to the reaction mixture. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×15 ml). The combined organic layers were washed with brine, dried over MgSO4, concentrated under vacuum and purified by column chromatography on silica gel, eluting with EtOAc-hexane 1:20 to give 0.248 g of the desired product as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[N:8][N+:9]([O-:11])=[O:10])[NH:6][CH2:5][O:4][CH2:3]1.[Cl:12][C:13]1[S:14][C:15]([CH2:18]Cl)=[CH:16][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:12][C:13]1[S:14][C:15]([CH2:18][N:6]2[CH2:5][O:4][CH2:3][N:2]([CH3:1])[C:7]2=[N:8][N+:9]([O-:11])=[O:10])=[CH:16][N:17]=1
Reactant: CN1COCNC1=N[N+](=O)[O-]
Reactant: ClCc1cnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1COCN(Cc2cnc(Cl)s2)C1=N[N+](=O)[O-]
Yield: 67 %

Procedure:
A mixture of 1.62 g of 3-methyl-4-nitroimino-perhydro-1,3,5-oxadiazine, 2.44 g of 2-chloro-5-chloromethyl-thiazole, 4.2 g of potassium carbonate and 25 ml of N,N-dimethylformamide is heated for 5 h at 60° and then filtered. The filtrate is evaporated in vacuo on a rotary evaporator, and the residue is purified by chromatography [silica gel; dichloromethane/methanol (95:5)]. This gives the title compound, which melts at 132-134°, in a yield of 67%.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:12]=[C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[NH:15][C:14]2=[O:23])=[C:9]([CH3:11])[CH:10]=1)=[O:5])C.[OH-].[K+]>CO.C(O)C>[Cl:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:23])[C:13]2=[CH:12][C:8]1[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]=1[CH3:11]
Reactant: CCOC(=O)c1cc(C)c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: Cc1cc(C(=O)O)[nH]c1C=C1C(=O)Nc2ccc(Cl)cc21
Yield: 72.3 %

Procedure:
A mixture of 5-(5-chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (1.3 g, 4 mmol) and potassium hydroxide in methanol (25 mL) and ethanol (25 mL) was heated to reflux for overnight. Insoluble materials were removed by filtration and the mixture was neutralized with 6N hydrochloric acid to give 0.876 g (70%) of the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.C(=O)(O)[O-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([N:6]1[CH2:5][C@H:4]([CH3:8])[NH:3][C@H:2]([CH3:1])[CH2:7]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccccc2)C[C@H](C)N1
Yield: 51.8 %

Procedure:
To a solution of (cis)-2,6-dimethylpiperazine (900 mg, 8.49 mmol) and sodium bicarbonate (0.2 ml of saturated solution) in THF (5 ml) was added benzyl bromide (1.02 ml, 8.49 mmol). The mixture was exposed to microwave irradiation at 80° C. for 15 minutes. The solvent was removed in vacuo and the residue was washed with sodium bicarbonate solution and extracted with dichloromethane. The residue was purified by flash chromatography eluting with 5-10% (v/v) methanol in dichloro-methane to afford 1-N-benzyl-(cis)-3,5-dimethylpiperazine as a clear oil (900 mg, 4.40 mmol).