Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:17]1[C:18]2[C:19](=[C:23]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)[N:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[N:25]=2)[N:20]=[CH:21][N:22]=1>CN(C)C=O.C(OC)(C)(C)C>[CH2:3]([N:10]1[CH2:14][CH2:13][CH:12]([O:15][C:17]2[C:18]3[C:19](=[C:23]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)[N:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:32])[N:25]=3)[N:20]=[CH:21][N:22]=2)[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Clc1ccc(-c2c3ncnc(Cl)c3nn2-c2ccccc2Cl)cc1
Reactant: OC1CCN(Cc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: Clc1ccc(-c2c3ncnc(OC4CCN(Cc5ccccc5)C4)c3nn2-c2ccccc2Cl)cc1
Reaction time: 2 h
Yield: 31.3 %

Procedure:
Sodium hydride (24 mg of a 60% dispersion in mineral oil, 0.6 mmol) was added to a solution of 1-benzylpyrrolidin-3-ol (0.1 ml, 0.6 mmol) in dimethylformamide (1 ml), and the resultant mixture was stirred at room temperature for 5 min. Next, 7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine 1-2A-1c (50 mg, 0.13 mmol) was added in one portion, and the mixture was stirred for 2 hours. The reaction mixture was diluted with methyl tert-butyl ether and washed with water (3×). The organic phase was dried over anhydrous magnesium sulfate and concentrated. Purification of the residue by flash column chromatography (50% ethyl acetate in hexanes) provided the title compound 7-(1-benzylpyrrolidin-3-yloxy)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine 7A-1 (21 mg): MS: 516.1 (M+1)+; 1H NMR (400 MHz, CDCl3) δ 8.6 (s, 1H), 7.5 (m, 6H), 7.3 (m, 7H), 5.8 (m, 1H), 3.7 (s, 2H), 3.2 (m, 1H), 2.9 (m, 1H), 2.8 (m, 1H), 2.7 (m, 1H), 2.5 (m, 1H), 2.2 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][C:3]1=[O:9].[Br:11]Br>CC(O)=O>[Br:11][CH:4]1[C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[CH2:7][CH2:6][C:5]1=[O:8]
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: BrBr
Solvent: CC(=O)O
Product: CC1(C)CCC(=O)C(Br)C1=O

Procedure:
To a stirred solution of 4,4-dimethylcyclohexane-1,3-dione (1.4 g, 10 mmol) in AcOH (20 mL) at r.t. was added bromine (1.6 g, 0.51 mL, 10 mmol) dropwise. The reaction was carried out according to Method A to give the title compound in quantitative yield as a light brown solid which was used without further purification. LCMS (ES+) 218.9 (+H)+.
Reaction SMILES: C(O[CH:5]([O:9]C(=O)C)[C:6](Cl)=[O:7])(=O)C.[Cl:13][C:14]1[C:15]([N+:21]([O-:23])=[O:22])=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C(=O)([O-])O.[K+].[Cl-].O[NH3+].S(=O)(=O)(O)O>C1COCC1.O>[Cl:13][C:14]1[C:15]([N+:21]([O-:23])=[O:22])=[C:16]2[C:18]([C:6](=[O:7])[C:5](=[O:9])[NH:17]2)=[CH:19][CH:20]=1
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Reactant: CC(=O)OC(OC(C)=O)C(=O)Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1Nc2c(ccc(Cl)c2[N+](=O)[O-])C1=O
Temperature: 25 °C
Yield: 58.7 %

Procedure:
A solution of 2-chloro-2-oxoethane-1,1-diyl diacetate (70.7 g, 363 mmol) in THF (225 mL) was added dropwise to a mixture of 3-chloro-2-nitroaniline (44.7 g, 259 mmol) and potassium hydrogen carbonate (130 g, 1.30 mmol) in THF (450 mL) at 0° C. The resultant mixture was stirred at room temperature for 4 h, filtered and concentrated in vacuo. The residue was diluted with ethanol (450 mL) and a solution of hydroxylammonium chloride (90.0 g, 1.30 mmol) in water (225 mL) was added to the mixture at room temperature. The resultant mixture was refluxed for 2 h and concentrated in vacuo. Water (225 mL) was added to the residue and the resultant mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to afford a crude solid. The crude solid was added portionwise to conc. sulfuric acid (260 mL) at 50° C., and the resultant mixture was stirred at 70° C. for 2 h, cooled to room temperature and poured into iced water (780 mL). The resultant mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, filtered through silica gel and concentrated in vacuo. Diisopropyl ether (800 mL) was added to the residue, and the resultant suspension was refluxed and cooled to room temperature with stirring. The precipitate was collected by filtration and washed with diisopropyl ether to afford the title compound as a brown solid (33.5 g, 152 mmol 59%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)[C:2]#[C:3]C.C([Li])CCC.[CH3:21][O:22][C:23]1[C:32]([CH:33]=[O:34])=[CH:31][C:30]([N+:35]([O-:37])=[O:36])=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:39])([CH3:38])[O:28]2.CCOCC>C1COCC1.O=[Mn]=O>[CH3:15][O:14][C:8]1[CH:7]=[C:6]([O:5][CH2:1][C:2]#[C:3][C:33]([C:32]2[C:23]([O:22][CH3:21])=[C:24]3[C:29](=[C:30]([N+:35]([O-:37])=[O:36])[CH:31]=2)[O:28][C:27]([CH3:39])([CH3:38])[CH:26]=[CH:25]3)=[O:34])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1c(C=O)cc([N+](=O)[O-])c2c1C=CC(C)(C)O2
Reactant: CC#CCOc1ccc(OC)c(OC)c1
Agent: O=[Mn]=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(OCC#CC(=O)c2cc([N+](=O)[O-])c3c(c2OC)C=CC(C)(C)O3)cc1OC
Reaction time: 0.5 h

Procedure:
To a solution of 4-but-2-ynyloxy-1,2-dimethoxybenzene (1.66 g, 8.66 mmol) in THF (75 mL) is added n-butyl lithium (5.54 ml of 1.6 M solution in THF, 8.86 mmol) at −78° C. After 30 min., 5-methoxy-2,2-dimethyl-8-nitro-2H-chromene-6-carbaldehyde (2.17 g, 8.25 mmol) in THF (50 mL) is added. The reaction is stirred for 1 h and then quenched with sat. NH4Cl and extracted with ethyl acetate. The combined organic layers are washed with brine and dried over Na2SO4. The resulting crude material is dissolved in dichloromethane (20 mL) and MnO2 (5.3 g, 61 mmol) is added. After the reaction is stirred overnight at room temperature, ether is added and the suspension is filtered through a pad of celite and silica gel to afford 4-(3,4-dimethoxy-phenyoxy)-1-(5-methoxy-2,2-dimethyl-8-nitro-2H-chromen-6-yl)-but-2-yn-1-one.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]=O)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[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].[CH3:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:54]6[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[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]
Reactant: CN1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCN(C)CC4)c3)c2C)c1

Procedure:
A mixture of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-2-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.000152 mol) in 1,2-dichloroethane (4 mL) with 1-methylpiperazine (26.6 mg., 0.00024 mol) and sodium triacetoxyborohydride (68 mg, 0.00032 mol) and AcOH (12 μL) was placed on an oscillating shaker overnight at room temperature. The reaction was quenched with sat. aq. NaHCO3, then extracted with 1,2-dichloroethane (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. Purification was carried out on Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of 1,2-dichloroethane and transferred to a vial and pumped down to afford the title compound as a pale brown colored solid [55.1 mg (49%). LC-MS m/z 743.9 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([CH3:12])[C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([CH3:13])[CH:3]=1.[C:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)([OH:16])=[O:15].[F-].[Cs+].O1CCOCC1>C(OCC)(=O)C.O.C(O)C>[OH:9][CH2:8][CH2:7][O:6][C:5]1[C:10]([CH3:12])=[CH:11][C:2]([C:20]2[CH:21]=[CH:22][C:17]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=2)=[CH:3][C:4]=1[CH3:13]
Reactant: Cc1cc(Br)cc(C)c1OCCO
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(=O)O)cc2)cc(C)c1OCCO
Temperature: 90 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
A mixture of 2-(4-bromo-2,6-dimethylphenoxy)ethanol (0.645 g), 4-carboxyphenylboronic acid (0.873 g), tetrakis-(triphenylphosphine)palladium(0) (0.152 g), cesium fluoride (2.398 g), 1,4-dioxane (7.5 mL), ethanol (2.5 mL) and water (1.5 mL) was stirred at 90° C. overnight under an atmosphere of argon. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethylacetate/n-hexane=1/1-2/1) to afford the title compound (0.292 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].CS[C:11](=[NH:13])[NH2:12].OS(O)(=O)=O>O>[NH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8])[C:11]([NH2:13])=[NH:12]
Reactant: CSC(=N)N
Reactant: NCCCCCCN
Agent: O=S(=O)(O)O
Solvent: O
Product: N=C(N)NCCCCCCN
Reaction time: 15 h

Procedure:
To 2.3 g. of 1,6-diaminohexane dissolved in 50 ml. of H2O was added dropwise with vigorous stirring a solution of 2 g. of S-methylthiopseudourea.H2SO4 in 20 ml. of H2O. After the completion of addition, the stirring was continued for 15 hours, after which the precipitate (the diadduct) was filtered. The filtrate was concentrated to a viscous oil which upon the addition of 50 ml. of MeOH precipitated 718 mg. of white powder.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[N:7][C:8]([S:12][CH2:13][CH3:14])=[N:9][CH:10]=2)[N:5]=[CH:4][NH:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16].N1C=CC=CC=1.C>[OH-].[Na+]>[S:16]=[C:2]1[C:11]2[C:6](=[N:7][C:8]([S:12][CH2:13][CH3:14])=[N:9][CH:10]=2)[N:5]=[CH:4][NH:3]1
Reactant: CCSc1ncc2c(=O)[nH]cnc2n1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCSc1ncc2c(=S)[nH]cnc2n1
Yield: 95.9 %

Procedure:
A mixture of 4-oxo-7-ethylthio-3H-pyrimido[4,5-d]pyrimidine (1.33 g, 6.7 mmol), P2S5 (1.48 g, 6.6 mmol) and pyridine (15 mL) is refluxed under N2 for 3 h. The pyridine is then stripped under reduced pressure, and the residue is dissolved in NaOH solution (0.5M, 75 mL) and boiled with charcoal. After filtration, the filtrate is neutralized with acetic acid to generate a gold brown solid. Buchner filtration and drying in a vacuum oven affords 4-thiono-7-ethylthio-3H-pyrimido[4,5-d]pyrimidine (1.42 g, 95%). 1H NMR (DMSO) δ 9.47 (1H, s), 8.46 (1H, s), 3.20 (2H, q, J=7.3 Hz), 1.35 (3H, t, J=7.3 Hz).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].O[CH2:36][C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:36][C:37]3[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:24])([CH3:25])[CH2:22][CH2:23]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccc(CO)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccc(C#N)cc3)cc2)c1N1CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (0.04 g, 0.085 mmol), 4-(hydroxymethyl)benzonitrile (0.057 g, 0.427 mmol) and Ph3P (0.067 g, 0.256 mmol) in THF (5 mL) was added DEAD (0.041 ml, 0.256 mmol) at 0° C. After 1 h, the cold bath was removed and stirred for 16 h at rt. Then, the reaction mixture was concentrated and the residue purified by prep-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(5-(4-((4-cyanobenzyl)oxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate (0.0324 g, 0.056 mmol, 65.0% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.74-7.70 (m, 2H), 7.61 (d, J=8.5 Hz, 2H), 7.22-7.18 (m, 1H), 7.12-7.09 (m, 1H), 7.06-7.01 (m, 2H), 6.07 (s, 1H), 5.26-5.19 (m, 2H), 4.27 (dq, J=10.7, 7.1 Hz, 1H), 4.18 (dq, J=10.7, 7.1 Hz, 1H), 3.19 (d, J=12.1 Hz, 1H), 2.84 (t, J=12.1 Hz, 1H), 2.61 (s, 3H), 2.28 (d, J=11.3 Hz, 1H), 2.20 (s, 3H), 2.03 (t, J=11.6 Hz, 1H), 1.57-1.53 (m, 1H), 1.42-1.34 (m, 1H), 1.26 (t, J=7.1 Hz, 3H), 1.21 (s, 9H), 1.18 (br. s., 1H), 1.07 (d, J=13.4 Hz, 1H), 0.91 (s, 3H), 0.63 (s, 3H). LCMS (M+H)=584.4.
Reaction SMILES: [C:1]([C:3]1[C:11]2[S:10][C:9]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])=[N:8][C:7]=2[CH:6]=[CH:5][C:4]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25]C(=O)C(F)(F)F)[CH:20]=1)#[N:2].O.[OH-].[Li+].Cl>O1CCCC1.CO.O>[NH2:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][C:4]1[CH:5]=[CH:6][C:7]2[N:8]=[C:9]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[S:10][C:11]=2[C:3]=1[C:1]#[N:2]
Reactant: N#Cc1c(Oc2cccc(NC(=O)C(F)(F)F)c2)ccc2nc(NC(=O)C3CC3)sc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(Oc2cccc(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.1 %

Procedure:
N-(7-Cyano-6-{3-[(trifluoroacetyl)amino]phenoxy}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide (1.06 g, 2.37 mmol) was dissolved in a mixed solvent of tetrahydrofuran (25 mL)/methanol (25 mL)/water (25 mL), lithium hydroxide monohydrate (1.05 g, 25.7 mmol) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and concentrated under reduced pressure. The obtained residue was repeatedly washed with water to give the title compound (0.79 g, 95%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH2:15][CH2:14]2)([CH3:4])([CH3:3])[CH3:2].Cl.Br[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[N:16]([C:30]1[CH:29]=[CH:28][CH:33]=[CH:32][N:31]=1)[CH2:15][CH2:14]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)Cc1cccc2c1NCC2
Reactant: Brc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)Cc1cccc2c1N(c1ccccn1)CC2
Temperature: 110 °C
Reaction time: 16 h
Yield: 33.1 %

Procedure:
Bubble nitrogen through benzyl-(2,3-dihydro-1H-indol-7-ylmethyl)carbamic acid tert-butyl ester (3.7 g, 10.9 mmol) in 1,4-dioxane (50 mL) in a sealed tube. Mix with 4-bromopyridine hydrochloride (4.3 g, 21.9 mmol), palladium diacetate (0.5 g, 2.18 mmol), 2-(dicyclohexylphosphino)biphenyl (0.76 g, 2.18 mmol) and sodium tert-butoxide (3.1 g, 32.7 mmol). Stir the mixture 110° C. for 16 hours. Cool and filter, then concentrate the filtrate. Purify by chromatography (silica gel; hexane/ethyl acetate; 3:1 to 0:1) to isolate a solid as the title compound (1.5 g, 33%). MS (ESI) m/z 416 (M+H)+.
Reaction SMILES: C([O:4][N:5]1[C:10]([NH2:11])=[CH:9][C:8](Cl)=[N:7][C:6]1=[NH:13])(=O)C.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[OH-].[Na+]>C(O)C>[NH2:11][C:10]1[N:5]([OH:4])[C:6](=[NH:13])[N:7]=[C:8]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:9]=1
Reactant: C1CCNCC1
Reactant: CC(=O)On1c(N)cc(Cl)nc1=N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=c1nc(N2CCCCC2)cc(N)n1O
Reaction time: 0.5 h

Procedure:
1.01 g (5 mmoles) of 1-acetoxy-6-amino-4-chloro-1,2-dihydro-2-iminopyrimidine are added under stirring to a mixture containing 10 ml of ethanol and 3 ml of piperidine. The mixture is refluxed while stirring for 30 minutes, then 5 ml of 1N aqueous sodium hydroxide solution are added and the boiling is continued for additional 30 minutes. Thereafter, the mixture is evaporated under reduced pressure and the residue is mixed with 10 ml of water. The crystalline precipitate is filtered, washed with water and dried to give the aimed compound in a yield of 0.85 g (82%), m.p.: 262°-266° C.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:30][CH3:31])=[CH:12][CH:13]=[C:14]2[C:19]=1[O:18][C:17](=[O:20])[CH:16]=[C:15]2[NH:21][C:22]1[C:27]([Cl:28])=[CH:26][N:25]=[CH:24][C:23]=1[Cl:29]>>[Cl:29][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:28])[C:22]=1[NH:21][C:15]1[C:14]2[C:19](=[C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][NH:2][CH3:1])[C:11]([O:30][CH3:31])=[CH:12][CH:13]=2)[O:18][C:17](=[O:20])[CH:16]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Reactant: CN
Product: CNCCCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12

Procedure:
The title compound was prepared from methylamine and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 27. 1H NMR (400 MHz, DMSO-d6): δ 8.44 (br s, 2H), 8.33 (s, 2H), 7.78 (d, 1H), 6.92 (d, 1H), 3.94 (t, 2H), 3.85 (s, 1H), 3.84 (s, 3H), 2.93 (t, 2H), 2.53 (s, 3H), 1.82-1.56 (m, 6H); MS (ESI): 452.0.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:37][C:32]1[CH:31]=[C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:29])[F:28])[N:25]=[C:20]([C:16]3[CH:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[CH:19]=[CH:18][CH:17]=3)[N:21]=2)[CH:35]=[CH:34][C:33]=1[F:36]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)c2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 33.1 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[6-(3,4-difluoro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.37 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.11 g, 22%). MS (ISP) 498.1 [(M+H)+]; mp 238° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[N:20]=[C:19]([N:21]([CH3:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:18]([C:28]#[N:29])=[C:17]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[C:16]=3[C:36]#[N:37])[N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[NH2:29][C:28]1[C:18]2[C:19](=[N:20][C:15]([S:14][CH2:13][C:11]3[N:12]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[S:9][CH:10]=3)=[C:16]([C:36]#[N:37])[C:17]=2[N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[N:21]([CH3:27])[C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)CN(C)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(N2CCCCC2)c1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1c(N)c2c(N3CCCCC3)c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc2n1C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
80 mg (0.15 mmol) of the compound from Example 47A were initially charged in 3 ml of acetonitrile, and 189 mg (0.58 mmol) of cesium carbonate were added. The mixture was stirred at 50° C. for 4 h. After cooling, the mixture was filtered and the filtrate was freed from the solvent on a rotary evaporator. The residue was dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:29]([NH:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=[O:30])=[CH:19][N:20](COCC[Si](C)(C)C)[C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[OH:34][CH2:33][C:32]([NH:31][C:29]([C:18]1[C:16]2[C:15](=[N:14][CH:13]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:17]=2)[NH:20][CH:19]=1)=[O:30])([CH3:36])[CH3:35]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CO)c3n2)c2ccc(Cl)cc21
Reaction time: 3 h
Yield: 16.5 %

Procedure:
2-(6-Chloro-1-methyl-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (0.04 g, 0.076 mmol), trifluoroacetic acid (0.582 mL, 7.56 mmol) and dichloromethane (3.00 mL) were combined and stirred for 3 h. The reaction mixture was concentrated to dryness and diluted with dichloromethane (3 mL), then ethylenediamine (0.510 mL, 7.56 mmol) was added. After 1 h the mixture was concentrated to dryness and ice water (1 mL) added. The solid formed was collected by filtration then triturated with ethyl acetate to obtain 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (5 mg, 16%). MS (M+H)+=399; 1H NMR (DMSO-d6) δ: 8.94-9.36 (m, 1H), 8.51-8.76 (m, 1H), 8.37 (s, 1H), 7.80-8.08 (m, 2H), 7.29 (t, J=8.8 Hz, 1H), 4.17 (d, J=5.8 Hz, 3H), 3.48-3.80 (m, 2H), 1.45 (d, J=3.3 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH:19]([CH3:21])[CH3:20])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 18.0 g of 5-fluoro-2-nitrophenol, 29.0 g of caesium carbonate and 13.7 ml of 2-iodopropane in 119 ml of DMF is stirred at ambient temperature overnight. The mixture is concentrated under vacuum and the residue is taken up with 250 ml of water and extracted twice with 250 ml of ethyl acetate. The organic phases are washed twice with 200 ml of a saturated sodium chloride solution, dried over magnesium sulfate and concentrated under vacuum, so as to obtain 17 g of crude product. The crude product is purified on 400 g of silica, elution being carried out with cyclohexane/ethyl acetate (95/5), so as to obtain 13.0 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene in the form of a light yellow oil.