Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:13])[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1>C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH:3]([O:13][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:14]1)[CH2:4][P:5](=[O:12])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11]
Reactant: C1=COCCC1
Reactant: CCOP(=O)(CC(O)CBr)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: CCOP(=O)(CC(CBr)OC1CCCCO1)OCC
Yield: 128.1 %

Procedure:
(1)-(b) To a mixture of diethyl 3-bromo-2-hydroxypropylphosphonate (82.5 g) and p-toluenesulfonic acid (1.03 g) was added dropwise 3,4-dihydro-2H-pyrane (250 g) under ice-cooling and with stirring. After the reaction mixture was stirred at the same temperature for 10 minutes and at ambient temperature for 1.5 hours. The dihydropyrane was removed off by evaporation under reduced pressure to give a residue, which was dissolved in ethyl acetate (500 ml). The ethyl acetate solution was washed with saturated aqueous sodium bicarbonate solution (100 ml) and with saturated aqueous sodium chloride solution (100 ml), dried over magnesium sulfate and evaporated to dryness under reduced pressure to give oily diethyl 3-bromo-2-(tetrahydro-2H-pyran-2-yloxy)propylphosphonate (138 g).
Reaction SMILES: [Na].[SH:2][C:3]1[NH:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=1.Cl[CH2:13][C:14]1[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=1>CO.CN(C=O)C>[F:21][C:20]([F:22])([F:23])[C:16]1[CH:15]=[C:14]([CH2:13][S:2][C:3]2[NH:4][C:5]3[CH:10]=[CH:9][N:8]=[CH:7][C:6]=3[N:11]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Sc1nc2cnccc2[nH]1
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CO
Product: FC(F)(F)c1cccc(CSc2nc3cnccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.15 g (0.0065 g atom) of sodium in 35 mL of methanol was added 1.0 g (0.0066 mol) of 2-mercapto-1H-imidazo[4,5-c]pyridine. After stirring for 15 minutes at room temperature, the methanol was removed in a rotary evaporator. The residue was dissolved in 20 mL of DMF and 1.28 g (0.0066 mol) of α'-chloro-α,α,α-trifluoro-m-xylene in 2 mL of DMF was added dropwise to the reaction solution. The reaction mixture was stirred at room temperature overnight and was then poured into 150 mL of ice water. The product which crystallized was collected and amounted to 1.61 g. An analytical sample (m.p. 148°-150° C.) was obtained by recrystallization from acetonitrile.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=1>>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:33](=[O:34])[CH2:32][O:31][C:30]3[CH:36]=[CH:37][C:27]([Cl:26])=[CH:28][CH:29]=3)[CH2:21][CH2:22]2)[C:15]2[N:16]=[C:8]([CH2:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:25][CH:24]=3)[S:9][C:10]=2[N:11]=1
Reactant: Cc1ccc(CCc2nc3c(N4CCNCC4)nc(N)nc3s2)cc1
Reactant: O=C(O)COc1ccc(Cl)cc1
Product: Cc1ccc(CCc2nc3c(N4CCN(C(=O)COc5ccc(Cl)cc5)CC4)nc(N)nc3s2)cc1
Yield: 51 %

Procedure:
This compound was prepared from 2-(4-methylphenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-chlorophenoxyacetic acid in a yield of 51%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:21])[CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH:5]=[CH:6][CH:7]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:21])[C:9]([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:24][N:25]([CH3:27])[CH3:26])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)c1cccc(Cl)c1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C(=O)c1cccc(Cl)c1)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 79.9 %

Procedure:
A stirred mixture of 2-(2-(3-chlorophenyl)-2-oxoethyl)isoindoline-1,3-dione (782.2 mg, 2.610 mmol, 1 equiv) and 1,1-dimethoxy-N,N-dimethylmethanamine (1.5 mL, 11 mmol, 4.3 equiv) was heated at 100° C. for 18 hours. Excess 1,1-dimethoxy-N,N-dimethylmethanamine was removed by rotary evaporation. The crude product was purified by flash column chromatography on silica gel (50 to 100% ethyl acetate in heptane) to yield 740 mg (80%) of 2-(3-(3-chlorophenyl)-1-(dimethylamino)-3-oxoprop-1-en-2-yl)isoindoline-1,3-dione. LCMS (ESI) m+H=355.2; 1H NMR (400 MHz, CDCl3) δ: 7.90 (d of d, 2H), 7.77 (d of d, 2H), 7.57 (s, 1H), 7.44 (d, 1H), 7.37 (overlapping d and s, 2H), 7.31 (t, 1H), 3.00 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].C1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)[OH:22]>O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:22])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(CN)cc1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: N#Cc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 33 %

Procedure:
39.6 g of p-cyanobenzylamine, 42.1 g of hexamethylenetetramine and 400 ml of water were mixed and after adjusting the pH of the solvent to 2.5 by sulfuric acid, the mixture was reacted at 90° C. for 2 hours while stirring. The reaction solution was cooled to room temperature and then cooled on ice. The crystals precipitated were collected by filtration, washed with water and dried to obtain 13.2 g (yield: 33%) of p-cyanobenzaldehyde. The purity was 99.8% or more.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=3[N:18]=2)=[CH:10][CH:9]1[CH3:24])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.[OH-].[Na+]>[CH3:23][C:19]1[C:17]2[N:18]=[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH:9]([CH3:24])[CH:10]=3)[S:15][C:16]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cccc2sc(C3=CC(C)N(C(=O)OC(C)(C)C)CC3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc2sc(C3=CC(C)NCC3)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
Scheme IIA, Step B: To a mixture of 1-(t-butyloxycarbonyl)-4-(4-methylbenzothiazol-2-yl)-2-methyl-1,2,5,6-tetrahydropyridine (1.297 g, 3.77 mmol) in dichloromethane (12 mL) at 0° C. was added trifluoroacetic acid (12 mL). The mixture was stirred at 0° C. for 30 minutes, then at 20° C. for 30 minutes. The mixture was diluted with 2 N sodium hydroxide and extracted 3 times with ethyl acetate. The combined organics were dried over sodium sulfate then filtered and evaporated. The residue was chromatographed over silica gel (dichloromethane/10% methanol/1% ammonium hydroxide in dichloromethane gradient elution) to give the intermediate title compound as a yellow oil (0.738 g, 85%). FDMS m/e=245 (M++1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O.[F:25][C:26]1[CH:27]=[C:28]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:29]=[CH:30][C:31]=1[OH:32]>C(OCC)(=O)C>[F:25][C:26]1[CH:27]=[C:28]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH:29]=[CH:30][C:31]=1[O:32][C:2]1[CH:7]=[N:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(S(C)(=O)=O)nc2)c(F)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
4.00 g of 5-chloro-2-methanesulfonyl-pyridine and 8.80 g of cesium carbonate were added to an N-methylpyrrolidinone (50 ml) solution of 4.74 g of tert-butyl (3-fluoro-4-hydroxy-phenyl)-carbamate obtained in (step 1), and the reaction liquid was stirred at 100° C. for 2 hours. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1) to obtain the entitled compound.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:26]3[CH:27]=[C:28]([F:32])[C:29]([F:31])=[CH:30][C:25]=3[O:24][CH2:23]1)[C:5](=[O:22])[N:6]2[CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])=[O:13].[N:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[N:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[F:32][C:28]1[C:29]([F:31])=[CH:30][C:25]2[O:24][CH2:23][C:4]3([C:3]4[C:7](=[CH:8][CH:9]=[CH:10][C:2]=4[C:37]4[CH:38]=[N:33][CH:34]=[N:35][CH:36]=4)[N:6]([CH2:11][C:12]([NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[F:21])=[O:13])[C:5]3=[O:22])[C:26]=2[CH:27]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C(CN1C(=O)C2(COc3cc(F)c(F)cc32)c2c(Br)cccc21)Nc1ccccc1F
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: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(CN1C(=O)C2(COc3cc(F)c(F)cc32)c2c(-c3cncnc3)cccc21)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.2 %

Procedure:
To a solution of 2-(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide (0.15 g, 0.30 mmol) in anhydrous 1,4-dioxane (5.00 mL) was added Pd(PPh3)4 (0.03 g, 0.03 mmol) and stirred at ambient temperature for 10 min. Pyrimidine-5-boronic acid (0.06 g, 0.45 mmol) and sodium carbonate (0.90 mL of 2 M solution, 1.80 mmol) were added. The reaction mixture was reluxed at 120° C. for 16 h, diluted with ethyl acetate (50.0 mL). The organic layer was washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/1) to give the title compound (0.13 g, 84%): 1H NMR (300 MHz, CDCl3) δ 9.13 (s, 1H), 8.29-8.10 (m, 3H), 7.62 (s, 1H), 7.44 (t, 1H), 7.16-7.03 (m, 4H), 6.91 (d, 1H), 6.85-6.76 (m, 1H), 6.46-6.37 (m, 1H), 4.85-4.73 (m, 2H), 4.61-4.47 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.1, 163.9, 157.7, 156.4, 155.7, 141.9, 132.9, 130.0, 126.0, 124.7, 121.9, 115.0, 111.6, 109.8, 100.2, 79.4, 57.9, 44.7; MS (ES+) m/z 503.5 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH2:18]([O:25][C:26](=[O:38])[CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+]>>[CH2:31]([O:30][C:28](=[O:29])[CH:27]([C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])[C:26]([O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Product: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F

Procedure:
2-Chloro-1,5-dinitro-3-(trifluoromethyl)benzene was treated with malonic acid dibenzyl ester in the presence of sodium hydride to obtain [2,4-dinitro-6-(trifluoromethyl)phenyl]malonic acid dibenzyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:1][C:2]1[C:11]([NH2:12])=[C:10]([C:15]([F:16])([F:17])[F:18])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1N
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)c1ccc(C(F)(F)F)c(N)c1N
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirring solution of methyl 2-amino-3-nitro-4-(trifluoromethyl)benzoate (5.80 g, 0.022 mol), ammonium formate (30.0 g, 0.476 mol) in ethanol (300 ml) was added 10% palladium on carbon (500 mg) at room temperature and stirred for 2 h. Insoluble was filtered off and filtrates were concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 20% ethyl acetate/n-hexane to give 5.10 g (0.022 mol, 99%) of the title compound as a yellow powder.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C([Li])(C)(C)C.[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15].O>C1COCC1>[CH2:21]([Sn:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[C:6]1[O:1][CH2:2][CH2:3][CH2:4][CH:5]=1)[CH2:22][CH2:23][CH3:24]
Reactant: C1=COCCC1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1=CCCCO1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3,4-dihydro-2H-pyran (500 mg, 5.94 mmol) in THF (10 mL) was brought to −78° C. followed by the addition of tert-butyllithium (12.2 mL, 20.8 mmol, 1.7 M in pentane). The resulting yellow solution was brought to 0° C. and stirred for 15 min. The reaction was then cooled to −78° C. and tributyltin chloride (4.8 mL, 17.8 mmol) was slowly added. The reaction was monitored by TLC. Upon completion by TLC, water was added (20 mL) to the reaction. The organic phase was separated, washed with water, dried over MgSO4, concentrated and chromatographed on silica gel using hexanes (500 ml hexanes and 0.5 mL triethylamine). The title compound was obtained as a colorless oil. MS m/z: 375 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3]1.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18]>C(Cl)(Cl)Cl>[CH:7]1([N:4]2[CH2:5][CH2:6][CH:2]([NH:1][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][CH:22]=[C:14]([Br:13])[CH:15]=3)[CH2:3]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: NC1CCN(C2CCCCC2)C1
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCN(C2CCCCC2)C1)c1cccc(Br)c1

Procedure:
To 16.2 g. (0.1 mole) of 3-amino-1-cyclohexylpyrrolidine in 100 ml. of chloroform was added with stirring 15.1 g. (0.07 mole) of 3-bromobenzoyl chloride. After stirring for one hour, the solution was extracted with dilute sodium hydroxide. The chloroform layer was dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized twice from ethyl acetate-isopropyl ether. The impure crystalline material was then partitioned between ethyl acetate and dilute hydrochloric acid. The acid layer was made basic with sodium hydroxide and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, concentrated, and the residue recrystallized from ethyl acetate-isopropyl ether solvent. The yield was 9.1 g. (36.6%); m.p. 128°-130°C.
Reaction SMILES: [NH:1]([C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][N:11]=[C:10]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([OH:31])[CH2:27][N:28]([CH3:30])[CH3:29])=[CH:20][CH:19]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCCCC=1>C(O)C.[Pd]>[NH2:14][C:13]1[C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9][C:10]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([OH:31])[CH2:27][N:28]([CH3:30])[CH3:29])=[CH:20][CH:19]=2)=[N:11][CH:12]=1
Reactant: CN(C)CC(O)COc1ccc(Nc2ncc([N+](=O)[O-])c(Nc3ccccc3)n2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CN(C)CC(O)COc1ccc(Nc2ncc(N)c(Nc3ccccc3)n2)cc1
Reaction time: 18 h
Yield: 84.5 %

Procedure:
4-Anilino-2-{4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]anilino}-5-nitropyrimidine (Example 20, 400 mg, 0.90 mmol) was dissolved in ethanol (20 ml). Under an atmosphere of nitrogen, cyclohexene (5 ml) was added followed by 10% palladium-on-carbon (100 mg). The mixture was heated under reflux for 5 hours, and then a further portion of 10% palladium on carbon (100 mg) was added and heating was continued for 18 hours. The catalyst was removed by filtration through diatomaceous earth and the filtrate was concentrated by evaporation. The resulting oil was purified by column chromatography, eluting with 0-10% 2.0M methanolic ammonia in DCM to give the product as a white solid (300 mg, 80%). NMR: 2.15 (s, 6H), 2.3 (m, 2H), 3.8 (m, 3H), 4.3 (s, 2H), 4.7 (s, 1H), 6.8 (d, 2H), 7.0 (t, 1H), 7.3 (t, 2H), 7.5 (d, 2H), 7.6 (s, 1H), 7.8 (d, 2H), 8.1 (s, 1H), 8.4 (s, 1H); MS (MH+): 395.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>O1CCCC1.C(O)C.[Pd]>[N:11]1[CH:12]=[CH:13][N:14]=[CH:15][C:10]=1[C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:1]
Reactant: O=[N+]([O-])c1cccc(-c2cnccn2)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cccc(-c2cnccn2)c1
Yield: 96.4 %

Procedure:
A suspension of 2-(3-nitrophenyl)pyrazine (500 mg) in tetrahydrofuran (5 ml) and ethanol (5 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 200 mg) under hydrogen atmosphere for 6 hours. The catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from dichloromethanediisopropyl ether to give 3-(pyrazin-2-yl)aniline (410 mg, 96.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=2[CH3:16])[N:5]=[C:4]([S:17][CH2:18][C:19]([O:21]CC)=O)[N:3]=1.[OH-].[NH4+:25]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=2[CH3:16])[N:5]=[C:4]([S:17][CH2:18][C:19]([NH2:25])=[O:21])[N:3]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CSc1nc(Cl)cc(Nc2cccc(C)c2C)n1
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(Nc2cc(Cl)nc(SCC(N)=O)n2)c1C
Reaction time: 72 h

Procedure:
5.0 g of [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid, ethyl ester was added to 40 ml of concentrated ammonium hydroxide. Ethanol (40 ml) was then added and the reaction mixture was boiled to give a clear solution. This solution then stood at room temperature for three days. The precipitate thus formed was collected and recrystallized from ethanol giving 3.0 g of product, mp. 188°-191°C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[C:8]([F:22])=[CH:9][C:10]([N:12]3[CH2:16][C@H:15]([C:17]([O:19]C)=O)[O:14][C:13]3=[O:21])=[CH:11][C:6]=2[O:5][C:4]1=[O:23])[CH3:2].[NH3:24]>CO>[CH2:1]([N:3]1[C:7]2[C:8]([F:22])=[CH:9][C:10]([N:12]3[CH2:16][C@H:15]([C:17]([NH2:24])=[O:19])[O:14][C:13]3=[O:21])=[CH:11][C:6]=2[O:5][C:4]1=[O:23])[CH3:2]
Reactant: CCn1c(=O)oc2cc(N3C[C@H](C(=O)OC)OC3=O)cc(F)c21
Reactant: N
Solvent: CO
Product: CCn1c(=O)oc2cc(N3C[C@H](C(N)=O)OC3=O)cc(F)c21

Procedure:
Prepared from methyl (5R)-3-(3-ethyl-4-fluoro-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate (Step 4, 0.250 g, 0.771 mmol) and ammonia in methanol (5 ml) according to the method of EXAMPLE 86, Step 10 (0.15 g, 63%); MS for C13H12FN3O5 m/z 310 (M+H)+; 1H NMR (DMSO-d6, 300 Mhz) δ 7.87 (br s, 1H), 7.63 (br s, 1H), 7.52 (d, 1H), 7.44 (dd, 1H), 5.03 (dd, 1H), 4.26 (t, 1H), 4.02 (dd, 1H), 3.86 (q, 2H), 1.28 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+].O>CN(C)C=O>[N:15]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)=[N+:16]=[N-:17]
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC1
Temperature: 60 °C
Yield: 79.2 %

Procedure:
To a solution of N-t butyloxycarbonyl-4-bromopiperidine (8.8 g, 33.5 mmol) in N,N-dimethylformamide (50 ml) was added sodium azide (6.5 g, 100.4 mmol) and the reaction mixture was heated at 60° C. for 18 hrs., cooled to room temperature, poured into water (200 ml) and extracted with dichloromethane (2×200 ml). The combined organic layers were washed with brine (2×50 ml), dried (MgSO4), filtered and concentrated under vacuum, to give the required product (6.0 g). 1H NMR (CDCl3) δ 1.28 (9H, s), 1.56 (2H,m), 1.88 (2H,m), 3.10 (2H,m), 3.58 (1H,m), 3.82 (2H,m).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH2:19]O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH2:19][Cl:23])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CO)nn2Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)c(CCl)nn2Cc1ccccc1
Temperature: 25 °C
Yield: 47.3 %

Procedure:
To a solution of (1-benzyl-5-methoxy-1H-indazol-3-yl)methanol (18 g; 0.07 mol) in chloroform (200 ml) stirred at room temperature was slowly added thionyl chloride (15.8 g; 0.13 mol). Once the addition was complete, the solution was refluxed for 24 hours. The reaction was then stopped by cooling the mixture to room temperature and evaporating off the solvent under reduced pressure. The residue was then taken up several times in toluene and concentrated under reduced pressure. The crude residue obtained was purified by crystallization from hexane to give 9.5 g of 1-benzyl-3-(chloromethyl)-5-methoxy-1H-indazole with a melting point of 78-80° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:17](=[CH:18][CH:19]=2)[CH:16]2[CH2:20][CH2:21][CH:12]3[CH2:13][N:14]([CH2:22][C:23]#C)[CH2:15]2)=[N:6][CH:7]=1.BrCC#[N:39]>>[Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:17](=[CH:18][CH:19]=2)[CH:16]2[CH2:20][CH2:21][CH:12]3[CH2:13][N:14]([CH2:22][C:23]#[N:39])[CH2:15]2)=[N:6][CH:7]=1
Reactant: C#CCN1CC2CCC(C1)c1cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc12
Reactant: N#CCBr
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(CC#N)C2)ncc1Cl

Procedure:
2-[5-Chloro-2-(10-cyanomethyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide was prepared from 2-[5-chloro-2-(10-prop-2-ynyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide and bromo-acetonitrile in an analogous manner to Example 279. Product isolated as a yellow foam (83 mg, 76%). LCMS (m/e) 488 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 11.02 (s, 1H), 8.64 (d, 1H, J=7.8 Hz), 8.09 (s, 1H), 7.52-7.40 (m, 2H), 7.39 (d, 1H, J=2.2 Hz), 7.32-7.25 (m, 1H), 7.11-7.00 (m, 2H), 6.92 (s, 1H), 6.21 (bs, 1H), 3.54 (s, 2H), 3.03 (d, 3H, J=4.9 Hz), 3.39-2.95 (m, 2H), 2.90-2.81 (m, 2H), 2.61-2.56 (m, 2H), 2.16-2.12 (m, 2H), 1.72-1.65 (m, 2H).