Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]I>C1COCC1>[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCCCCI
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: ClCCCCCCc1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a stirred solution of thiophene (5.0 g, 59.5 mmol) in dry THF (50 ml) was added n-butyllithium (2.5 M in hexanes, 20.0 ml, 50.0 mmol) dropwise at −78° C. under nitrogen. After complete addition, the mixture was allowed to warm to room temperature, with stirring, over 2 h, followed by the addition of 1-chloro-6-iodohexane (12.3 g, 50.0 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with sat. aq. ammonium chloride, and the reaction mixture was extracted with ethyl acetate (3×70 ml). The combined organic extracts were washed with water, brine, and dried over magnesium sulphate. The solvent was removed under reduced pressure and the residue was chromatographyed (silica gel, petroleum ether), to afford the product as a pale yellow oil (9.3 g, 92%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.06 (dd, J=5.1 Hz, 1.2 Hz, 1H, Ar—H), 6.87 (dd, J=5.1 Hz, 3.4 Hz, 1H, Ar—H), 6.75 (m, 1H, Ar—H), 3.48 (t, J=6.6 Hz, 2H, ClCH2), 2.80 (t, J=7.4 Hz 2H, ArCH2), 1.61-1.78 (m, 4H, CH2), 1.29-1.50 (m, 4H, CH2); 13C NMR (75 MHz, CDCl3): δ (ppm) 145.5 (quat.), 126.7 (CH), 124.1 (CH), 122.9 (CH), 45.1 (CH2), 32.6 (CH2), 31.7 (CH2), 29.9 (CH2), 28.4 (CH2) 26.7 (CH2); MS (m/e) 204 (M+, 9%), 202 (M+, 3%), 97 (100).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH:18]1([NH2:22])[CH2:21][CH2:20][CH2:19]1.O>CN1C(=O)CCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:18]2[CH2:21][CH2:20][CH2:19]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Reactant: NC1CCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1nc(NC2CCC2)c2c(n1)C(c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (160 mg, 0.60 mmol) in NMP (2 mL) was added cyclobutanamine (129 mg, 1.81 mmol) dropwise. The mixture was stirred at RT for 3 hrs. 8 mL of water was added to precipitate out the product. The solid was filtered out and air-dried to give a crude 2-chloro-N-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (177 mg, 0.57 mmol, 94% yield), which was used for the next step without any purification. LC-MS (M+H)+=300.1
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:34])=[C:4]([C:30]([Cl:33])=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[C:18]([O:28][CH3:29])=[CH:17][N:16]=2)=[N:7]1.C(N(CC)CC)C.[C:42](OC(=O)C)(=[O:44])[CH3:43].C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:34][C:3]1[C:4]([CH2:5][N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([C:15]3[N:20]=[C:19]([NH:21][C:22]4[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=4)[C:18]([O:28][CH3:29])=[CH:17][N:16]=3)=[N:7]2)=[C:30]([Cl:33])[CH:31]=[CH:32][C:2]=1[NH:1][C:42](=[O:44])[CH3:43]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cnc(-c2nn(Cc3c(Cl)ccc(N)c3Cl)c3ccccc23)nc1Nc1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cnc(-c2nn(Cc3c(Cl)ccc(NC(C)=O)c3Cl)c3ccccc23)nc1Nc1ccncc1
Reaction time: 3.5 h

Procedure:
50 mg of 2-[1-(3-amino-2,6-dichlorobenzyl)-1H-indazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine (40-1, 0.102 mmol, 1.0 eq.) were dissolved in 0.6 ml of dry N,N-dimethylformamide. 0.014 ml N,N-diethylethanamine (0.102 mmol, 1.0 eq.) and 0.010 ml acetic anhydride (0.102 mmol, 1.0 eq.) were added at 0° C. and stirred for 3.5 h Then again 0.014 ml N,N-diethylethanamine (0.102 mmol, 1.0 eq.) and 0.010 ml acetic anhydride (0.102 mmol, 1.0 eq.) were added at 0° C. and stirred over night at room temperature. Saturated sodium hydrogen carbonate solution and ethyl acetate were added and the reaction mixture was stirred for 30 min. The organic layer was washed with ethyl acetate twice. The combined organic layers were dried over a silicone filter and concentrated in vacuum. The residue was purified by flash chromatography to yield 17.3 mg (0.03 mmol, 30%) of the analytically pure target compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([S:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N.[H][H]>CO.[Ni]>[F:1][C:2]1[CH:9]=[C:8]([S:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5]
Reactant: CSc1ccc(C#N)c(F)c1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CSc1ccc(CN)c(F)c1

Procedure:
A mixture of 2-fluoro-4-methylsulfanyl-benzonitrile (8.0 g, 45.5 mmol), Raney-Nickel (20.0 g) and concentrated aqueous ammonia (300 mL) in methanol (3.0 L) is treated with hydrogen (3.4 bar) at room temperature and stirred over night. The mixture is filtered through a pad of silica gel, and the filtrate is concentrated under reduced pressure. Yield: 6.3 g (81% of theory); ESI mass spectrum: [M+H−NH3]+=155; r.t. HPLC: 1.38 min (0-30AB).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:23]=[C:22]([CH3:24])[C:21]([CH3:25])=[CH:20][C:16]=1[C:17](O)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][C:22]([CH3:24])=[C:21]([CH3:25])[CH:20]=3)[NH:14][C:12]2=[O:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1cc(N)c(C(=O)O)cc1C
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Product: Cc1cc2[nH]c(=O)n(S(=O)(=O)c3ccc(Cl)cc3)c(=O)c2cc1C
Yield: 15.7 %

Procedure:
365 mg (1.68 mmol) of 4-chlorobenzenesulfonylisocyanate and 230 mg (1.40 mmol) of 2-amino-4,5-dimethylbenzoic acid were treated in the same way as in Example 1 to obtain 80 mg of the above-identified compound (yield 15.7%). Properties: colorless crystal, Melting point: 221°-222° C., PMR (δppm, DMSO-d6): 2.23 (3H,s), 2.27 (3H,s), 6.89 (1H,s), 7.60 (1H,s), 7.75 (2H,d), 8.15 (2H,d), 11.40 (1H,br).
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:3])([CH3:1])[CH3:4]
Reactant: c1ccccc1
Reactant: C=C(C)C
Product: CC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
Benzene was alkylated with isobutylene in batch-type reactor. The reactor was loaded with 1.25 g of Beta Zeolite CP 814E (Zeolyst International) and 55.5 mL (48.75 g) of benzene, sealed into the reactor, and the reactor was then purged with nitrogen. 11.4 g of isobutylene were then loaded into the reactor and the reactor was pressurized with N2 to 500 psi. The reaction was carried out at 180° C. for 2 hours. The reactor was then cooled to room temperature, depressurized and the liquid product was analyzed by GC. t-Butylbenzene was produced in 38% yield.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[O:11]1[C:19]2[CH2:18][CH2:17][N:16]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[OH:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:15][C:14]=2[CH:13]=[CH:12]1.C(N(CC)CC)C>ClCCl>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([S:20]([N:16]2[CH2:17][CH2:18][C:19]3[O:11][CH:12]=[CH:13][C:14]=3[CH2:15]2)(=[O:22])=[O:21])=[CH:28][CH:27]=1)(=[O:30])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=S(=O)(c1ccc(C(O)c2ccccc2)cc1)N1CCc2occc2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)c1ccc(S(=O)(=O)N2CCc3occc3C2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 0.16 ml (1.2 mmol) of oxalyl chloride in 30 ml of dichloromethane, 0.17 ml (2.5 mmol) of dimethyl sulfoxide was added dropwise at -78° C., followed by stirring for 5 minutes. To the solution, a solution of 0.303 g (0.820 mmol) of 4-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-ylsulfonyl)phenylphenylmethanol in 10 ml of dichloromethane was added at -78° C., followed by stirring for 15 minutes. To this mixture, 0.69 ml (4.9 mmol) of triethylamine was added; the mixture was allowed to warm to room temperature. After the reaction mixture was washed with water, the water layer was re-extracted with diethyl ether. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) and washed with diethyl ether-hexane to yield the desired product.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19].[C:20](OCC)(=[O:22])[CH3:21]>C1COCC1.CCCCCC>[C:20]([CH:16]1[CH2:17][CH2:18][N:14]([CH3:13])[C:15]1=[O:19])(=[O:22])[CH3:21]
Reactant: CN1CCCC1=O
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)C1CCN(C)C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
20.40 g (0.20 mol) of diisopropylamine were placed in 200 ml dry THF under nitrogen and 80 ml n-butyl lithium in hexane (2.5 M) were added dropwise. It was allowed to stir for 20 minutes and then 20.00 g (0.20 mol) of 1-methyl-2-pyrrolidinone were added dropwise at −78° C. After stirring the reaction mixture for 1 hour 17.64 g (0.20 mol) of dry ethyl acetate were added at −78° C. The reaction mixture was warmed to room temperature and stirred for 14 hours. The THF was removed on a rotary evaporator under reduced pressure and the residue was taken up in 80 ml of 6 N HCl. The acidic aqueous phase was saturated with NaCl and extracted 5 times with 300 ml ethyl acetate. The combined organic layers were dried over Na2SO4, and the solvent was removed on a rotary evaporator. The remaining yellow oil was purified by column chromatography. This gave 5.10 g product as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([CH2:12][C:13]([OH:15])=O)[CH:8]=[CH:7][CH:6]=2.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[C:25]([F:28])([F:27])[F:26])[CH2:20][NH2:21].FC(F)(F)OC1C=CC(CN)=CC=1>CN(C=O)C>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[C:25]([F:26])([F:27])[F:28])[CH2:20][NH:21][C:13](=[O:15])[CH2:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:2]([CH3:1])[N:3]=[CH:4]2
Reactant: Cc1cc2c(CC(=O)O)cccc2cn1
Reactant: NCc1ccc(C(F)(F)F)c(F)c1
Agent: NCc1ccc(OC(F)(F)F)cc1
Solvent: CN(C)C=O
Product: Cc1cc2c(CC(=O)NCc3ccc(C(F)(F)F)c(F)c3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 222B using (3-methyl-5-isoquinolinyl)acetic acid and 3-fluoro-4-(trifluoromethyl)benzylamine instead of 5-isoquinolinylacetic acid and 4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 377 (M+H)+; MS (ESI−) m/z 375 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 2.77 (s, 3H), 4.14 (s, 2H), 4.38 (d, J 6.1, 2H), 7.33 (m, 2H), 7.72 (t, J 7.8, 1H), 7.86 (t, J 7.5, 1H), 8.04 (d, J 6.8, 1H), 8.36 (m, 2H), 9.07 (t, J 6.1, 1H), 9.77 (s, 1H); Anal. Calcd for C20H16F4N2O+1.2HCl+0.3 DMF: C, 56.62; H, 4.20; N, 7.48. Found: C, 56.79; H, 4.40; N, 7.29.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[C:9]([O:16][CH3:17])(=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH:10]([C:9]([O:16][CH3:17])=[O:15])[C:11]([O:13][CH3:14])=[O:12])=[N:3][CH:4]=1
Reactant: Fc1ccc(Br)nc1
Reactant: COC(=O)CC(=O)OC
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1ccc(F)cn1
Temperature: 25 °C
Yield: 31 %

Procedure:
The solution of 2-bromo-5-fluoropyridine (1.0 g, 5.68 mmol), dimethyl malonate (3.0 g, 22.7 mmol) picolinic acid (559.6 mg, 4.54 mmol), CuI (431.8 mg, 2.27 mmol) and Cs2CO3 (5.6 g, 17.05 mmol) in DMF (30 mL) was stirred at 100 degree for 12 h. After cooling to room temperature, the reaction mixture was filtered, diluted with H2O and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a standard method to give desired compound (400 mg). LC-MS: m/z (M+H)=228.2
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)([Cl:8])=O.[CH3:11][C:12]1([CH3:19])[CH2:17][CH2:16][CH2:15][C:14](=O)[CH2:13]1>ClCCl>[Cl:8][C:14]1[CH2:13][C:12]([CH3:19])([CH3:11])[CH2:17][CH2:16][C:15]=1[CH:3]=[O:4]
Reactant: CC1(C)CCCC(=O)C1
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)CCC(C=O)=C(Cl)C1
Temperature: -10 °C

Procedure:
Into a 250 ml round-bottomed flask was added N,N-dimethylformamide (3.5 mL) in dichloromethane (30 mL). The mixture was cooled to −10° C., and phosphoryl trichloride (4 mL) was added dropwise. The solution was warmed up to room temperature and 3,3-dimethylcyclohexanone (5.5 mL) was added slowly. The mixture was heated to reflux overnight. The reaction mixture was quenched by 0° C. solution of sodium acetate (25 g in 50 mL water). The aqueous layer was extracted with ether (3×200 mL). The organic layers were combined, dried over Na2SO4, filtered, and dried under vacuum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]([N:26]([CH2:28][C:29]([O:31]C)=[O:30])[CH3:27])=[O:25])[CH:22]=3)[C:17]([S:33][CH3:34])=[CH:16]2)=[N:13][CH:14]=1.O.[OH-].[Li+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]([N:26]([CH2:28][C:29]([OH:31])=[O:30])[CH3:27])=[O:25])[CH:22]=3)[C:17]([S:33][CH3:34])=[CH:16]2)=[N:13][CH:14]=1
Reactant: COC(=O)CN(C)C(=O)c1ccc2c(SC)cn(-c3ncc(-c4cc(C)ccc4F)cn3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSc1cn(-c2ncc(-c3cc(C)ccc3F)cn2)c2cc(C(=O)N(C)CC(=O)O)ccc12

Procedure:
Ester hydrolysis of 304b) (0.5 g, 1.05 mmol) with lithium hydroxide monohydrate in THF/water. White solid. Yield: 0.48 g (98% of theory)
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:17])[CH2:6][C:7]([CH3:16])([O:9][O:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:8])=[O:3].C([OH:20])C.N1[CH:26]=[CH:25]C=CC=1>C(OCC)C>[C:2](=[O:20])([O:3][CH2:25][CH3:26])[O:4][CH:5]([CH3:17])[CH2:6][C:7]([CH3:16])([O:9][O:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:8]
Reactant: c1ccncc1
Reactant: CCOC(=O)OOC(C)(C)CC(C)OC(=O)Cl
Reactant: CCO
Solvent: CCOCC
Product: CCOC(=O)OOC(C)(C)CC(C)OC(=O)OCC

Procedure:
To a solution of 24.4 g. (0.0786 mole) of (86.4%) 1,3-dimethyl-3(ethoxycarbonylperoxy)butyl chloroformate in 100 ml of diethyl ether, cooled at 10°±1° C. was added a solution of 4.6 g (0.1 mole) of ethanol and 7.9 g. (0.1 mole) of pyridine in 25 ml of diethyl ether over a period of 20 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:32]([O:33][CH3:34])=[CH:31][C:6]2[NH:7][C:8]([C:10]3[C:14]([NH:15][C:16]([CH:18]4[O:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)=[O:17])=[CH:13][NH:12][N:11]=3)=[N:9][C:5]=2[CH:4]=1.C1(OC)C=CC=CC=1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>ClCCl>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[CH3:34][O:33][C:32]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[NH:9][C:8]([C:10]3[C:14]([NH:15][C:16]([CH:18]4[O:23][CH2:22][CH2:21][NH:20][CH2:19]4)=[O:17])=[CH:13][NH:12][N:11]=3)=[N:7][C:6]=2[CH:31]=1
Reactant: COc1cc2nc(-c3n[nH]cc3NC(=O)C3CN(C(=O)OC(C)(C)C)CCO3)[nH]c2cc1OC
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nc(-c3n[nH]cc3NC(=O)C3CNCCO3)[nH]c2cc1OC
Reaction time: 3 h

Procedure:
N-[3-(5,6-dimethoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-rac-4-BOC-2-morpholine carboxamide (65 mg, 0.14 mmol) and anisole (60 μl, 0.56 mmol) were dissolved in a mixture of trifluoroacetic acid and dichloromethane (1:1; 2 ml). After 3 hours at room temperature, the mixture was evaporated to dryness to give N-[3-(5,6-dimethoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-rac-2-morpholine carboxamide-trifluoroacetic acid salt (73 mg) as a colourless solid (LC/MS (acidic method): Rt 1.42 min, [M−H+]− 371.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([N:18]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)C(=O)C(F)(F)F)[CH:10]=2)[CH2:5][CH2:4]1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[F:42][C:43]1[CH:60]=[CH:59][C:58]([F:61])=[CH:57][C:44]=1[CH2:45][O:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][CH:55]=1)[NH:52][N:51]=[C:50]2[NH2:56]>C(Cl)Cl.N1C=CC=CC=1>[F:42][C:43]1[CH:60]=[CH:59][C:58]([F:61])=[CH:57][C:44]=1[CH2:45][O:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][CH:55]=1)[NH:52][N:51]=[C:50]2[NH:56][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([N:6]2[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]2)=[CH:10][C:11]=1[NH:18][CH:25]1[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: Nc1n[nH]c2ccc(OCc3cc(F)ccc3F)cc12
Reactant: CN1CCN(c2ccc(C(=O)O)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(OCc5cc(F)ccc5F)cc34)c(NC3CCOCC3)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.8 %

Procedure:
4-(4-Methylpiperazin-1-yl)-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoic acid hydrochloride (590 mg, 1.31 mmol) in dry DCM (10 mL), under nitrogen, was cooled with an ice bath and treated first with a drop of DMF and then with oxalyl chloride (2.62 mmol, 0.228 mmol). After stirring for 4 hours at room temperature, the solution was evaporated and the solid was dried under vacuum. The crude acid chloride was dissolved in 20 mL of dry pyridine, cooled with an ice bath and treated drop-wise with 5-[(2,5-difluorobenzyl)oxy]-1H-indazol-3-amine (300 mg, 1.09 mmol) in 15 mL of pyridine. The reaction was left overnight at 4° C. Volatiles were evaporated and the residue was diluted with water (300 mL) and extracted with EtOAc (3×300 mL). Organic phases were collected, dried over sodium sulfate and evaporated. Crude product was diluted with MeOH (10 mL) and heated at 80° C. in the presence of triethylamine (2.5 mL). After 3 hours, volatiles were evaporated and the residue was dissolved in DCM (100 mL), washed with NaHCO3 satured solution, water and brine. The organic layer was dried over sodium sulfate, filtered and evaporated under vacuum. Crude product was purified by flash chromatography over silica gel (DCM/MeOH 92:8) affording 470 mg (yield 75%) of title compound
Reaction SMILES: C(OC([N:11]1[CH2:15][C@@H:14]([OH:16])[C@H:13]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[OH-].[Pd+2].[OH-]>[OH:16][C@@H:14]1[CH2:15][NH:11][CH2:12][C@H:13]1[NH:17][C:18](=[O:19])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H]1O
Yield: 85.3 %

Procedure:
To a solution of trans-3-tert-butoxycarbonylamino-4-hydroxy-pyrrolidine-1-carboxylic acid benzyl ester (3.9 g) in methanol (31 mL) and tetrahydrofuran (7 mL) was added palladium hydroxide (20 wt % Pd on carbon, 500 mg) and the mixture was stirred at room temperature under 40-45 psi of hydrogen atmosphere overnight. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated in the mixture of ethyl acetate and diisopropylether and filtered to remove the insoluable materials. The filtrate was concentrated in vacuo to afford 2.0 g of trans-tert-butyl [4-hydroxypyrrolidin-3-yl]carbamate (yield was 94%) as a powder. MS obsd. (ESI+) [(M+H)+] 203.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[C:15]([NH:21][C:22](=[O:28])[O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[N:16][CH:17]=[C:18]([CH3:20])[N:19]=1>>[Cl:1][C:2]1[C:7]([S:8]([N:21]([C:22]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:28])[C:15]2[C:14]([O:13][CH3:12])=[N:19][C:18]([CH3:20])=[CH:17][N:16]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: COc1nc(C)cnc1NC(=O)OCC(C)C
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1Cl

Procedure:
reaction of 2-chloropyridine-3-sulfonyl chloride with isobutyl N-(3-methoxy-5-methylpyrazin-2-yl)carbamate in the presence of an alkali metal hydride in an inert solvent to give 2-chloro-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamide;
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH2:21][CH2:20][NH:19][CH2:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:23]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH2:21][CH2:20][N:19]([C:23]4[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)c1cccnc1Cl
Reactant: CC(C)(C)c1ccc(Nc2ncnc3c2CCNC3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(Nc2ncnc3c2CCN(c2ncccc2S(C)(=O)=O)C3)cc1
Temperature: 150 °C
Yield: 48.7 %

Procedure:
A mixture of N-(4-tert-butylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (0.066 g, 0.23 mmol), 2-chloro-3-(methylsulfonyl)pyridine (Ponticello et al, J. Org. Chem., 44(17), 1979), (0.088 g, 0.47 mmol) and N,N-diisopropylethlamine (0.041 mL, 0.23 mmol) was heated in a sealed tube via microwave (Emrys Optimizer model, Personal Chemistry) for 30 min at 150° C. The reaction mixture was cooled to r.t. and poured into water (20 mL). The mixture was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated to leave an oil which was purified by silica gel chromatography (ethyl acetate/hexane gradient) to give the title compound as a white solid (0.049 g).
Reaction SMILES: [CH2:1]([O:8][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10]N1C(=O)C2=CC=CC=C2C1=O>C(#N)C1C=CC=CC=1>[C:1]([O:8][CH3:9])(=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: N#Cc1ccccc1
Product: COC(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
A mixture of 2 mmole of benzylmethylether, 2 mole % of N-hydroxyphthalimide relative to benzylmethylether, and 5 ml of benzonitrile was stirred for 12 hours at 100° C. under an oxygen atmosphere. The products in the reaction mixture were analyzed by gas chromarography, and, as a result, methyl benzoate (yield 60%) was formed.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([CH3:14])[C:6]1=[O:15].[H][H]>CO.[Pt](=O)=O>[NH2:11][C:9]1[CH:8]=[C:7]([CH3:14])[C:6](=[O:15])[N:5]([CH2:4][C:3]2[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:2]=2[CH3:1])[CH:10]=1
Reactant: Cc1ccc(Cn2cc([N+](=O)[O-])cc(C)c2=O)c(C)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: Cc1ccc(Cn2cc(N)cc(C)c2=O)c(C)c1
Reaction time: 1 h
Yield: 62.2 %

Procedure:
To a solution containing 0.2 g (0.73 mmol) of 1-(2,4-dimethylbenzyl)-3-methyl-5-nitropyridin-2(1H)-one in 50 ml of methanol was added 0.017 g (0.073 mmol) of platinum (IV) oxide (Adam's catalyst). The flask was fitted with a balloon of hydrogen and allowed to stir for 1 h. The reaction was filtered through GF/F paper and the filtrate concentrated under reduced pressure to afford 0.11 g (62%) of product.