Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].I[CH3:20].O>CN(C)C=O>[F:17][C:14]([F:15])([F:16])[C:13]([NH:12][CH2:11][CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([NH:1][CH3:20])[CH:3]=1)=[O:18]
Reactant: CI
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1N
Solvent: O
Solvent: CN(C)C=O
Product: CNc1cc(CCNC(=O)C(F)(F)F)ccc1OC
Yield: 22.1 %

Procedure:
N-[2-[3-Amino-4-methoxyphenyl]ethyl]-2,2,2-trifluoro acetamide (26.2 g., 0.1 mole) and iodomethane (14.0 g., 6.2 ml., 0.1 mole) in dry dimethylformamide (500 ml) were stirred under nitrogen for 3 hr. The solution was poured into water and the suspension extracted with ethyl acetate. Evaporation of the extracts afforded an oil which was separated by high pressure liquid chromatography on silica using 1% methanol in dichloromethane as eluant. Evaporation of the fractions containing the major bond afforded the sub-title compound (6.1 g) as a white solid mp 65°-67°. The hydrochloride, prepared in the usual way, had mp 153°-155°.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:35])[C:5]2[N:10]=[N:9][N:8]([CH:11]3[CH:15]([O:16]C(=O)C4C=CC=CC=4)[CH2:14][CH:13]([CH:25]=[CH:26][P:27]([O:32]CC)([O:29]CC)=[O:28])[O:12]3)[C:6]=2[N:7]=1.[Si](Br)(C)(C)C.[NH4+].[OH-]>CC#N.CO>[NH2:1][C:2]1[N:3]=[C:4]([NH2:35])[C:5]2[N:10]=[N:9][N:8]([CH:11]3[O:12][CH:13]([CH:25]=[CH:26][P:27](=[O:28])([OH:29])[OH:32])[CH2:14][CH:15]3[OH:16])[C:6]=2[N:7]=1
Reactant: CCOP(=O)(C=CC1CC(OC(=O)c2ccccc2)C(n2nnc3c(N)nc(N)nc32)O1)OCC
Agent: C[Si](C)(C)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: Nc1nc(N)c2nnn(C3OC(C=CP(=O)(O)O)CC3O)c2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
Compound 53.1 (183 mg, 0.36 mmol) was dissolved in 7 mL of anhydrous CH3CN and treated with TMS—Br (240 uL, 1.82 mmol). The solution was stirred at rt for 6 hrs. Added more TMS—Br (100 uL, 0.75 mmol) and stirred at room temperature for 16 hrs. Concentrated the reaction under reduced pressure. The residue was dissolved in methanol and added aqueous NH4OH solution, stirred for another 3 hrs and concentrated under reduced pressure. The residue was subjected to a reverse phase HPLC to give compound 53.2 (110 mg, 81% yield). 1H NMR (D2O, 300 MHz): δ 6.32 (m, 1H), 6.07 (s, 1H), 5.83 (m, 1H), 4.96 (m, 1H), 4.73 (m, 1H), 2.27 (m, 2H). 31P NMR: 11.17 ppm LC/MS: C10H14N7O5P Exact Mass: 343.08. Found: [M−H]− 342.0, [M+H]+ 344.1.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6](O)=O)=[CH:4][C:3]=1[CH3:12].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:24][C:25]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:26]=1[C:27]([NH2:29])=[O:28]>C(Cl)Cl.C1COCC1>[Br:34][C:31]1[CH:30]=[C:26]2[C:25](=[CH:33][CH:32]=1)[N:24]=[C:6]([C:5]1[CH:9]=[C:10]([CH3:11])[C:2]([OH:1])=[C:3]([CH3:12])[CH:4]=1)[NH:29][C:27]2=[O:28]
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Reactant: NC(=O)c1cc(Br)ccc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(-c2nc3ccc(Br)cc3c(=O)[nH]2)cc(C)c1O
Reaction time: 1.25 h
Yield: 94.8 %

Procedure:
To a solution of 4-hydroxy-3,5-dimethylbenzoic acid (2.00 g, 12.0 mmol) in CH2Cl2 (60.2 mL) cooled to 0-5° C. was added oxalyl chloride (1.47 mL, 16.8 mmol) followed by dropwise addition of DMF (93.3 μL, 1.20 mmol). The mixture was stirred for 1.25 h, the volatiles were removed under vacuum to give crude acid chloride, which was used immediately without further purification. A mixture of 2-amino-5-bromobenzamide (1.99 g, 9.23 mmol) and the acid chloride (crude residue described above) in THF (92.3 mL) was stirred at room temperature for 17 h, then heated at reflux for 4 h. The volatiles were removed under vacuum, the residue was triturated with EtOAc, and filtered to afford the amide (3.02 g, 90%) as a yellow solid. A mixture of the amide (3.01 g, 8.29 mmol), 2 M NaOH (20.0 mL), water (40.0 mL), and MeCN (20.0 mL) was heated at reflux for 15 h, cooled to 5° C., and neutralized with 2 M aqueous HCl. After stirring for 30 min, the white solid was filtered, triturated with acetone, and filtered again to afford 6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one (2.28 g, 80%). Selected data: 1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, J=2.29 Hz, 1H), 7.93 (dd, J=8.72, 2.42 Hz, 1H), 7.86 (s, 2H), 7.63 (d, J=8.70 Hz, 1H), 5.75 (s, 1H), 2.24 (s, 6H); MS (APCI) m/z 346 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.Br[CH2:26][C:27]1[O:28][C:29](=[O:33])[O:30][C:31]=1[CH3:32].C(=O)(O)[O-].[K+]>CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:26][C:27]5[O:28][C:29](=[O:33])[O:30][C:31]=5[CH3:32])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: Cc1oc(=O)oc1CBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Reaction time: 48 h

Procedure:
1.15 g (3.5 mmoles) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid are stirred in 20 ml of dimethylformamide with 0.85 g (4.4 mmoles) of 4-bromomethyl-5-methyl-1,3-dioxol-2-one and 0.42 g (4.2 mmoles) of powdered potassium bicarbonate for 3 days, while cooling with ice. The mixture is concentrated in vacuo, the residue is stirred with 20 ml of water, the resulting greasy product is dissolved in methanol and the solution is filtered. The filtrate is left to stand at room temperature for 2 days and the colorless crystals which have precipitated are isolated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9]=2[CH:10]=1.N1C=CC=CC=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]([Cl:28])=O)[S:24][CH:25]=1.C(=O)(O)[O-:30].[Na+]>ClCCl.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([NH:12][C:20]([C:21]2[N:22]=[C:23]([CH2:26][Cl:28])[S:24][CH:25]=2)=[O:30])[CH:3]=1
Reactant: O=C([O-])O
Reactant: Cn1ncc2c(N)cc(Br)cc21
Reactant: O=C(Cl)c1nc(CCl)cs1
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: Cn1ncc2c(NC(=O)c3csc(CCl)n3)cc(Br)cc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
6-Bromo-1-methyl-1H-indazol-4-amine (1 g, 4.42 mmol) was dissolved in dichloromethane (DCM) (10 mL) and pyridine (0.429 mL, 5.31 mmol) added. The mixture was cooled to 0° C. in an ice-water bath and 4-(chloromethyl)-1,3-thiazole-2-carbonyl chloride (0.867 g, 4.42 mmol) in DCM (10 ml) was added portionwise over 5 mins. The mixture was stirred for 2 hours and allowed to warm to room temperature. Saturated sodium bicarbonate solution (15 ml) was added and the mixture stirred vigorously for 10 mins. The mixture was diluted with water (50 ml) and DCM (50 ml), but a precipitate was still present. This was collected by filtration, washed with DCM and air dried to afford the title compound as a yellow/brown solid (860 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21]>ClCCl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][Si:23]([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCc1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCCc1ccc(Br)cc1
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of the product of step (i) (32.25 g, 0.15 mol) in anhydrous dichloromethane (400 mL) was added triethylamine (45 g, 0.45 mol), DMAP (915 mg, 7.5 mmol) and TBSCl (33 g, 0.215 mol) sequentially. The resulting solution was stirred overnight. The reaction mixture was extracted with dichloromethane and washed with water (×3). The combined organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography with PE to afford the subtitle compound (ii) as a pale brown oil (40 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[C:15]1[S:23][C:22]2[C:21]([NH:24][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[NH:30][CH:29]=[CH:28]4)=[N:20][CH:19]=[N:18][C:17]=2[CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[S:23][C:22]3[C:21]([NH:24][C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[NH:30][CH:29]=[CH:28]5)=[N:20][CH:19]=[N:18][C:17]=3[CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Product: COc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1OC

Procedure:
The title compound was prepared from 3,4-dimethoxybenzeneboronic acid and (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 2. M.P. 171-178° C.; LC-MS: 403 (MH+); HPLC RT: 4.11 minutes.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][C:23](=[O:28])[C:22]=3[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[O:28]=[C:23]1[CH2:24][CH2:25][CH2:26][C:27]2[C:18]([C:16]([NH:15][C:6]3([C:4]([OH:5])=[O:3])[CH2:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:7]3)=[O:17])=[CH:19][CH:20]=[CH:21][C:22]1=2
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3=O)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1CCCc2c1cccc2C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
The mixture of 2-[(5-oxo-5,6,7,8-tetrahydro-naphthalene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (65) (250 mg, 0.66 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (10 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate formed. After the filtration, the solid is purified by HPLC to give a pure product (66) as white solid (150 mg, 65%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:5](=[C:7](N)[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[N:10]=2)[CH:6]=1.BrCCCC(Cl)=O>C(Cl)(Cl)Cl.CN(C)C=O>[CH2:14]1[C:8]2[C:9](=[N:10][C:4]3[C:5]([CH:7]=2)=[CH:6][CH:1]=[CH:2][CH:3]=3)[CH2:11][CH2:12][CH2:13]1
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Agent: O=C(Cl)CCCBr
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: c1ccc2nc3c(cc2c1)CCCC3
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tacrine (4 g, 20.17 mmoles) in chloroform (50 ml) and N,N-dimethylformamide (15 ml), 4-bromobutyroylchloride (3.5 ml, 30.25 mmoles) is added. The reaction mixture is maintained under stirring at room temperature for 6 hours and then diluted with chloroform and washed with water. The organic phase, anhydrified with sodium sulphate, is evaporated at reduced pressure. The crude product is purged by chromatography on silica gel, eluting with n-hexane/ethyl acetate 8/2 (ratio by volume). 9-[4-bromo)butyroylamino]-1,2,3,4-tetrahydroacridine is obtained.
Reaction SMILES: [O:1]1[CH2:4][C:3](=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2]1.[NH3:11]>C(O)C>[NH2:11][C:3]1([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][O:1][CH2:2]1
Reactant: CCOC(=O)C=C1COC1
Reactant: N
Solvent: CCO
Product: CCOC(=O)CC1(N)COC1
Temperature: 100 °C
Yield: 100 %

Procedure:
Ethyl oxetan-3-ylideneacetate (Preparation 38, 781 g, 5.49 mol) was dissolved in 2M ammonia in ethanol (8.24 L) and heated to 100° C. in a bomb for 5 hours. The reaction was concentrated in vacuo to afford the title compound as a mobile oil (750 g, 100% yield).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[C:13]([NH:21][CH:22]=[O:23])[CH:12]=1)C1C=CC=CC=1.CO>[Pd].C(Cl)Cl>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[C:13]([NH:21][CH:22]=[O:23])[CH:12]=1
Reactant: CC(C)(C)c1ccc(NC(=O)OCc2ccccc2)cc1NC=O
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1ccc(N)cc1NC=O
Reaction time: 20 h
Yield: 95.7 %

Procedure:
A 100 mL flask was charged with (4-tert-butyl-3-formylamino-phenyl)-carbamic acid benzyl ester (650 mg, 1.99 mmol), methanol (30 mL) and 10% Pd—C (50 mg), and stirred under H2 (1 atm) for 20 h. CH2Cl2 (5 mL) was added to quench the catalyst, and the mixture then filtered through Celite, and concentrated to afford N-(5-amino-2-tert-butyl-phenyl)-formamide as an off-white solid (366 mg, 96%). Rotameric by 1H and 13C NMR (DMSO-d6). 1H NMR (400 MHz, DMSO-d6, rotameric) δ □9.24□ (d, J=10.4 Hz, 1H), 9.15 (s, 1H), 8.23 (d, J=1.5 Hz, 1H), 8.06 (d, J=10.4 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 6.51 (d, J=2.5 Hz, 1H), 6.46 (dd, J=2.5, 8.5 Hz, 1H), 6.39 (dd, J=2.5, 8.5 Hz, 1H), 6.29 (d, J=2.5 Hz, 1H), 5.05 (s, 2H), 4.93 (s, 2H), 1.27 (s, 9H); 13C NMR (100 MHz, DMSO-d6, rotameric) δ 164.0, 160.4, 147.37, 146.74, 135.38, 135.72, 132.48, 131.59, 127.31, 126.69, 115.15, 115.01, 112.43, 112.00, 33.92, 33.57, 31.33, 30.92; ESI-MS 193.1 m/z (MH+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:8]([N+:17]([O-])=O)=[C:9]3[CH2:16][O:15][CH2:14][CH2:13][C:10]3=[N:11][CH:12]=2)=[N:2]1.ClC(Cl)(Cl)C(NC1C=[N+]([O-])C2CCCCC=2C=1)=O>CO.[C].[Pd]>[NH2:17][C:8]1[C:7]([NH:6][C:3]2[CH:4]=[CH:5][O:1][N:2]=2)=[CH:12][N:11]=[C:10]2[CH2:13][CH2:14][O:15][CH2:16][C:9]=12
Reactant: O=[N+]([O-])c1c(Nc2ccon2)cnc2c1COCC2
Agent: [Pd]
Agent: O=C(Nc1cc2c([n+]([O-])c1)CCCC2)C(Cl)(Cl)Cl
Solvent: CO
Product: Nc1c(Nc2ccon2)cnc2c1COCC2
Yield: 72.7 %

Procedure:
To a solution of 435 mg of Compound 7 obtained in (3) above in 95% aqueous methanol is added 10% palladium carbon (40 mg) as catalyst, and the resultant mixture is hydrogenated at ordinary temperature under atmospheric pressure. The reaction mixture is filtered, and the hardly soluble solid is washed out with dimethylformamide. The filtrate is concentrated in vacuo, and the residue is recrystallized from methanol-methylene chloride to give 280 mg of the titled compound (II2b) as light brown crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1cnccc1C(=O)O
Solvent: ClCCl
Product: Cc1cnccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 3-methylisonicotinic acid (100 mg, 0.729 mmol) suspended in DCM (2.5 mL) was added thionyl chloride (260 mg, 2.188 mmol). The reaction mixture was stirred at room temperature for about 3 hours. The solvent was removed under reduced pressure and the residue was dried under high vacuum for 1 hour to give 3-methyl-isonicotinoyl chloride.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3]1=[O:14].C(N(CC)CC)C.[CH:22]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C=O)C>[O:9]=[C:8]1[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3](=[O:14])[CH:2]1[NH:1][C:27]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:28]
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Reactant: O=C(Cl)C1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1C(=O)Nc2ccccc2NC1=O)C1CCCC1
Reaction time: 8 h
Yield: 87 %

Procedure:
Combine 3-amino-1H-1,5-benzodiazepine-2,4-(3H, 5H)-dione (7.0 g, 36.6 mmol) and triethyl amine (4.07 g, 40.3 mmol) in 120 mL DMF and add dropwise cyclopentanecarbonyl chloride (5.34 g, 40.3 mmol) at RT. After stirring overnight, remove DMF under reduced pressure, suspend the residue in a mixed solvent (CHCl3/i-PrOH=3/1, 400 mL). Collect an off-white solid via suction filtration to give the title compound. Wash the filtrate with NaHCO3 (sat.2×100 mL) and dry with Na2SO4. Concentrate the the solvent to give second crop of title compound, total 9.13 g, yield 87%: 1H NMR (300 MHz, DMSO-d6): 10.70 (s, 2H), 8.11 (d, 1H, J=7.8 Hz), 7.24–7.15 (m, 4H), 4.73 (d, 1H, J=7.5 Hz), 2.96–2.87 (m, 1H), 1.74–1.45 (m, 8H).
Reaction SMILES: CN(OC)[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[NH2:11].[C:15]([O:19][C:20]([NH:22][CH2:23]C1C=CC=C(Br)C=1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[CH3:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C([Li])CCC>O1CCCC1.O>[NH2:11][C:5]1[C:6]([CH2:23][NH:22][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])=[C:7]([Cl:10])[CH:8]=[CH:9][C:4]=1[C:3]([C:33]1[CH:32]=[CH:31][CH:36]=[CH:35][CH:34]=1)=[O:12]
Reactant: CCCCCC
Reactant: CC(C)(C)OC(=O)NCc1cccc(Br)c1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1N
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1c(Cl)ccc(C(=O)c2ccccc2)c1N
Temperature: -78 °C

Procedure:
N-methyl-N-methyloxy-2-amino-4-chlorobenzamide (3.6 g) and N-tert-butoxycarbonyl-3-bromobenzylamine (5.5 g) were dissolved in tetrahydrofuran (50 ml). The solution was cooled to −78° C., to which was added dropwise, while stirring, a hexane solution of n-butyl lithium (1.6 mol/L, 60 ml) over 40 minutes. To the reaction mixture was added water, which was subjected to extraction with ethyl acetate (150 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was purified by means of a silica gel column chromatography to give 2-amino-3-tert-butoxycarbonylaminomethyl-4-chlorobenzophenone as a yellow oily product (2.3 g).
Reaction SMILES: Cl.[Br:2][C:3]1[N:7]([CH2:8]Cl)[N:6]=[C:5]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:4]=1.[F:14][C:15]([F:24])([F:23])[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:2][C:3]1[N:7]([CH2:8][C:18]([CH2:17][CH2:16][C:15]([F:14])([F:23])[F:24])([C:19]#[N:20])[C:21]#[N:22])[N:6]=[C:5]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:4]=1
Reactant: CC(C)(C)c1nc(Br)n(CCl)n1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1nc(Br)n(CC(C#N)(C#N)CCC(F)(F)F)n1
Yield: 28.6 %

Procedure:
2.03 g of 5-bromo-3-t-butyl-l-(chloromethyl)-1H-1,2,4-triazole hydrochloride and 1.30 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 24 ml of N,N-dimethylformamide. 2.21 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.76 g of [(5-bromo-3-t-butyl-1H-1,2,4-triazole 1-yl)methyl](3,3, 3-trifluoropropyl)malononitrile (referred as the compound of the present invention (32), hereinafter) shown by below formula.
Reaction SMILES: [Cl-].[NH4+].[C:3]([O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=3)[N:18]=[C:17]([C:29]([F:32])([F:31])[F:30])[CH:16]=2)=[CH:11][CH:10]=1)(=[O:5])[CH3:4]>O.CCO.[Fe]>[C:3]([O:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=3)[N:18]=[C:17]([C:29]([F:31])([F:30])[F:32])[CH:16]=2)=[CH:13][CH:14]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)OCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(=O)OCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(N)cc2)cc1
Temperature: 25 °C
Yield: 42.6 %

Procedure:
To a solution of ammonium chloride 58.8 mg in H2O 0.5 ml was added iron powder 368 mg and EtOH 2 ml. The reaction mixture was warmed in oil bath, and a solution of 2-{4-[1-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethyl acetate 460.7 mg in EtOH 3 ml was added. After being refluxed for 3 hours, the reaction mixture was cooled to ambient temperature and unsoluble matter was removed by filtration. The filtrate was concentrated in vacuo. The residue was dissolved in AcOEt, and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was recrystallized from IPE to give 2-{4-[1-(4-aminophenyl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl]phenyl}ethyl acetate 182.3 mg as a powder.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.CC1C=CC(S(O[CH2:46][CH2:47][S:48]([CH3:51])(=[O:50])=[O:49])(=O)=O)=CC=1>>[N:21]1([C:19]2[N:20]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][N:2]([CH2:46][CH2:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:3]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[CH:16]=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: Cc1ccc(S(=O)(=O)OCCS(C)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)CC1
Product: CS(=O)(=O)CCn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCNCC3)n2)cn1
Yield: 40.6 %

Procedure:
Following the procedures as described in Example 61 and starting with tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and 2-(methylsulfonyl)ethyl 4-methylbenzenesulfonate, 157 was obtained as a white solid (50 mg, 40.6%) over two steps. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 9.16 (s, 1H), 8.58 (s, 1H), 8.56 (s, 1H), 8.39 (s, 1H), 8.02 (s, 1H), 7.76-7.79 (t, J=16 Hz, 1H), 7.23-7.24 (d, J=7.5 Hz, 1H), 6.71-6.73 (d, J=8.5 Hz, 1H), 4.64-4.67 (t, J=13.5 Hz, 2H), 4.01-4.03 (t, J=9.5 Hz, 2H), 3.89-3.87 (t, J=11.5 Hz, 2H), 3.76-3.79 (t, J=14 Hz, 2H), 3.32 (s, 2H), 3.17-3.20 (t, J=10.5 Hz, 2H), 2.94 (s, 3H), 2.13-2.14 (d, J=4.5 Hz, 2H); MS (ESI) m/z: 467 [M+H]+.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:9]=1[C:10]([NH2:12])=[O:11].Cl.[C]=O>C1(C)C=CC=CC=1>[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:9]=1[C:10]([N:12]=[C:2]=[O:3])=[O:11]
Reactant: NC(=O)c1c(F)cccc1F
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Agent: [C]=O
Solvent: Cc1ccccc1
Product: O=C=NC(=O)c1c(F)cccc1F

Procedure:
Twenty-eight grams (0.22 mol) of oxalyl chloride were added dropwise to a solution of 31.4 gm (0.20 mol) of 2,6-difluorobenzamide in 250 ml of toluene. The solution thus obtained was boiled under reflux for five hours, during which time hydrogen chloride and carbon monoxide were liberated. The solvent was then distilled off, in vacuo at the end. The product which remained was distilled in an oil pump vacuum.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.C([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(OC(C)(C)C)=O.Cl.N1C=CN=C1C=O>>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:36][C:35]4[NH:31][CH:32]=[CH:33][N:34]=4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: O=Cc1ncc[nH]1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCN(Cc4ncc[nH]4)CC3)cc2n1

Procedure:
ia 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine, prepared from 1-BOC-piperazine followed by treatment with HCl and subsequent reaction with imidazole-2-carboxaldehyde using standard reductive amination conditions. The amine, 2-chloro-6-[4-(1H-imidazol-2-ylmethyl)-piperazin-1-ylmethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was subsequently isolated.