Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[NH:23][C:22](=[O:24])[C:21]4[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=4[O:25][CH3:26])[N:15]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[O:32].CCN(CC)CC.[OH-].[Na+]>C1COCC1>[CH3:26][O:25][C:20]1[CH:19]=[C:18]([O:27][CH3:28])[CH:17]=[C:16]2[C:21]=1[C:22](=[O:24])[NH:23][C:14]([C:11]1[CH:12]=[CH:13][C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:31](=[O:32])[N:30]([CH3:34])[CH3:29])[CH2:7][CH2:6]3)=[CH:9][CH:10]=1)=[N:15]2
Reactant: CN(C)C(=O)Cl
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(N)CC4)cc3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(NC(=O)N(C)C)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.4 %

Procedure:
A mixture of 2-(4-(4-aminopiperidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.105 g, 0.28 mmol), dimethylcarbamic chloride (0.032 g, 0.30 mmol), and Et3N (0.085 g, 0.84 mmol) in THF (10 mL) was stirred at room temperature for 18 hours. The mixture was then heated at reflux for 24 hours, then cooled to room temperature. 2 M NaOH (20 mL) was added and the mixture was stirred for 30 minutes. The reaction mixture was adjusted to pH 8, extracted with CH2Cl2 (3×100 mL), dried over anhydrous MgSO4, filtered, and concentrated. The residue was dissolved in CHCl3/MeOH and concentrated, then CH3CN was added and concentrated to afford the title compound as a white solid (0.065 g, 51%): 1H NMR (300 MHz, CDCl3): δ 11.72 (s, 1H), 8.08 (d, J=9.0 Hz, 2H), 7.00 (d, J=9.0 Hz, 2H), 6.78 (d, J=2.2 Hz, 1H), 6.46 (d, J=2.2 Hz, 1H), 5.99 (d, J=7.8 Hz, 1H), 3.90-3.94 (m, 2H), 3.88 (s, 3H), 3.83 (s, 3H), 3.66-3.69 (m, 1H), 2.88-2.93 (m, 2H), 2.76 (s, 6H), 1.75-1.80 (m, 2H), 1.45-1.52 (m, 2H); ESI MS m/z 452 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:26][CH2:27][CH2:28][CH3:29])[NH:7][C:6](=[O:30])[CH:5]=1)([CH3:3])[CH3:2].[Cl:31]Cl>>[Cl:31][C:5]1[C:6](=[O:30])[NH:7][C:8]([C:10]2[CH:15]=[C:14]([S:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:26][CH2:27][CH2:28][CH3:29])=[N:9][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: ClCl
Reactant: CCCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc(C(C)C)cc(=O)[nH]1
Product: CCCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc(C(C)C)c(Cl)c(=O)[nH]1

Procedure:
The compound of example 221 was prepared by reacting the compound of example 1 with chlorine gas in the same manner as that of example 207. 1H NMR (CDCl3) 8.86 (1H, d), 7.88 (1H, dd), 7.16 (1H, d), 4.27 (2H, t), 3.49 (1H, m), 3.09 (4H, t), 2.50 (4H, t), 2.27 (3H, s), 2.03 (2H, m), 1.26 (6H, d), 1.16 (3H, t).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].[N+:10]([O-])([O-:12])=[O:11].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:10]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[OH:9])([O-:12])=[O:11]
Reactant: O=[N+]([O-])[O-]
Reactant: N#Cc1cccc(O)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc([N+](=O)[O-])c(O)c1
Reaction time: 24 h
Yield: 27.7 %

Procedure:
3-cyanophenol (2.38 g, 20 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (1.88 g, 22 mmol). The addition of sulfuric acid (20 mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product(910 mg, 28%). 1H NMR (CD3COCD3): d 8.30 (d,1H), 7.67 (s,1H), 7.49 (d, 1H).
Reaction SMILES: [C@H:1]12[N:8](C(OC(C)(C)C)=O)[C@H:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH:2]2[C:16]([O:18][CH3:19])=[O:17].Cl>CCO.O1CCOCC1>[C@H:1]12[NH:8][C@H:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH:2]2[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C1CC[C@H]2CC[C@@H]1N2C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COC(=O)C1CC[C@H]2CC[C@@H]1N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To (1S,5S)-8-tert-butyl 2-methyl 8-azabicyclo[3.2.1]octane-2,8-dicarboxylate (5.49 g) in EtOH (1 mL) was added 4M HCl in dioxane (5 mL). The reaction mixture was stirred at room temperature for 2 hours. Concentrated to give crude product (3.45 g).
Reaction SMILES: Cl.[CH2:2]([N:5]1[C:13]2[N:12]=[C:11]([CH2:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=4)[CH:18]=[N:17][CH:16]=3)[NH:10][C:9]=2[C:8](=[O:29])[N:7]([CH3:30])[C:6]1=[O:31])[CH:3]=[CH2:4].C(N(C(C)C)CC)(C)C.[OH-:41].[Na+].OO>C1COCC1>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[CH:18]=[N:17][CH:16]=[C:15]2[CH2:14][C:11]1[NH:10][C:9]2[C:8](=[O:29])[N:7]([CH3:30])[C:6](=[O:31])[N:5]([CH2:2][CH2:3][CH2:4][OH:41])[C:13]=2[N:12]=1
Reactant: C=CCn1c(=O)n(C)c(=O)c2[nH]c(Cc3cncc4cc(OC)c(OC)cc34)nc21
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CCCO)c2cc1OC
Temperature: 50 °C

Procedure:
A suspension of the product of Example 13, 3-allyl-8-(6,7-dimethoxy-isoquinolin4-ylmethyl)-1-methyl-3,7-dihydro-purine-2,6-dione hydrochloride salt (0.760 g, 1.87 mmol), 9-borabicyclo[2.2.0]nonane (0.5M THF solution, 18.7 ml, 9.35 mmol) and diisopropylethylamine (0.33 ml, 1.89 mmol) in THF (9 ml) is heated to reflux for 2.5 hours. Sodium hydroxide (4M aqueous solution, 6 ml) and hydrogen peroxide (27.5%, 3 ml) are added sequentially and the reaction heated at 50° C. for 1.5 hours. After evaporation, the crude product is purified by flash chromatography (19:1 CH2Cl2:-methanol elution) and triturated with water to afford 8-(6,7-dimethoxy-isoquinolin4-ylmethyl)-3-(3-hydroxy-propyl)-1-methyl-3,7-dihydro-purine-2,6-dione, [MH]+ 426.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Cl:26][C:27]1[N:32]=[CH:31][C:30]([NH:33][CH:34]=[C:35]([S:41]([CH3:44])(=[O:43])=[O:42])[C:36]([O:38]CC)=O)=[CH:29][CH:28]=1>>[Cl:26][C:27]1[N:32]=[C:31]2[C:30](=[CH:29][CH:28]=1)[N:33]=[CH:34][C:35]([S:41]([CH3:44])(=[O:42])=[O:43])=[C:36]2[OH:38]
Reactant: CCOC(=O)C(=CNc1ccc(Cl)nc1)S(C)(=O)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CS(=O)(=O)c1cnc2ccc(Cl)nc2c1O
Temperature: 25 °C
Reaction time: 0.62 h

Procedure:
To a flask containing Dowtherm™ A (500 mL) at 250° C. was added ethyl 3-(6-chloropyridin-3-ylamino)-2-(methylsulfonyl)acrylate (8.2 g, 30 mmol) portion wise over 3 to 5 min and the reaction mixture was stirred for an additional 30 to 45 min. The reaction mixture was removed from the heat source, cooled to room temperature and diluted with hexanes to facilitate precipitation. The solids were collected by filtration, filtered, washed with hexanes and dried under vacuum to afford the intermediate 6-chloro-3-(methylsulfonyl)-1,5-naphthyridin-4-ol which was stirred with heat at 70° C. in neat phosphorus oxychloride (31 mL) with catalytic N,N-dimethylformamide for 4 h. The reaction was cooled and poured slowly into a vigorously stirring mixture of ice-cold satd. aq. sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica, hexanes/ethyl acetate) to provide the desired product (2.7 g, 33% over two steps) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 9.50 (s, 1H), 8.46 (d, J=8.8 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 3.41 (s, 3H); ESI MS m/z 278 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:46])[CH2:5][N:6]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]2[NH:31][C:30](=[O:32])[C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[NH:27][C:26]2=[O:37])=[CH:20][C:19]=1[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[S:7]([NH:10]C(OC(C)(C)C)=O)(=[O:9])=[O:8])[CH3:2]>C(Cl)Cl.FC(C(O)=O)(F)F.C([SiH](CC)CC)C>[CH2:1]([O:3][C:4](=[O:46])[CH2:5][N:6]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]2[NH:31][C:30](=[O:32])[C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[NH:27][C:26]2=[O:37])=[CH:20][C:19]=1[O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[S:7]([NH2:10])(=[O:8])=[O:9])[CH3:2]
Reactant: CCOC(=O)CN(c1ccc(CC2NC(=O)c3ccccc3NC2=O)cc1OCc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CN(c1ccc(CC2NC(=O)c3ccccc3NC2=O)cc1OCc1ccccc1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title M compound, N-[2-benzyloxy-4-(2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepin-3-ylmethyl)-phenyl]-N-[t-butyloxycarbonylaminosulfonyl]-amino-acetic acid ethyl ester (124 mg, 0.19 mmol) is dissolved in CH2Cl2-TFA-triethylsilane (2.5:7:0.5, 1.5 mL) and the solution is stirred at RT for 1 h and evaporated. The residue is dissolved in EtOAc and the solution is washed twice with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered and evaporated to give N-[2-benzyloxy-4-(2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepin-3-ylmethyl)-phenyl]-N-[aminosulfonyl]-amino-acetic acid ethyl ester as a foam: [M+1]+=553.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([NH:19][C:20]([C:22]3([C:25]4[CH:35]=[CH:34][C:28]5[O:29][C:30]([F:33])([F:32])[O:31][C:27]=5[CH:26]=4)[CH2:24][CH2:23]3)=[O:21])[N:10]=2)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[C:43](Cl)(=[O:45])[CH3:44]>CN(C=O)C>[C:43]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([NH:19][C:20]([C:22]3([C:25]4[CH:35]=[CH:34][C:28]5[O:29][C:30]([F:33])([F:32])[O:31][C:27]=5[CH:26]=4)[CH2:23][CH2:24]3)=[O:21])[N:10]=2)[CH:6]=[CH:7][CH:8]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)Cl
Reactant: NCc1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NCc1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-(1-(3-(aminomethyl)phenyl)isoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (47 mg, 0.1 mmol) and Et3N (28 μL, 0.2 mmol) in DMF (2 mL) was added acetyl chloride (7.1 μL, 0.1 mmol). The reaction was stirred at room temperature for 10 minutes, then filtered and purified by reverse-phase HPLC to yield the product, N-(1-(3-(acetamidomethyl)phenyl)isoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 515.2. found 516.5 (M+1)+. Retention time 1.97 minutes. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.43-8.40 (m, 2H), 7.98 (d, J=8.2 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.74-7.70 (m, 1H), 7.61 (d, J=1.1 Hz, 1H), 7.50-7.38 (m, 7H), 4.33 (d, J=6.0 Hz, 2H), 1.85 (s, 3H), 1.57-1.55 (m, 2H), 1.22-1.19 (m, 2H).
Reaction SMILES: C[O-].[Na+].Cl.[CH:5](OC(C1N(CCN(CC)CC)C(C2C=CC=CC=2)=C2C=1C=CC(Cl)=C2)=O)(C)C.C(Cl)Cl.[CH2:37]([O:39][C:40]([CH:42]1[N:48]=[C:47]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:46]2[CH:55]=[C:56]([Cl:59])[CH:57]=[CH:58][C:45]=2[NH:44][C:43]1=[O:60])=[O:41])[CH3:38]>C(O)(=O)C>[CH:37]([O:39][C:40]([CH:42]1[N:48]=[C:47]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:46]2[CH:55]=[C:56]([Cl:59])[CH:57]=[CH:58][C:45]=2[NH:44][C:43]1=[O:60])=[O:41])([CH3:5])[CH3:38]
Reactant: CCN(CC)CCn1c(C(=O)OC(C)C)c2ccc(Cl)cc2c1-c1ccccc1
Reactant: CCOC(=O)C1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)OC(=O)C1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
500 Ml. of propanol-(2) are treated with 14 g. of sodium methylate; the methanol formed is removed by concentration in vacuo to half the volume and the suspension obtained is diluted with 250 ml. of methylene chloride. Then, 34.2 g. of 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid ethyl ester are added and the mixture is subsequently stirred at 25° C. for 40 minutes. The orange solution is made acidic with glacial acetic acid and evaporated to dryness under reduced pressure. The residue is partitioned between water and chloroform; the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. The solid crude product is triturated with ether, removed by filtration, washed with ether and recrystallized from methylene chloride/ether, whereby there is obtained 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid isopropyl ester having a melting point of 234°-238° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([N+:16]([O-])=O)[CH:10]=2)=[CH:5][CH:4]=1>[Pd].CO>[NH2:16][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:14]=[CH:13][C:12]=1[CH3:15]
Reactant: COc1ccc(-c2ccc(C)c([N+](=O)[O-])c2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(-c2ccc(C)c(N)c2)cc1
Reaction time: 12 h

Procedure:
A suspension of 4′-methoxy-4-methyl-3-nitrobiphenyl (630 mg, 2.95 mmol) and 10% palladium on charcoal (63 mg, 0.059 mmol) in methanol (6 mL) is stirred under hydrogen atmosphere for 12 hours. Palladium catalyst is removed by filtration and the resulting solution is evaporated in vacuo to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].C([O-])(=O)C.[NH2+]1CCCCC1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[CH:16][C:14](=[O:15])[CH2:13][C:12]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1)=[O:17])([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OCCNC(=O)c1cccnc1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: O=C(C=Cc1cccc([N+](=O)[O-])c1)CC(=O)OCCNC(=O)c1cccnc1
Yield: 86.2 %

Procedure:
A solution of 9.07 g (0.06 mole) of m-nitrobenzaldehyde, 15.0 g (0.06 mole) of 2-nicotinoylaminoethyl acetoacetate and 1.74 g (0.012 mole) of piperidinium acetate in 100 ml of benzene was heated at reflux under azeotropic dehydration conditions for 2 hours. After the reaction, the mixture was extracted with benzene, and the extract was washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave 19.82 g of 2-nicotinoylaminoethyl 3-nitrobenzilideneacetoacetate as white crystals.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3([O:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]4[CH:28]=[CH:29][CH:30]=[C:19]34)[CH2:15][CH2:14]2)=[O:12])=[CH:7][C:6]=1[O:31][CH3:32])([CH3:4])[CH3:3].[H-].[Na+].[CH3:35]I>C1COCC1.CN(C=O)C>[CH3:32][O:31][C:6]1[CH:7]=[C:8]([C:11]([N:13]2[CH2:14][CH2:15][C:16]3([O:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]4[CH:28]=[CH:29][CH:30]=[C:19]34)[CH2:17][CH2:18]2)=[O:12])[CH:9]=[CH:10][C:5]=1[C:2]([O:1][CH3:35])([CH3:3])[CH3:4]
Reactant: CI
Reactant: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)ccc1C(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)ccc1C(C)(C)OC
Reaction time: 0.03 h
Yield: 35 %

Procedure:
(4-(2-Hydroxypropan-2-yl)-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (crude material from step 1) was dissolved in a mixture of THF (3 mL) and DMF (3 mL). NaH (28 mg, 0.69 mmol) was added and the reaction mixture was allowed to stir for 2 minutes. MeI (54 μL, 0.86 mmol) was then added and the reaction mixture was allowed to stir for 1 h. The reaction mixture was evaporated to dryness and the residue was suspended in 25 mL of dichloromethane. The suspension was washed two times with a 1M solution of hydrochloric acid, followed by two washes with a saturated aqueous solution of sodium bicarbonate, followed by two washes of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to yield the crude product. The crude material was purified by column chromatography utilizing a gradient of 0-35% ethyl acetate in hexanes give (3-methoxy-4-(2-methoxypropan-2-yl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (94 mg, 35% over 2 steps). ESI-MS m/z calc. 446.2. found 447.5 (M+1)+; Retention time: 7.60 minutes (15 min run). 1H NMR (400 MHz, DMSO) δ 7.68-7.65 (m, 1H), 7.50-7.49 (m, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.17-6.98 (m, 5H), 6.29-6.28 (m, 1H), 6.18-6.17 (m, 1H), 4.49-4.34 (m, 1H), 3.83 (s, 3H), 3.80-3.41 (m, 3H), 3.13 (s, 3H), 2.11-1.81 (m, 4H) and 1.50 (s, 6H).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=[O:11])=O)(C)(C)C.[ClH:13].[C:14]1([CH:20]([NH2:31])[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[ClH:13].[NH2:8][CH2:9][C:10]([NH:31][CH:20]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][CH:22]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NC(c1ccccc1)c1ccc(C(F)(F)F)cc1
Agent: Cl
Product: NCC(=O)NC(c1ccccc1)c1ccc(C(F)(F)F)cc1

Procedure:
Prepared in analogy to example 3.1, starting from N-tert.butyloxycarbonyl glycine and C-phenyl-C-(4-trifluoromethyl-phenyl)-methylamine hydrochloride (CA [49703-60-8]).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[C:9]([C:14]#[N:15])=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:22]1[N:26]2[CH:27]=[CH:28][C:29]([C:31]([F:34])([F:33])[F:32])=[N:30][C:25]2=[N:24][CH:23]=1)CCC>>[F:16][C:5]1[CH:4]=[CH:3][C:2]([C:22]2[N:26]3[CH:27]=[CH:28][C:29]([C:31]([F:32])([F:33])[F:34])=[N:30][C:25]3=[N:24][CH:23]=2)=[CH:7][C:6]=1[C:8]1[C:9]([C:14]#[N:15])=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: N#Cc1ncccc1-c1cc(Br)ccc1F
Product: N#Cc1ncccc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F

Procedure:
3-(5-Bromo-2-fluorophenyl)pyridine-2-carbonitrile was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine by the method of Example 32. Purification by chromatography on silica gel eluting with dichloromethane containing 4% methanol, then crystallisation from hot toluene, gave 3-[2-fluoro-5-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)phenyl]pyridine-2-carbonitrile: δH (400 MHz, DMSO) 9.39 (1H, d, J 7), 8.87 (1H, dd, J 5 and 1.5), 8.33 (1H, s), 8.30 (1H, dd, J 8 and 1), 8.09 (1H, dd, J 7 and 2), 8.00-8.03 (1H, m), 7.94 (1H, dd, J 8 and 5), 7.72 (1H, dd, J 10 and 9), 7.54 (1H, d, J 7); m/z (ES+) 384.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:9]([O:11][CH3:12])=[O:10])=[N:6][C:7]=1[CH3:8].[F:13][C:14]([F:18])([F:17])[CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:8][C:7]1[N:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]=[N:3][C:2]=1[O:16][CH2:15][C:14]([F:18])([F:17])[F:13]
Reactant: OCC(F)(F)F
Reactant: COC(=O)c1cnc(Cl)c(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OCC(F)(F)F)c(C)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
A mixture of methyl 5-chloro-6-methylpyrazine-2-carboxylate (3.00 g, 16.1 mmol), 2,2,2-trifluoroethanol (32.2 g, 322 mmol), and potassium carbonate (3.33 g, 24.1 mmol) in DMF (30 mL) is stirred at 60° C. for 2 hours. After cooling to rt, the mixture is filtered off, and the filtrate is diluted with EtOAc (300 mL). The organic layer is washed with water (100 mL×3) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting EtOAc to give 3.91 g (97% yield) of the title compound as white solid.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:34][C@H:35]1[CH2:40][NH:39][CH2:38][CH2:37][NH:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][N:39]5[CH2:38][CH2:37][NH:36][C@@H:35]([CH3:34])[CH2:40]5)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Reactant: C[C@H]1CNCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H]1CN(Cc2ccc(-c3ccc(C(CC4CCOCC4)c4ccc(S(=O)(=O)C5CC5)cc4)[nH]3)nc2)CCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (250 mg) in tetrahydrofuran (10 mL) was added (2S)-2-methylpiperazine (270 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (230 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give the title compound (111 mg, yield 38%) as a colorless amorphous solid. MS: 549 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[C:4]([F:12])[CH:3]=1.C([Li])CCC.[CH3:18][S:19]C.[Cl-].[NH4+]>O1CCCC1.O>[F:12][C:4]1[CH:3]=[C:2]([S:19][CH3:18])[CH:7]=[CH:6][C:5]=1[O:8][CH2:9][O:10][CH3:11]
Reactant: CSC
Reactant: COCOc1ccc(Br)cc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1ccc(SC)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5 g of 4-bromo-2-fluoro-1-methoxymethoxybenzene was dissolved in 50 mL anhydrous tetrahydrofuran, and 13.4 mL n-butyl lithium (1.59 M hexane solution) was added dropwise thereto at −70° C. After the mixture was stirred for 1 hour, 2.1 ml dimethyl sulfide was added dropwise thereto and stirred at −70° C. for 1 hour, and after the temperature of the reaction solution was raised to 0° C., the solution was stirred for 1 hour. An aqueous saturated ammonium chloride solution was added thereto, the mixture was stirred for 30 minutes, and water added to the mixture which was then extracted with ethyl acetate. The extract was dried over sodium sulfate and purified by silica gel chromatography (hexane/ethyl acetate) to give 3.67 g of 2-fluoro-1-methoxymethoxy-4-methylsulfanyl benzene. 4 mL solution of 4 N hydrogen chloride in ethyl acetate was added to this reaction product and left for 1 hour. Water was added to the product which was then extracted with ethyl acetate and purified by silica gel chromatography (hexane/ethyl acetate) to give 1.01 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([CH2:13][OH:14])=[CH:8][C:7]=1[F:15].Cl[C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([CH2:13][O:14][C:20]2[CH:30]=[C:24]3[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]3[C:22](=[O:31])[N:21]=2)=[CH:8][C:7]=1[F:15]
Reactant: OCc1cc(F)c(Oc2cccc(Cl)c2)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1cc(F)c(Oc3cccc(Cl)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-(3-chlorophenoxy)-3,5-difluorophenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.