Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])[CH:7]=[CH:8][CH:9]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]=[C:30]=[O:31])[CH:24]=1>>[CH:18]([O:17][CH:11]([CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][CH2:2][O:1][C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=2)=[O:31])[CH:5]=1)[C:12]([OH:14])=[O:13])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C(Cc1cccc(CCO)c1)OC(C)C
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: CC(C)OC(Cc1cccc(CCOC(=O)Nc2cccc(C(F)(F)F)c2)c1)C(=O)O

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and α,α,α-trifluoro-m-tolylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:16](=[O:19])[CH2:17][CH3:18])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: CCC(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Product: CCC(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1

Procedure:
The title compound was prepared according to the general procedure for acylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using propionyl chloride (48 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]propanamide (0.012 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37]>CN(C=O)C>[CH2:14]([C:11]1[CH:12]=[N:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37])=[CH:7][CH:6]=2)=[N:9][CH:10]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: OCCCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCCCCCO)cc2)nc1
Temperature: 100 °C

Procedure:
42.0 g (0.14 mol) of 2-(4-hydroxyphenyl)-5-octylpyrimidine are dissolved in 400 ml of DMF, and 38.7 g (0.28 mol) of K2CO3 and 36.0 g (0.21 mol) of 8-chlorooctan-1-ol are added. The mixture is subsequently heated at 100° C. with monitoring by TLC until the reaction is complete. The mixture is poured into 3 l of ice water, and the precipitated product is filtered off with suction, washed with water, dried under reduced pressure and recrystallized from cyclohexane.
Reaction SMILES: [CH2:1]1[O:34][C:33]2[CH:32]=[CH:31][C:5]([CH2:6][N:7]([S:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([O:28][CH3:29])=[CH:23][C:22]=3[CH3:30])(=[O:20])=[O:19])[C@H:8]([CH2:16][NH2:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=2[O:2]1.C[Si](C#N)(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].C(OCC)(=O)C>C(#N)C>[CH2:1]1[O:34][C:33]2[CH:32]=[CH:31][C:5]([CH2:6][N:7]([S:18]([C:21]3[C:22]([CH3:30])=[CH:23][C:24]([O:28][CH3:29])=[CH:25][C:26]=3[CH3:27])(=[O:20])=[O:19])[C@H:8]([CH2:16][NH:17][S:42]([CH3:41])(=[O:44])=[O:43])[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[CH:4][C:3]=2[O:2]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CN)C(=O)OC(C)(C)C)c(C)c1
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)C#N
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNS(C)(=O)=O)C(=O)OC(C)(C)C)c(C)c1
Reaction time: 8 h
Yield: 122.7 %

Procedure:
To a mixture of tert-butyl 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-amino-propionate (1.02 g, 2.0 mmol), with trimethylsilyl cyanide (0.7 ml, 5.2 mmol) in dry acetonitrile (15 ml) was added methanesulfonyl chloride (0.18 ml, 2.3 mmol) and the material was stirred overnight. Ethyl acetate (80 ml) was added and the material was partitioned with aqueous hydrochloric acid (1.5%, 80 ml). The organic phase was collected and washed with an equal volume of brine. The aqueous phases were back extracted with ethyl acetate (2×80 ml) and the organic phases combined, dried (MgSO4), filtered and condensed to provide tert-butyl 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-methanesulfonylamino-propionate as a pale yellow semi-viscous oil (1.4 g).
Reaction SMILES: C[N:2]([CH3:19])[CH:3]=[CH:4][C:5](=O)[C:6]([CH3:17])([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:7].Cl.C(N)=[NH:22].CC[O-].[Na+]>O.CCOC(C)=O>[CH3:17][C:6]([C:5]1[CH:4]=[CH:3][N:2]=[CH:19][N:22]=1)([C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)[CH3:7]
Reactant: CN(C)C=CC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Reactant: N=CN
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(c1ccc([N+](=O)[O-])cc1)c1ccncn1
Temperature: 150 °C

Procedure:
A mixture of 1-dimethylamino-4-methyl-4-(4-nitro-phenyl)-pent-1-en-3-one (0.5 g, 1.9 mmol), formamidine hydrochloride (0.305 g, 3.8 mmol), and NaOEt (1.29 g, 4.0 mmol) was heated in Smith synthesizer under microwave for 10 min at 150° C. The resultant was diluted with H2O and EtOAc. The organic layer was dried, and the residue was used without further purification. MS: (ES+) 244 (M+H). Calc'd for C13H14N3O2—244.10.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:7][CH:6]1[C:8]1[S:9][C:10]([C:13](=[O:39])[NH:14][CH2:15][C@H:16]([NH:24][C:25]([O:27][CH2:28][C:29]23[CH2:38][CH:33]4[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]4)[CH2:30]2)[CH2:36]3)=[O:26])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:12]=1)=O.[NH2:40][C:41]1[NH:42][CH2:43][CH2:44][CH2:45][N:46]=1>CN(C)C=O>[C:20]([O:19][C:17](=[O:18])[C@@H:16]([NH:24][C:25]([O:27][CH2:28][C:29]12[CH2:38][CH:33]3[CH2:32][CH:31]([CH2:37][CH:35]([CH2:34]3)[CH2:36]1)[CH2:30]2)=[O:26])[CH2:15][NH:14][C:13]([C:10]1[S:9][C:8]([CH:6]2[CH2:7][CH:5]2[C:3](=[O:2])[NH:40][C:41]2[NH:46][CH2:45][CH2:44][CH2:43][N:42]=2)=[CH:12][CH:11]=1)=[O:39])([CH3:21])([CH3:23])[CH3:22]
Reactant: COC(=O)C1CC1c1ccc(C(=O)NC[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)OC(C)(C)C)s1
Reactant: NC1=NCCCN1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(C2CC2C(=O)NC2=NCCCN2)s1)NC(=O)OCC12CC3CC(CC(C3)C1)C2

Procedure:
The product obtained in step b) was dissolved in 4 ml of anhydrous dimethylformamide and stirred under an argon atmosphere with 99 mg of 2-amino-1,4,5,6-tetrahydropyrimidine for 7 hours at room temperature. The solvent was removed in vacuo and the residue was chromatographed (silica gel; ethyl acetate/methanol (1/1, v/v)). The fractions containing the title compound were pooled and evaporated under reduced pressure to give 53 mg of a colourless resin.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH:33]=O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:28][CH2:29][CH:30]([CH2:33][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)[CH3:13])[CH2:31][CH2:32]1)=[O:26])([CH3:21])([CH3:22])[CH3:23]
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Product: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)CC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Reaction between (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amine (described above) and 4-formyl-piperidine-1-carboxylic acid tert-butyl ester using standard reductive amination conditions yielded 4-{[(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester, which was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A, followed by treatment with HCl to cleave the BOC group to yield 320. 400 MHz 1H NMR CDCl3: 9.21 (s, 2H); 7.18 (s, 1H); 5.18 (brs, NH2); 3.96 (t, 4H, J=4.7 HZ); 3.81 (t, 4H, J=4.7 Hz); 3.71 (s, 2H, CH2); 3.01 (d, 2H, J=12.2 Hz); 2.56-1.50 (m, 2H); 2.23 (m, 5H, CH2&Me); 1.73 (d, 2H, J=12.8 Hz); 1.65-1.50 (m, 1H); 1.07-0.97 (m, 2H). LC-MS (m+1)=455.34
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:27])[C:11]([O:25][CH3:26])=[C:12]([CH2:14][NH:15][C:16]3[C:17]([CH3:24])=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=3[CH3:22])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37].O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:27])[C:11]([O:25][CH3:26])=[C:12]([CH2:14][NH:15][C:16]3[C:17]([CH3:24])=[C:18]([CH:19]=[CH:20][C:21]=3[CH3:22])[O:23][CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)CBr
Reactant: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(C)ccc(O)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(C)ccc(OCC(=O)OC(C)C)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.4 %

Procedure:
To a solution of 3-[[5-(3-fluorophenyl)-2-methoxy-3-methyl-phenyl]methylamino]-2,4-dimethyl-phenol (115 mg, 0.31 mmol, 1.0 eq) in acetone (4 mL) was added Cs2CO3 (154 mg, 0.47 mmol, 1.5 eq). The reaction mixture was stirred for 30 min at room temperature then isopropyl bromoacetate (68.4 mg, 0.38 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for a further 2 h then poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc 30:1 to 20:1) to give the title compound as a colorless oil (155 mg, 100%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[F:12][C:13]([F:35])([F:34])[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21]/[N:22]=[CH:23]/[C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)=[CH:17][CH:16]=1>C(Cl)Cl>[Cl:1][C:23](=[N:22][NH:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:13]([F:34])([F:35])[F:12])=[CH:16][CH:17]=1)[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(/C=N/Nc2ccc(OC(F)(F)F)cc2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CSC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(Cl)=NNc2ccc(OC(F)(F)F)cc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a magnetically stirred solution of N-chlorosuccinimide (0.59 g, 4.43 mmoL) in CH2Cl2 (8 mL) at 0° C. was added dimethyl sulfide (0.85 mL, 8.87 mmoL) and the reaction mixture was stirred for 15 minutes (min) and then cooled to −78° C. To this solution was added (E)-methyl 4-((2-(4-(trifluoromethoxy)-phenyl)hydrazono) methyl)benzoate dissolved in 8 mL of CH2Cl2 and the reaction mixture was stirred at this temperature for 1 hour (h), warmed to room temperature and stirred for 2 h. The solution was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (15 mL) and added to a silica gel (SiO2) loading cartridge and purified via flash column chromatography (Gradient EtOAc/hexanes). The title compound was obtained as a yellow solid as a mixture of E and Z isomers: mp 159-162° C.; 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 8.07 (d, J=8.8 Hz, 2H), 7.98 (d, J=8.8 Hz, 2H), 7.20 (s, 4H), 3.95 (s, 3H); 19F NMR (376 MHz, CDCl3) δ−58.32; ESIMS m/z 372 ([M+H])+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)=[O:3].C([Sn](CCCC)(CCCC)[C:16]1[S:17][CH:18]=[CH:19][N:20]=1)CCC.C(Cl)(Cl)Cl.Cl>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:17]1[CH:18]=[CH:19][N:20]=[C:16]1[C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(=O)c1ccc(-c2nccs2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 126 %

Procedure:
4-Bromoacetophenone (500 mg, 2.51 mmol) and 2-(tributylstannyl)thiazole (0.948 ml, 3.014 mmol) were dissolved in 1,4-dioxane (8 ml), and bis(triphenylphosphine)palladium dichloride (176 mg), was added to the solution under an argon gas atmosphere. The mixture was stirred at 90° C. for 8 hours. After the reaction solution was cooled to room temperature, chloroform and 1 N—HCl were added to the solution, and the extraction/separation step was carried out. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified on silica gel column chromatography (EtOAc:hexane=1:3) to yield the title compound (643 mg) as an opaque white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:26])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:26])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: COc1ccc(CCC(C)Nc2c(C)noc2-c2ccc(Br)cc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccc(OC)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(4-methoxy-phenyl)-1-methyl-propyl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[ClH:7].[Cl:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[F:16][C:17]([F:46])([F:45])[C:18]1[CH:19]=[C:20]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=1)=[O:22].O>CN(C)C=O>[ClH:8].[ClH:7].[F:46][C:17]([F:16])([F:45])[C:18]1[CH:19]=[C:20]([CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:40]=1)[C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:25][C@H:24]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=1)=[O:22]
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C[C@@H]2CN(Cc3ccccn3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
Potassium carbonate (187 mg) and 2-(chloromethyl)pyridine hydrochloride (81 mg) were added to a solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (200 mg) in N,N-dimethylformamide (4 ml) at room temperature with stirring. After 2 hours, the reaction mixture was poured into water (50 ml) and extracted with ethyl acetate. The organic layer was washed with water and then dried over magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and toluene (1:3) and treated with 4N hydrogen chloride in ethyl acetate solution to afford (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-pyridylmethyl)piperazine dihydrochloride (123 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][NH:30][CH2:31]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][N:30]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:31]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: COc1cccc2c1CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1cccc2c1CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c1F)C2
Yield: 32.7 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 90 mg of 4-methoxyisoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 77 mg of the target compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19](=[C:24]([F:26])[F:25])[CH2:20][C:21](Cl)=[O:22]>ClCCl.O>[F:18][C:19](=[C:24]([F:26])[F:25])[CH2:20][C:21]([NH:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[N:7]=1)=[O:22]
Reactant: O=C(Cl)CC(F)=C(F)F
Reactant: COc1cc(OC)nc(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1cc(OC)nc(NC(=O)CC(F)=C(F)F)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 10.7 %

Procedure:
To an ice-cooled stirred suspension of 2-amino-4,6-dimethoxypyrimidine (1.55 g, 10 mmol) in dichloromethane (50 mL) and potassium carbonate (2.76 g, 20 mmol) in water (20 mL) was added 3,4,4-trifluoro-3-butenoyl chloride (3.17 g, 20 mmol). The reaction mixture was stirred in cold for 10 min and at r.t. for 15 min. The organic layer was washed with 3N HCl (2×25 mL), saturated sodium bicarbonate (25 mL) and brine, and dried. Evaporation of the solvent gave 0.296 g (10%) of the title compound as a white solid. m.p. 127°-130° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[N:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[C:20](=O)([O:23]C)[O:21][CH3:22].[NH4+].[Cl-]>C1COCC1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][C:20]([O:21][CH3:22])=[O:23])[N:15]=1
Reactant: Cc1cccnn1
Reactant: COC(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)Cc1cccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
To a solution of diisopropylamine (19 ml, 130 mmol, 1.3 equiv) in dry THF (100 mL) at 0° C. under a N2, was added n-butyllithium (81 ml, 130 mmol, 1.3 equiv) slowly. The mixture was stirred at 0° C. for 30 min and then cooled to −78° C. A solution of 3-methylpyridazine (9 ml, 100 mmol, 1.0 equiv) in THF (50 mL) was added dropwise over a period of 1:5 min. The resulting mixture was stirred at −78° C. for 1 h, and a solution of dimethyl carbonate (17 ml, 200 mmol, 2 equiv) in THF (50 mL) was added dropwise. The mixture was allowed to warm slowly to 25° C. and stirred for 2 days. Sat.NH4Cl was added and the resulting solution was extracted with 10% MeOH/DCM. The combined organics were washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (2.5% MeOH/DCM) to give 1.6 g of methyl 2-(pyridazin-3-yl)acetate as a brown liquid (11 mmol, 11%).
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][Cl:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH2:14]>C(O)(=O)C>[Cl:13][CH2:12][C:11]1[C:2](=[O:14])[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O
Reactant: ClCc1cc2ccccc2nc1Cl
Solvent: CC(=O)O
Product: O=c1[nH]c2ccccc2cc1CCl

Procedure:
2.8 Grams of 2-chloro-3-chloromethylquinoline was dissolved in 30 ml of acetic acid and the solution was refluxed for 2 hours. The reaction mixture was poured into water and the crystals precipitated were collected by filtration, and were recrystallized from methanol to obtain 2.1 g of 3-chloromethylcarbostyril in the form of colorless needle-like crystals.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:21])[O:17][CH2:18][CH2:19][CH3:20])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:22]([N:21]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH2:19][CH3:20])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccccc1
Product: CCCOC(=NC(=O)c1ccccc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from propyl 5,7-dihydro-6H-dibenz[c,e]-azepine-6-carboximidate and benzoyl chloride, there is obtained propyl N-benzoyl-5,7-dihydro-6H-dibenz[c,e]-azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 384 (7), 341 (13), 194 (100), 179 (23), 105 (59);
Reaction SMILES: Cl[C:2]([N:4]1[CH2:7][CH:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH2:5]1)=[O:3].[CH2:16]([NH2:19])[CH:17]=[CH2:18]>O1CCCC1>[Cl:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH:6]1[CH2:7][N:4]([C:2]([NH:19][CH2:16][CH:17]=[CH2:18])=[O:3])[CH2:5]1
Reactant: O=C(Cl)N1CC(Oc2cccc(Cl)c2)C1
Reactant: C=CCN
Solvent: C1CCOC1
Product: C=CCNC(=O)N1CC(Oc2cccc(Cl)c2)C1
Reaction time: 2 h
Yield: 37.5 %

Procedure:
A solution of 5.4 g (0.017 mole) of 1-chlorocarbonyl-3-(3-chlorophenoxy)azetidine in 20 ml of tetrahydrofuran was treated with 2.3 g (0.04 mole) of 2-propenylamine and stirred for 2 hr. The reaction solution was concentrated in vacuo to a rose beige solid. Trituration of the solid with water gave, after filtering, 4.4 g of crude product. After drying, the solid was recrystallized with charcoal treatment from 2% acetone/isopropyl ether to yield 1.7 g (37.5%) of pale beige crystals, m.p. 87°-89° C.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:18][CH2:19][C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[CH3:25].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH3:25][N:21]1[CH2:22][CH2:23][CH2:24][C@H:20]1[CH2:19][O:18][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN1CCC[C@H]1CO
Reactant: Clc1ncccc1OCCOC1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CN1CCC[C@H]1COc1ncccc1OCCO
Temperature: 50 °C
Reaction time: 48 h
Yield: 79.5 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), (S)-(−)-2-hydroxymethyl-1-methylpyrrolidine (69 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of water and 2 mL of brine. The organic phase was shaken at 50° C. with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 78 mg (0.31 mmol, 79%) of the title compound as a colorless oil. LC-UV purity 95%. MS m/z 253 (M+1)+, calc. 253 (M+1)+.
Reaction SMILES: [CH3:1][NH2:2].C(O)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:2][CH3:1])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CN
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
A round bottom flask was charged with methylamine solution 40% (0.88 ml, 26 mmol) in ethanol (10 ml, 171 mmol). The mixture was chilled to 0° C. in an ice bath, with stirring under inert atmosphere. Then 4-fluorobenzenesulfonyl chloride (1.00 g, 5.1 mmol) was added into the mixture. The resulting mixture was allowed to stir at 0° C., while under inert atmosphere for 30 minutes. The progress of the reaction was monitored by LC/MS, which showed mostly desired product peak. The mixture was diluted with DCM and saturated sodium bicarbonate solution, then extracted the organic layer with DCM (3×25 ml). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuo. This gave 4-fluoro-N-methylbenzenesulfonamide (0.918 g, 94% yield) as an off-white crystalline solid. MS (ESI pos. ion) m/z: 190 (MH+). Calc'd exact mass for C7H8FNO2S: 189. 1H NMR (400 MHz, chloroform-d): 2.64-2.71 (m, 3H), 4.63 (s, 1H), 7.18-7.28 (m, 2H), 7.88-7.93 (m, 2H).