Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])OC1=O.CN(C)C=O.[NH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]2[N:32]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C:31]3[CH:41]=[CH:42][CH:43]=[CH:44][C:30]=3[N:29]=2)[CH2:23][CH2:22]1>O>[NH2:1][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([NH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]2[N:32]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C:31]3[CH:41]=[CH:42][CH:43]=[CH:44][C:30]=3[N:29]=2)[CH2:23][CH2:22]1)=[O:11]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccccc1C(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 3 h
Yield: 80 %

Procedure:
To a stirred and hot (50° C.) mixture of 4.1 parts of 2H-3,1-benzoxazine-2,4(1H)-dione and 31.5 parts of N,N-dimethylformamide was added dropwise a solution of 9.4 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine in 31.5 parts of N,N-dimethylformamide at 50° C. Upon completion, stirring was continued for 3 hours at 50° C. Water was added and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile, yielding 9.8 parts (80%) of 2-amino-N-[2-[4-[[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1piperidinyl]ethyl]benzamide; mp. 171.7° C. (intermediate 157).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1.O.ON1C2C=CC=CC=2N=N1.[CH3:30][NH:31][C:32]1[S:33][C:34]([S:38]([NH2:41])(=[O:40])=[O:39])=[C:35]([CH3:37])[N:36]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH2:41][S:38]([C:34]1[S:33][C:32]([N:31]([CH3:30])[C:16](=[O:18])[CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])=[CH:14][CH:13]=2)=[N:36][C:35]=1[CH3:37])(=[O:39])=[O:40]
Reactant: CNc1nc(C)c(S(N)(=O)=O)s1
Reactant: O=C(O)Cc1ccc(-c2cc(F)ccc2F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N(C)C(=O)Cc2ccc(-c3cc(F)ccc3F)cc2)sc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
At room temperature, 1.00 g (4.0 mmol) of (2′,5′-difluoro[1,1′-biphenyl]-4-yl)acetic acid and 0.54 g (4.0 mmol) of 1-hydroxy-1H-benzotriazole hydrate are initially charged in 15 ml of dimethylformamide. 0.84 g (4.0 mmol) of 2-methylamino-4-methyl-1,3-thiazole-5-sulphonamide and 0.77 g (4.0 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride are added, and the mixture is stirred at room temperature for 18 h. Most of the dimethylformamide is removed at 50° C. under high vacuum, and the residue is stirred 3 times with in each case 50 ml of water and filtered off, stirred with 50 ml of isopropanol and filtered off once more. Removal of the solvent under reduced pressure gives the compound of Example 87 in the form of a slightly yellow solid.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9](I)[CH:8]=1.B(F)(F)F.CCOCC.[N:24]1[O:25][CH2:26][CH:27]2[CH2:31][N:30]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:29][C:28]=12>O1CCCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([C:28]23[CH2:29][N:30]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:31][CH:27]2[CH2:26][O:25][NH:24]3)[CH:8]=1
Reactant: O=C(OCc1ccccc1)N1CC2=NOCC2C1
Reactant: Fc1ccc(Br)cc1I
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CC2CONC2(c2cc(Br)ccc2F)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 26.5 %

Procedure:
A 1.6 M hexanes solution of n-butyl lithium (25.4 mL, 40.6 mmol) is added drop wise to a −78° C. solution of 4-bromo-1-fluoro-2-iodobenzene (12.22 g, 40.6 mmol) in tetrahydrofuran (60 mL) to give a yellow solution that is stirred at −78° C. for 15 minutes. Boron trifluoride etherate (5.14 mL, 40.6 mmol) is added to a separate −78° C. solution of benzyl 3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate (5 g, 20.3 mmol) in tetrahydrofuran (60 mL) and the mixture is stirred at −78° C. for 5 minutes. This solution is added to the previously prepared −78° C. organolithium mixture via cannula. The combined mixture is stirred for 30 minutes at −78° C. The mixture is quenched with saturated aqueous ammonium chloride and warmed to room temperature. The mixture is extracted with ethyl acetate (3×) and the organic extracts are combined, dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude product is purified over silica gel with a 35 minute 5% to 100% ethyl acetate in hexanes gradient to give the title compound (2.27 g, 27%). ES/MS (m/e): (79Br/81Br) 421/423 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].II>C(#N)C>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:3]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1cc(C)[nH]n1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)n1nc(C)cc1C
Reaction time: 24 h

Procedure:
A suspension of 3,5-dimethyl-1H-pyrazole (Aldrich, 8 g, 0.083 mol), anhydrous K2CO3 (11.50 g, 0.083 mol) and ethyl 2-bromopropanoate (Aldrich, 15 g, 0.083 mol) in 50 mL of dry ACN was refluxed with mechanical stirring for 24 h. Reaction was checked by TLC (iodine), and starting material was detected, so 0.2 equivalents of K2CO3 were added to the mixture which was refluxed over weekend. Reaction was checked, starting material was still detected. 0.2 eq. of K2CO3 were added to the mixture, which was refluxed during 24 h. Reaction was stopped, no advances were observed. Reaction mixture was filtered. Solvent was evaporated under reduced pressure. Residue was diluted with 50 ml of DCM, and washed with water. Organic layer was separated and aqueous fraction was extracted three times with 70 mL of DCM. Combined organic extracts were washed with brine, dried over Na2SO4 (anh), filtered and concentrated under reduce pressure. Residue was purified by chromatographic column 70 g cartridge (ISOLUTE silica) using Hex/EtOAc 100/0 to 20/80 giving (11.6 g 71%) colourless oil. 1H NMR (300 MHz, CDCl3) δ ppm: 5.83 (s, 1H), 4.85 (q, 1H), 4.08-4.25 (m, 2H), 2.22-2.23 (m, 6H), 1.79 (d, 3H), 1.23 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](I)=[C:4]([CH3:10])[CH:3]=1.C([Li])CCC.[B:16](OC)([O:19]C)[O:17]C.Cl>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([B:16]([OH:19])[OH:17])=[C:4]([CH3:10])[CH:3]=1
Reactant: COB(OC)OC
Reactant: Cc1cc(Br)cc(C)c1I
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1B(O)O
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
To a solution of 4-bromo-2,6-dimethyl-1-iodobenzene (150 g, 0.48 mol) in tetrahydrofuran (1500 ml) at −75° C. is added n-butyl lithium (1.6 M in hexanes, 364 ml, 0.58 mol) dropwise maintaining the temperature of the reaction mixture below −70° C. When the addition is complete the mixture is stirred at −75° C. for an additional 30 minutes and then trimethyl borate (302 g, 2.9 mol) is added dropwise. After the addition is complete the reaction is stirred at −75° C. for 1 hour, then allowed to come to room temperature and stirred for 2 hours, followed by cooling in an ice bath and acidification with 0.5 N aqueous hydrochloric acid. The mixture is extracted with ethyl acetate (3×1000 ml) and the organic extracts are combined, washed with brine, dried over anhydrous sodium sulphate. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2,6-dimethylphenylboronic acid (48 g) as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][CH2:11][C:12]([O:14]CC)=[O:13].[OH-].[Na+].Cl>CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)COc1nc2ccccc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1nc2ccccc2s1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
To a solution of 60 (1.32 g, 5.6 mmol) in MeOH was added NaOH (3M, 75 mL, 0.22 mol) dropwise. The mixture was stirred at room temperature over night. It was then cooled in an ice-water bath and acidified to pH<2 with HCl (2N). The mixture was then extracted with CHCl3 (3×). The combined organic layers were dried over Na2SO4 and concentrated in vacuum to yield 61 as a white solid (1.0 g, 86%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:36])[CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:36])/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:13]=2)[N:6]=1
Reactant: [N-]=[N+]=NCCNC(=O)C=Cc1ccccc1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)/C=C/c3ccccc3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.106 g, 0.384 mmol) was reacted with N-(2-azidoethyl)cinnamamide (0.083 g, 0.384 mmol) following the general click procedure to give (E)-tert-butyl 2-amino-4-(5-(1-(2-cinnamamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), δ 7.51 (d, 1H), δ 7.28 (m, 6H), δ 6.45 (t, 2H), δ 6.08 (s, 2H), δ 4.47 (s, 2H), δ 3.79 (s, 2H), δ 2.57 (s, 2H), δ 2.23 (s, 2H), δ 1.50 (bs, 13H), δ 1.28 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 166.9, 150.4, 149.5, 148.3, 141.2, 138.9, 134.9, 129.9, 128.9, 128.0, 122.1, 120.8, 106.5, 84.8, 53.7, 49.5, 39.9, 31.1, 29.3, 28.9, 28.3, 28.2, 25.6 ppm; HRMS (ESI) calcd for C26H35N7O3(M+) 493.2801, found 493.2800, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)cinnamamide hydrochloride (0.097 g, 59% yield). 1H NMR (400 MHz, CD3OD) δ 8.10 (s, 1H), δ 7.49 (s, 3H), δ 7.32 (s, 3H), δ 6.30 d, 1H), δ 6.39 (s, 1H), δ 4.66 (s, 2H), δ 3.83 (s, 2H), δ 2.73 (s, 2H), δ 2.40 (s, 2H), δ 1.57 (s, 2H), δ 1.55 (s, 2H), δ 1.36 (s, 2H) ppm; 13C NMR (100 MHz, CD3OD) δ 167.8, 160.5, 150.2, 147.3, 141.1, 134.8, 130.7, 129.9, 128.8, 127.8, 127.6, 124.9, 23 9, 120.2, 108.5, 108.3, 53.1, 39.3, 36.5, 30.6, 28.4, 28.1, 27.6, 26.5, 24.2, 24.1, 23.7 ppm; HRMS (ESI) calcd for C21H27N7O (M+) 393.2277, found 393.2273.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([S:15](Cl)(=[O:17])=[O:16])=[C:10]([F:19])[CH:9]=1>ClCCl>[Br:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([S:15]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:16])=[O:17])=[C:10]([F:19])[CH:9]=1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=S(=O)(c1cc(F)c(Br)cc1F)N1CCOCC1
Reaction time: 8 h

Procedure:
Morpholine (0.16 ml) was added to a stirred solution of 4-bromo-2,5-difluoro-benzenesulfonyl chloride (0.18 g) in dichloromethane (6 ml) under nitrogen. The reaction mixture was stirred overnight and then quenched with water. The organic phase was dried (MgSO4) and concentrated in vacuo to give the sub-title compound as a white solid (200 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:13])[CH:5]=[N:6][C:7]=1[NH:8][CH2:9][CH:10]=[CH2:11].[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][CH:23]=1)[CH3:20]>ClCCl>[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:1][C:2]2[CH:3]=[C:4]([C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:13])[CH:5]=[N:6][C:7]=2[NH:8][CH2:9][CH:10]=[CH2:11])=[O:30])=[CH:24][CH:23]=1)[CH3:20]
Reactant: CCOc1ccc(CC(=O)Cl)cc1
Reactant: C=CCNc1ncc(C(=O)N(CC)CC)cc1N
Solvent: ClCCl
Product: C=CCNc1ncc(C(=O)N(CC)CC)cc1NC(=O)Cc1ccc(OCC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 2585.9 %

Procedure:
To a solution of 5-amino-N,N-diethyl-6-(2-propenylamino)-3-pyridinecarboxamide (1.61 g, 6.50 mmol) in dichloromethane (50 mL) at 0° C. was added 4-ethoxy-benzeneacetyl chloride (1.35 g, 6.80 mmol). The mixture was stirred for 3 hours at room temperature. The reaction was then quenched with NaHCO3 saturated aqueous solution (100 mL) and extracted with dichloromethane (50 mL). The aqueous phase was back-extracted with additional dichloromethane (2×50 mL). The organic phases were combined, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified using silica gel flash chromatography ([2% MeOH+0.5% NH4OH aq] in CH2Cl2) to provide 1:69 g of the title compound 5-[[(4-ethoxyphenyl)acetyl]amino]-NN-diethyl-6-(2-propenylamino)-3-pyridinecarboxamide (63.3% yield from 5-amino-N,N-diethyl-6-(2-propenylamino)-3-pyridinecarboxamide). 1H-NMR (400 MHz, CDCl3): δ 1.18 (t,J=7.2 Hz, 6H), 1.41 (t,J=7.8 Hz, 3H), 3.42 (br s, 1H), 3.69 (s, 2H), 4.02 (m, 8H), 5.13 (m, 2H), 5.92 (m, 1 H), 6.90 (m, 2H), 7.27 (m, 2H), 7.34 (m, 1H), 8.00 (m, 1H). MS (ES) (M+H)+: 411.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]OS(C)(=O)=O)[CH2:10][C@H:9]1[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:7].[NH:41]1[CH2:46][CH2:45][S:44][CH2:43][CH2:42]1.C(N(CC)CC)C>C(#N)C>[F:38][C:35]([F:37])([F:36])[C:33]1[CH:32]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:40])[F:39])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:41]2[CH2:46][CH2:45][S:44][CH2:43][CH2:42]2)[CH2:10][C@H:9]1[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:7]
Reactant: CS(=O)(=O)OCCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reactant: C1CSCCN1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCN2CCSCC2)C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 90 °C
Reaction time: 15 h

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (0.2 g), thiomorpholine (0.042 g) and triethylamine (0.09 ml) in dry acetonitrile (2 ml) was stirred at 90° C. for 15 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel using ethyl acetate-methanol (10:1) as an eluent to give (2R)-1-(3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-thiomorpholinopropyl)piperazine. The product obtained was dissolved in ethanol and treated with 17.6% hydrogen chloride in ethanol solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-thiomorpholinopropyl)piperazine dihydrochloride (0.19 g) as a powder.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:10]=[C:9]2[O:22][CH2:23][C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25].C(N(CC)CC)C>C(Cl)Cl>[C:1]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:10]=[C:9]2[O:22][CH2:23][C:24]([N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1)=[O:25])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2nc(-c3ccccc3)cc(OCC(=O)N3CCOCC3)c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc2nc(-c3ccccc3)cc(OCC(=O)N3CCOCC3)c2c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of acetyl chloride (0.55 cc) in methylene chloride (5 cc) is added in the course of 10 minutes to a stirred solution of 4-[(6-amino-2-phenyl-4-quinolyl)oxyacetyl]morpholine (2.55 g), prepared according to Example 39, and triethylamine (1.2 cc) in methylene chloride (25 cc). The mixture is stirred for 1 hour at room temperature (approximately 20° C.) and the solvent evaporated off under reduced pressure. The residue is stirred for 10 minutes in an ethyl acetate/water (5:2 by volume) mixture, filtered off, dissolved in a toluene/acetic acid (50:50 by volume) mixture and precipitated with ethyl ether. After filtration and drying, 4-[(6-acetylamino-2-phenyl-4-quinolyl)oxyacetyl]morpholine (2 g), m.p. 261° C., is isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:12]3[NH:13][C:14](=[O:18])[C:15](=[O:17])[NH:16][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:21].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[N:33]=[C:34]=[O:35]>>[O:18]=[C:14]1[NH:13][C:12]2[C:7]([O:6][C:5]3[CH:19]=[CH:20][C:2]([NH:1][C:34]([NH:33][C:24]4[CH:25]=[C:26]([C:29]([F:30])([F:32])[F:31])[CH:27]=[CH:28][C:23]=4[F:22])=[O:35])=[C:3]([F:21])[CH:4]=3)=[CH:8][CH:9]=[N:10][C:11]=2[NH:16][C:15]1=[O:17]
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c(=O)[nH]c23)cc1F
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)c(=O)[nH]c23)cc1F)Nc1cc(C(F)(F)F)ccc1F

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)pyrido[3,2-b]pyrazine-2,3(1H,4H)-dione and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene to give the title compound as a beige solid. Yield: 52 mg (51%).
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.I(O)(=O)(=O)=[O:15].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.[Fe](Cl)(Cl)Cl>[CH:1]1([S:4]([C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)=[O:15])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(SC2CC2)cc1
Reactant: [O-][I+3]([O-])([O-])O
Agent: Cl[Fe](Cl)Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(S(=O)C2CC2)cc1
Temperature: 25 °C
Yield: 76 %

Procedure:
1-Cyclopropylsulphanyl-4-nitrobenzene in acetonitrile was admixed with iron(III) chloride and stirred at room temperature. Periodic acid was then added in portions. The mixture was stirred for 30 minutes and then added, with stirring, to a cooled, saturated sodium thiosulphate solution. Extraction was carried out with acetic ester (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. The residue obtained was purified by means of chromatography (hexane/acetic ester 1:1) (yield: 76%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:21]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[K+].[C:29]([C:31]1[N:32]=[C:33]([C:44]([O-])=[O:45])[N:34]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH:35]=1)#[N:30].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:44]([C:33]3[N:34]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH:35]=[C:31]([C:29]#[N:30])[N:32]=3)=[O:45])=[C:16]([C:21]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(C3=CCCCCC3)c2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 88.4 %

Procedure:
A solution of 108 mg (0.292 mmol) 4-(4-amino-3-cyclohept-1-enyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (as prepared in the previous step) in 10 mL CH2Cl2 was treated with 97.9 mg (0.321 mmol) 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), 204 mg (0.437 mmol) PyBrOP, and 152 μL (0.874 mmol) DIEA and stirred at RT for 17 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with saturated NaHCO3 (1×15 mL) and water (1×15 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a Varian MegaBond Elut 50-gm column with 10-25% EtOAc-hexane afforded 160 mg (88%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C30H42N5O4Si, 563.3 (M−C4H9+2H), found 563.9.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:27][CH3:28])=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][N:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1)[O:8][CH2:7][CH2:6]2)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:28][O:27][C:4]1[C:3]([C:1]#[N:2])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][O:8][CH:9]2[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: COc1c(C#N)ccc2c1CCOC2CN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C#N)ccc2c1CCOC2CN1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-[(6-cyano-5-methoxy-3,4-dihydro-1H-isochromen-1-yl)methyl]piperazine-1-carboxylate (30 mg, 0.08 mmol) in 5 mL of DCM was added 5 mL of TFA was stirred at room temperature for 1 hours, and the reaction was concentrated to afford 5-methoxy-1-(piperazin-1-ylmethyl)-3,4-dihydro-1H-isochromene-6-carbonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1]
Reactant: Cc1ccc(I)cc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(I)ccc1CBr
Temperature: 25 °C
Yield: 57.2 %

Procedure:
To a solution of 2-fluoro-4-iodotoluene (2.83 g, 12 mmol) in CCl4 (120 mL) were added NBS (2.24 g, 12.6 mmol) and BPO (0.06 g, 0.24 mmol). The reaction mixture was refluxed for 9 h under N2, then cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE) to give the title compound as a white solid (2.16 g, 57%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].Cl[C:12]([O:14][CH2:15][CH3:16])=O.C>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:15]([O:14][C:12]1[O:9][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1)[CH3:16]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccccc1C(=O)O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOc1nc2ccccc2c(=O)o1
Reaction time: 2 h

Procedure:
To a solution of anthranilic acid (0.1 mol., 13.71 gm) in dry pyridine (100 ml) at room temperature under anhydrous conditions was added ethyl chloroformate (4 equiv., 38.25 ml) in a dropwise manner over 15 minutes. After stirring for 2 hours, excess pyridine was removed under reduced pressure at 40° C. (bath temperature) and the residue was stirred vigorously in ice cold water (250 ml) for 15 minutes. The pale yellow powder was collected by filtration, washed with water (100 ml), and air-dried to give 18.6 gm of crude product. The crude product was treated with active charcoal (2 gm) in ethyl acetate (150 ml) to afford a white solid after removal of solvent. Recrystallization from EtOAc-ether gave 17.02 (89%) of the title compound, 2-ethoxy-4H-3,1-benzoxazin-4-one, as colorless crystals; m.p. 88°-90.5° C.; IR (KBr): νmax 1760 cm-1 (C=O), 1630 cm-1 (C=N); H'NMR (CDCl3); δ1.46 ppm (t, J=7.1 Hz, 3H,)CH2CH3), 4.53 ppm (q, J=7.1 Hz, 2H, OCH2CH3), 7.30-8.20 ppm (m, 4H, aromatic protons).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:15]([CH3:20])[C:16]([CH3:19])=[CH:17][N:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[CH3:20][N:15]1[C:16]([CH3:19])=[CH:17][N:18]=[C:14]1[N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:7][CH:6]=2)[CH2:13][CH2:12]1
Reactant: Cc1cnc(N2CCN(c3ccc(N)cc3)CC2)n1C
Reactant: CS(=O)(=O)Cl
Product: Cc1cnc(N2CCN(c3ccc(NS(C)(=O)=O)cc3)CC2)n1C

Procedure:
Treatment of 1-(4-aminophenyl)-4-(1,5-dimethylimidazol-2-yl)piperazine with methanesulphonylchloride followed by chromatography as described in Example 5(v) gave the title compound, m.p. 257° C. (decomp). Found: C,55.00; H,6.70; N,19.55. C16H23N5O2S requires: C,54.99; H,6.63; N,20.04%.