Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:20]=[CH:21]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:36])C(=O)C1.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:36][C:23]1[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[CH:15][CH:16]=[C:17]2[C:22]=1[CH:21]=[N:20][C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2cn1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(Br)c2cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of compound ethyl 7-(4-(tert-butoxycarbonyl)piperazin-1-yl)isoquinoline-3-carboxylate (1.1 g, 2.85 mmol) in DCM (10 mL) was added NBS (508 mg, 2.85 mmol) following by stirring at 0° C. for 1 h. To the reaction mixture was added saturated Na2SO3 (20 ml). The combined organic layers were dried by anhydrous Na2SO4, concentrated in vacuo, and washed by PE to afford ethyl 8-bromo-7-(4-(tert-butoxycarbonyl)piperazin-1-yl)isoquinoline-3-carboxylate as a light yellow solid (900 mg, yield: 70%).
Reaction SMILES: [OH-].[Na+].[C:3]1([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:15](Br)[CH:16]=[C:17]([CH3:19])[CH3:18].Cl>>[O:14]=[C:10]([CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[C:11]([OH:13])=[O:12]
Reactant: O=C(O)C(=O)Cc1ccccc1
Reactant: CC(C)=CCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)=CCC(C(=O)C(=O)O)c1ccccc1

Procedure:
A 1N aqueous solution of sodium hydroxide (20 ml: 20 mmoles) was added to 1.64 g (10 mmoles) of phenylpyruvic acid to form a solution. Then 1.49 g (10 mmoles) of prenyl bromide was added, and the mixture was reacted at room temperature for 13 hours. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with three 50 ml portions of the ether. The organic layers were dried over magnesium sulfate, and the ether was evaporated under reduced pressure to give 2-oxo-3-phenyl-6-methyl-5-heptenoic acid as a pale yellowish white solid. The product was converted to a methyl ester using diazomethane, and the methyl ester was purified by silica gel column chromatography to give methyl 2-oxo-3-phenyl-6-methyl-5-heptenoate as a nearly pure product (1.72 g; yield 70 %).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH:16]1([N:19]2[CH:24]=[C:23]([CH:25]=[CH2:26])[CH:22]=[CH:21][C:20]2=[O:27])[CH2:18][CH2:17]1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:23]3[CH:22]=[CH:21][C:20](=[O:27])[N:19]([CH:16]4[CH2:17][CH2:18]4)[CH:24]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1ccc(=O)n(C2CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2ccc(=O)n(C3CC3)c2)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 1-cyclopropyl-5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: O=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C(O)(=O)C.S([O-])([O-])(=O)=O.[Mg+2]>C(O)C>[F:12][C:13]([F:21])([F:22])[C:14]1[CH:15]=[C:16]([NH:17][C:2]([CH2:9][CH2:10][CH3:11])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCCC(=O)CC(=O)OCC
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCC(=CC(=O)OCC)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
0.85 g (5.4 mmol) Ethyl 3-oxohexanoate, 1.0 g (6.21 mmol) 3-trifluoromethylaniline and 5 mg (0.08 mmol) acetic acid are dissolved in 15 ml ethanol, and 0.78 g (6.5 mmol) magnesium sulfate are added. The reaction mixture is stirred at reflux overnight. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with dichloromethane as eluent.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[C:29]([N:8]([CH2:9][C:10]1([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:11][CH2:12]1)[C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)C1(CNc2ccc(Cl)nc2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1(CN(C(=O)c2ccccc2)c2ccc(Cl)nc2)CC1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
10.17 g of the compound obtained in Step 1 of Example 9 are dissolved in 200 ml of tetrahydrofuran, 4.88 ml of triethylamine are added, cooling to 5° C. is carried out and, over a period of 30 minutes, 5.05 g of benzoyl chloride are poured in. Stirring is carried out for one hour at 5° C. and then for one hour at ambient temperature, and subsequently refluxing is carried out for 2 hours. Concentration to dryness is carried out and the residue is taken up in dichloromethane and washed with 50% aqueous potassium carbonate solution. The organic phase is dried over sodium sulphate and concentrated, and chromatography of the residue on silica gel (dichloromethane/tetrahydrofuran: 96/4) allows 13.9 g of expected product to be obtained.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36])(OCC)=O>C(#N)C.O>[C:27]1(=[O:36])[N:1]([CH:2]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[CH2:3][C:4]([OH:6])=[O:5])[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: COc1ccc(C(N)CC(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a stirred mixture of 3-amino-3-(4-methoxyphenyl)propionic acid (1.95 g, 10.0 mmol) and sodium carbonate (1.11 g, 10.5 mmol) in 200 mL of acetonitrile-water 1:1 is added N-carboethoxyphthalimide (2.26 g, 10.0 mmol). After 1 hour, the reaction slurry is filtered. The filtrate is concentrated to remove the acetonitrile and the pH adjusted to 1-2 with 4 N hydrochloric acid and stirred over night. The resulting slurry is filtered and the solid washed with water. The solid is dried in vacuo (60 C, <1 mm) to afford 2.82 g (87%) of 3-phthalimido-3-(4-methoxyphenyl)propionic acid as a white powder: mp 160-164° C.; 1H NMR (DMSO-d6, 250 MHz) δ12.5 (br s, 1H), 7.95-7.80 (m, 4H), 7.36 (d 2H, J=8.7), 6.92 (d, 2H, J=8.4 Hz), 5.18-5.10 (m, 1H), 3.70-3.15 (m, 2H); 13C NMR (DMSO-d6) δ171.7, 167.6, 158.6, 134.6, 131.0, 130.8, 128.3, 123.1, 113.9, 55.0, 49.6, 35.9. Anal. Calculated for C18H15NO5. Theoretical: C, 66.46; H, 4.63; N, 4.31. Found: C, 66.25; H, 4.65; N, 4.28.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C:16]3[C@@H:15]4[CH2:17][C@@H:14]4[CH2:13][C:12]=3[C:11]([C:18](O)=[O:19])=[N:10]2)[CH:4]=1)#[N:2].[NH2:21][C:22]([CH3:27])([CH2:25][OH:26])[CH2:23][OH:24].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:24][CH2:23][C:22]([NH:21][C:18]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:17][C@H:15]3[C:16]=2[N:9]([C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][N:6]=2)[N:10]=1)=[O:19])([CH2:25][OH:26])[CH3:27]
Reactant: CC(N)(CO)CO
Reactant: N#Cc1ccnc(-n2nc(C(=O)O)c3c2[C@@H]2C[C@@H]2C3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(CO)(CO)NC(=O)c1nn(-c2cc(C#N)ccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
To a solution of (1aR,5aR)-2-(4-cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (100 mg, 0.376 mmol), 2-amino-2-methylpropane-1,3-diol (39.5 mg, 0.376 mmol), and triethylamine (0.105 mL, 0.751 mmol) in DMF (2 mL) was added HATU (157 mg, 0.413 mmol). The reaction was stirred at 23° C., for 30 min then concentrated. The residue was purified by silica gel flash column chromatography to give the title compound (125 mg) as a white solid. LCMS m/z=354.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.46 (td, J=4.7, 3.3 Hz, 1H), 1.27 (td, J=8.0, 4.9 Hz, 1H), 1.36 (s, 3H), 2.27-2.33 (m, 1H), 2.78-2.89 (m, 2H), 3.00 (dd, J=16.8, 6.4 Hz, 1H), 3.72-3.77 (m, 4H), 3.87-3.94 (m, 2H), 7.23 (m, 1H), 7.42 (dd, J=5.1, 1.0 Hz, 1H), 8.16-8.17 (m, 1H), 8.62 (d, J=5.1 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][C:8]([OH:10])=O)[C:3](=[O:5])[CH3:4].[CH:11]1([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:25]=[C:26]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[C:27]4[CH2:32][NH:31][CH2:30][C:28]=4[N:29]=3)=[CH:20][CH:19]=2)=[O:16])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][C:15](=[O:16])[NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[N:25]=[C:26]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[C:27]4[CH2:32][N:31]([C:8](=[O:10])[CH2:7][CH2:6][N:2]([CH3:1])[C:3](=[O:5])[CH3:4])[CH2:30][C:28]=4[N:29]=3)=[CH:22][CH:23]=2)[CH2:13][CH2:12]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Reactant: CC(=O)N(C)CCC(=O)O
Product: CC(=O)N(C)CCC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3)nc(N3CCOC[C@@H]3C)c2C1
Yield: 26 %

Procedure:
Method as example 127 using 3-(N-methylacetamido)propanoic acid and (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 3) as starting materials to yield a white solid (36.8 mg, 0.071 mmol, 26%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccn1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccn2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-pyridin-2-yl-methanone and 116 mg of 4-tert-Butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.24 (s, 9H), 7.34-7.38 (m, 2H), 7.47 (dd, 1H, J=8.8 Hz, 2.4 Hz), 7.60 (m, 1H), 7.65-7.68 (m, 4H), 7.85 (d, 1H, J=8 Hz), 8.00 (td, 1H, J=7.6 Hz, 2 Hz), 8.71 (bd, 1H, J=4.8 Hz). MS: m/z 429.9 (M++1).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[N:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10](=[O:11])[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)[C@@H:3]1[CH2:2][NH:1][C:25]1[N:30]=[N:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1
Reactant: N#Cc1ccc(Cl)nn1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C#N)nn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 6-chloropyridazine-3-carbonitrile. ESI-MS (m/z): 417 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2].[S:23]([O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32]OS(=O)(=O)C)(=[O:26])(=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][S:23]([CH3:24])(=[O:26])=[O:25])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2]
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1O
Reactant: CS(=O)(=O)OCCOCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOS(C)(=O)=O
Yield: 66.5 %

Procedure:
A mixture of 4 g (0.013 mol) of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester, 17 g (0.065 mol) of diethylene glycol dimesylate and 3.6 g (0.026 mol) of anhydrous potassium carbonate in 80 ml of anhydrous acetone and 40 ml of anhydrous dimethylformamide was stirred at reflux for 20 hours. An additional 1.8 g of potassium carbonate was added and reflux was continued for a total of 44 hours. The reaction mixture was filtered and concentrated in vacuo to an orange oil which was treated with ethyl acetate and sodium chloride solution. The yellow oil obtained on concentration of the ethyl acetate was purified by HPLC, eluting with 15% ethyl acetate/toluene to yield 4.1 g (67% yield) of 4-[4-acetyl-3-[2-[2-[(methylsulfonyl)oxy]ethoxy]-ethoxy]-2-propylphenoxy]butanoic acid ethyl ester as a yellow oil.
Reaction SMILES: C(O[CH2:5][CH:6]=[CH:7][CH2:8][N:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)C.C1([CH:30]([NH2:37])[CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)CCCCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]1([CH2:17][N:9]([CH2:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:8][CH:7]=[CH:6][CH2:5][N:37]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(=O)OCC=CCN(Cc1ccccc1)Cc1ccccc1
Reactant: NC(C1CCCCC1)C1CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C(=CCN(CC1CCCCC1)CC1CCCCC1)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-acetoxy-4-dibenzylamino-2-butene (10.1 g, 33 mmol) and dicyclohexylmethylamine (6.8 g, 32 mmol) in 50 ml of THF is treated with tetrakis(triphenylphosphine)palladium (0) (1.0 g, 0.9 mmol) and stirred at room temperature overnight. The reaction mixture is concentrated in vacuo to a solid which is redissolved in 100 ml of THF and treated with 25 ml of 20% aqueous sodium hydroxide. The mixture is stirred for one hour, concentrated and extracted with diethyl ether. The ether extracts are dried and concentrated to give a solid which is then purified by crystallization from isopropanol. The title compound is obtained in a yield of 9.7 g (65%) as a white solid melting at 61°-62° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:37]=[CH:36][C:17]2[NH:18][C:19]([S:21][CH2:22][C:23]3[C:28]([F:29])=[C:27]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:26]=[CH:25][N:24]=3)=[N:20][C:16]=2[CH:15]=1.N>ClCCl>[O:33]1[CH2:34][CH2:35][N:30]([C:27]2[CH:26]=[CH:25][N:24]=[C:23]([CH2:22][S:21]([C:19]3[NH:18][C:17]4[CH:36]=[CH:37][C:14]([O:13][CH3:12])=[CH:15][C:16]=4[N:20]=3)=[O:9])[C:28]=2[F:29])[CH2:31][CH2:32]1
Reactant: COc1ccc2[nH]c(SCc3nccc(N4CCOCC4)c3F)nc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: N
Solvent: ClCCl
Product: COc1ccc2[nH]c(S(=O)Cc3nccc(N4CCOCC4)c3F)nc2c1
Reaction time: 0.33 h
Yield: 73 %

Procedure:
m-Chloroperbenzoic acid (1.06 g) in dichloromethane (50 ml) was added dropwise to a stirred solution of 5-methoxy-2-(4-morpholino-3-fluoro-2-pyridylmethylthio)-(1H)-benzimidazole (2.31 g) in dichloromethane (50 ml) at -30° to -35°. After 0.5 hour at -30° a further addition of m-chloroperbenzoic acid (0.106 g) in dichloromethane (15 ml) was made and the mixture stirred for a further 20 minutes at -30°. Ammonia gas was then passed through the solution and the precipitated benzoate salts filtered off. The filtrate was evaporated to dryness and the residue crystallised from ethyl acetate to yield 2-(4-morpholino-3-fluoro-2-pyridylmethylsulphinyl)-5-methoxy-(1H)-benzimidazole (1.75 g) m.p. 142°-46°
Reaction SMILES: Cl.Cl[C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[CH:17][CH:18]=1)[N:8]=[C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[N:10]=2.C(N(CC)CC)C.Cl[C:27]1[N:36]=[C:35]([NH2:37])[C:34]2[C:29](=[CH:30][C:31]([O:40][CH3:41])=[C:32]([O:38][CH3:39])[CH:33]=2)[N:28]=1>C(O)CCC>[N:8]1[C:7]2=[CH:17][CH:18]=[CH:3][CH:4]=[CH:5][C:6]2=[N:10][C:9]=1[N:11]1[CH2:16][CH2:15][N:14]([C:27]2[N:36]=[C:35]([NH2:37])[C:34]3[C:29](=[CH:30][C:31]([O:40][CH3:41])=[C:32]([O:38][CH3:39])[CH:33]=3)[N:28]=2)[CH2:13][CH2:12]1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: Clc1ccc2nc(N3CCNCC3)nc-2cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1cc2nc(N3CCN(c4nc5cccccc-5n4)CC3)nc(N)c2cc1OC
Reaction time: 1 h
Yield: 95 %

Procedure:
A mixture of 2-(1-piperazinyl)cycloheptimidazole hydrochloride (4.53 g, described in Example 1) and triethylamine (3.64 g) in butanol (500 ml) was stirred for one hr and 2-chloro-4-amino-6,7-dimethoxyquinazoline [4.35 g, prepared as described by T. H. Althuis and H.-J. Hess, J. Med. Chem., 20, 146 (1977)] was added. The mixture was refluxed for 18 hr. The resulting precipitate was collected on a filter. The filtrate was evaporated to dryness. A suspension of the precipitate and the evaporated filtrate in a cold, aqueous solution of sodium bicarbonate (5% w/v) was stirred for 30 min and filtered. The precipitate was washed with water, air-dried and crystallized from methanoldichloromethane to give the title compound (6.3 g): mp 294°-296° C.; ir (nujol mull) 3300, 3180, 1650, 1625, 1598 and 1560 cm-1 ; uv max (MeOH) 251 nm (ε=63670); nmr (DMSO-d6) δ 3.85 (m, 14H) and 7.4 (m, 7H); and Anal. Calcd for C22H23N7O2 : C, 63.29% H, 5.55% N, 23.49% and Found: C, 62.96% H, 5.60% N, 23.61%.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH:14]([C:23]1[CH:24]=[N:25][C:26]([N:29]([CH3:31])[CH3:30])=[N:27][CH:28]=1)[N:15]1[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17][CH2:16]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:12][CH2:13][CH:14]([N:15]1[CH2:16][CH2:17][C:18]([F:21])([F:22])[CH2:19][CH2:20]1)[C:23]1[CH:24]=[N:25][C:26]([N:29]([CH3:31])[CH3:30])=[N:27][CH:28]=1)=[O:6]
Reactant: CN(C)c1ncc(C(CN)N2CCC(F)(F)CC2)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: CN(C)c1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCC(F)(F)CC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 5-(2-amino-1-(4,4-difluoropiperidin-1-yl)ethyl)-N,N-dimethylpyrimidin-2-amine.
Reaction SMILES: CS[S:3][CH3:4].N(OC(C)(C)C)=O.N[C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=2[Cl:30])[C:14]=1[N+:31]([O-:33])=[O:32]>C(Cl)Cl>[Cl:25][C:24]1[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=[C:20]([Cl:30])[C:19]=1[C:15]1[C:14]([N+:31]([O-:33])=[O:32])=[C:13]([S:3][CH3:4])[N:17]([CH3:18])[N:16]=1
Reactant: CSSC
Reactant: Cn1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c([N+](=O)[O-])c1N
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: CSc1c([N+](=O)[O-])c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
First 1.4 g of dimethyl disulfide and then 0.96 g of tert-butyl nitrite were added at 0° C. to a solution of 1.1 g of 5-amino-3-(2,6-dichloro-4-trifluoromethylphenyl)-1-methyl-4-nitropyrazole (14) in 25 ml of anhydrous methylene chloride, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the resulting residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) to afford 0.6 g of the desired compound in the form of a yellow consistent liquid (yield 60.1%).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH3:24][N:25]([CH3:36])[CH2:26][C:27]#[C:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>>[CH3:36][N:25]([CH3:24])[CH2:26][C:27]#[C:28][C:29]1[CH:30]=[CH:31][C:32]([NH:33]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:34][CH:35]=1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CN(C)CC#Cc1ccc(N)cc1
Product: CN(C)CC#Cc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 89 by reacting 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone with 4-(3-dimethylaminoprop-1-ynyl)-aniline.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:21](OC)(OC)(OC)[CH2:22][CH2:23][CH3:24]>C1(C)C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:22]([C:21]1[N:12]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:23][CH3:24]
Reactant: CCOC(=O)CCCNc1c(N)cnc2ccccc12
Reactant: CCCC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Reaction time: 8 h
Yield: 83.4 %

Procedure:
A solution of ethyl 4-[(3-aminoquinolin-4-yl)amino]butanoate (49.7 g, 182 mmol, prepared as described in Parts A and B of Example 3) in toluene (500 mL) was heated at reflux for 10 minutes and then cooled slightly. Trimethyl orthobutyrate (29.0 g, 197 mmol) and pyridinium p-toluenesulfonate (0.70 g, 2.8 mmol) were added, and the reaction was heated at reflux under a Dean-Stark trap for 1.5 hours while the distillate was periodically removed. The reaction was allowed to stand overnight at ambient temperature. The toluene was removed under reduced pressure; chloroform (500 mL) and charcoal (4 g) were sequentially added. The resulting mixture was heated at reflux for one hour and then filtered through a layer of CELITE filter agent. The filtrate was washed with saturated aqueous sodium bicarbonate (100 mL), dried over potassium sulfate, filtered, and concentrated under reduced pressure to provide 49.4 g of ethyl 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanoate as a dark oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:10][C:11]([F:23])([F:22])[O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[F:10][C:11]([F:22])([F:23])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]#[N:9])=[CH:15][CH:14]=1
Reactant: N#Cc1cccnc1Cl
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: N#Cc1cccnc1-c1ccc(OC(F)(F)F)cc1
Yield: 70 %

Procedure:
Prepared in 70% yield from 2-chloro-3-cyanopyridine and 4-trifluoromethoxyphenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 265.0 (M+H)+; 1H NMR (CDCl3) δ 7.37-7.44 (m, 3H), 7.98-8.03 (m, 2H), 8.10 (dd, J=8.0, 1.9 Hz, 1H), 8.89 (dd, J=4.7, 1.7 Hz, 1H).