Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10](=O)[C:11]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13][C:12]=2[N:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:41]>C(#N)C>[CH2:1]([C:8]1[N:9]=[C:10]([Cl:41])[C:11]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13][C:12]=2[N:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(OCc1ccccc1)N1CCc2nc(Cc3ccccc3)[nH]c(=O)c2CC1
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: O=C(OCc1ccccc1)N1CCc2nc(Cc3ccccc3)nc(Cl)c2CC1
Temperature: 80 °C
Yield: 85.8 %

Procedure:
To a suspension of the product from step A (4 g, 10 mmol) in acetonitrile (100 ml) was added N,N-dimethylaniline (1.4 ml, 11.3 mmol), followed by careful addition of POCl3 (9.6 ml, 100 mmol). The resulting brown solution was heated at 80° C. for 4 h. The reaction mixture was concentrated in vacuo, azeotroped with PhMe (×2) and DCM. The residue was partitioned between 2 N HCl and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo to yield 3.5 g (84%) of title compound as brown oil, which solidified on standing.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.Cl[C:11]1[N:19]=[C:18]2[C:14]([N:15]=[C:16]([CH2:21][N:22]3[CH2:27][CH2:26][N:25]([C:28]([CH3:32])([CH3:31])[CH2:29][OH:30])[CH2:24][CH2:23]3)[N:17]2[CH3:20])=[C:13]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:12]=1.[F:39][CH:40]([F:44])[C:41](O)=O>>[F:39][C:40]([C:2]1[N:3]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][N:25]([C:28]([CH3:32])([CH3:31])[CH2:29][OH:30])[CH2:24][CH2:23]4)[N:17]3[CH3:20])=[C:13]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:12]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1)([F:44])[CH3:41]
Reactant: O=C(O)C(F)F
Reactant: c1ccc2[nH]cnc2c1
Reactant: Cn1c(CN2CCN(C(C)(C)CO)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCN(C(C)(C)CO)CC2)nc2c(N3CCOCC3)nc(-n3c(C(C)(F)F)nc4ccccc43)nc21

Procedure:
Following General Procedure J for Multi-Step Benzimidazole formation, 2-(4-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-1-yl)-2-methylpropan-1-ol was converted to 473 with difluoroacetic acid. LCMS: M+H+=570.3
Reaction SMILES: CN(C)C=O.[CH2:6]([C:12]1[CH:27]=[CH:26][C:15]([CH2:16][S:17][C@@H:18]2[CH2:22][NH:21][C@H:20]([C:23]([OH:25])=[O:24])[CH2:19]2)=[CH:14][CH:13]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:28]([S:36][CH2:37][C@@H:38]([CH3:51])[C:39](OC1C=CC([N+]([O-])=O)=CC=1)=[O:40])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(N(CC)CC)C>[C:28]([S:36][CH2:37][C@@H:38]([CH3:51])[C:39]([N:21]1[CH2:22][C@@H:18]([S:17][CH2:16][C:15]2[CH:26]=[CH:27][C:12]([CH:6]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:13][CH:14]=2)[CH2:19][C@H:20]1[C:23]([OH:25])=[O:24])=[O:40])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCCCCCc1ccc(CS[C@@H]2CN[C@H](C(=O)O)C2)cc1
Reactant: C[C@H](CSC(=O)c1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](CSC(=O)c1ccccc1)C(=O)N1C[C@@H](SCc2ccc(C3CCCCC3)cc2)C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Dimethylformamide (4.5 ml) is added to (4S)-4-(4-hexylbenzylthio)-L-proline (430 mg), and the mixture is cooled to 0° C. To the mixture are added successively triethylamine (0.21 ml) and 4-nitrophenyl (2S)-3-(benzoylthio)-2-methylpropionate, and the obtained mixture is stirred at room temperature overnight. To the reaction mixture is added 10% citric acid, and the whole is extracted with ethyl acetate. The organic layer is washed with water and a saturated sodium chloride aqueous solution successively and dried over sodium sulfate. The residue obtained by concentration under reduced pressure is purified by silica gel column chromatography to give 580 mg (81%) of the titled compound as an amorphous substance.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[OH:5][C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][CH2:20][CH2:21][C:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:24])[CH3:23])([CH2:10][CH2:11][CH3:12])[CH2:7][CH2:8][CH3:9].C(N(CC)CC)C.N>C1COCC1.CCOC(C)=O>[C:28]([O:27][C:26](=[O:32])[NH:25][C:22]([CH3:23])([CH3:24])[CH2:21][CH2:20][N:19]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:6]([CH2:7][CH2:8][CH3:9])([CH2:10][CH2:11][CH3:12])[O:5][C:1]1=[O:2])([CH3:30])([CH3:29])[CH3:31]
Reactant: O=C(Cl)Cl
Reactant: CCCC(O)(CCC)c1ccccc1NCCC(C)(C)NC(=O)OC(C)(C)C
Agent: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC1(CCC)OC(=O)N(CCC(C)(C)NC(=O)OC(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.85 mL (16.81 mmol) of phosgene solution (20 wt. % in toluene) is slowly added dropwise at 0° C. to a solution of 6.00 g (15.28 mmol) of tert-butyl {3-[2-(1-hydroxy-1-propylbutyl)phenylamino]-1,1-dimethylpropyl}carbamate and 5.32 mL (38.21 mmol) of triethylamine in absolute THF (80 mL). The mixture is stirred for 2 hours at RT, diluted with EtOAc, combined with ice, and made basic with saturated aqueous ammonia solution. The aqueous phase is exhaustively extracted with EtOAc and the combined organic phases are washed with saturated aqueous NaCl, dried with sodium sulfate, and evaporated down in vacuo. After column chromatography (silica gel, cyclohexane/EtOAc 6:1) the product is obtained as a yellow oil. Yield: 4.57 g (71%).
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].Br.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1([CH:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([O:27][CH3:28])[CH:25]=3)[CH2:20][CH2:19]N2)[CH2:16][CH2:15]1.C=O>CO>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1([CH:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([O:27][CH3:28])[CH:25]=3)[CH2:20][CH2:19][N:2]2[CH3:1])[CH2:16][CH2:15]1
Reactant: [BH3-]C#N
Reactant: COc1cc2c(cc1F)CCNC2C1(c2ccc(Cl)cc2Cl)CC1
Agent: Br
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(cc1F)CCN(C)C2C1(c2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium cyanoborohydride (2.8 g) was added at 5° C. to a mixture of 1-[1-(2,4-dichlorophenyl)cyclopropyl]-6-fluoro-7-methoxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (10 g, prepared as described in Example RC4), methanol (100 ml) and 37-40% aqueous formaldehyde solution (7.2 ml). The mixture was warmed to ambient temperature and stirred for 1.5 hours. The solvent was removed in vacuo and the residue partitioned between water and dichloromethane. The organic phase was washed with concentrated ammonia solution, then water, and dried over magnesium sulphate. The solvent was removed in vacuo to yield 1-[1-(2,4-dichlorophenyl)cyclopropyl]-6-fluoro-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline as a gum which solidified on standing.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:47])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[N:18]=[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]3[C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32]C3C=CC(OC4CCNCC4)=CC=3C)[N:27]=2)[CH:12]=1.[CH3:48][O:49][C:50]1[CH:56]=[C:55]([N:57]2[CH2:62][CH2:61][N:60]([S:63]([CH3:66])(=[O:65])=[O:64])[CH2:59][CH2:58]2)[CH:54]=[CH:53][C:51]=1N.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:78]([OH:83])[C:79](F)(F)F.N>CO.C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[NH:9][C:10](=[O:47])[C:11]1[CH:12]=[C:13]([C:17]2[N:18]=[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]3[C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:51]3[CH:53]=[CH:54][C:55]([N:57]4[CH2:62][CH2:61][N:60]([S:63]([CH3:66])(=[O:65])=[O:64])[CH2:59][CH2:58]4)=[CH:56][C:50]=3[O:49][CH3:48])[N:27]=2)[CH:14]=[CH:15][C:16]=1[O:83][CH2:78][CH3:79]
Reactant: COc1cc(N2CCN(S(C)(=O)=O)CC2)ccc1N
Reactant: OCC(F)(F)F
Reactant: Cc1cc(OC2CCNCC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3ccc(N4CCN(S(C)(=O)=O)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 100 °C
Yield: 56 %

Procedure:
[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (100 mg, 0.2 mmol), 2-(methyloxy)-4-[4-(methylsulfonyl)-1-piperazinyl]aniline (51 mg, 0.18 mmol), and p-toluenesulfonicacid (90 mg, 0.47 mmol) were weighed into a 20 mL vial. 1 mL of trifluoroethanol was added and the mixture was heated to 100° C. for 72 h. 2 mL of 2 N ammonia in MeOH was added. The solvent was rotovaped down. The residue was taken up in 3 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-absorbed solids were purified by flash chromatography to give the title compound (75 mg, 0.099 mmol, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.74 (s, 1H), 9.37 (s, 1H), 8.48 (s, 1H), 8.21 (d, J=5.13 Hz, 1H), 8.04 (d, J=1.83 Hz, 1H), 7.74 (dd, J=8.61, 2.38 Hz, 1H), 7.69 (d, J=8.80 Hz, 1H), 7.42-7.49 (m, 2H), 7.34-7.40 (m, 1H), 7.26 (d, J=8.80 Hz, 1H), 7.19 (t, J=8.07 Hz, 2H), 6.96 (t, J=7.15 Hz, 1H), 6.73 (d, J=2.57 Hz, 1H), 6.50-6.56 (m, 2H), 4.26 (q, J=6.97 Hz, 2H), 3.81 (s, 3H), 3.25 (br. s., 8H), 2.92 (s, 3H), 1.43 (t, J=6.97 Hz, 3H); MS (ESI): 755 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([NH:15][C@H:16]([C:20]([O:22][CH2:23][C@H:24]([CH2:37][CH2:38][O:39][C:40](=[O:58])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:25][N:26]1[CH:34]=[N:33][C:32]2[C:31](=[O:35])[NH:30][C:29]([NH2:36])=[N:28][C:27]1=2)=[O:21])[CH:17]([CH3:19])[CH3:18])(OC(C)(C)C)=O>>[NH2:15][C@H:16]([C:20]([O:22][CH2:23][C@H:24]([CH2:37][CH2:38][O:39][C:40](=[O:58])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:25][N:26]1[CH:34]=[N:33][C:32]2[C:31](=[O:35])[NH:30][C:29]([NH2:36])=[N:28][C:27]1=2)=[O:21])[CH:17]([CH3:19])[CH3:18].[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC[C@@H](COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Reactant: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCCC(=O)OCC[C@@H](COC(=O)[C@@H](N)C(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Product: O=C([O-])C(F)(F)F
Reaction time: 1 h

Procedure:
Chilled trifluoroacetic acid (2.0 g) was added to (R)-9-[2-(N-Boc-L-valyloxymethyl)-4-(stearoyloxy)butyl]guanine (180 mg; 0.25 mmol) and the solution kept at room temperature for 1 h, evaporated to a small volume, and lyophilized repeatedly with dioxane until a white amorphous powder was obtained. The yield of title compound, obtained as the trifluoracetate salt, was quantitative.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][CH:6]=[N:5]1)[C:2]#[CH:3].C(NC(C)C)(C)C.I[C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[C:40]2[CH:45]=[CH:44][C:43]([S:46][CH3:47])=[CH:42][CH:41]=2)=[CH:24]\[CH2:25][O:26][C:27]2[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[C:29]([CH3:39])[CH:28]=2)=[CH:19][CH:18]=1>O1CCCC1.[Cu]I.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>[CH3:39][C:29]1[CH:28]=[C:27]([O:26][CH2:25]/[CH:24]=[C:23](/[C:40]2[CH:45]=[CH:44][C:43]([S:46][CH3:47])=[CH:42][CH:41]=2)\[C:20]2[CH:21]=[CH:22][C:17]([C:3]#[C:2][CH2:1][N:4]3[CH:8]=[CH:7][CH:6]=[N:5]3)=[CH:18][CH:19]=2)[CH:38]=[CH:37][C:30]=1[O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: C#CCn1cccn1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(SC)cc2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCn3cccn3)cc2)c2ccc(SC)cc2)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-Propargylpyrazole (0.530 g, 5.0 mmol) and diisopropylamine (1.6 mL, 11.7 mmol) were added to a solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(4-methylsulfanylphenyl)allyloxy]-2-methylphenoxy]acetate (1.40 g, 2.5 mmol; prepared as described in example 40) in tetrahydrofuran (35 mL). The mixture was degassed and copper(I) iodide (38.0 mg, 0.2 mmol) and bis(triphenylphosphine)palladium(II) dichloride (87.5 mg, 0.12 mmol) were added. The reaction mixture was stirred at ambient temperature for 20 h and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3) yielding methyl (E)-[2-methyl-4-[3-(4-methylsulfanylphenyl)-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]allyloxy]-phenoxy]acetate as yellow oil.
Reaction SMILES: O[CH:2]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].C(Br)(Br)(Br)[Br:26].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[Br:26][CH:2]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: CCCCCCCCCCCCC#CC(O)CCCCC(=O)OC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCCCCCCCC#CC(Br)CCCCC(=O)OC

Procedure:
This compound was prepared by reaction of methyl 6-(±) -hydroxy-7-eicosynoate (preparative example V) with CBr4 /Ph3P reagent in exactly the same manner as described in preparative example VIII.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6]CN)[CH3:2].[CH3:15][NH:16]CC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39](=[O:58])[CH2:40][N:41]2[CH2:47][C:46]3[CH:48]=[C:49](/[CH:52]=[CH:53]/[C:54]([OH:56])=O)[CH:50]=[N:51][C:45]=3[NH:44][C:43](=[O:57])[CH2:42]2)[CH2:35][CH2:34]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[ClH:31].[CH2:1]([O:3][C:4]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][N:16]([CH3:15])[C:54](=[O:56])/[CH:53]=[CH:52]/[C:49]1[CH:50]=[N:51][C:45]2[NH:44][C:43](=[O:57])[CH2:42][N:41]([CH2:40][C:39]([N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)=[O:58])[CH2:47][C:46]=2[CH:48]=1)[CH3:2]
Reactant: CCCc1c(CNC)ccc2ccccc12
Reactant: CCOc1c(CCN)cccc1OC
Reactant: CN1CCN(C(=O)CN2CC(=O)Nc3ncc(/C=C/C(=O)O)cc3C2)CC1
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CC(=O)N2CCN(C)CC2)CC(=O)N3)cccc1OC
Yield: 47 %

Procedure:
According to the procedure of Example 1, except substituting (2-ethoxy-3-methoxy-benzyl)methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-{4-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl}acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (82 mg, 47%) was prepared as an off-white powder: 1H NMR (300 MHz, DMSO-d6) δ 10.97 (br s, 1H), 10.67 (br s, 1H), 8.64-8.60 (m, 1H), 8.23-8.14 (m, 1H), 7.58-7.52 (m, 1H), 7.39-7.33 (m, 1H), 7.07-6.94 (m, 2H), 6.69-6.63 (m, 1H), 4.80-4.64 (m, 2H), 4.42-4.38 (m, 1H), 4.09-3.93 (m, 3H), 3.79 (s, 3H), 3.68 (br s, 2H), 3.47-3.37 (m, 8H), 3.11-2.97 (m, 5H), 2.75 (br s, 3H), 1.31-1.24 (m, 3H); MS (ESI) m/e 551 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClC1(C=CC=CC1Cl)C(Cl)=O.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21].[CH3:26][N:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH2:32][C:33]#[N:34]>ClCCCl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([C:31]1[N:27]([CH3:26])[C:28]([CH2:32][C:33]#[N:34])=[CH:29][CH:30]=1)=[O:21]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Cn1cccc1CC#N
Agent: O=C(Cl)C1(Cl)C=CC=CC1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cn1c(CC#N)ccc1C(=O)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To a cooled suspension of 16.6 g. (0.12 mole) aluminum chloride in 60 ml. 1,2-dichlorobenzoylchloride is added dropwise 23 g. (0.12 mole) m-chlorobenzoylchloride. The resulting suspension is added dropwise to a cooled solution of 15 g. (0.12 mole) 1-methylpyrrole-2-acetonitrile in 60 ml. 1,2-dichloroethane. The reaction mixture is stirred for about twenty minutes at room temperature and then heated and refluxed for three minutes. The reaction is terminated by pouring the mixture into ice acidified with 3N hydrochloric acid. The resulting two fractions are separated. The aqueous fraction is washed with chloroform. The organic fraction is then dried over anhydrous magnesium sulfate. The solvent is evaporated, and the resulting residue is triturated with cold methanol to yield a precipitate of the desired product which is filtered off and set aside. The methanol filtrate is concentrated in vacuo and the remaining oily residue is chromatographed on a column packed with neutral alumina using hexane, benzene and ether as the successive solvents. About 2.5 g. of the desired product are isolated by evaporation of the first few compound-bearing (ether) fractions. The solids are combined and recrystallized from methanol to yield about 3.6 g. of 5-(m-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile, M.P. 122°-127° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:4][CH:3]=1.[CH:16](O)=[O:17]>O>[CH:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:6][CH:7]=1)=[O:17]
Reactant: Nc1ccc(C2=NNC(=O)C3CC23)cc1
Reactant: O=CO
Solvent: O
Product: O=CNc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 67 %

Procedure:
6.0 g (29.8 millimoles) of 2-(p-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one (see Example 8a) and 30 ml of formic acid are refluxed for 1 hour. The solution is then poured into 500 ml of water and the precipitate which separates out is filtered off, washed with water and recrystallized from a methanol/water mixture. 4.6 g (67% of theory) of 2-(p-formylaminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are isolated as almost colorless crystals, of melting point 239°-240° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH3:15])=[CH:9][C:8]=1[C:16]([F:19])([F:18])[F:17].[C:20](=[O:22])=[O:21].Cl>CCCCCC.CCOCC>[CH2:14]([S:13][C:10]1[CH:11]=[CH:12][C:7]([C:20]([OH:22])=[O:21])=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:9]=1)[CH3:15]
Reactant: O=C=O
Reactant: CCSc1ccc(Br)c(C(F)(F)F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCSc1ccc(C(=O)O)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A solution of n-butyllithium in hexane (2.5M, 115 ml) was added dropwise with cooling to a stirred solution of 2-bromo-5-(ethylsulphenyl)benzotrifluoride (80.0 g) in anhydrous ether whilst maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 1.5 hours and poured onto solid carbon dioxide pellets. The mixture was stirred for 20 minutes then treated with hydrochloric acid (2M). The layers were separated and the organic layer was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness. The residue was triturated with cyclohexane and filtered to give 4-(ethylsulphenyl)-2-trifluoromethylbenzoic acid as an off-white solid, m.p. 133.5° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:7](=[O:14])[N:8]([CH3:13])[N:9]=[CH:10][C:11]=1Cl)[CH2:2][CH2:3][CH3:4].[F:15][C:16]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:17]=1[C:18]([N:20]=[C:21]=[S:22])=[O:19]>O1CCOCC1>[CH2:1]([N:5]1[C:6]2[C:7](=[O:14])[N:8]([CH3:13])[N:9]=[CH:10][C:11]=2[S:22]/[C:21]/1=[N:20]\[C:18](=[O:19])[C:17]1[CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:26][C:16]=1[F:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1c(Cl)cnn(C)c1=O
Reactant: O=C(N=C=S)c1cc(C(F)(F)F)ccc1F
Solvent: C1COCCO1
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)sc2cnn(C)c(=O)c21
Yield: 38.9 %

Procedure:
A mixture of 4-(butylamino)-5-chloro-2-methylpyridazin-3(2H)-one from Example 4A (130 mg, 0.60 mmol) and 2-fluoro-5-(trifluoromethyl)benzoyl isothiocyanate (248 mg, 1 mmol) in dioxane (20 mL) was heated at reflux for 72 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 and brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (hexanes-EtOAc 3:1) to afford 100 mg of the title compound. MS (ESI) m/z 215 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([I:18])[CH:16]=2)[N:11]=[CH:10][C:9]=1[C:19]#[N:20].[H-].[K+]>C1COCC1>[CH2:2]([CH:3]([O:6][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([I:18])[CH:16]=2)[N:11]=[CH:10][C:9]=1[C:19]#[N:20])[CH2:4][CH3:5])[CH3:1]
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Reactant: CCC(O)CC
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(CC)Oc1c(C#N)cnc2ccc(I)cc12

Procedure:
Similar procedure as described in example 28a was used, starting from 3-pentanol, 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c) and potassium hydride in a solvent system of THF to give 4-(1-ethyl-propoxy)-6-iodo-quinoline-3-carbonitrile. LC-MS m/e 367 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.[C:25]1([CH3:31])C=CC=C[CH:26]=1.ClC(Cl)([O:35][C:36](=O)[O:37]C(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CC(O)C.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:36](=[O:35])[O:37][CH:25]([CH3:31])[CH3:26])=[C:18]([CH3:24])[CH:17]=1
Reactant: Cc1ccccc1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OC(C)C)cc3C)c2cc1OC
Yield: 75 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-propanol (14 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (50 mg, yield 75%).