Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O>CN(C)C=O>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(F)ccc([N+](=O)[O-])c1F
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(F)ccc([N+](=O)[O-])c1F
Temperature: 80 °C
Yield: 99.1 %

Procedure:
To 2,6-difluoro-3-nitro-benzoic acid (48, 5.50 g, 27.1 mmol), thionyl chloride (20 mL, 300 mmol) is added, followed by N,N-dimethylformamide (0.1 mL, 2.0 mmol) and the reaction is heated in an oil bath at 80° C. After overnight reaction, the reaction mixture is concentrated under vacuum, azeotroped with toluene (2×) to provide the desired compound (49, 5.95 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:16]([CH3:19])([O-:18])=[O:17].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:19]/[N+:16]([O-:18])=[O:17])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: C[N+](=O)[O-]
Reactant: Cc1ccc(C=O)cc1C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(/C=C/[N+](=O)[O-])cc1C
Yield: 66.2 %

Procedure:
A solution of 3,4-dimethylbenzaldehyde (20 mL, 0.15 mol), ammonium acetate (12.5 g, 0.16 mol), glacial acetic acid (65 mL), nitromethane (34 mL, 0.63 mol), and acetic anhydride (3.0 mL, 0.032 mol) is refluxed for 2 hours. The reaction is concentrated to an oil, then dichloromethane (100 mL) is added, and the solution is washed with water (2×) and brine. The organic phase is dried (MgSO4), and concentrated to a dark green solid. This material is re-crystallized (treated with Darco) from 50% cyclohexane/hexanes to afford 17.6 g (66% yield) of the desired compound. 1H NMR (CDCl3) δ 8.08 (dd, J=2.4 Hz, 13.5 Hz, 1H), 7.61 (dd, J=2.4 Hz, 13.5 Hz, 1H), 7.31-7.36 (m, 2H), 7.25 (d, J=7.8 Hz, 1H), 2.36 (s, 3H), 2.35 (s, 3H); MS 329 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[O:9][CH:10]([CH3:12])[CH3:11].FC(F)(F)C(O)=O.[N:20]1([CH2:24][CH2:25][N:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]([F:41])([F:40])[F:39])[CH:32]=3)[N:28]=[C:27]2[CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[N:20]1([CH2:24][CH2:25][N:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]([F:41])([F:39])[F:40])[CH:32]=3)[N:28]=[C:27]2[CH:42]2[CH2:43][CH2:44][N:45]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=3[O:9][CH:10]([CH3:12])[CH3:11])[CH2:46][CH2:47]2)[CH2:21][CH2:22][CH2:23]1
Reactant: Fc1ccc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)cc1C(F)(F)F
Reactant: CC(C)Oc1c(N)ncnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CC(C)Oc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Temperature: 120 °C
Reaction time: 48 h
Yield: 55.7 %

Procedure:
A reaction mixture of 6-Chloro-5-isopropoxy-pyrimidin-4-ylamine (40.00 mg; 0.21 mmol; 1.00 eq.), 4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine trifluoroacetate (2) (133.13 mg; 0.21 mmol; 1.00 eq.), and Cs2CO3 (277.84 mg; 0.85 mmol; 4.00 eq.) in DMSO 5.0 ml was stirred at 120° C. for 2 days, purified the product by HPLC, collected title compound 64 mg, yield 45.5%. LC-MS: (M+1=548, obsd.=548).
Reaction SMILES: O[CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:5]=[CH:4][C:3]1=2.O=S(Cl)[Cl:24]>>[Cl:24][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3O)nc1
Reactant: O=S(Cl)Cl
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3Cl)nc1
Reaction time: 3.5 h

Procedure:
Charge flask with 6-(5-Hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yloxy) nicotinamide (288 mg, 1.01 mmol) and SOCl2 (5 ml) and beat at 50° C. under nitrogen atmosphere with stirring. After 3.5 hours, concentrate on rotary evaporator to give the title compound as a yellow oil. Due to instability, use this material without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14]CC)=[O:13])[C:6]1[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:5]2=1.[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]1[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:5]2=1
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CCN(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCc2c(n(CC(=O)O)c3ccc(Cl)cc23)C1
Temperature: 75 °C
Yield: 21.6 %

Procedure:
Ethyl 2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetate (0.3 g, 2.9 mmol) in THF (10 mL) was added to a solution of sodium hydroxide (0.177 g, 2.9 mmol) in water (3 mL) and heated at 75° C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was removed; water (10 mL) was added to the residue and the aqueous layer was washed with ethyl acetate (2×10 mL). The pH of aqueous layer was adjusted to 2-3, and the aqueous layer was washed with ethyl acetate. The aqueous layer was evaporated, the residue was extracted with methanol, filtered, the filtrate was concentrated under reduced pressure to yield 2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetic acid (175 mg). 1H NMR (CD3OD): 7.50 (s, 1H) 7.30 (d, 1H), 7.10 (d, 1H), 5.1 (d, 1H), 5.0 (d, 1H), 4.4 (s, 2H), 4.2 (m, 1H), 4.0 (m, 1H), 3.4 (s, 3H), 3.2 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24]>>[OH:25][CH:22]([CH2:23][OH:24])[CH2:21][NH:20][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: NCC(O)CO
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1ccccc1
Product: O=C(Nc1nc2cccc(NCC(O)CO)n2n1)c1ccccc1

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 50 mg; 0.18 mmol; 1.0 eq.) and 3-amino-1,2-propanediol (1.0 mL) as a white powder (6 mg, 7%). HPLC, Rt: 1.65 min. (purity 99.5%). LC/MS, M+(ESI): 328.1, M−(ESI): 326.1.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([C:22]1([CH3:66])[CH2:27][C@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C@@H:25]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[N:24]([C@@H:42]([CH:62]2[CH2:64][CH2:63]2)[CH2:43][O:44][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C:23]1=[O:65])[CH:20]=[CH2:21]>C1COCC1.C(OCC)(=O)C>[CH2:19]([C@@:22]1([CH3:66])[CH2:27][C@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C@@H:25]([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[N:24]([C@@H:42]([CH:62]2[CH2:63][CH2:64]2)[CH2:43][OH:44])[C:23]1=[O:65])[CH:20]=[CH2:21]
Reactant: C=CCC1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C2CC2)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tetrabutylammonium fluoride in THF (1M, 2.10 mL, 2.10 mmol) was added to a solution of diastereomers (5R,6S)-3-allyl-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example 251, Step D, 488 mg, 0.700 mmol) in THF (10 ml).The reaction was stirred at ambient temperature for 2 hours. The mixture was diluted in ethyl acetate and washed with water and sat. aq. NaCl solution. The organic layer was dried over sodium sulfate. Silica gel chromatography eluting with ethyl acetate/hexane gave the title compound as a single diastereomer.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[F:18])=[N:5]1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[O:31][N:30]=[C:29]([C:32](O)=[O:33])[CH:28]=2)[CH2:22][CH2:21]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[C:10]([F:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:32]([C:29]3[CH:28]=[C:27]([CH2:26][N:23]4[CH2:22][CH2:21][O:20][CH2:25][CH2:24]4)[O:31][N:30]=3)=[O:33])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1cc(CN2CCOCC2)on1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1)NC(=O)c1cc(CN2CCOCC2)on1

Procedure:
The title compound was synthesized from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile (0.2 g, 0.72 mmol), 5-(morpholinomethyl)isoxazole-3-carboxylic acid (0.15 g, 0.72 mmol), HOBt (0.145 g, 1.07 mmol), DIPEA (0.37 mL, 2.15 mmol) and EDCI (0.2 g, 1.07 mmol) using DMF (10 mL) as the solvent using the method of Example 34(d). Yield 72 mg. 1H NMR (400 MHz; d6-DMSO): δ 1.17 (d, 3H), 2.39 (m, 4H), 3.56 (m, 4H), 3.71 (s, 2H), 4.34 (m, 2H), 4.46 (m, 1H), 6.62 (s, 1H), 6.76 (m, 1H), 7.83 (m, 1H), 7.88 (d, 1H), 8.03 (m, 1H).
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][CH2:34][O:35]CC2C=CC=CC=2)[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][CH2:34][OH:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCCOCc3ccccc3)c3ccccc3)ccc21
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCCO)c3ccccc3)ccc21
Yield: 61 %

Procedure:
Prepared from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)amide hydrochloride by hydrogenation over palladium/charcoal (10%) at 5 bar hydrogen pressure and at ambient temperature. Yield: 61% of theory, C26H28N6O2 (456.6); Rf value: 0.70 (Reversed Phase silica gel RP-18; methanol/5% aqueous saline solution=9:1); EKA mass spectrum: (M+H)+=457; (M+H+Na)++=240.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11](O)=[C:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9]1.Cl.[NH2:23][OH:24]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11](=[N:23][OH:24])[CH:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)C1=C(O)C(=O)N(c2ccccc2F)C1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)C1CN(c2ccccc2F)C(=O)C1=NO
Temperature: 25 °C
Reaction time: 120 h
Yield: 57.4 %

Procedure:
To a solution of the title compound of Example H (3.16 g, 10.8 mmol) in pyridine (50 ml) was added hydroxylamine hydrochloride (3.73 g, 54. mmol) and the reaction was stirred for 5 days(d) at room temperature. After the reaction was concentrated in vacuo, HO was added and the mixture was extracted with CH2Cl2. Drying of the organic phase (MgSO4) and concentration gave a solid which was chromatographed on silica gel eluting with 2% EtOH/CH2Cl2 to give the title compound (1.91 g, 57%). Anal calcd for C15H17N2O4F: C, 58.44; H, 5.56; N, 9.09. Found: C, 58.43; H, 5.62; N, 8.75. DSC=175.1°-180.2° C. at 225.6 J/g.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:51]4[CH2:52][CH2:53][CH2:54][N:48]([CH3:47])[CH2:49][CH2:50]4)=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCCN(C)CC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with 1-methyl-[1,4]diazepane (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C42H55Cl2N6O3 [(M+H)+] 761.3707, observed 761.3707.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25](O)=[O:26])=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH3:31][NH:32][CH2:33][CH3:34]>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([N:32]([CH2:33][CH3:34])[CH3:31])=[O:26])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: CCNC
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Agent: Cl
Product: CCN(C)C(=O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 149) and 13.9 mg (0.23 mmol) of methylethylamine are reacted together by general method E. 19.8 mg (29.4% of theory) of the title compound are obtained.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:34]2)=[CH:29][CH:28]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: NNc1ccc(F)cc1
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1ccc(F)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 4-fluoro-phenylhydrazine according to the method described for example 43. MS: M=417.1 (M+H)+
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6]P(OCC)(OCC)=O)=[O:5].[H-].[Na+].[CH3:17][N:18]1[CH2:25][CH:24]2[C:26](=O)[CH:20]([C@H:21]([CH3:29])[CH2:22][C@H:23]2[CH3:28])[CH2:19]1.C(OCC)(=O)C>O1CCCC1>[CH3:17][N:18]1[CH2:25][CH:24]2[C:26](=[CH:6][C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:20]([C@H:21]([CH3:29])[CH2:22][C@H:23]2[CH3:28])[CH2:19]1
Reactant: C[C@@H]1C[C@@H](C)C2CN(C)CC1C2=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C=C1C2CN(C)CC1[C@H](C)C[C@H]2C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.5 %

Procedure:
To a solution of 130 g of triethyl phosphono acetate in tetrahydrofuran (600 ml) was added 25 g of sodium hydride (oily: 60% or above) under ice-cooling and the resulting mixture was stirred at room temperature for 10 minutes. Then a solution of 70 g of the crude (6R*,8R*)-3,6,8-trimethyl-3-azabicyclo[3.3.1]nonan-9-one in tetrahydrofuran (300 ml) was added thereto and the reaction mixture was heated under reflux for 2 hours. After adding ethyl acetate, the reaction mixture was washed twice with a saturated aqueous solution of sodium chloride and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 31.5 g of the title compound as a pale yellow oily substance.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([N+]([O-])=O)[CH3:13])=[CH:7][CH:6]=1)([OH:4])=[O:3].[OH2:17]>O1CCOCC1.[Fe]>[CH2:11]([C:8]1[CH:9]=[CH:10][C:5]([C:2]([OH:4])=[O:3])=[CH:6][CH:7]=1)[C:12]([CH3:13])=[O:17]
Reactant: O
Reactant: CC(=Cc1ccc(C(=O)O)cc1)[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)Cc1ccc(C(=O)O)cc1

Procedure:
Concentrated hydrochloric acid (367 ml) was added dropwise to a mixture of 1-(4-carboxyphenyl)-2-nitroprop-1-ene (61.17 g) and iron powder (61.17 g) in dioxan (500 ml) at reflux. The heating was continued for 1 hour at the end of addition. The solution was cooled, water added, the dioxan evaporated and the residue extracted with chloroform and dried (MgSO4). Removal of the solvent gave a solid which was recrystallised from ethyl acetate to give 26 g of the title compound. τ (d6DMSO) 7.83 (3H, s), 6.14 (2H, s), 2.69 (2H, d, J=9 Hz), 2.05 (2H, d, J=9 Hz).
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([N+:18]([O-])=O)=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1.C(O)(=O)C>C(O)C>[NH2:18][C:5]1[C:4]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:3][C:2]([Br:1])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1c(Br)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1c(Br)nc(-c2ccccc2)c(N)c1C(=O)OCC
Temperature: 60 °C

Procedure:
In 25 ml of ethanol was dissolved 550 mg of 2-bromo-3,4-diethoxycarbonyl-5-nitro-6-phenylpyridine, whereto 0.36 g (5 eq.) of reduced iron was added, followed by heating to 60° C. After 1.5 ml (16 eq.) of acetic acid was added dropwise, the mixture was refluxed for 1 hour.
Reaction SMILES: C(O)C.O.NN.[CH3:7][N:8]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]([CH3:17])([CH3:16])[C:10]2[CH:18]=[C:19]([N+:22]([O-])=O)[CH:20]=[CH:21][C:9]1=2>[Pd].O>[NH2:22][C:19]1[CH:20]=[CH:21][C:9]2[N:8]([CH3:7])[C:14](=[O:15])[CH2:13][CH2:12][C:11]([CH3:17])([CH3:16])[C:10]=2[CH:18]=1
Reactant: CN1C(=O)CCC(C)(C)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Yield: 98.7 %

Procedure:
Added 16 mL of ethanol, 10% Palladium on activated carbon, 50% wet with water for safety (129 mg), and hydrazine monohydrate (200 ul) to 1,5,5-Trimethyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (257 mg, 1.035 mmol). Heated reaction to 60° C. overnight. Filtered reaction through Celite, and concentrated under reduced pressure to obtain a colorless sticky solid, 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (223 mg, 99%). LCMS: m/z=219.04 (M+H+), 1H NMR (400 MHz, DMSO-d6) δ 6.95 (d, 1H, J=8.3 Hz), 6.57 (d, 1H, J=1.5 Hz), 6.48 (dd, 1H, J=8.3, 1.3 Hz), 5.09 (s, 2H), 3.07 (s, 3H), 2.09 (m, 2H), 1.88 (m, 2H), 1.19 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:5]2.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([N:34]=[C:35]=[O:36])[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1>>[CH3:33][O:32][C:30]1[CH:29]=[C:28]([NH:34][C:35]([NH:15][CH2:14][CH2:13][CH2:12][N:7]2[CH:6]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)=[O:36])[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=1
Reactant: NCCCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1
Reactant: COc1cc(N=C=O)cc(OC)c1
Product: COc1cc(NC(=O)NCCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)cc(OC)c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 238-b) as a starting material, and using 3,5-dimethoxyphenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)O)=[O:5])[CH3:2].[NH2:24][CH:25]1[CH2:30][N:29]([CH3:31])[C:28](=[O:32])[CH2:27][CH2:26]1.Cl>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[NH:24][CH:25]1[CH2:26][CH2:27][C:28](=[O:32])[N:29]([CH3:31])[CH2:30]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Reactant: CN1CC(N)CCC1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(NC1CCC(=O)N(C)C1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 using 2-bromo-5-[(4-chlorophenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylic acid ethyl ester (intermediate B) and 5-amino-1-methylpiperidin-2-one (ChemBridge, free base was made from the purchased HCl salt) as starting materials. The crude reaction mixture was diluted with EtOAc and washed with aqueous NaHCO3 solution and brine. tr: 1.07 min (LC-MS 2); ESI-MS: 511.1 [M+H]+ (LC-MS 2); 1H-NMR (DMSO-d6, 400 MHz) δ ppm 7.42 (m, 2H), 7.30 (m, 2H), 6.28 (NH, br, 1H), 4.85-5.00 (m, 1 H), 4.25 (quin, 2 H), 3.15-3.05 (m, 2H), 2.84-2.75 (m, 1H), 2.72 (d, 3H), 2.38-1.85 (m, 4H), 1.75-1.58 (m, 1), 1.45 (d, 3 H), 1.24 (t, 3 H), 0.83 (t, 3H).
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:9].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:10]
Reactant: Clc1cccc(Cl)c1Br
Reactant: Cc1ccccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1c(Cl)cccc1Cl
Yield: 92.8 %

Procedure:
1-Bromo-2,6-dichlorobenzene (90 mg,-0.40 mmol) reacted with 2-methylphenylboronic acid (82 mg, 0.60 mmol) using 2/4 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and K3PO4 (254 mg, 1.20 mmol) in toluene at 100° C. to give the title compound (88 mg, 76%): 1H-NMR (400 MHz, CDCl3): δ 8.07 (d, 2H, J=8.07 Hz), 7.28-7.18 (m, 3H), 7.15 (t, 1H, J=8.13 Hz), 7.00 (d, 1H, J=7.25 Hz), 1.99 (s, 3H). 13C{1H}-NMR (125 MHz, CDCl3): δ 139.23, 136.91, 136.16, 135.09, 129.90, 129.04, 129.01, 128.39, 127.88, 125.81, 19.30. GC/MS(EI): (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[N:14]([CH3:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[C:6]([CH:17]=[O:18])=[CH:5][CH:4]=1.S(=O)(=O)([OH:21])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[CH3:1][O:2][C:3]1[C:15]2[N:14]([CH3:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[C:6]([C:17]([OH:21])=[O:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)c2c3ccccc3n(C)c12
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(C(=O)O)c2c3ccccc3n(C)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.9 %

Procedure:
To a solution of 1-methoxy-9-methyl 9H-4-carbazolecarbaldehyde (100 mg 0.4184 mmoles) in a mixture of 8 mL acetone and 4 mL water, sulfamic acid (48.7 mg 0.502 mmoles) was added followed by a solution of sodium chlorite (37.8 mg, 0.4184 mmoles) in 2 mL water and the reaction mixture was stirred at 25° C. for 4 hrs. Acetone from the reaction mixture was evaporated under reduced pressure, diluted with ethyl acetate 30 mL. Organic layer was separated and basified with freshly prepared sodium bicarbonate solution and separated the aqueous layer and acidified with 1N HCl and extracted with ethyl acetate (2×25 mL). Ethyl acetate layer was washed with brine (2×20 mL), dried over sodium sulfate and concerted to give 95 mg of the tide compound.