Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[C:10](=[O:11])[O:9][C:7](=O)[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[C:12]1([NH:18][C:19](=[O:32])[CH:20]([O:23][C:24]2[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:25]=2[Cl:31])[CH2:21][CH3:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C>O>[Cl:31][C:25]1[CH:26]=[CH:27][C:28]([N:30]2[C:10](=[O:11])[C:1]3[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=3[C:7]2=[O:9])=[CH:29][C:24]=1[O:23][CH:20]([C:19](=[O:32])[NH:18][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:21][CH3:22]
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: CCC(Oc1cc(N)ccc1Cl)C(=O)Nc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CCC(Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.52 g. of cyclohexane-1,2-dicarboxylic anhydride, 3.05 g. of N-phenyl-α-(5-amino-2-chlorophenoxy)butyramide (melting point of 78° to 80° C.) and 10 ml. of acetic acid was refluxed with stirring for 2 hours and the reaction mixture was cooled to room temperature and water was added to obtain a crude crystal. The product was recrystallized from a mixture of ethyl acetate and n-hexane to obtain 3.86 g. of Compound No. 294 shown in Table 1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][C@@H:19]2[C@H:10]([NH:11][CH2:12][C:13]3[C:14]([CH3:21])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:20][C@@H:19]2[C@H:10]([N:11]([C:29](=[O:31])[CH3:30])[CH2:12][C:13]3[C:14]([CH3:21])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2c1CN[C@@H]1CN(Cc3ccccc3)C[C@@H]21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2c(C)cccc2[C@@H]2CN(Cc3ccccc3)C[C@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (±)-trans-2-benzyl-6-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,4-c]isoquinoline from Example 105, Part A (28 mg, 0.1 mmol) in 1 mL of methylene chloride was added triethylamine (0.021 mL, 0.15 mmol) and acetyl chloride (0.009 mL, 0.15 mmol). The reaction was allowed to stir at ambient temperature for 2 h. The solution was concentrated and purified (ISCO, elution with 0-5% methanol/methylene chloride) to afford 25 mg of the title compound of Example 108 as an off-white solid. 1H NMR (CDCl3): δ 7.74-7.68 (m, 2H), 7.50-7.42 (m, 3H), 7.21-7.13 (m, 2H), 6.80-6.75 (m, 1H), 4.78 and 4.38 (ABq, 2H), 4.31-4.25 (m, 1H), 4.16-4.03 (m, 2H), 3.89-3.80 (m, 1H), 3.71-3.63 (m, 1H), 3.49 (s, 2H), 3.07-2.98 (m, 1H), 2.35 (s, 3H), 2.21 (s, 3H). LRMS (ESI): 321.3 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH:23][CH:24]([CH3:26])[CH3:25])[N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[OH:4].CCN(C(C)C)C(C)C.[S:36](Cl)([CH3:39])(=[O:38])=[O:37]>C(Cl)Cl>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH:23][CH:24]([CH3:26])[CH3:25])[N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][NH:1][S:36]([CH3:39])(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(-c2nc(-c3ccc(C(O)CN)cc3)no2)nc(NC(C)C)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(-c2nc(-c3ccc(C(O)CNS(C)(=O)=O)cc3)no2)nc(NC(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
To a solution of rac-2-amino-1-{4-[5-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethanol (39 mg, 0.11 mmol) and DIPEA (30 μL, 0.176 mmol) in DCM (6 mL) at 0° C. is added dropwise a solution of mesylchloride (10 μL, 0.132 mmol) in DCM (2 mL). The reaction mixture is stirred at 0° C. for 1 h, and then at rt for another hour. The reaction mixture is evaporated and purified by prep. TLC eluting with DCM/7M NH3 in MeOH 10:1 to give rac-N-(2-hydroxy-2-{4-[5-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethyl)-methanesulfonamide (19 mg) as a white solid; tR=0.89 min; [M+H]+=432.99.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.O(CC)CC.C([Li])CCC.[CH2:17]([N:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH:30]=[O:31])=[CH:29][C:24]=2[N:23]=[N:22]1)[CH2:18][CH2:19][CH3:20]>CCCCCC>[CH2:17]([N:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH:30]([C:2]3[CH:6]=[CH:5][S:4][CH:3]=3)[OH:31])=[CH:29][C:24]=2[N:23]=[N:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: Brc1ccsc1
Reactant: CCCCn1nnc2cc(C=O)ccc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCn1nnc2cc(C(O)c3ccsc3)ccc21
Temperature: 0 °C
Yield: 58.9 %

Procedure:
To a stirred and cooled (-78° C.) solution of 7.2 parts of 3-bromothiophene in 70 parts of 1,1'-oxybisethane were added 30 parts of a 1-butyllithium solution 1.6M in hexane. After stirring for 20 minutes at this low temperature, a solution of 6 parts of butyl-1H-benzotriazole-5-carboxaldehyde was added to the previous mixture. The reaction mixture was stirred for 2 hours at -78~-40° C. The whole was poured into 200 parts of ice water and the product was extracted three times with 56 parts of 1,1'-oxybisethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98.2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 5 parts (58.9%) of 1-butyl-α-(3-thienyl)-1H-benzotriazole-5-methanol; mp. 80° C. (int. 58).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:26])[NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH2:27][C:28]([OH:30])=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:26])[NH:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:14][CH:15]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccccc3)cc2)c(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(CC(=O)O)ccc1Oc1ccc(C(=O)NCCc2ccccc2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution of tert-butyl 2-(3-cyano-4-(4-(phenethylcarbamoyl)phenoxy)phenyl)acetate 0.120 g) in 2 ml of dichloromethane was added 2 ml of TFA and the reaction was stirred at ambient temperature. After 1 hour the reaction was concentrated and dried under vacuum to give 2-(3-cyano-4-(4-(phenethylcarbamoyl)phenoxy)phenyl)acetic acid (0.100 g). MS−355.3 [M−CO2H].
Reaction SMILES: C([Si](C)(C)[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[C:9]2[CH2:8][CH2:7]1)(C)(C)C.[C:30]1([CH2:36]Br)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1.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>[CH2:36]([C:13]1[CH:14]=[C:9]2[CH2:8][CH2:7][NH:6][C:10]2=[N:11][CH:12]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2c(c1)CCN2[Si](C)(C)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: c1ccc(Cc2cnc3c(c2)CCN3)cc1
Reaction time: 2.5 h
Yield: 14.1 %

Procedure:
To a stirred solution of the crude stannane 17 (172 mg, 0.33 mmol) in THF (2.5 mL) was added PhCH2Br (0.03 mL, 0.27 mmol) and (Ph3P)2PdCl2 (5 mg, 0.007 mmol). The mixture was refluxed under N2 for 19 h, cooled, and partitioned between AcOEt-brine. The aqueous layer was extracted with AcOEt (2×). The combined organic solutions were dried (MgSO4), and concentrated in vacuum. The residual yellow oil was dissolved in MeOH (3 mL) and treated with a 10% solution of HCl in MeOH (2 mL). The mixture was stirred for 2.5 h, neutralized with saturated aqueous NaHCO3 solution and extracted with AcOEt (2×). The combined organic extracts were dried (MgSO4), concentrated, and purified by PTLC with CH2Cl2:MeOH=95:5 as eluent to afford the 5-benzyl derivative 18 (8 mg, 11% over 2 steps). 1H NMR (400 MHz; CDCl3) δ 2.99 (t, J=8.1 Hz, 2H), 3.60 (t, J=8.3 Hz, 2H), 3.79 (s, 2H), 7.06-7.31 (m, 7H), 7.69 (br s, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][C:20]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=1)[C@:7]1([C@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([OH:15])[C@@H:9]([CH2:16]O)[O:8]1)[CH2:6][CH2:5]2.CCN(S(F)(F)[F:36])CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][C:20]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=1)[C@:7]1([C@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([OH:15])[C@@H:9]([CH2:16][F:36])[O:8]1)[CH2:6][CH2:5]2
Reactant: CCN(CC)S(F)(F)F
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CC[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Solvent: ClCCl
Product: CCc1ccc(Cc2cc3c(cc2Cl)CC[C@]32O[C@H](CF)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
To a solution of (1S,3′R,4′S,5′S,6′R)-5-chloro-6-(4-ethylbenzyl)-6′-(hydroxymethyl)-2,3,3′,4′,5′,6′-hexahydrospiro[indene-1,2′-pyran]-3′,4′,5′-triol (10 mg, 0.024 mmol) in CH2Cl2 (1 mL), was added DAST (9 μL, 0.072 mmol) at −78° C. The mixture was stirred for 30 min at −78° C., then allowed to warm to room temperature and stirred for another 3 h. The reaction was quenched by aqueous saturated NaHCO3. The organic layer was separated, dried with Na2SO4 and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 4 mg (40%) of title compound as a colorless solid. 1H NMR (CD3OD, 300 MHz): δ 7.24 (s, 1H), 7.19 (s, 1H), 7.08 (m, 4H), 4.63 (d, J=3.3 Hz, 1H), 4.47 (d, J=3 Hz, 1H), 4.04 (m, 2H), 3.59-3.38 (m, 4H), 2.93 (t, J=7.2 Hz, 2H), 2.58 (q, J=7.8 Hz, 2H), 2.54 (dt, J=13.5, 7.8 Hz, 1H), 2.08 (dt, J=13.5, 7.8 Hz, 1H), 1.19 (t, J=7.8 Hz, 3H).
Reaction SMILES: [N:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:6]([CH3:23])[CH:5]=1)=[C:2]=[O:3].[CH3:24][N:25]([CH3:42])[CH2:26][CH2:27][CH2:28][N:29]([CH3:41])[C:30]1[C:31]([NH2:40])=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1>C1(C)C=CC=CC=1>[CH3:42][N:25]([CH3:24])[CH2:26][CH2:27][CH2:28][N:29]([CH3:41])[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][C:31]=1[NH:40][C:2]([NH:1][C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:6]([CH3:23])[CH:5]=1)=[O:3]
Reactant: Cc1cc(N=C=O)ccc1Oc1ncccc1-c1ccncn1
Reactant: CN(C)CCCN(C)c1ccc(C(F)(F)F)cc1N
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)Nc2cc(C(F)(F)F)ccc2N(C)CCCN(C)C)ccc1Oc1ncccc1-c1ccncn1

Procedure:
To 4-(2-(4-isocyanato-2-methylphenoxy)pyridin-3-yl)pyrimidine (93 mg, 0.33 mmol) in toluene (3 mL) was added N1-(3-(dimethylamino)propyl)-N1-methyl-4-(trifluoromethyl)benzene-1,2-diamine (82 mg, 0.30 mmol).
Reaction SMILES: Cl[C:2]1[N:10]2[CH:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][O:13][C:8]3=[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[C:20]2[C:21]([CH3:26])=[N:22][O:23][C:24]=2[CH3:25])[N:3]=1.Cl.[NH:28]1[CH2:31][CH:30]([OH:32])[CH2:29]1>CO>[CH3:26][C:21]1[C:20]([C:7]2[C:8]3[O:13][CH2:12][CH:11]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)[N:10]4[C:2]([N:28]5[CH2:31][CH:30]([OH:32])[CH2:29]5)=[N:3][C:4]([C:9]=34)=[CH:5][CH:6]=2)=[C:24]([CH3:25])[O:23][N:22]=1
Reactant: Cc1noc(C)c1-c1ccc2nc(Cl)n3c2c1OCC3c1cccnc1
Reactant: OC1CNC1
Agent: Cl
Solvent: CO
Product: Cc1noc(C)c1-c1ccc2nc(N3CC(O)C3)n3c2c1OCC3c1cccnc1

Procedure:
The title compound was prepared by methods analogous to Example 157, substituting 2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine, azetidin-3-ol hydrochloride and extending the reaction time to 60 min. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to give the title compound as a racemic mixture (16 mg, 23%). LCMS calc. for C22H22N5O3 (M+H)+: m/z=404.2. found: 404.2. The isomers were separated by prep chiral column chromatography using the following conditions: Column: phenomenex Lux Cellulose C-2 5 μm, 21, 2×250 mm, Mobile phase: 45% EtOH/Hexanes, gradient condition: isocratic at 18 mL/min, Loading: 2.0 mg in 900 μL, run time: 24 min, peak time: 12.0, 14.0, 16.0 and 21.0 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH3:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)=[O:21]>C(O)CCC>[NH:22]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:25][CH:24]=1)[C:20]([CH3:19])=[O:21]
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: CC(=O)Nc1ccc(N)cc1
Solvent: CCCCO
Product: CC(=O)Nc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 110 °C

Procedure:
A mixture of 0.511 g (2 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine, 0.901 g (6 mmol) 4-aminoacetanilide and 5 ml 1-butanol is heated for 3 h at 110° C. The reaction mixture is then evaporated under vacuum, the crystalline residue is taken up in a mixture of 20 ml dichloromethane and 10 ml 20% aqueous potassium carbonate solution while stirring, then filtered and the filter residue washed with water and dichloromethane. After recrystallization from dichloromethane/methanol and drying under HV (8 h, 1 00° C.), title compound is obtained with a methanol content of 1.27%;
Reaction SMILES: C(OC(C1C=CC=CC=1O[C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)=O)C.Cl.[NH:40]1[CH2:47][CH2:46][CH2:45][C@H:41]1[C:42]([NH2:44])=[O:43]>>[CH3:34][S:31]([C:28]1[CH:29]=[CH:30][C:25]([O:24][C:23]2[C:9]([N:40]3[CH2:47][CH2:46][CH2:45][C@H:41]3[C:42]([NH2:44])=[O:43])=[CH:10][C:11]3[NH:15][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[N:13][C:12]=3[CH:22]=2)=[CH:26][CH:27]=1)(=[O:32])=[O:33]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: CCOC(=O)c1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1
Agent: Cl
Product: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2N2CCC[C@H]2C(N)=O)cc1

Procedure:
The entitled compound was obtained as a pale yellow solid in the same method as in Example 15 or in accordance with the method or by combining it with an ordinary method but using 5-fluoro-4-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine obtained in Example 14, and L-prolinamide hydrochloride.
Reaction SMILES: [C:1]1([Bi:7](C2C=CC=CC=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][Bi](Br)Br>C1COCC1>[C:1]1([Bi:7]([Br:20])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Bi](Br)Br
Reactant: c1ccc([Bi](c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Br[Bi](c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
In 400 ml of THF was dissolved 22.014 g (50 mmol) of triphenylbismuthine (Tokyo Kasei Co., Ltd.) under nitrogen atmosphere. The solution was cooled to 0° C. and thereto was slowly added dropwise 11.231 g (25 mmol) of tribromobismuthine (Aldrich Corp.) (30 minutes). The mixture was stirred to room temperature for 1 hour. The yellow precipitate was filtered and dried in a vacuum. The obtained precipitate was recrystallized from benzene, giving 27.422 g (62 mmol: yield 83%) of yellow powdery product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([O:14][CH3:15])=[C:4]([C:16]2[CH:21]=[CH:20][C:19](CC(C)C)=[CH:18][CH:17]=2)[N:3]=1.[F-:26].[Cs+]>CS(C)=O.C(OC(=O)C)C>[F:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([O:14][CH3:15])=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:12][CH:8]([CH3:9])[CH3:7])=[CH:18][CH:17]=2)[N:3]=1
Reactant: [F-]
Reactant: COc1ccc2c(Cl)nc(-c3ccc(CC(C)C)cc3)c(OC)c2c1
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(F)nc(-c3ccc(OC(C)C)cc3)c(OC)c2c1
Temperature: 140 °C
Yield: 175.8 %

Procedure:
To a solution of 1-chloro-3-(4-isobutylphenyl)-4,6-dimethoxyisoquinoline (142 mg, 0.4 mmol) in DMSO (2 mL), was added CsF (122 mg, 0.800 mmol) and the mixture was heated to 140° C. for 4 hrs. The reaction was diluted with ethylacteate and washed with water, and brine. The organic phase was collected, dried over sodium sulfate, and concentrated under vacuum to give the crude product which was purified by silica gel chromatography using a gradient of 5-25% EtOAc/Hexanes. The product fractions were collected and the solvent removed under vacuum to give 120 mg of the desired product as a white solid containing starting material. MS: MS m/z 342.1 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:20][CH3:21])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2OS(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CO[CH2:30][CH2:31]OC.O>>[CH:30]([C:7]1[C:6]2[C:11](=[C:2]([F:1])[CH:3]=[C:4]([O:20][CH3:21])[CH:5]=2)[N:10]=[CH:9][CH:8]=1)=[CH2:31]
Reactant: COc1cc(F)c2nccc(OS(=O)(=O)C(F)(F)F)c2c1
Reactant: COCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1ccnc2c(F)cc(OC)cc12
Temperature: 90 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To a solution of 1,1,1-trifluoromethanesulfonic acid 8-fluoro-6-methoxy-quinolin-4-yl ester (1.0 g, 3.1 mmol), potassium carbonate (1.28 g, 9.3 mmole), tetrakis-triphenylphosphine (350 mg, 0.3 mmole) in DME/H2O (20 mL, 3:1) was added 2,4,6-trivinylcycloborane-pyridine complex (460 mg, 1.5 mmole). After stirring for 3 h at 90° C., the mixture contents were cooled to room temperature and extracted with diethyl ether. The ether fractions were combined, concentrated and purified by column chromatography (silica, 0-10% ethyl acetate in hexane) to give the title compound as a light yellow solid (428 mg, 65%): LC/MS (ES) m/e 212 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][CH2:17][CH2:18][O:19][CH2:20][C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1.[H][H]>[Pd].C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCOCC#Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCOCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 75.8 %

Procedure:
2-Methyl-1-{3-[(3-phenylprop-2-ynyl)oxy]propyl}-1H-imidazo[4,5-c]quinolin-4-amine (1.4 g, 3.779 mmol) was combined with toluene (15 mL) in a Parr flask and heated to reflux. The resulting solution was cooled to room temperature and purged with nitrogen. Palladium (0.6 g 10% palladium on carbon) was added to the solution under nitrogen, and the flask was pressurized with hydrogen at 310 kPa for 2.75 hours. Monitoring by HNMR indicated incomplete reaction. More 10% palladium on carbon (0.16 g) was added, and after an additional 2.5 hours at 310 kPA of hydrogen, the reaction was determined to be complete. The catalyst was filtered off, and the volatiles were removed under reduced pressure. The resulting white solid was recrystallized from acetonitrile and dried for 5 days to provide 1.0723 g of 2-methyl-1-[3-(3-phenylpropoxy)propyl]-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 145.0-146.1° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([O:11][CH3:12])[C:3]=1[N:13]1[CH:17]=[N:16][C:15]([CH3:18])=[N:14]1>[Pd].CO>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([O:11][CH3:12])[C:3]=1[N:13]1[CH:17]=[N:16][C:15]([CH3:18])=[N:14]1)[NH2:8]
Reactant: COc1cc([N+](=O)[O-])cc(F)c1-n1cnc(C)n1
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)cc(F)c1-n1cnc(C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 133.8 %

Procedure:
Step S (2): 10% Palladium on carbon (0.776 g, 0.730 mmol) was added under an atmosphere of nitrogen to a chilled (ice-water bath) solution of 1-(2-fluoro-6-methoxy-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (1.84 g, 7.30 mmol) dissolved in methanol (150 mL). The flask was repeatedly evacuated and flushed with hydrogen gas (double balloon). The resulting mixture was allowed to warm to rt and left to stir for 18 h under the hydrogen atmosphere. The vessel was subsequently purged with nitrogen gas. The crude reaction mixture was filtered through a short plug of diatomaceous earth (Celite®). The reaction vessel and the Celite® were rinsed with fresh methanol. The combined filtrates were concentrated in vacuo. The residue was dried under high vacuum overnight to afford 3-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (2.17 g, quantitative % yield) as a blackish/gray solid. LC-MS (M+H)+ 223.2. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.02 (s, 1 H), 6.11 (dd, J=11.1, 2.3 Hz, 1 H), 6.06 (d, J=1.5 Hz, 1 H), 4.04 (br. s., 2 H), 3.74 (s, 3 H), 2.48 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:21]([OH:23])=[O:22])[CH2:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH2:9][N:8]=[C:7]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3Cl)[C:6]=2[CH:31]=1.[N+](=[CH2:34])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:21]([O:23][CH3:34])=[O:22])[CH2:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH2:9][N:8]=[C:7]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:6]=2[CH:31]=1
Reactant: CN(C)CCCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)C(=O)O
Reactant: C=[N+]=[N-]
Product: COC(=O)C(CCCN(C)C)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 14, 7-chloro-2-[[1-carboxy-4-(dimethylamino)butylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-chloro-2-[[1-(methoxycarbonyl)-4-(dimethylamino)butylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: N1C=CC=C1[C:6]1[CH2:12][CH2:11][CH2:10][CH:9]=[C:8]([C:13]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14])[C:7]=1[C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21].O1CCCC1>O>[C:8]1([C:13]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14])[C:7]([C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])=[CH:6][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: CC(C)COC(=O)C1=CCCCC(c2ccc[nH]2)=C1C(=O)OCC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)COC(=O)C1=CCCCC=C1C(=O)OCC(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.4 %

Procedure:
To a four-necked two litter flask purged with nitrogen, 165.4 g (455.0 mmol) of diisobutyl 3-pyrrolylcyclohepta-2,7-diene-1,2-dicarboxylate obtained in Reference Example 2 and 1,158 mL of tetrahydrofuran were charged. Thereto, 500.0 mL (containing 455.0 mmol of borane-tetrahydrofuran complex) of a tetrahydrofuran solution (concentration: 0.91M) of a borane-tetrahydrofuran complex was added dropwise over 1.5 hour. The mixture was stirred for 6 hours at room temperature. The reaction mixture was provided with water, and the resultant mixture was subjected to toluene extraction. The extraction liquid was washed with water, and was dried over anhydrous magnesium sulfate. The dried liquid was filtered, and volatile matters contained therein were distilled away under reduced pressure to obtain orange colored oil. The oil was purified with silica-gel column chromatography (developing solvent: mixed solvent of 4 parts by volume of hexane with one part by volume of ethyl acetate), thereby obtaining 105.0 g (yield: 78.0%) of diisobutyl cyclohepta-2,7-diene-1,2-dicarboxylate as pale yellow oil with a purity of 99.6% determined by a gas chromatography measurement, its NMR and GCMS data being shown below: