Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][O:12][CH2:13]Cl>CN(C=O)C.C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:11][O:12][CH3:13])=[CH:6][N:7]=1
Reactant: COCCl
Reactant: Oc1ccc(F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(F)nc1
Reaction time: 1 h
Yield: 109.5 %

Procedure:
Add 6-fluoro-pyridin-3-ol (3.5 g, 30.95 mmol) to a suspension of sodium hydride (1.49 g, 37.1 mmol) in DMF (20 mL). Stir the mixture for 1 h. Add chloromethyl methyl ether (2 g, 25.0 mmol). Stir the mixture at RT overnight. Dilute the mixture with ethyl acetate and water. Wash the organic layer with water and aqueous saturated sodium chloride. Dry the mixture over sodium sulfate. Concentrate the solution in vacuo to a brown oil. Purify by column chromatography (10% ethyl acetate in hexane) to afford the title compound (4.30 g, 88%) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 3.48 (s, 3H), 5.15 (s, 2H), 6.85 (dd, J=3.6 Hz, J=8.8 Hz, 1H), 7.47 (m, 1H), 7.96 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.FC(F)(F)C(O)=O.[CH3:32][NH:33][C:34]([C@@H:36]1[CH2:41][CH2:40][CH2:39][NH:38][CH2:37]1)=[O:35].C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:38]3[CH2:39][CH2:40][CH2:41][C@@H:36]([C:34]([NH:33][CH3:32])=[O:35])[CH2:37]3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:21])[CH3:22]
Reactant: CNC(=O)[C@@H]1CCCNC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CNC(=O)[C@@H]1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
In a 2 mL microwave vial were placed N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 437 mg, 1.3 mmol) and (R)-N-methylpiperidine-3-carboxamide, trifluoroacetate salt (585 mg, 2.2 mmol). To the sealed vial were then added NMP (6 ml) and diisopropylethylamine (0.67 ml, 3.85 mmol), and the mixture was then heated in the microwave at 100° C. for 15 minutes. After cooling to room temperature, the reaction mixture was filtered by syringe filter and was then directly purified by preparatory HPLC (25-50% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white powder (510 mg, 88% yield). 1H NMR (400 MHz, DMSO-d6) δ=10.96 (br. s., 1 H), 8.11 (br. s., 1 H), 8.00 (d, J=8.1 Hz, 3 H), 7.61 (d, J=8.1 Hz, 2 H), 7.35 (s, 1 H), 6.39 (br. s., 1 H), 4.48-4.25 (m, 2 H), 3.29 (t, J=11.1 Hz, 1 H), 3.08 (br. s., 1 H), 2.61 (s, 3 H), 2.60 (m, 1 H), 2.08 (s, 1 H), 1.94 (br. s., 1 H), 1.83 (br. s., 1 H), 1.73 (br. s., 2 H), 1.46 (s, 6 H); ESI-MS: m/z 437.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:38]([OH:40])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(N(CC)CC)C>[CH3:37][O:36][C:35]1[C:23]2[N:22]=[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:12]3[CH2:11][C@@H:10]([C:38]([N:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)=[O:40])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13]3)=[O:20])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]=2[CH:32]=[CH:33][CH:34]=1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2c(OC)cccc21
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCCCC3)CN(C(=O)OC(C)(C)C)C2)nc2c(OC)cccc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-{{{4-methoxy-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-3-carboxylic acid (205 mg), piperidine (69 μl), HOBt (40 mg) and triethylamine (140 μl) were dissolved in DMF (10 ml), WSC.HCl (134 mg) was added, and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9)-ethyl acetate was concentrated under reduced pressure to give the object product (65 mg).
Reaction SMILES: [CH2:1]([N:8]([CH:33]([CH3:35])[CH3:34])[C:9](=[O:32])[CH2:10][N:11]1[C:20](=[O:21])[CH2:19][C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[CH:29][CH:30]=[CH:31][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([CH:45]=O)=[CH:37]1>>[CH2:1]([N:8]([CH:33]([CH3:35])[CH3:34])[C:9](=[O:32])[CH2:10][N:11]1[C:20](=[O:21])[C:19](=[CH:45][C:38]2[C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[NH:36][CH:37]=2)[C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[CH:29][CH:30]=[CH:31][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21
Reactant: O=Cc1c[nH]c2ccccc12
Product: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)C(=Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Yield: 104.7 %

Procedure:
Following the procedure described for Example 1 (A), Step A, N-benzyl-N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetamide (Preparation 10) (13.9 g, 29.8 mmol) was condensed with 1H-indole-3-carbaldehyde (5.2 g, 35.8 mmol) for 48 hours. The volatiles were concentrated in vacuo to provide 18.5 g of N-benzyl-2-[4-(1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide. 1H NMR (CDCl3) δ 8.01 (d, 1H), 7.67-7.50 (m, 4H), 7.43-7.11 (m, 12H), 6.99 (m, 1H), 6.99 (m, 1H), 6.80 (m, 1H), 4.96 (m, 1H), 4.71-4.49 (m, 4H), 4.23 (m, 1H), 1.20 (m, 6H); MS 593.3 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[O:12])[N:7]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][C@@H:27]([C:38](OC)=[O:39])[N:28](C(=O)C(F)(F)F)[CH2:29]3)=[CH:24][CH:23]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.CN.[CH2:45]([N:47](CC)CC)C.[CH3:52][C:53]([O:56][C:57]([O:59]C(OC(C)(C)C)=O)=O)([CH3:55])[CH3:54]>CO.O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[O:12])[N:7]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][C@@H:27]([C:38](=[O:39])[NH:47][CH3:45])[N:28]([C:57]([O:56][C:53]([CH3:55])([CH3:54])[CH3:52])=[O:59])[CH2:29]3)=[CH:24][CH:23]=2)[N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)[C@@H]1Cc2ccc(-n3nc(C(C)(C)C)cc3NC(=O)Nc3cccc(Cl)c3Cl)cc2CN1C(=O)C(F)(F)F
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN
Agent: Cl
Solvent: CO
Solvent: O
Product: CNC(=O)[C@@H]1Cc2ccc(-n3nc(C(C)(C)C)cc3NC(=O)Nc3cccc(Cl)c3Cl)cc2CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
A solution of (3S)-methyl 7-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-2-(2,2,2-trifluoro-acetyl)-1,2,3,4-tetrahydroiso-quinoline-3-carboxylate from Example A42 (0.153 g, 0.250 mmol), methylamine hydrochloride (1.000 g, 14.8 mmol) and triethylamine (2.05 mL, 1.49 g, 14.7 mmol) in MeOH (5 mL) was stirred at 60° C. for 24 h. H2O was added (50 mL) and the mixture was extracted with CH2Cl2 (3×50 mL), dried (MgSO4) and concentrated. The residue was redissolved in CH2Cl2 (5 mL). Boc anhydride (0.055 g, 0.250 mmol) was added and the solution was stirred at RT for 30 min. The solvent was evaporated and the residue was purified by column chromatography to yield (3S)-t-butyl 7-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-3-(methyl-carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (52 mg, 34% yield) as a white solid. 1H NMR (400 MHz, acetone-d6) shows rotameric mixture. MS (EI) m/z: 615.2 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]([F:14])[C:8]([C:9](O)=[O:10])=[C:7]([CH:15](OC)OC)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:21][NH2:22]>C(O)C.C(O)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:8](=[C:12]([F:14])[CH:13]=1)[C:9](=[O:10])[NH:22][N:21]=[CH:15]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(OC)c1cc(C(C)(C)C)cc(F)c1C(=O)O
Reactant: NN
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(F)c2c(=O)[nH]ncc2c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 86 %

Procedure:
4-tert-Butyl-2-dimethoxymethyl-6-fluoro-benzoic acid (220.3 g, 0.815 moles) was dissolved in ethanol (2 vol, 440 mL) and acetic acid (0.5 vol, 110 mL). Hydrazine hydrate (1.5 eq, 61 mL) was added and the solution stirred at 80° C. for 6 hours. The mixture was cooled to rt overnight, then in an ice bath and then filtered and washed with cold ethanol. The fine white crystals were dried at 100° C. in a vacuum oven with N2 sweep, to provide 154.7 g (86%) of 6-tert-butyl-8-fluoro-2H-phthalazin-1-one.
Reaction SMILES: CO.C[O-].[Na+].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.Br[CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]>C1C=CC=CC=1.O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:9][CH:8]=1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(C#N)cc2)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(Oc2ccc(C#N)cc2)cc1

Procedure:
To a solution of 40 ml of methanol, 1.19 g of sodium methoxide and 3.21 g of p-chlorophenol is added 7.4 g of methyl α-bromo-α-[p-(p-cyanophenoxy)phenyl]acetate in 15 ml of benzene. The mixture is refluxed for 20 hours, poured into ice and water, and extracted with ether. The ether extracts are washed with 10% potassium carbonate and with water. Drying over magnesium sulfate and removal of the solvent under vacuum gives a tan oil. Filtration once through silica gel with chloroform as solvent gives an oil in the first fractions. The oil is filtered through silica gel with benzene as the solvent to give, in the first fractions, a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[CH3:8].N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17].O>O1CCCC1>[CH3:7][C:4]1[C:3]([CH3:8])=[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])[O:6][N:5]=1
Reactant: Cc1noc(N)c1C
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Yield: 62.8 %

Procedure:
To a solution of 5-amino-3,4-dimethylisoxazole (1.00 g, 8.92 mmol) and pyridine (0.873 ml, 10.7 mmol) in tetrahydrofuran (30 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.48 ml, 10.7 mmol), and the mixture was stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 1.61 g (62.9%) of the desired product as an oil.
Reaction SMILES: [N:1]1([C:7]2[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl[CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=1)=[O:27]>C1(C)C=CC=CC=1>[C:13]([C:12]1[C:7]([N:1]2[CH2:2][CH2:3][N:4]([CH2:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=3)=[O:27])[CH2:5][CH2:6]2)=[N:8][CH:9]=[CH:10][CH:11]=1)#[N:14]
Reactant: N#Cc1cccnc1N1CCNCC1
Reactant: O=C(CCl)Nc1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccnc1N1CCN(CC(=O)Nc2cccc([N+](=O)[O-])c2)CC1
Temperature: 90 °C
Yield: 24.6 %

Procedure:
2-(1-Piperazinyl)-3-pyridinecarbonitrile (640 mg, 3.40 mmol) and N,N-diisopropylethylamine (1.0 mL) in toluene (15 mL) at room temperature were treated with N-chloroacetyl-3-nitroaniline (Lancaster, 610 mg, 2.84 mmol) and the reaction was heated at 90° C. for 18 hours. The mixture was allowed to cool to room temperature, transferred to a separatory funnel and washed with saturated aqueous sodium bicarbonate. The organic phase was dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (elution with 85% hexanes:ethyl acetate) to provide 256 mg (25% yield) of the title compound as a light tan solid. mp 143-145° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.69 (m, 4H), 3.27 (s, 2H), 3.70 (m, 4H), 6.93 (dd, 1H, J=7.4, 5.0 Hz), 7.61 (dd, 1H, J=8.1, 8.1 Hz), 7.93 (br d, 1H, J=8.2 Hz), 8.06 (dd, 2H, J=7.8, 7.8 Hz), 8.42 (m, 1H), 8.70 (br s, 1H), 10.28 (br s, 1H); MS (DCI/NH3) m/e 367 (M+H)+; Anal. calcd for C18H18N6O3: C, 59.01; H, 4.95; N, 22.94. Found: C, 59.31; H, 5.25; N, 22.66.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=[O:25])[CH3:24])=[CH:18][C:17]=1[S:26](Cl)(=[O:28])=[O:27]>O1CCOCC1.O>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=[O:25])[CH3:24])=[CH:18][C:17]=1[S:26]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:27])=[O:28]
Reactant: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: Nc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)Nc2ccccc2)c1
Reaction time: 8 h

Procedure:
Aniline hydrochloride (64.8 mg, 0.05 mmol) is dissolved in 1,4-dioxane (1 ml) in a reaction tube and Na2CO3(85 mg) dissolved in water (0.5 ml) is added. To this mixture is added 2-Chloro-5-(2-oxo-propyl)-benzenesulfonyl chloride (115 mg, 0.43 mmol) (Intermediate A, prepared as described in WO03072557, page 77) in 1,4-dioxane (1 ml). The reaction mixture is left at room temperature overnight and monitored by LC-MS. The reaction mixture is shaken overnight with amino polystyrene (300 mg) and macroporous-isocyanate (300 mg), filtered and the resin is washed with MeOH (0.5 ml). The filtrate is concentrated in vacuo to afford the title compound.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC(C2C=COC=2)=CC=1.Br[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[Br:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:28][CH:27]=1
Reactant: Brc1ccncc1
Reactant: OB(O)c1ccc(Br)cc1
Agent: c1ccc(-c2ccc(-c3ccoc3)cc2)cc1
Product: Brc1ccc(-c2ccncc2)cc1
Yield: 100 %

Procedure:
According to the procedure described in Example 1(a) for the preparation of 3-biphenyl-4-yl-furan, 4-bromopyridine (700 mg, 3.00 mmol) underwent coupling to 4-bromophenylboronic acid to give 2.38 g (100%) of 4-(4-bromo-phenyl)-pyridine as a yellow solid, which had an NMR that matched literature (Boy, P.; Combellas, C.; Thiebault, A.; Amatore, C.; Jutand, A. Tetrahedron Lett. 1992, 33, 491-494) and was used without further purification. IR (KBr): 1593, 1474, 1412, 1075, 1006, 807, 756, 693, 498 cm-1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].N1C=CC=CC=1.[Br:26]Br>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([Br:26])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccccc3c2c1C
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ncc2[nH]c3ccc(Br)cc3c2c1C
Reaction time: 1 h
Yield: 38 %

Procedure:
0.5 g of 4-methyl-β-carbolin-3-carboxylic acid ethyl ester (melting point 235°-239° C.) is dissolved in 25 ml of chloroform and 1.7 ml of pyridine and a solution of 1 ml of bromine in 21 ml of chloroform is added dropwise thereto at 0° C. After standing for one hour while cooling with ice and after dilution with 50 ml of the methylene chloride, the mixture is extracted by washing with sodium thiosulphate solution, dilute aqueous ammonia solution and water. After drying with sodium sulphate, filtering off and distilling off the solvent in vacuo, 6-bromo-4-methyl-β-carbolin-3-carboxylic acid ethyl ester is obtained in 38% yield, Melting point 231°-232° C. (from acetone).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C@@H:14]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[NH:13]1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1.[C:54](O)(=[O:58])[C:55]([CH3:57])=[O:56]>C(Cl)(Cl)Cl>[C:54]([N:13]1[C@H:14]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12]1)(=[O:58])[C:55]([CH3:57])=[O:56]
Reactant: CC(=O)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1Cc2ccccc2CN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: CC(=O)C(=O)N1Cc2ccccc2C[C@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
13.17 g of benzyl (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate tosylate (N. Yoneda, et al., Chem.Pharm.Bull., 31, 312 (1983)) was suspended in 30 mL CHCl3. N-methylmorpholine was added until the pH was 7, 6.8 g of dicyclohexylcarbodiimide and 3.17 g of pyruvic acid was added at -5° C. The reaction mixture was stirred at -50° C. for one hour and 0° C. for 48 hours. The reaction mixture was filtered, and the filtrate was concentrated to dryness to give a semi-solid, which was purified by passing through a silica gel column and eluting with ethyl acetate:hexane (1:1) to give benzyl N-pyruvoyl-(S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate as a yellow oil, [α]D25 -10.3°.
Reaction SMILES: [C:1]([N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[H][H].C(N1C[C@H]2[C@H](CCCC2)C1)(=O)C>[C].[Ru].CO>[C:1]([N:4]1[CH2:12][C@H:11]2[C@@H:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)N1Cc2ccccc2C1
Agent: [Ru]
Agent: CC(=O)N1C[C@H]2CCCC[C@H]2C1
Solvent: CO
Product: CC(=O)N1C[C@@H]2CCCC[C@H]2C1
Yield: 0.2 %

Procedure:
In a 3-liter GL autoclave fitted with a electromagnetic stirrer are added 175 g of N-acetylisoindoline, 825 g of methylalcohol and 17 g of 5% ruthenium-carbon catalyst (50% water-containing). The reaction mixture is subjected to a hydrogen-pressure of 20 kg/cm2 and a temperature of 110° C. After a 8 hour hydrogen introduction, the drop in the rate of the hydrogen-absorption is observed, at this point the introduction of hydrogen is ceased to terminate the reaction. After the termination of reaction, the catalyst is filtered out from the reacted solution. By the result of the capillary chromatographic analysis, the yield of cis-hexahydro-N-acetylisoindoline is 93.7%. In addition, 0.2% of trans-hexahydro-N-acetylisoindoline is formed.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(=[O:18])C.Cl.[Cl:21][CH2:22][CH2:23]Cl>O>[Cl:21][CH2:22][CH2:23][CH2:2][CH2:3][CH2:4][C:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:18]
Reactant: CC(=O)Cl
Reactant: ClCCCCc1ccccc1
Reactant: ClCCCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(CCCCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 250 ml round-bottomed flask were added 5.0 g (29.65 mmol) 1-chloro-4-phenylbutane and 10 ml 1,2-dichloroethane. To the stirred solution was added a solution of 4.35 g (32.62 mmol) aluminum chloride and 4.22 ml (59.31 mmol) acetyl chloride in 50 ml 1,2-dichloroethane. The solution evolved HCl as it was stirred at room temperature for 1 hour. It was then poured into water, the layers separated, and the organic layer washed with 1N HCl, aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, and evaporated to an oil, 6.7 g (>100%). NMR (delta, CDCl3): 1.76 (m, 4H), ~2.5 (s, 3H), 3.50 (m, 2H), 7.2 and 7.85 (m, 4H). IR cm-1, neat): 1678 (C=O).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1Cc2ccccc2C1
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: c1ccc(NC2Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-indanone (5 g, 37.83 mmol) in DCM (135 mL) were successively added aniline (3.4 mL, 37.83 mmol), AcOH (2.16 mL, 37.83 mmol) and Na(OAc)3BH (11.22 g, 52.96 mmol) portion-wise at ice cold conditions. The reaction mixture was stirred at rt for 16 hours. The reaction mixture was then diluted with EtOAc (450 mL) and washed with water (150 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by Combiflash® chromatography and eluted with 1.7% EtOAc in hexane to obtain compound 7.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9]C=[C:11](C(O)=O)[N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:19].O.C[CH2:22][O:23][C:24]([CH3:26])=[O:25]>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:11])[CH:19]=[C:26]([C:24]([O:23][CH3:22])=[O:25])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: O=C(O)c1c[nH]c(-c2ccc(I)cc2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C)c(-c2ccc(I)cc2)n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(4-iodophenyl)-1H-imidazole-4-carboxylic acid prepared above (257 mg, 0.818 mmol) and NaH (60% suspension, washed with hexane, 82 mg, 2.1 mmol) in DMF (8 mL) was added iodomethane (0.130 mL, 2.1 mmol). The mixture was heated at 50° C. for 2 h. More iodomethane (0.100 mL) was added to the reaction mixture. After being stirred at 50° C. for an additional 2 h, water and EtOAc were added. The organic layer was separated, dried over Na2SO4, concentrated in vacuo to give methyl 2-(4-iodophenyl)-1-methyl-1H-imidazole-4-carboxylate (152 mg). MS 342.8 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[F:13][C:14]([F:30])([F:29])[O:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][O:24][CH2:25][C:26]([NH2:28])=[NH:27])[CH:19]=[CH:20][CH:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:28][C:26](=[NH:27])[CH2:25][O:24][CH2:23][CH2:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C:14]([F:29])([F:30])[F:13])[CH:17]=1)=[O:6]
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Reactant: N=C(N)COCCc1cccc(OC(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N=C(COCCc1cccc(OC(F)(F)F)c1)NC(=O)c1cc(Cl)cnc1Cl

Procedure:
In analogy to the procedure described in example 78.3, 2,5-dichloronicotinic acid was reacted with 2-[2-(3-trifluoromethoxy-phenyl)-ethoxy]-acetamidine hydrochloride in the presence of TBTU and DIPEA to give 2,5-dichloro-N-{1-imino-2-[2-(3-trifluoromethoxy-phenyl)-ethoxy]-ethyl}-nicotinamide as orange oil. MS: m/e=436.2 [M+H+].