Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>COCCOC>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH:22]=[C:23]([C:3]2[C:2]([NH2:1])=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[N:4]=2)[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Nc1ccc(C(F)(F)F)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2nc(C(F)(F)F)ccc2N)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
A solution of 3-amino-2-chloro-6-trifluoromethyl-pyridine (0.890 g), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.4 g) (prepared as described in WO 2006/003494) and tetrakis(triphenyl-phosphine)palladium (0.200 g) in 1,2-dimethoxyethane (45 ml) was treated with aqueous potassium phosphate (1.1 M) (1.92 g). The reaction mixture was stirred at 80° C. for 3 hours. Aqueous workup with ethyl acetate furnished a residue which was purified by chromatography on silica gel (eluent: hexane/ethyl acetate 1:1) to give 3-amino-6-trifluoromethyl-3′,6′-dihydro-2′H-[2,4]bipyridinyl-1′-carboxylic acid tert-butyl ester (1.5 g) as a white solid. MS (ES+) 288 (M-isoprene); 1H NMR (400 MHz, CDCl3) 1.50 (s, 9H), 2.61 (m, 2H), 3.67 (t, 2H), 4.10 (m, 2H), 4.21 (s, 2H), 6.11 (s, 1H), 7.03 (d, 1H), 7.33 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=[O:12])=[CH:5]2.[CH2:13](B(O)O)[CH2:14][CH:15]([CH3:17])[CH3:16]>>[CH2:13]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=[O:12])=[CH:5]2)[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: O=Cc1cc2cc(Br)ccc2[nH]1
Reactant: CC(C)CCB(O)O
Product: CC(C)CCc1ccc2[nH]c(C=O)cc2c1
Yield: 37.1 %

Procedure:
5-Isopentyl-1H-indole-2-carbaldehyde was synthesized as in Example 3.1 using 5-bromo-1H-indole-2-carbaldehyde (300 mg, 1.34 mmol) in place of 5-bromo-2-formylfuran and isopentylboronic acid (256 mg, 2.21 mmol) in place of hexylboronic acid to give 5-isopentyl-1H-indole-2-carbaldehyde (107 mg, 37%). Used without further characterization.
Reaction SMILES: [CH2:1]([N:3]([CH2:39][CH3:40])[CH2:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:37][CH3:38])=[C:13]([NH:16][C:17]3[NH:22][C:21]4=[N:23][CH:24]=[CH:25][C:20]4=[C:19]([NH:26][C:27]4[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:28]=4[C:29]([NH2:31])=[O:30])[N:18]=3)[CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:2].[CH3:41]N.CO.C[O-].[Na+]>C1COCC1>[CH2:39]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:37][CH3:38])=[C:13]([NH:16][C:17]3[NH:22][C:21]4=[N:23][CH:24]=[CH:25][C:20]4=[C:19]([NH:26][C:27]4[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:28]=4[C:29]([NH:31][CH3:41])=[O:30])[N:18]=3)[CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:40]
Reactant: CCN(CC)CC(=O)N1CCc2cc(OC)c(Nc3nc(Nc4cccc(F)c4C(N)=O)c4ccnc-4[nH]3)cc21
Reactant: CN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(CC)CC(=O)N1CCc2cc(OC)c(Nc3nc(Nc4cccc(F)c4C(=O)NC)c4ccnc-4[nH]3)cc21
Reaction time: 48 h

Procedure:
The remaining half of the reaction mixture from the preparation of 2-[(2-{[1-(N,N-diethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide was diluted with THF (100 mL) and a solution of methylamine (1M in THF, 10 mL). After 4 h the reaction mixture was concentrated, the resulting residue was sonicated in CH2Cl2 (10 mL) and filtered. The filtrate was purified by silica gel chromatography using 0-5% MeOH (containing 0.2% NH3)/CH2Cl2. The product was dissolved in THF (10 mL) and MeOH (20 mL) and treated with a solution of sodium methoxide (0.5M in MeOH, 4 mL, 2 mmol). The reaction mixture was stirred for 2 days, then concentrated onto Celite and purified by silica gel chromatography using 4% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 2-[(2-{[1-(N,N-diethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide as a yellow solid (60 mg, 30% for 3 steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98 (t, J=7.15 Hz, 6H) 2.58 (q, J=6.72 Hz, 4H) 2.80 (d, J=4.77 Hz, 3H), 3.12 (t, J=8.43 Hz, 2H),3.77 (s, 3H), 4.24 (t, J=8.43 Hz, 2H), 6.27 (dd, J=3.30, 1.83 Hz, 1H), 6.76-7.03 (m, 3H), 7.26-7.39 (m, 1H), 7.57 (s, 1H), 8.36 (d, J=8.43 Hz, 1H), 8.54 (s, 1H), 8.62 (s, 1H), 10.16 (s, 1H), 11.26 (s, 1H), a CH2 signal with 2 protons is missing, may overlap with water peak in sample; ESIMS (M+H)+=561.27.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22]([CH:24]1[CH2:27][C:26]([F:29])([F:28])[CH2:25]1)=[O:23])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:29][C:26]1([F:28])[CH2:27][CH:24]([C:22]([NH:21][NH:20][C:18]([C@@H:13]2[CH2:12][CH2:11][C@@H:10]3[CH2:17][N:14]2[C:15](=[O:16])[N:9]3[OH:8])=[O:19])=[O:23])[CH2:25]1
Reactant: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C1CC(F)(F)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O)C1CC(F)(F)C1
Yield: 96.2 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-N′-[(3,3-difluorocyclobutyl)carbonyl]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 283 (0.32 g, 0.78 mml) in methanol (25 mL) was added 10% Pd/C (0.40 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give 284 (0.24 g, 96%) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15](Cl)=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.Cl.[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.N1C=CC=CC=1.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([NH:30][C:29]3[CH:31]=[CH:32][C:26]([O:25][C:24]([F:23])([F:33])[F:34])=[CH:27][CH:28]=3)=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: CC(Oc1ccc(Oc2ncc(Cl)cc2F)cc1)C(=O)Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2F)cc1)C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
A solution of 4.8 mmol of 2-(4-((5-chloro-3-fluoro-2-pyridinyl)oxy)phenoxy)propanoyl chloride (previously prepared from the corresponding acid) in 15 ml of methylene chloride was added, under N2, to an ice-cooled mixture of 1.03 g (4.8 mmol) of 4-(trifluoromethoxy)aniline hydrochloride, 0.95 g (12 mmol) of pyridine and 25 ml of methylene chloride. The resulting mixture was stirred at ambient temperature overnight and then poured into dilute aqueous HCl. The aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were washed twice with saturated aqueous sodium bicarbonate, treated with charcoal and MgSO4 and filtered. The filtrates were evaporated to dryness and the residue recrystallized from methylcyclohexane to give 0.34 g of the above-named product as colorless crystals, m.p. 92°-93.5° C. (Compound 37)
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:11][CH:10]=1.[ClH:22]>O>[OH2:13].[ClH:22].[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:20][CH:21]=1
Reactant: CCOC(=O)COc1ccc(Cc2ncc[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)COc1ccc(Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.9 %

Procedure:
To a solution of 0.42 g of sodium hydroxide in 30 ml of water was added 2.3 g of ethyl 4-(1-imidazolylmethyl)phenoxyacetate and the mixture was stirred at room temperature for 20 minutes. After completion of the reaction, an adequate amount of diluted hydrochloric acid was added to the solution to make it acidic. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was recrystallized from water to obtain 2.4 g of 4-(1-imidazolylmethyl)phenoxyacetic acid hydrochloride monohydrate (94.9% yield). Colorless needles.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15](#[N:18])[CH2:16][OH:17].C(=O)([O-])O.[Na+].Cl>O.CC(C)=O>[N+:12]([C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([F:8])=[CH:7][C:2]=1[O:17][CH2:16][C:15]#[N:18])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(F)cc1F
Reactant: N#CCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: N#CCOc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 4.5 h
Yield: 84.6 %

Procedure:
To a mixture of 1,5-difluoro-2,4-dinitrobenzene (2 g), acetone (20 g) and 50% aqueous glycolonitrile solution (1.2 g), a solution of sodium hydrogen carbonate (0.9 g) in water (18 g) was dropwise added at 27° to 30° C. in 5 minutes, and stirring was continued at 27° to 41° C. for 4.5 hours. After completion of the reaction, the reaction mixture was poured into 1% hydrochloric acid, extracted with ethyl acetate and concentrated. The precipitated crystals were collected by filtration and dried to give 2,4-dinitro-5-fluorophenoxyacetonitrile (2.0 g; yield, 83.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=[C:9]2S(C)(=O)=O)=[CH:4][CH:3]=1.O1CCCC1.O.[NH2:29][NH2:30]>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=[C:9]2[NH:29][NH2:30])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1nc(C(F)(F)F)cc(=O)n1-c1ccc(Cl)cc1
Reactant: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NNc1nc(C(F)(F)F)cc(=O)n1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-(4-chlorophenyl)-3,4-dihydro-2-methanesulfonyl-6-trifluoromethylpyrimidin-4-one (2.0 g) and tetrahydrofuran (20 ml) was added with hydrazine monohydrate (NH2NH2. H2O) (0.5 g). After stirring for 30 minuets at room temperature, the mixture was added with saturated brine (30 ml) and then extracted with ethyl acetate. The extract layer was washed with water and then dried on anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the compound of interest (1.5 g) as a milk white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]2[CH:45]=[C:46]([C:48]([OH:50])=O)[N:47]=[C:41]2[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[N:51]1[CH:56]=[CH:55][C:54]([N:57]2[CH2:62][CH2:61][C:60]3([CH2:67][CH2:66][NH:65][CH2:64][CH2:63]3)[CH2:59][CH2:58]2)=[CH:53][CH:52]=1>C(Cl)Cl>[N:51]1[CH:52]=[CH:53][C:54]([N:57]2[CH2:62][CH2:61][C:60]3([CH2:63][CH2:64][N:65]([C:48]([C:46]4[N:47]=[C:41]5[CH2:40][N:39]([C:37]([O:36][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:38])[CH2:44][CH2:43][N:42]5[CH:45]=4)=[O:50])[CH2:66][CH2:67]3)[CH2:59][CH2:58]2)=[CH:55][CH:56]=1
Reactant: c1cc(N2CCC3(CCNCC3)CC2)ccn1
Reactant: CC(C)(C)OC(=O)N1CCn2cc(C(=O)O)nc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCn2cc(C(=O)N3CCC4(CC3)CCN(c3ccncc3)CC4)nc2C1
Reaction time: 0.5 h
Yield: 63 %

Procedure:
DIPEA (5.96 mmol, 4.0 equiv.), EDCl (2.24 mmol, 1.5 equiv.) and HOBt (2.24 mmol, 1.5 equiv.) were added at 0° C. to a solution of 7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (1.49 mmol, 1.0 equiv.) in DCM (20 ml), and the mixture was stirred for 30 min. A solution of 3-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane (F-19) (1.49 mmol, 1.0 equiv.) in DCM (5 ml) was added at 0° C., and then the reaction mixture was stirred for 16 h at 25° C. The mixture was diluted with DCM (100 ml) and washed with sat. sodium carbonate solution (65 ml), sat. ammonium chloride solution (65 ml), water (50 ml) and sat. sodium chloride solution (50 ml), dried over Na2SO4 and concentrated in vacuo. The resulting crude product was used directly in the following stage. Yield: 63%
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].[CH2:9](N)[C:10]1[O:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>O>[CH2:9]([NH:6][C:5]1[CH:7]=[CH:8][NH:1][C:2](=[O:3])[N:4]=1)[C:10]1[O:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: NCc1ccco1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: O=c1nc(NCc2ccco2)cc[nH]1
Reaction time: 72 h
Yield: 88.9 %

Procedure:
To the reaction flask with 40 g cytosine (0.36 mol), 190 ml furfurylamine (6 mol) (FIG. 1 IV and V), the same amount of water and 5.67 g catalyst ammonium chloride (0.3 mol) was added. The mixture was heated till boiling within 48-96 h. After cooling, the mixture was extracted with dichloromethane (ca. 300 ml). The organic layer was filtered to isolate the product. The raw product was crystallized and 61.196 g of pure product was obtained with yield 89%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([F:13])([F:12])[F:11])=[C:6]([CH:9]=1)[CH2:7]Cl.[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([CH2:7][C:6]4[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:10]([F:13])([F:12])[F:11])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: FC(F)(F)c1ccc(Cl)cc1CCl
Product: O=C(NCCC1CC1)c1ccc(N2CCN(Cc3cc(Cl)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 11, making variations only as required to use 5-chloro-2-trifluoromethylbenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (48% yield). 1H NMR (300 MHz, CDCl3) δ 7.96-8.05, 7.87, 7.58, 7.34, 6.97, 3.80, 3.70, 3.56, 2.64, 1.53, 1.51, 0.70-0.83, 0.43-0.51, 0.07-0.13. MS (ES+) m/z 468 (M+1).
Reaction SMILES: C(OC([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH3:24])[C:13]=2[CH2:12]1)=O)C1C=CC=CC=1.[ClH:25]>CO.CCOC(C)=O.[Pd]>[ClH:25].[CH3:24][N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH2:22][CH2:23][NH:11][CH2:12][C:13]1=2
Reactant: Cn1c2c(c3ccccc31)CCN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1c2c(c3ccccc31)CCNC2
Reaction time: 6 h
Yield: 92 %

Procedure:
To a solution of 2-benzyloxycarbonyl-9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole (5.17 g. 16.2 mmole) in methanol (100 mL), EtOAc (25 mL) and HCl (17 mL, 1M in dioxane) at RT in a Parr hydrogenation flask was added 10% Pd/C (0.5 g). The reaction mixture was shaken under 45 psi of H2 for 6 hr. The suspension was filtered through celite®), and the filter pad was washed with methanol. The filtrate was concentrated on the rotavap, and the residue was dried under high vacuum to afford the titled compound (3.19 g. 92%) as a white solid: MS (ES) m/e 187 (M+H−HCl)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Cl:12]C1C=CC=CC=1>>[Cl:12][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: Clc1ccccc1
Product: O=C(O)Cc1ccc(CCl)cc1

Procedure:
4-chloromethylphenylacetic acid was prepared in the same manner as in Example 1 except for using 30 g of 4-methyl phenylacetic acid instead of 2-methyl phenylacetic acid and using 90 g of monochlorobenzene.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[C:15]1([CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][NH2:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:23][CH2:22][CH:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: CO
Product: N#CNC(=NCC(c1ccccc1)c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 2,2-diphenylethylamine (0.58 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C 200, 30 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure to give N-cyano-N'-(2,2-diphenylethyl)-3-pyridinecarboximidamide (0.61 g, 1.9 mmol, yield: 71%) as colorless syrup. Next, to this syrup was added a 5% hydrogen chloride solution in methanol (2.5 ml). The solution was crystallized from methanol-diethyl ether to give N-cyano-N'-(2,2-diphenylethyl)-3-pyridinecarboximidamide hydrochloride as colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([CH:19]([C:30]([O:32][CH3:33])=[O:31])[CH2:20][CH2:21][O:22][Si](C(C)(C)C)(C)C)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.B(Cl)(Cl)Cl>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([CH:19]([C:30]([O:32][CH3:33])=[O:31])[CH2:20][CH2:21][OH:22])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(CCO[Si](C)(C)C(C)(C)C)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Agent: ClB(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)C(CCO)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.53 g (3.20 mmol) of (rac)-4-[3-(tert-butyl-dimethyl-silanyloxy)-1-methoxycarbonyl-propyl]-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester (evaporated twice with toluene) in 25 ml of dichloromethane was treated at 0° C. with 3.20 ml (3.20 mmol, 1 M in dichloromethane) of boron trichloride and kept 1 h at this temperature. The solution was stirred 17 h at room temperature and then extracted with cold sat. aq. sodium hydrogencarbonate solution and ethyl acetate (3×). The organic phases were washed with sat. aq. sodium hydrogencarbonate solution, 10% aq. sodium chloride solution, dried over Na2SO4 evaporated to give 1.34 g (quantitative) of the title compound as yellow viscous oil. MS: 365.1 (MH+).
Reaction SMILES: [N:1]1([C:6]2[CH:18]=[CH:17][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9](C4CCCCO4)[C:8]=3[CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.CS(O)(=O)=O>CO>[N:1]1([C:6]2[CH:18]=[CH:17][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]=3[CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1ccc2c(c1)c1ccc(-n3cccn3)cc1n2C1CCCCO1
Agent: CS(=O)(=O)O
Solvent: CO
Product: c1ccc2c(c1)[nH]c1cc(-n3cccn3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
5 mmol of 2-(1H-pyrazol-1-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-carbazole was dissolved in 100 mL of methanol before 25 mmol of methylsulfonic acid was added slowly. The solution was stirred at room temperature for 2 hours, then at 50° C. for 2 hours further. The reaction was cooled, quenched with sodium bicarbonate, and separated between dichloromethane and water. The water was washed twice with dichloromethane, the organic fractions combined and washed once with brine. The organic fraction was then dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting solid was subjected to column chromatography, using silica and dichloromethane/ethyl acetate as the eluent. After concentration under reduced pressure, 2-(1H-pyrazol-1-yl)-9H-carbazole was isolated in 90% yield.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C(N(CC)C(C)C)(C)C.[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][CH2:24][CH2:25]Br)([CH3:19])([CH3:18])[CH3:17].[C:28]([C:30]1[CH:60]=[CH:59][C:33]([O:34][C:35]2[N:49]=[C:48]([O:50][C:51]3[CH:56]=[CH:55][C:54]([C:57]#[N:58])=[CH:53][CH:52]=3)[CH:47]=[CH:46][C:36]=2[C:37]([NH:39][CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:38])=[CH:32][CH:31]=1)#[N:29]>CN(C=O)C>[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][CH2:24][CH2:25][N:43]1[CH2:44][CH2:45][CH:40]([NH:39][C:37]([C:36]2[C:35]([O:34][C:33]3[CH:32]=[CH:31][C:30]([C:28]#[N:29])=[CH:60][CH:59]=3)=[N:49][C:48]([O:50][C:51]3[CH:56]=[CH:55][C:54]([C:57]#[N:58])=[CH:53][CH:52]=3)=[CH:47][CH:46]=2)=[O:38])[CH2:41][CH2:42]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: N#Cc1ccc(Oc2ccc(C(=O)NC3CCNCC3)c(Oc3ccc(C#N)cc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCN1CCC(NC(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(C#N)cc2)CC1
Temperature: 45 °C
Yield: 88.7 %

Procedure:
0.117 g (0.85 mmol) of K2CO3 and N,N-diisopropylethylamine 0.072 g (0.56 mmol) followed by 0.201 g (0.85 mmol) of (3-bromo-propyl)-carbamic acid tert-butyl ester, dissolved in 5 ml of DMF, were added to a stirred solution of 0.373 g (0.85 mmol) of 2,6-bis-(4-cyano phenoxy)-N-piperidine-4-yl nicotinamide, dissolved in 5 ml of DMF over a period of 15 min at 20° C. Reaction mixture was allowed to attain RT and heated to 45° C. for 2 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was partitioned between water (150 ml) and ethyl acetate (150 ml). The organic phase was washed with 1 M Na2CO3 and saturated brine solution, and dried over sodium sulphate. The solution was concentrated and the oily residue was purified by column chromatography using hexane-ethyl acetate (10:2) to afford 0.45 g of the required product. Percentage purity (LCMS): 72.5%, (M+1)=596.2+1.
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=O.C(OC)(=O)[CH2:17][CH2:18][C:19]([O:21]C)=[O:20]>CCOCC>[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:11]
Reactant: COC(=O)c1cccc(Cl)c1
Reactant: COC(=O)CCC(=O)OC
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: O=C(O)CCC(=O)c1cccc(Cl)c1

Procedure:
Sodium (11 g, spheres) was added to 200 ml ethanol with stirring. When the gas evolution ceased, methyl 3-chlorobenzoate (10 g, 0.057 mole) and dimethyl succinate (9.0 g, 0.615 mole) were added rapidly and the mixture was stirred for 5 minutes at room temperature. The mixture was slowly concentrated on a rotary evaporator to yield a greenish paste which was slurried in 100 ml ether and an additional 2 ml of dimethyl succinate was added. The reaction was evaporated to a paste, quenched with water and extracted with ether. The ether extracts were washed with water and brine, dried and evaporated in vacuo.
Reaction SMILES: [C:1]1([CH:7](O)[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)[Cl:18]>C(Cl)Cl>[C:10]1([C:8](=[CH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][Cl:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClP(Cl)Cl
Reactant: C=C(c1ccccc1)C(O)c1ccccc1
Solvent: ClCCl
Product: ClCC(=Cc1ccccc1)c1ccccc1

Procedure:
A solution comprised of 14 parts of 1,2-diphenyl-2-propen-1-ol and 24.3 parts of methylene chloride is added dropwise to a solution comprised of 12.6 parts of phosphorous trichloride and 30.4 parts of methylene chloride at a temperature of -15°. That reaction mixture is allowed to warm to 0° over a 3 hour period. Then ice is added while stirring rapidly and the oil which separates is extracted with ethyl ether. The ethereal extracts are washed with water and then with 10% potassium bicarbonate solution. After drying over anhydrous sodium sulfate, the solution is reduced to an oil by evaporating the solvent under a nitrogen stream and reduced pressure to yield pure 2,3-diphenylallyl chloride.