Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]=[CH:6][CH:7]([N:16]([CH3:33])[C:17](=[O:32])[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH3:2].ClC1C=CC=CC=1Cl>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH:7]([N:16]([CH3:33])[C:17](=[O:32])[C:18]1[CH:19]=[C:20]([C:28]([F:30])([F:29])[F:31])[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)C=CC(Cc1ccc(Cl)cc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Product: CCOC(=O)CCC(Cc1ccc(Cl)cc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A solution of 29 g of 4-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(4-chlorophenyl)-pent-2-enoic acid ethyl ester [see example 2b)] in 300 ml of tetrahydrofuran is hydrogenated for 0.5 hour in the presence of 3 g of palladium/activated carbon (10%) and 6 g of 1,2-dichlorobenzene. The reaction mixture is then filtered and concentrated by evaporation. The residue is chromatographed (silica gel, hexane/ethyl acetate 3:1). In this way the title compound is obtained in the form of a colourless oil. 1H-NMR, 500 MHz, DMSO, 140°, delta (ppm): 7.99(s, 1H), 7.51(s, 2H), 7.30(td, 2H), 7.18(d, 2H), 4.5(b, 1H), 4.06(q, 2H), 2.9(m, 1H), 2.8(m, 4H), 2.35(m, 2H), 2.02(m, 1H), 1.90(m, 1H), 1.19(t, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][C:8]2([NH2:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.Cl[C:18]1[C:19]2[CH:26]=[CH:25][NH:24][C:20]=2[N:21]=[CH:22][N:23]=1.C(N(CC)CC)C>C(O)CCC>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2([NH2:14])[CH2:9][CH2:10][N:11]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH2:12][CH2:13]2)=[CH:15][CH:16]=1
Reactant: NC1(Cc2ccc(Cl)cc2)CCNCC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: NC1(Cc2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Yield: 49.3 %

Procedure:
A solution of 4-(4-chlorobenzyl)piperidin-4-yl amine hydrochloride (0.060 g, 0.2016 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.031 g, 0.2016 mmol) and triethylamine (0.140 ml, 1.0079 mmol) in n-butanol (2.0 ml) was heated to 100° C. for 24 hours. Concentration and purification by preparative silica TLC gave a white solid (0.034 g, 49%). LC-MS (LCT) m/z 342 [M+H+], Rt 3.25 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=[C:12]([N+]([O-])=O)[CH3:13].C(O)(=[O:19])C.S(=O)(O)[O-].[Na+]>CC(C)=O.O.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12](=[O:19])[CH3:13]
Reactant: CC(=Cc1c[nH]c2ccc(Cl)cc12)[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [Fe]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Cc1c[nH]c2ccc(Cl)cc12
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A mixture of 104g of 5-chloro-3-(2-nitropropen-1-yl)indole, 115g of powdered iron and 6g of ferric chloride dissolved in 1250 ml of acetone is brought to reflux. Heating ceases as soon as reflux commences and a solution of 265 ml of acetic acid in 800 ml of water is added over 30 minutes. The reaction mixture is again brought to reflux and maintained thereat for 4 hours; 25.6g of sodium bisulphite are then added, the mixture cooled to 20°C and filtered. The residue is washed with acetone. The combined filtrate and washings are concentrated after filtering and redissolved in 105 ml of hydrochloric acid and 520 ml of water, extracted with ethyl acetate, washed and dried.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[H-].[Na+].Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1)([O-:3])=[O:2]
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)OCCN2CCN1CCCC1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
A solution of 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (300 mg, 1.665 mmol) in DMF (10 mL) was treated with NaH (213 mg, 5.33 mmol, 60% wt in mineral oil) at 0° C., resulting in a bright orange suspension. The mixture was stirred for 10 minutes. 2-chloroethyl-pyrrolidine hydrochloride (566 mg, 3.33 mmol) was then added, and the reaction turned into a bright red suspension. The reaction was heated to 90° C. for 1 hour and then cooled to room temperature. The mixture was then diluted with water (20 mL), transferred to a separatory funnel, and extracted into EtOAc (2×15 mL). The combined organic layers were washed with brine (3×5 mL), dried (Na2SO4), filtered, and concentrated. The residue was subjected to flash chromatography on silica gel using CH2Cl2 followed by 5:95 (2M NH3 in MeOH):CH2Cl2 to give a solid (330 mg, 72%). 1H-NMR (DMSO-d6) δ 7.75 (dd, J=2.7, 9.3 Hz, 1H), 7.47 (d, J=2.7 Hz, 1H), 6.80 (d, J=9.0 Hz, 1H), 4.18 (t, J=4.2 Hz, 2H), 3.58-3.55 (m, 4H), 2.63 (t, J=6.9 Hz, 2H), 2.58-2.48 (m, 4H), 1.70-1.63 (m, 4H); ESI-MS (m/z, %): 278 (MH+, 100), 98 (20).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12](B(O)O)=[CH:11][C:10]=3[CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)S(O[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH2:30][N:29]([CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:28][CH2:27]2)(=O)=O.C(N(CC)CC)C>C(O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]1([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[CH2:30][N:29]([CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:28][CH2:27]5)=[CH:11][C:10]=3[CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1cc2cc(C3CCCC3)ccc2o1
Reactant: CC(C)(C)OC(=O)CCN1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCN1CCc2cc(-c3cc4cc(C5CCCC5)ccc4o3)ccc2C1
Yield: 33.2 %

Procedure:
A mixture of 5-cyclopentylbenzofuran-2-ylboronic acid (78 mg, 0.34 mmol), tert-butyl 3-(6-(trifluoromethylsulfonyloxy)-3,4-dihydroisoquinolin-2(1H)-yl)propanoate (93 mg, 0.23 mmol), triethylamine (0.95 mL, 6.8 mmol) and bis(triphenylphosphine) palladium(II) chloride (16 mg, 0.02 mmol) in ethanol (5 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was purification by silica gel chromatography on ISCO system yielding the title compound (34 mg, 34% yield). 1H NMR (400 MHz, CDCl3) δ 7.59 (m, 2H), 7.40 (d, 2H), 7.15 (dd, 1H), 7.07 (d, 1H), 6.91 (s, 1H), 3.70 (s, 2H), 3.08 (m, 1H), 2.96 (dd, 2H), 2.85 (dd, 2H), 2.78 (dd, 2H), 2.54 (dd, 2H), 2.11 (m, 2H), 1.84 (m, 2H), 1.68 (m, 4H), 1.46 (s, 9H). MS (ESI) m/z: Calculated: 445.26; Observed: 446.00 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:32]([C:31]3[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3ccc(Cl)cc3)CC2)c1[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5ccc(Cl)cc5)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-chloro-4-(4-(4-chlorobenzyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.027 g, 0.07 mmol), and ethanol (3.0 ml) was added 4-methoxybenzaldehyde (0.014 g, 0.10 mmol) with the aid of ethanol (1 ml) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.3 ml, 0.3 mmol). The reaction mixture was heated at 70° C. for 4.5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 30% ethyl acetate in dichloromethane, and then 2% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a white solid (0.009 g, 28%); 1H-NMR (500 MHz, DMSO-d6) 2.59 (br s, 4H, piperazine N(CH2)2), 3.56 (s, 2H, NCH2), 3.69 (br s, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 7.10 (d, J=8.86 Hz, 2H) and 8.12 (d, J=8.82 Hz, 2H) (3,5-C6H4OMe and 2,6-C6H4-Ome), 7.41 (s, 4H) (3,5-ArH and 2,6-ArH), 8.07 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.35 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[N:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29](Cl)=[O:30].O>>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[N:22]=[CH:21][C:20]([NH:23][C:29]([C:25]4[S:24][CH:28]=[CH:27][CH:26]=4)=[O:30])=[CH:19][CH:18]=3)[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Reactant: O=C(Cl)c1cccs1
Solvent: O
Product: O=C(Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1)c1cccs1

Procedure:
The title compound is prepared from 6-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-1-butynyl]-3-pyridinamine (Example 20) and 2-thiophenecarbonyl chloride, containing 0.3 mol of water; mp 187°-188° C.
Reaction SMILES: [CH:1]12[NH:7][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2.C(N(CC)CC)C.[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([F:29])[C:24]=1[O:25][CH2:26][C:27]#[CH:28])[C:19](Cl)=[O:20]>C(OCC)(=O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([F:29])[C:24]=1[O:25][CH2:26][C:27]#[CH:28])[C:19]([N:7]1[CH:6]2[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:20]
Reactant: C1CCC2NC2C1
Reactant: C#CCOc1c(F)cc(C(=O)Cl)cc1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCOc1c(F)cc(C(=O)N2C3CCCCC32)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
A mixture of 1.45 g of 7-azabicyclo[4.1.0]heptane, 2 ml of triethylamine and 3 ml of ethyl acetate was added dropwise to a mixture of 10 ml of ethyl acetate and 2.3 g of 3,5-difluoro-4-(2-propynyloxy)benzoic acid chloride under ice-cooling. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.8 g of 7-[3,5-difluoro-4-(2-propynyloxy)benzoyl]-7-azabicyclo[4.1.0]heptane represented by the formula:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([OH:13])(=O)[CH2:8][CH2:9][CH:10]=[CH2:11].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl.CN(C=O)C>[C:15]1([NH:14][C:7](=[O:13])[CH2:8][CH2:9][CH:10]=[CH2:11])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=CCCC(=O)O
Reactant: Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
To a stirred solution of oxalyl chloride (2.0 M in CH2Cl2, 11.5 mL, 23.1 mmol) in CH2Cl2 (100 mL) and DMF (1 drop) at 0° C. was added 4-pentenoic acid (2.25 mL, 22.0 mmol). This was allowed to warm to ambient temperature. Upon cessation of gas evolution, the mixture was returned to 0° C. and a solution of aniline (2.00 mL, 22.0 mmol) and TEA (6.72 mL, 26.3 mmol) in CH2Cl2 (5 mL) was added dropwise. After warming to ambient temperature, the reaction was allowed to proceed for 3 h. The mixture was concentrated under reduced pressure, and then partitioned between HCl (1 N, 10 mL) and EtOAc (30 mL) and the layers separated. The aqueous portion was extracted with EtOAc (3×15 mL) and the organic layers combined, washed with brine, dried over MgSO4, and filtered. Concentration under reduced pressure gave a yellowish solid, which was recrystallized with toluene to obtain 42 as white crystals (1.97 g, 11.24 mmol, 51%). TLC Rf 0.68 (50% EtOAc/hexanes); 1H-NMR (300 MHz, CDCl3) δ 7.49 (d, 2H), 7.29 (t, 2H), 7.08 (t, 1H), 5.88 (m, 1H), 5.10 (dd, 2 H), 4.42 (br s, 4 H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:17])[N:10]([C@@H:18]3[O:35][C@H:34]([CH2:36][O:37]C(=O)C)[C@@H:29]([O:30]C(=O)C)[C@H:24]([O:25]C(=O)C)[C@H:19]3[O:20]C(=O)C)[CH:9]=2)=[CH:4][CH:3]=1.[F:41][C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1>>[F:41][C:42]1[CH:47]=[CH:46][C:45]([C:2]2[S:6][C:5]([CH2:7][C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][C:15]=4[CH3:17])[N:10]([C@@H:18]4[O:35][C@H:34]([CH2:36][OH:37])[C@@H:29]([OH:30])[C@H:24]([OH:25])[C@H:19]4[OH:20])[CH:9]=3)=[CH:4][CH:3]=2)=[CH:44][CH:43]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(Br)s3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: Cc1cccc2c1c(Cc1ccc(-c3ccc(F)cc3)s1)cn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
3-(5-Bromothiophen-2-yl-methyl)-4-methyl-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 45-(3) and 4-fluorobenzeneboronic acid were treated in a manner similar to Example 45-(4) and 2-(7) to give the titled compound as a yellow powder. APCI-Mass m/Z 484 (M+H). 1H-NMR (DMSO-d6) δ 2.50 (s, 3H), 3.25 (td, J=8.8, 5.4 Hz, 1H), 3.40 (td, J=9.0, 5.4 Hz, 1H), 3.43-3.48 (m, 2H), 3.67-3.71 (m, 2H), 4.37 (s, 2H), 4.54 (t, J=5.5 Hz, 1H), 5.09 (d, J=5.1 Hz, 1H), 5.15 (d, J=5.1 Hz, 1H), 5.17 (d, J=6.1 Hz, 1H), 5.36 (d, J=9.2 Hz, 1H), 6.75 (d, J=7.1 Hz, 1H), 6.80 (d, J=3.5 Hz, 1H), 7.00 (t, J=7.7 Hz, 1H), 7.19 (t, J=8.8 Hz, 2H), 7.30 (d, J=3.5 Hz, 1H), 7.32 (s, 1H), 7.36 (d, J=8.3 Hz, 1H), 7.59 (dd, J=8.7, 5.3 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][C:8]3[C:16]4[C:15]([CH:5]2[CH:4]([C:17]([OH:19])=[O:18])[CH2:3]1)=[CH:14][CH:13]=[CH:12][C:11]=4[NH:10][CH:9]=3.S(=O)(=O)(O)O.[CH3:25]O>>[C:17]([CH:4]1[CH:5]2[CH:6]([CH2:7][C:8]3[C:16]4[C:15]2=[CH:14][CH:13]=[CH:12][C:11]=4[NH:10][CH:9]=3)[N:2]([CH3:1])[CH2:3]1)([O:19][CH3:25])=[O:18]
Reactant: CN1CC(C(=O)O)C2c3cccc4[nH]cc(c34)CC21
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1CN(C)C2Cc3c[nH]c4cccc(c34)C12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of the free indole 9-carboxylic acid (Example 13) (0.203 g) in methanol (5 cm3) was added with stirring concentrated sulphuric acid (0.15 cm3) and the reaction heated to reflux. After 2 hours further concentrated sulphuric acid (0.1 cm3) was added, reaction was indicated to be complete after 15 hours. The resultant solution was allowed to cool to room temperature to give after evaporation under vacuum and trituration with chloroform a dark orange solid (0.329 g).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH2:22][CH3:23])=[O:20])=[CH:15][C:14]=3[OH:24])[C:11]=2[CH3:12])=[O:6])[CH2:3][CH2:2]1.Br[CH2:26][CH2:27][Cl:28]>C(OCC)(=O)C.CCCCCC>[Cl:28][CH2:27][CH2:26][O:24][C:14]1[CH:15]=[C:16]([C:19]([NH:21][CH2:22][CH3:23])=[O:20])[CH:17]=[CH:18][C:13]=1[N:10]1[C:11]([CH3:12])=[C:7]([C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:6])[N:8]=[N:9]1
Reactant: ClCCBr
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2C)c(O)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2C)c(OCCCl)c1

Procedure:
In the same manner as in Example 145, a product was obtained from N-cyclopropyl-1-{4-[(ethylamino)carbonyl]-2-hydroxyphenyl}-5-methyl-1H-1,2,3-triazole-4-carboxamide (0.17 g) obtained in Example 141 and 1-bromo-2-chloroethane (0.05 ml), and the title compound was obtained as a white powder (0.06 g, 31%) by recrystallization from ethyl acetate-hexane.
Reaction SMILES: [CH3:1][NH2:2].Cl.C[Al](C)C.[N:8]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][C:9]=1[C:18]([O:20]C)=O>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:1][NH:2][C:18]([C:9]1[N:8]=[CH:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=1)=[O:20]
Reactant: COC(=O)c1ccc(C(=O)OC)nc1
Reactant: CN
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CNC(=O)c1ccc(C(=O)OC)cn1
Temperature: 25 °C
Yield: 104.6 %

Procedure:
To a stirred solution of MeNH2.HCl (173 mg, 5.12 mmol) in toluene (5 mL) at 0° C., was added AlMe3 (2 M solution in Hexanes, 1.28 mL, 2.56 mmol). After 30 minutes the solution was canulated into a stirred solution dimethyl pyridine-2,5-dicarboxylate (500 mg, 2.56 mmol) in DCM (5 mL) at 0° C. before stirring over night at room temperature. An aliquot was taken and analysed by NMR, indicating that there was a 0.8:1 ratio of product to starting material. MeNH2.HCl (173 mg, 5.124 mmol) and AlMe3 (2M solution in Hexanes, 1.28 mL, 2.56 mmol) were added and the reaction stirred for 12 hours. The reaction was quenched by addition of H2O (2 mL) and extracted with EtOAc (2×10 mL). The organics were combined, dried (MgSO4), filtered and concentrated at reduced pressure to give the title compound (520 mg, quant. yield) which was used without further purification.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:12]([C:13]#[N:14])=[CH:11][N:10](COCC[Si](C)(C)C)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(NC2N(C[O:36]CC[Si](C)(C)C)N=CC=2C#N)C=CC=CC=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>CCO.O>[C:1]1([NH:7][C:8]2[C:12]([C:13]([NH2:14])=[O:36])=[CH:11][NH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c(Nc2ccccc2)n1
Reactant: C[Si](C)(C)CCOCn1ncc(C#N)c1Nc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)c1c[nH]nc1Nc1ccccc1
Temperature: 0 °C

Procedure:
To a solution containing a mixture of 3-(phenylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile and 5-(phenylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (2.6 g, 7.8 mmol) in EtOH (40.3 mL) was added 2N aqueous HCl (40.3 mL). The resulting mixture was heated at 0° C. for 1 hour. The mixture was cooled to ambient temperature and carefully neutralized with 3N aqueous Na2CO3 until pH ˜9. The solution was further diluted with H2O (400 mL), the layers were partitioned and the aqueous mixture was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was adsorbed on silica gel in vacuo and purified by MPLC on silica gel (using a gradient elution of 0-100% EtOAc/DCM) to afford the title compound, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:10]([CH:11]=O)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[NH2:13]/[C:14](/[CH3:18])=[CH:15]\[C:16]#[N:17]>C(O)(=O)C.C(OCC)(=O)C>[F:1][C:2]1[C:10]([CH:11]2[C:15]([C:16]#[N:17])=[C:14]([CH3:18])[NH:13][C:2]([CH3:10])=[C:3]2[C:4]#[N:5])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: O=Cc1ccc2[nH]ncc2c1F
Reactant: C/C(N)=C/C#N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC1=C(C#N)C(c2ccc3[nH]ncc3c2F)C(C#N)=C(C)N1
Temperature: 25 °C
Yield: 104.1 %

Procedure:
250 mg (1.52 mmols) 4-fluoro-1H-indazole-5-carbaldehyde (Synthetic Preparation 11) and 250.1 mg (3.05 mmols) 3-aminocrotononitrile were dissolved in 1.74 mL acetic acid and refluxed for 1.5 hours. The mixture was allowed to cool to room temperature, filtered and washed with a little amount of acetic acid. The product was dried under vacuum at 40° C. to yield a first crop. The mother liquors were diluted with ethyl acetate, washed with water and saturated sodium hydrogen carbonate solution and dried over sodium sulfate to yield a second crop. Together 232 mg (51, 9%) 4-(4-fluoro-1H-indazol-5-yl)-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarbonitrile were obtained (Cpd. No. 311). 1H-NMR (DMSO-d6): δ=13.42 (br s, 1H), 9.58 (br s, 1H), 8.21 (s, 1H), 7.44 (d, 1H), 7.32 (dd, 1H), 4.86 (s, 1H), 2.04 (s, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14](C(=O)C)[C:13](=[O:21])[C:12]23[CH2:23][CH2:22]2)[CH:5]=[C:4]([F:24])[C:3]=1[C:25]([F:28])([F:27])[F:26].OS(O)(=O)=O>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:21])[C:12]23[CH2:22][CH2:23]2)[CH:5]=[C:4]([F:24])[C:3]=1[C:25]([F:28])([F:27])[F:26]
Reactant: CC(=O)N1C(=O)C2(CC2)c2cc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)ccc21
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1Nc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc2C12CC2

Procedure:
A mixture of 5'-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl)oxy]-1'-acetyl-spiro [cyclopropane-1,3'-indolin]-2'-one (0.60 g, 1.95 mmol), 5 mL of 1 N H2SO4 and tetrahydrafuran is heated at reflux for about 24 hours (until reaction is complete by gas chromatographic analysis). The reaction mixture is diluted with ethyl acetate and water and the phases are separated. The organic phase is dried (MgSO4) and concentrated in vacuo to give a residue. The residue is chromatographed using silica gel and ethyl acetate/hexane 25/75 to give the title product as a white solid, 0.41 g, (76%), mp 168°-170° C. identified by H1NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([C:10]#[N:11])=[CH:5][CH:4]=1.CO[C:14](OC)([N:16]([CH3:18])[CH3:17])[CH3:15].CN(C)C=O>CO>[CH3:17][N:16]([CH3:18])[C:14]([CH3:15])=[CH:9][C:7]1[C:6]([C:10]#[N:11])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=1
Reactant: COc1ccc(C#N)c(C)n1
Reactant: COC(C)(OC)N(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(C#N)c(C=C(C)N(C)C)n1
Temperature: 130 °C
Reaction time: 0.75 h

Procedure:
A mixture containing 47.2 g of 6-methoxy-2-methyl-3-pyridinecarbonitrile, 100 ml of dimethylacetamide dimethyl acetal and 100 ml of dimethylformamide was heated with stirring in an oil bath at 130° C. for 1 hour and 45 minutes. The temperature of the oil bath was raised to 150° C. and the methanol formed by the reaction was distilled off using a 12" distillation column (Vigreux) while continuing the heating at 150° C. for 14 hours. The reaction mixture was concentrated, 50 ml of ether was added to the concentrated solution whereupon the product crystallized out. The mixture was chilled and the crystalline solid collected. The solid was washed with cold ether, dried and recrystallized from ethyl acetate using decolorizing charcoal to yield 33.5 g of 2-[2-(dimethylamino)-1-propenyl]-6-methoxy-3-pyridinecarbonitrile, m.p. 103°-104° C.