Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:24])=O>O1CCCC1>[Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:24])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(C(=O)Cl)c2Cl)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-chloro-3-(1-cyanocyclopropyl)benzoic acid (16.0 g, 72.2 mmol) in tetrahydrofuran (150 mL) was added N,N-dimethylformamide (0.1 mL), and oxalyl chloride (7.2 mL, 84.0 mmol) was further added dropwise at 0° C., and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated under reduced pressure to dryness to give 2-chloro-3-(1-cyanocyclopropyl)benzoyl chloride as a pale-yellow oil.
Reaction SMILES: [CH:1]1[CH:8]=[CH:7][C:5](=[O:6])[C:4](O)=[CH:3][CH:2]=1.S(Cl)([Cl:12])=O>C1C=CC=CC=1>[CH:1]1[CH:8]=[CH:7][C:5](=[O:6])[C:4]([Cl:12])=[CH:3][CH:2]=1
Reactant: O=c1cccccc1O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=c1cccccc1Cl
Reaction time: 1.5 h

Procedure:
To a solution of tropolone (1,680 mg) dissolved in benzene (36 ml) is added thionyl chloride (1.12 ml). The mixture is stirred for 1.5 hr with refluxing. After concentrating the reaction mixture under reduced pressure, the resulting residue is purified by silica gel chromatography and recrystallized from cyclohexane to give 1.08 g of 2-chlorotropone as yellow needles. To a solution of the 2-chlorotropone (75 mg) dissolved in dimethylformamide (4 ml) is added potassium thiocyanate (270 mg). The mixture is stirred at 110° C. for 26 hr. To the reaction mixture is added water (50 ml), followed by cooling with ice. The resulting precipitate is recovered by filtration, purified by silica gel chromatography and recrystallized from ethanol to give 59 mg of 2-thiocyanatotropone as light brown needles.
Reaction SMILES: N=[C:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[N:5]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:4](=[S:17])[N:3]1[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=1.C[OH:31].O>Cl>[O:31]=[C:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[N:5]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:4](=[S:17])[N:3]1[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=1
Reactant: Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=N)C23CCC3)cc1
Reactant: CO
Agent: Cl
Solvent: O
Product: Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: 25 °C

Procedure:
A mixture of 7b (0.041 g, 0.1 mmol) in HCl aq., 2N (3 ml) and methanol (1 ml) was heated to reflux for 2 h. After being cooled to room temperature, the reaction mixture was poured into cold water (5 ml) and extracted with ethyl acetate (6 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane) to yield 4-(8-oxo-6-thioxo-5-(4-methylphenyl)-5,7-diazaspiro[3.4]oct-7-yl)-2-trifluoromethylbenzonitrile, 4-(8-oxo-6-thioxo-5-(4-methylphenyl)-5,7-diazaspiro[3.4]oct-7-yl)-2-trifluoromethylbenzonitrile, 7c (0.04 g, 0.096 mmol, 96%) as a white powder.
Reaction SMILES: Cl.C(O)C.[N+:5]([C:8]1[CH:19]=[CH:18][C:11]([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[CH:10][CH:9]=1)([O-])=O>O.[Pd]>[NH2:5][C:8]1[CH:19]=[CH:18][C:11]([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Cn2cncn2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(Cn2cncn2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A stainless steel vessel was inerted with nitrogen and connected via its vent to a mobile scrubber unit. The scrubber was charged with very dilute hydrochloric acid. The vessel was charged with 96% ethanol (40 kg) followed by 1-(4-nitrobenzyl)-1,2,4-triazole (9.62 kg). The vessel was re-inerted with nitrogen and a slurry of 10% Pd/c catalyst (Engelhardt type 4505, 192 g) in water added to the stirred batch via the addition funnel. The vessel, funnel and line were rinsed with water. Total water used was 16 l. The batch was well stirred and heated to 60° C. A solution of ammonium formate (13.95 kg) in water (3 l) was metered into the reactor over 1 hour. Batch temperature settled at 65° C. At the end of this addition, the batch was heated at 70°-75° C. for a further 1 hour. Tlc showed complete reaction and single spot formation. The batch was cooled to 60° C. and passed through a pressure filter coated with hyflo (1.5 kg) to another vessel. The reaction vessel, filter and lines were washed with water (10 l). A further batch of 1-(4-nitrobenzyl)-1,2,4-triazole (9.585 kg) was then reduced in the same way. This batch was filtered and added to the previously filtered batch together with a 10 1 water wash of the vessel, filter and lines. The combined, filtered batch (215 l) was distilled at atmospheric pressure until 70 1 of distillate had been removed (vapour temperature was 83° C. at this point). Water (30 l) was added and the distillation continued until the vapour temperature reached 95° C. (106 1 total distillate). The pressure in the distillation vessel was then reduced to allow distillation at a boiling point of ≤70° C. A further 70 1 of distillate was removed to leave a residual volume of 69 l. The batch had crystallised at this point and the slurry was cooled to ≤20° C. over 1 hour. The batch was gently stirred and aged overnight. The batch was cooled to 0° C., aged for 1 hour and then filtered. The solid was washed with water at 0°-5° C. (10 l). The batch was dried overnight at 50° C., in vacuo with a nitrogen bleed to give 1-(4-aminobenzyl)-1,2,4-triazole in 96% yield.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:3]([OH:38])[CH2:4][C@@H:5]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=[CH:28][CH:27]=2)[C:21]1=[O:36])[C@@H:16]([CH3:19])[CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:46][O:47][C:48]([NH:50][C@@H:51]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:52](O)=[O:53])=[O:49].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH2:39]([C@H:2]([NH:1][C:52]([C@@H:51]([NH:50][C:48](=[O:49])[O:47][CH3:46])[C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@@H:3]([OH:38])[CH2:4][C@@H:5]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=[CH:28][CH:27]=2)[C:21]1=[O:36])[CH:16]([CH3:19])[CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1)N1CCN(Cc2ccnc3ccccc23)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCN(Cc2ccnc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.6 %

Procedure:
A solution containing the product from Example 134B (0.147 mmol) in DMF (2 mL) was treated with the product from Example 1F (0.035 g, 0.185 mmol), EDAC (0.045 g, 0.235 mmol), HOBT (0.030g, 0.222 mmol), and NMM (0.050 mL, 0.455 mmol) at 0° C., stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and water. The organic phase was washed with 10% citric acid, dilute sodium bicarbonate, and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column, eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.019 g, 17% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.68 (d, J=6.6 Hz, 3 H), 0.93 (m, 12 H), 0.88-0.97 (m, 1 H), 1.22-1.33 (m, 1H), 1.47-1.56 (m, 2H), 1.72-1.84 (m, 1H), 2.38-2.45 (m, 1H), 2.62-2.73 (m, 3H), 2.79-2.86 (m, 1H), 2.98-3.10 (m, 3H), 3.55-3.63 (m, 4H), 3.89-3.94 (m, 2H), 4.07-4.21 (m, 2H), 4.80 (s, 2H), 6.79 (d, J=9.56 Hz, 1 H), 6.93-7.20 (m, 10 H), 7.41 (d, J=4.41 Hz, 1 H), 7.48-7.53 (m, 1H), 7.57-7.62 (m, 1H), 7.75-7.80 (m, 1H), 7.87 (d, J=9.19 Hz, 1 H), 8.06 (d, J=8.45 Hz, 1 H), 8.30 (d, J=8.08 Hz, 1 H), 8.88 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[N+:13]([O-:15])=[O:14])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]Cl)=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([S:23][C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=3)=[CH:11][C:12]=2[N+:13]([O-:15])=[O:14])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc[nH]c1-c1ccc(Cl)cc1
Reactant: ClSc1ccc(Cl)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Sc2ccc(Cl)cc2)[nH]c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 29.8 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-nitropyrrole (4.88 g, 21.9 mmol) in methylene chloride is cooled to 0° C., treated dropwise over 30 minutes with a solution of p-chlorophenylsulfenyl chloride (4.32 g, 24 mmol) in methylene chloride, stirred at 0° C. for 3 hours, stirred overnight at room temperature, diluted with methylene chloride, washed sequentially with water, saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a dark residue. Flash column chromatography of the residue using silica gel and a 1:5 ethyl acetate/hexanes solution gives the title product as a yellow solid (2.38 g, mp 195°-197° C.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[N:5]=[C:4]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:28])[N:20]=2)[N:3]=1.C(N(CC)CC)C.[C:43](Cl)(=[O:46])[CH2:44][CH3:45]>C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:28])[N:20]=2)[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:43](=[O:46])[CH2:44][CH3:45])=[CH:12][CH:11]=2)[C:7]=1[C:8]#[N:9]
Reactant: CN1CCN(C(=O)CCc2cccc(CSc3nc(N)c(C#N)c(-c4ccc(N)cc4)n3)n2)CC1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(=O)Nc1ccc(-c2nc(SCc3cccc(CCC(=O)N4CCN(C)CC4)n3)nc(N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
The compound of Example 56 (150 mg) and triethylamine (0.5 mL) were dissolved in 10 mL of acetonitrile, and 0.1 g of propionyl chloride was added dropwise to the mixture and the mixture was stirred at room temperature for 30 minutes. After removing the solvent, the residue was dissolved in chloroform. Thereto water was added, the organic layer was washed with water (twice), then brine (once), and dried over magnesium sulfate. After the solvent was removed under reduced pressure, the resulting oil was purified by chromatography on silica gel (methylene chloride-methanol-aqueous ammonia=90:10:1) to give 50 mg of N-[4-(6-amino-5-cyano-2-{6-[3-(4-methylpiperazin-1-yl)-3-oxopropyl]pyridin-2-ylmethylsulfanyl}pyrimidin-4-yl)phenyl]propionamide as a light yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][CH2:6][C:7]1[C:8]2[CH2:29][NH:28][CH2:27][CH2:26][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])=[CH:16][CH:15]=2)[N:12]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][CH2:6][C:7]1[C:8]2[CH2:29][N:28]([C:33](=[O:35])[CH3:34])[CH2:27][CH2:26][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])=[CH:18][CH:19]=2)[N:12]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(CCc4cccc(F)c4)n2)CNCC3)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCc2nc(Nc3ccc(-n4ccnc4C)cc3)nc(CCc3cccc(F)c3)c2C1
Yield: 12 %

Procedure:
1-(4-(3-Fluorophenethyl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (15.8 mg, 12%) was synthesised from 4-(3-fluorophenethyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (Example 51a) and acetic anhydride according to the general procedure for N-acetylation. MS (ES+) m/z 471.3 (M+H)+
Reaction SMILES: [CH3:1][NH2:2].F[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]>CO>[F:10][C:8]1[CH:7]=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4]([CH:9]=1)[NH:2][CH3:1]
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CO
Product: CNc1cc(F)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
An aqueous solution of 40% methyl amine (61 mL, 0.71 mol) was added dropwise to a methanol solution (200 mL) of 2,4-difluoronitrobenzene (46.7 g, 0.29 mol) under ice cooling, and the mixture was stirred for 1 hour under the same temperature. The reaction solution was poured into ice water. Precipitated crystals were collected by filtration, followed by washing with water. The resulting crystals were dried at 50° C., thereby obtaining 47.6 g of a yellow, powdery target compound (yield: 95%).
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[N-:11]=[N+:12]=[N-:13].[Na+].CN(C)C=O>C(OCC)C>[CH:1]([CH:3]([N:11]=[N+:12]=[N-:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2]
Reactant: [N-]=[N+]=[N-]
Reactant: C=CC(Cl)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CC(N=[N+]=[N-])c1ccccc1
Yield: 100.7 %

Procedure:
A mixture of 100 grams (655 mmol.) of vinylbenzyl chloride (mixture of m- and p-isomers), 42.6 grams (655 mmol.) of sodium azide and 500 mi. of dimethylformamide was stirred at room temperature for 24 hours. Ethyl ether, 500 mi., was then added and the mixture was extracted with two 300-mi. portions of water. The combined aqueous phases were extracted with 500 mi. of ethyl ether, and the combined organic layers were dried over magnesium sulfate, filtered and evaporated to yield 105 grams (100% of theoretical) of vinylbenzyl azide. The structure was confirmed by proton and carbon-13 nuclear magnetic resonance spectroscopy and infrared spectroscopy.
Reaction SMILES: [CH2:1]1[CH:11]2[C:5](=[N:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[NH:9][C:10]2=[O:12])[CH2:4][CH2:3][CH2:2]1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C.CCCCCC>[CH2:17]([N:9]1[C:10](=[O:12])[CH:11]2[CH2:1][CH2:2][CH2:3][CH2:4][C:5]2=[N:6][C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]1=2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=C1Nc2ccccc2N=C2CCCCC12
Solvent: CCCCCC
Solvent: CCO
Product: O=C1C2CCCCC2=Nc2ccccc2N1Cc1ccccc1
Yield: 66 %

Procedure:
Using 1,2,3,4,10,11a-hexahydro-11H-dibenzo [b,e][1,4]diazepin-11-one and benzyl bromide, the titled compound was synthesized in substantially the same procedure as in Working Example 4. Yield 66%. m.p. 123°-125° C. (ethanol-hexane).
Reaction SMILES: [CH:1]1([CH:4]([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[N:5]2[CH2:10][CH2:9][C:8]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]2=[O:22])[CH2:3][CH2:2]1.Br[C:39]1[CH:44]=[CH:43][N:42]([CH3:45])[C:41](=[O:46])[CH:40]=1>>[CH:1]1([CH:4]([C:23]2[CH:28]=[CH:27][C:26]([C:39]3[CH:44]=[CH:43][N:42]([CH3:45])[C:41](=[O:46])[CH:40]=3)=[CH:25][CH:24]=2)[N:5]2[CH2:10][CH2:9][C:8]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]2=[O:22])[CH2:2][CH2:3]1
Reactant: CC(C)(O)CC1(c2ccccc2)CCN(C(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C2CC2)C(=O)O1
Reactant: Cn1ccc(Br)cc1=O
Product: Cn1ccc(-c2ccc(C(C3CC3)N3CCC(CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc1=O

Procedure:
The title compound was prepared from 3-{cyclopropyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]methyl}-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (for preparation see below) and 4-bromo-1-methyl-1H-pyridin-2-one following a procedure analogous to that described in Example 3. LC-MS (Method 1): tR=3.57 min; Mass spectrum (ESI+): m/z=487 [M+H]+.
Reaction SMILES: [H][H].[Cl:3][C:4]1[CH:26]=[CH:25][C:7]([C:8]([C:10]2[C:11]([CH3:24])=[C:12]([CH2:16][CH:17]=[CH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:6][CH:5]=1>CO.[Ni]>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:10]2[C:11]([CH3:24])=[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: [H][H]
Reactant: Cc1c(CC=CCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Agent: [Ni]
Solvent: CO
Product: Cc1c(CCCCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1

Procedure:
Hydrogen was passed through a mixture of 16.27 g of 6-[3'-(4-chlorobenzoyl)-2'-methyl-phenyl]-hex-4-enoic acid in 80 ml of methanol and 16.3 g of Raney nickel and then the catalyst was filtered off. The methoanol was distilled from the filtrate and the residue was taken up in methylene chloride. The solution was dried, treated with activated carbon, filtered and evaporated to dryness to obtain, after crystallization from a 1-1 isorpopyl ether-petroleum ether mixture, 11.15 g of 6-[3'-(4-chlorobenzoyl)-2'-methyl-phenyl]-hexanoic acid melting at 82° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13](=O)[CH3:14])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:14])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1
Reactant: CC(=O)c1cnc(OCC2CC2)c(Cl)c1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1cnc(OCC2CC2)c(Cl)c1
Yield: 90 %

Procedure:
The title compound is prepared in 90% yield (1.22 g, colorless oil) from 1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethanone (923 mg, 4.09 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (744 mg, 6.14 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][CH:12]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1OC1CCC(=O)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Cc1cccnc1OC1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(3-methyl-pyridin-2-yloxy)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[C:23]3[O:22]/[C:21](=[CH:24]\[C:25]4[C:33]5[C:28](=[CH:29][C:30]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=5)[NH:27][CH:26]=4)/[C:20](=[O:38])[C:19]=3[CH:18]=[CH:17][C:16]=2[OH:39])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[OH:39][C:16]1[CH:17]=[CH:18][C:19]2[C:20](=[O:38])/[C:21](=[CH:24]/[C:25]3[C:33]4[C:28](=[CH:29][C:30]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=4)[NH:27][CH:26]=3)/[O:22][C:23]=2[C:15]=1[CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COC(=O)c1ccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c[nH]c2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCNCC4)C3=O)c[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
A solution of methyl (Z)-3-[(7-{[4-(tert-butoxycarbonyl)piperazin-1-yl]methyl}-6-hydroxy-3-oxobenzofuran-2(3H)-ylidene)methyl]-1H-indole-6-carboxylate (0.020 g, 0.037 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, then the residue was added with an excessive amount of triethylamine, and the mixture was azeotroped with toluene. The resulting residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain methyl (Z)-3-{[6-hydroxy-3-oxo-7-(piperazin-1-ylmethyl)benzofuran-2(3H)-ylidene]methyl}-1H-indole-6-carboxylate (0.007 g, 43%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH:5]=[O:6].[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1>>[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:10][C:9]2[C:8]([O:11][CH2:12][CH3:13])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[Br:1])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CCOc1cc(C=O)cc(Br)c1O
Product: CCOc1cc(C=O)cc(Br)c1OCc1ccc(C(=O)OC)cc1

Procedure:
Alkylation of 3-bromo-5-ethoxy-4-hydroxy benzaldehyde (4 g) with 4-bromomethylbenzoic acid methyl ester (3.73 g) was performed according to the method described in example 1a. Yield: 6.4 g. MS-ESI: [M+H]+=393/395
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1)([O-:3])=[O:2].[Br:20]N1C(=O)CCC1=O.O>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[N:11]1[C:19]2[C:14](=[CH:15][C:16]([Br:20])=[CH:17][CH:18]=2)[CH2:13][CH2:12]1)([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1cc(Br)ccc1N1CCc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Br)ccc1N1CCc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
To a solution of 1-(2-nitro-4-bromophenyl)indoline (15 g, 0.047 moles) in dimethylformamide (150 ml) at -10° C. was added dropwise a solution of N-bromosuccinimide (9.4 g, 0.054 mole) in dimethylformamide (50 ml) over 10 minutes. The reaction mixture was stirred at 0° C. for 15 minutes. The solution was added slowly to water (1 1) with vigorous stirring. The solid was filtered, dried, and dissolved in dichloromethane (300 ml). The solution was added to boiling methanol (1 l). The precipitate was collected by filtration to give 12.7 g (68%) of product, mp 150°-152° C.
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=[O:11])[CH:9]=[C:8]([CH3:12])[O:7][C:6]1=[O:13])C.[CH:14]([NH2:17])([CH3:16])[CH3:15].CC(C)([O-])C.[Na+]>C(O)C>[CH:14]([N:17]1[C:8]([CH3:12])=[CH:9][C:10](=[O:11])[C:5]([C:6]([OH:13])=[O:7])=[CH:4]1)([CH3:16])[CH3:15]
Reactant: CC1=CC(=O)C(=CN(C)C)C(=O)O1
Reactant: CC(C)N
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(=O)c(C(=O)O)cn1C(C)C

Procedure:
A solution of 3-dimethylaminomethylene-6-methyl-pyran-2,4-dione (preparation 1a, 10.00 g, 38.6 mmol based on 70% purity), isopropylamine (5.00 mL, 58.4 mmol) and sodium tert-butoxide (5.50 g, 57.2 mmol) in ethanol (20 mL) is heated for 18 h at 90° C. The reaction mixture is evaporated under reduced pressure, treated with water and extracted with dichloromethane. The aqueous layer is acidified with 4 N aqueous HCl and extracted with dichloromethane. The combined organic layer is washed with water, dried over Na2SO4 and evaporated under reduced pressure. Yield: 7.16 g; ESI mass spectrum: [M+H]+=196; r.t. HPLC: 0.71 min (Z002_006).