Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][N:33]1[CH2:39][CH:38]2[NH:40][CH:35]([CH2:36][CH2:37]2)[CH2:34]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:40]5[CH:35]6[CH2:36][CH2:37][CH:38]5[CH2:39][N:33]([CH3:32])[CH2:34]6)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:30])[F:31])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CN1CC2CCC(C1)N2
Product: CN1CC2CCC(C1)N2C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-methyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 3-methyl-3,8-diaza-bicyclo[3.2.1]octane following General Procedure C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:10])[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][C:3]=1[C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1.O[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1.O>CN(C)C1C=CN=CC=1.ClCCl>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:10])[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][C:3]=1[C:20]1[CH:28]=[CH:27][C:23]([C:24]([O:26][C:30]2[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: CCCCCC[C@H](C)Oc1cc(N)c(-c2ccc(C(=O)O)cc2)cc1[N+](=O)[O-]
Reactant: O=Cc1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCCCC[C@H](C)Oc1cc(N)c(-c2ccc(C(=O)Oc3ccc(C=O)cc3)cc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.6 g of N,N'-dicyclodicyclohexylcarbodiimide was added at room temperature while stirring to a solution of 1.0 g of 4-[4-(2-amino-5-nitro-4-[(S)-2-octyloxy]phenyl)benzoic acid, 0.3 g of 4-hydroxybenzaldehyde and 0.04 g of 4-dimethylaminopyridine in 20 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight, poured into 100 ml of water and then extracted three times with 50 ml of dichloromethane each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate, filtered and the filtrate was subsequently concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 1:1) and two-fold recrystallization from ethanol of the fractions which were pure according to thin-layer chromatography gave 0.9 g of 4-[4-(2-amino-5-nitro-4-[(S)-2-octyloxy]phenyl)benzoyloxy]benzaldehyde; m.p. (C-I) 77°-78° C.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=O)[N:5]2[CH2:14][CH2:15][CH2:16][CH:4]2[C:3]1=[O:17].CN1C(=O)OC(=O)C2=CC=CC=C12.N1CCC[C@@H]1C(O)=O.B>O1CCCC1.CO>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]2[CH2:14][CH2:15][CH2:16][CH:4]2[C:3]1=[O:17]
Reactant: CN1C(=O)C2CCCN2C(=O)c2ccccc21
Agent: B
Agent: Cn1c(=O)oc(=O)c2ccccc21
Agent: O=C(O)[C@H]1CCCN1
Solvent: CO
Solvent: C1CCOC1
Product: CN1C(=O)C2CCCN2Cc2ccccc21

Procedure:
The above compound is obtained when (-)-1,2,3,11 a-tetrahydro-10-methyl-5H-pyrrolo[2,1-c] [1,4] benzodiazepin- 5,11(10H)-dione, melting point 120-122°C. [α]D 25 - 477°, (1.24%, methanol) and (prepared from N-methylisatoic anhydride and D-proline as described in Example 1) is treated with borane in tetrahydrofuran as described in Example 1.
Reaction SMILES: [CH2:1]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O)(=O)C.[N+:28]([O-])([OH:30])=[O:29]>O>[CH2:1]([C:13]1[CH:22]=[C:21]([N+:28]([O-:30])=[O:29])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1ccc2ccccc2c1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCCCc1cc([N+](=O)[O-])c2ccccc2c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 50 parts of 2-n-dodecyl-1-naphthol in 500 parts of glacial acetic acid was added 28 parts of nitric acid (specific gravity 1.4). The solution was stirred at ambient temperature for 1 hour and then poured into 2000 parts of water. The resulting mixture was extracted with 1400 parts of ether. The ether layer was separated; washed once with water (2000 parts), twice with 10% aqueous sodium bicarbonate solution (2000 parts), and finally with water (2000 parts). The ether solution was dried with anhydrous magnesium sulfate and evaporated to afford 56 parts of 2-n-dodecyl-4-nitro-1-naphthol as a viscous yellow oil, nD25 = 1.5454, which slowly crystallized to a waxy yellow solid on standing.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].[H-].[Na+].F[C:9]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:10]=1[C:11]#[N:12].O>CN(C)C=O>[I:17][C:14]1[CH:15]=[CH:16][C:9]([O:4][CH2:3][CH:2]([CH3:5])[CH3:1])=[C:10]([CH:13]=1)[C:11]#[N:12]
Reactant: CC(C)CO
Reactant: N#Cc1cc(I)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(I)cc1C#N
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 78.1 %

Procedure:
A solution of 2-methyl-1-propanol (0.56 mL, 6.06 mmol) in N,N-dimethylformamide (10 mL) was cooled to 0° C. and to this was added sodium hydride (242 mg, a 60% suspension in mineral oil, 6.06 mmol) in small portions. The turbid reaction mixture was stirred at 0° C. for 5 minutes and the temperature was raised to 23° C. Thereafter, the mixture was stirred at room temperature for 10 minutes and cooled again to 0° C. To the reaction mixture was added 2-fluoro-5-iodobenzonitrile (1.0 g, 4.04 mmol) and, after being warmed to room temperature, the reaction mixture was stirred for 1.5 hours. After the reaction was complete, water (20 mL) was added to the reaction mixture, which was extracted with ethyl acetate (3×30 mL). The organic phases were combined, washed with a saturated aqueous sodium chloride solution (3×30 mL), and thereafter dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration, the solvent was concentrated under reduced pressure. The crude product obtained was purified by silica gel chromatography (hexane/ethyl acetate=98/2) to obtain the title compound (950 mg). Yield, 78%.
Reaction SMILES: C(OC([NH:11][NH:12][CH2:13][CH:14]1[O:28][C:17]2=[C:18]3[C:23](=[C:24]([CH3:26])[CH:25]=[C:16]2[CH2:15]1)[NH:22][C:21](=[O:27])[CH2:20][CH2:19]3)=O)C1C=CC=CC=1.[H][H]>CN(C)C=O.CO.Cl.CO.[Pd]>[NH:12]([CH2:13][CH:14]1[O:28][C:17]2=[C:18]3[C:23](=[C:24]([CH3:26])[CH:25]=[C:16]2[CH2:15]1)[NH:22][C:21](=[O:27])[CH2:20][CH2:19]3)[NH2:11]
Reactant: [H][H]
Reactant: Cc1cc2c(c3c1NC(=O)CC3)OC(CNNC(=O)OCc1ccccc1)C2
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(CNN)C2
Yield: 88.6 %

Procedure:
The compound obtained in Example 339 (0.77 g, 2.0 mmol) was dissolved in a mixture of dimethylformamide (6 ml), methanol (11 ml), and 5% HCl-methanol solution (2 ml). To the resultant solution, 10% palladium-on-carbon (0.30 g) was added, followed by stirring at ambient temperature for 2 hours in the stream of hydrogen. The palladium-on-carbon was filtered off, and the solvent was distilled off under reduced pressure. 0.438 g of the title compound was obtained as pale yellow crystals (76.5%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH:16]1([NH2:19])[CH2:18][CH2:17]1.C(N(CC)CC)C>>[CH:16]1([NH:19][S:12]([C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[Cl:1])(=[O:14])=[O:13])[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC2CC2)c1Cl
Yield: 77.3 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.39 g, 4.78 mmol), cyclopropylamine (273 mg, 4.78 mmol) and triethylamine(1.0 mL, 7.17 mmol) were reacted to form the desired product (1.15 g, 77%). 1H NMR (MeOD-d4): δ 7.72 (d, 1H), 7.65 (d, 1H), 2.34 (m, 1H), 0.75 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:33]([NH:37][C:38](=[O:52])[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH:40]=1)([CH3:36])([CH3:35])[CH3:34]>C(#N)C>[C:33]([NH:37][C:38](=[O:52])[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]2[CH2:47][CH2:48][N:49]([C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=3[F:1])[CH2:50][CH2:51]2)[CH:40]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc([N+](=O)[O-])cc3F)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.8 %

Procedure:
2-Fluoro-4-nitrobenzoic acid (5 g, 27.01 mmol) was dissolved in acetonitrile (150 mL) and triethylamine (7.53 mL, 54.02 mmol). N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (7.8 g, 40.52 mmol) was added, followed by N-tert-butyl-3(piperazin-1-ylmethyl)benzamide (7.44 g, 27.01 mmol). The reaction was stirred at room temperature for 18 hours and concentrated under vacuum. The residue was dissolved in ethyl acetate, filtered through dicalite, washed consecutively with water (×2) and brine and concentrated under vacuum. The product was purified by strong cation exchange chromatography, eluting macroporous polystyrene sulfonic acid with 2M ammonia in methanol. The resulting solution was concentrated under vacuum to afford the title compound as a pale yellow oil (2.6 g). MS (ESI) m/z 443.7 [M+H]+
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=1[C:21]1[NH:26][C:25](=[O:27])[N:24]2[C:28]([CH3:34])=[N:29][C:30]([CH2:31][CH2:32][CH3:33])=[C:23]2[N:22]=1)[CH3:9]>ClCCl>[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)(=[O:19])=[O:18])=[CH:13][C:12]=1[C:21]1[NH:26][C:25](=[O:27])[N:24]2[C:28]([CH3:34])=[N:29][C:30]([CH2:31][CH2:32][CH3:33])=[C:23]2[N:22]=1)[CH3:9]
Reactant: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nc12
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
73 mg (0.73 mmol) of N-methylpiperazine are added to a solution of 100 mg (0.24 mmol) of 4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzenesulfonyl chloride (example VI) in 5 ml of dichloromethane and the reaction mixture is stirred at room temperature for 2 hours. After chromatographic purification (dichloromethane/methanol=95:5), 110 mg (95%) of 2-[2-ethoxy-5-(4-methyl-piperazine-1-sulfonyl)-phenyl]-6-methyl-8-propyl-3H-imidazo[1,5-a][1,3,5]triazin-4-one are obtained.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][CH:14]=[C:15]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])[N:16]=2)[CH2:8][CH2:7]1)(=O)=O.[C:30]([O-:33])(=[S:32])[CH3:31].[K+]>CN(C)C=O>[C:30]([S:32][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][CH:14]=[C:15]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=3)=[O:18])[N:16]=2)[CH2:8][CH2:7]1)(=[O:33])[CH3:31]
Reactant: CS(=O)(=O)OC1CCN(c2nc(C(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)CC1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CCN(c2nc(C(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)CC1
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 67.1 %

Procedure:
To a solution of 4-methanesulfonyloxy-1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)piperidine (1.2 g, 2.72 mmol) (obtained as described in Reference Example 14(5)) in dimethylformamide (60 ml) was added potassium thioacetate (625 mg, 5.47 mmol) at room temperature, and the reaction mixture was stirred in an oil bath (90° C.) for 3.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1) as the eluant to afford 4-acetylthio-1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)piperidine (769 mg, yield 88%) as a pale brown solid.
Reaction SMILES: [NH:1]([C:3](=[O:15])[CH2:4][N:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[N:6]1)[NH2:2].C(N(CC)CC)C.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>ClCCl>[O:15]=[C:3]([NH:1][NH:2][C:28]([C:27]1[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=1)=[O:29])[CH2:4][N:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[N:6]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cnn(CC(=O)NN)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(CC(=O)NNC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
The compound (6.0 g) obtained in Example 123a and triethylamine (8.33 g) were dissolved in dichloromethane (100 mL), and a solution of 3-(trifluoromethyl)benzoylchloride (10.0 g) in dichloromethane (20 ml) was added. The reaction mixture was stirred at room temperature overnight, an insoluble material was removed by filtration, and the filtrate was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: petroleum ether/ethyl acetate/triethylamine=5/1/0.001) to give the title compound (4.1 g) as an oil.
Reaction SMILES: C(O)[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO.[Cl:78][C:79]1[CH:84]=[C:83]([Cl:85])[CH:82]=[CH:81][C:80]=1[C:86](=O)[CH2:87][C:88]#[N:89].C1C(=O)N(Br)C(=O)C1.[NH2:99][C:100]([NH2:102])=[S:101]>O.CC(C)=O>[NH2:102][C:100]1[S:101][C:87]([C:88]#[N:89])=[C:86]([C:80]2[CH:81]=[CH:82][C:83]([Cl:85])=[CH:84][C:79]=2[Cl:78])[N:99]=1
Reactant: NC(N)=S
Reactant: N#CCC(=O)c1ccc(Cl)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1sc(N)nc1-c1ccc(Cl)cc1Cl
Temperature: 50 °C
Yield: 41.9 %

Procedure:
beta-Cyclodextrin (4.29 g, 3.78 mmol) was dissolved in water (75 mL) at 50° C. and a solution of 3-(2,4-dichlorophenyl)-3-oxopropanenitrile (810 mg, 3.8 mmol) in Acetone (3.80 mL) was added dropwise, followed by NBS (0.808 g, 4.54 mmol) and thiourea (0.346 g, 4.54 mmol). Reaction mixture was stirred at 50° C. 1 hr. LCMS indicated complete conversion. Reaction mixture was cooled to rt, extracted with ethyl acetate (3×50 mL), dried with MgSO4, filtered and concentrated under reduced pressure. The residue was purified by ISCO with 5-30% ethyl acetate in hexanes to give 0.43 g of the title compound (42%). LCMS; (FA) ES+, 270, 272, 1H NMR (400 MHz, d1-chloroform) δ 7.49 (d, J=1.84 Hz, 1H), 7.41 (d, J=8.30 Hz, 1H), 7.31 (dd, J=8.16, 1.74 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:8][CH2:7]1)[CH3:5].[Cl:28][C:29]1[CH:37]=[C:36]([CH3:38])[C:32]([C:33](O)=[O:34])=[C:31]([CH3:39])[N:30]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:28][C:29]1[CH:37]=[C:36]([CH3:38])[C:32]([C:33]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]2[CH2:11][CH2:10][CH:9]([N:12]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:8][CH2:7]2)[CH3:5])=[O:34])=[C:31]([CH3:39])[N:30]=1
Reactant: COc1ccc(N(Cc2cccnc2)C2CCN([C@H](C)CCN)CC2)cc1
Reactant: Cc1cc(Cl)nc(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(Cc2cccnc2)C2CCN([C@H](C)CCNC(=O)c3c(C)cc(Cl)nc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.4 %

Procedure:
(R)-[1-(3-Amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-pyridin-3-ylmethyl-amine (0.78 g, 2.12 mmol) was dissolved in DCM (10 mL). 6-Chloro-2,4-dimethyl-nicotinic acid (474 mg, 1.2 eq.), HOBT (430 mg, 1.5 eq.), DIPEA (760 μL, 2 eq.), and EDCI (612 mg, 1.5 eq.) were added sequentially. The mixture was stirred at room temperature for 6 h, and then quenched with saturated NaHCO3 (20 mL). The pH of the equilibrated aqueous was adjusted to 8 with 1N HCl, and the mixture was extracted with DCM (200 mL in 5 extracts). The combined organic was dried (Na2SO4) and concentrated. The residue was purified with flash chromatography on 150 mL silica using a gradient of 5%→10% MeOH in EtOAc containing 1% NH4OH as the eluent to give 6-chloro-N-((R)-3-{4-[(4-methoxy-phenyl)-pyridin-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (0.88 g, 77%) as light brown foam. 1H NMR (δ, CDCl3): 8.66 (1 H, d, br, J=5.7 Hz), 8.51 (1 H, s), 8.44 (1 H, d, J=4.8 Hz), 7.61 (1 H, d, J=8.1 Hz), 7.20 (1 H, dd, J=7.8, 4.8 Hz), 7.01 (1 H, s), 6.73 (2 H, d, J=9.0 Hz), 6.62 (2 H, d, J=9.0 Hz), 3.88 (2 H, s, an overlapping 1H, m), 3.71 (3 H, s), 3.33 (2 H, pentet, J=13.5 Hz), 2.80 (3 H, m), 2.51 (3 H, s, an overlapping 1 H, m), 2.30 (3 H, s), 2.12 (1 H, t, J=11.4 Hz), 1.82-1.66 (3 H, m), 1.60-1.46 (1 H, m), 1.11 (1 H, qd, J=12.3, 3.6 Hz), 0.99 (3 H, d, J=6.6 Hz), 0.92 (1 H, qd, J=12.0, 3.0 Hz); 13C NMR (δ, CDCl3): 167.2, 155.4, 152.9, 150.2, 148.9, 148.1, 147.5, 142.5, 135.7, 134.8, 123.3, 122.5, 117.8, 114.6, 60.5, 58.1, 55.6, 52.1, 47.5, 43.6, 40.1, 30.7, 29.4, 22.1, 18.8, 13.4; ES-MS m/z 536.5 (M+1). Anal. Calcd. for (C30H38N5ClO2) 0.2(H2O): C, 66.76; H, 7.17; N, 12.98; Cl, 6.57. Found: C, 66.80; H, 7.00; N, 12.86; Cl, 6.55.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:42])[NH:17][CH2:18][C:19]3[N:20]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:21](=[O:37])[C:22]4[C:27]([C:28]=3[O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:26][C:25]([C:34]([NH2:36])=[S:35])=[CH:24][CH:23]=4)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:44][C:45](=O)[C:46]([O:48][CH2:49][CH3:50])=[O:47].O>C(O)C>[CH2:30]([O:29][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:34]3[S:35][CH:44]=[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[N:36]=3)[CH:26]=2)[C:21](=[O:37])[N:20]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:19]=1[CH2:18][NH:17][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:42])[CH2:31][CH2:32][CH3:33]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCCCOc1c(CNC(=O)OCC2c3ccccc3-c3ccccc32)n(CC(C)C)c(=O)c2ccc(C(N)=S)cc12
Solvent: O
Solvent: CCO
Product: CCCCOc1c(CNC(=O)OCC2c3ccccc3-c3ccccc32)n(CC(C)C)c(=O)c2ccc(-c3nc(C(=O)OCC)cs3)cc12
Yield: 88.3 %

Procedure:
A solution of 9H-fluoren-9-ylmethyl[6-(aminocarbothioyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.29 g, 0.5 mmol) and ethyl bromopyruvate (0.19 g, 1 mmol) in ethanol (10 ml) was refluxed under heating for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give ethyl 2-[4-butoxy-3-[[[(9H-fluoren-9-ylmethoxy)carbony]amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylate (0.30 g, 90.9%) as crystals.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:10](C(OCC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].O.[Cl-].[Li+]>CS(C)=O.[Cl-].[Na+].O>[N+:1]([C:4]1[C:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1ncccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1ncccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 92 %

Procedure:
Diethyl (3-nitropyridin-2-yl)-malonate (12.5 g, 0.044 mol) was dissolved in DMSO (150 mL) and water (0.79 mL, 0.044 mol) and lithium chloride (4.65 g, 0.11 mol) were added at room temperature under nitrogen. The reaction was warmed to 100° C. 12 h and more lithium chloride (1 g) was added to the reaction. The reaction was heated for another 5 hours and cooled to room temperature. Brine (150 mL) was added to the reaction before extracting with EtOAc (3×, 275 mL each). The organics were combined and dried over sodium sulfate, then concentrated in vacuo. The resulting residue was triturated with diethyl ether and collected by filtration (8.6 g, 92% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[C:10]([C:16]#[CH:17])=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:21]=1>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[C:10]([C:16]#[C:17][C:24]2[CH:25]=[CH:20][CH:21]=[C:22]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])[CH:23]=2)=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1nc(C)ccc1OCC(=O)OC(C)(C)C
Reactant: CCCS(=O)(=O)c1cccc(Br)c1
Product: CCCS(=O)(=O)c1cccc(C#Cc2nc(C)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (2-ethynyl-6-methyl-pyridin-3-yloxy)-acetic acid tert-butyl ester (Intermediate 86) and 1-bromo-3-(propane-1-sulfonyl)-benzene (Intermediate 5), the title compound was obtained as a yellow sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: CN1CCOCC1.[C:8]([NH:12][C:13]([C:15]1[N:16]=[C:17]([O:23][CH3:24])[S:18][C:19]=1[C:20](O)=[O:21])=[O:14])([CH3:11])([CH3:10])[CH3:9]>C(Cl)Cl>[C:8]([N:12]1[C:20](=[O:21])[C:19]2[S:18][C:17]([O:23][CH3:24])=[N:16][C:15]=2[C:13]1=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: COc1nc(C(=O)NC(C)(C)C)c(C(=O)O)s1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1nc2c(s1)C(=O)N(C(C)(C)C)C2=O

Procedure:
3.75 g (37.1 mmol) of N-methylmorpholine, 1.20 g (10 mmol) of 4-N,N-dimethylaminopyridine and 8.70 g of a 50% strength solution (13.7 mmol) of propanephosphonic anhydride in CH2Cl2 were added in succession to a solution of 2.6 g (10 mmol) of 4-tert-butylaminocarbonyl-2-methoxythiazole-5-carboxylic acid in 100 ml of CH2Cl2 at -5° C. The mixture was refluxed for 6 hours, after which the solvent was removed and the residue was taken up with ethyl acetate. The solution was extracted twice with saturated sodium bicarbonate solution and once with 5% strength citric acid solution, washed with water and dried over MgSO4. After removal of the solvent, the crude product was purified by chromatography over silica gel (eluant: 1:1 cyclohexane/ethyl acetate) and 1.20 g (50%) of product of melting point 63°-66° C. were obtained in this manner (Active ingredient Example No. 4.014).