Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C(Cl)[Cl:23].C(N(CC)CC)C.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1>O1CCCC1>[OH2:41].[ClH:21].[ClH:23].[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][NH:4][C:40]([NH:39][C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)=[O:41])[CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: ClCCl
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C=Nc1ccc(F)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O
Product: O=C(NCCCN1CCN(Cc2ccc(Cl)cc2)CC1)Nc1ccc(F)cc1
Yield: 76 %

Procedure:
The procedure described in Example 3 was followed, using 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole), methylene chloride (50 ml), tetrahydrofuran (10 ml), triethylamine (4.2 ml; 30 mmole) and 4-fluorophenyl isocyanate (1.37 g; 10 mmole). Recrystallization from methanol/methylene chloride provided the title compound (3.75 g; 76% yield) as colorless crystals, m.p. 225°-228° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=1)[C:11]#[N:12].[C:20]([O-])([O-])=O.[K+].[K+].CI.O>CS(C)=O>[Cl:19][C:15]1[N:14]=[C:13]([C:10](=[C:2]2[N:3]([CH3:20])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1]2)[C:11]#[N:12])[CH:18]=[CH:17][N:16]=1
Reactant: O=C([O-])[O-]
Reactant: N#CC(c1ccnc(Cl)n1)c1nc2ccccc2s1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Solvent: O
Product: CN1C(=C(C#N)c2ccnc(Cl)n2)Sc2ccccc21
Reaction time: 48 h
Yield: 5 %

Procedure:
To a solution of 1 (0.1 g, 0.35 mmol) in dry DMSO was added dry K2CO3 then methyl iodide and the suspension was shaken at rt. for 2 days. The precipitate formed by addition of water was filtered off then washed with water until neutral pH. The crude residue, dried under vacuum at 40° C., was triturated in warm acetonitrile, filtered off then dried under vacuum at 40° C., affording 5.6 mg (5%) of the title compound as a yellow powder.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].CC[N:24]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:25]C.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C1C2C(=CC=CC=2)CN1>C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:9]=[CH:8][C:4]=1[C:5]([N:24]1[CH2:25][C:29]2[C:28](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27]1)=[O:6]
Reactant: CCN(CC)Cc1ccccc1
Reactant: O=C(Cl)c1ccc(OCCCN2CCCCC2)cc1Cl
Agent: C=Cc1ccc(C=C)cc1
Agent: Cl
Agent: c1ccc2c(c1)CNC2
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: O=C(c1ccc(OCCCN2CCCCC2)cc1Cl)N1Cc2ccccc2C1
Reaction time: 16 h
Yield: 134.5 %

Procedure:
A stirred mixture of 2-chloro-4-(3-piperidin-1-ylpropoxy)benzoyl chloride hydrochloride (D28) (0.10 g) and diethylaminomethyl polystyrene (3.2 mmol/g, 0.8 g) in DCM (10 ml) at rt was treated with isoindoline (0.031 g) and stirred for 16 h. The reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing the required product were evaporated, redissolved in DCM, treated with excess hydrogen chloride (1M solution in diethyl ether) and then concentrated. The residue was crystallised from acetone to yield the title compound (E61) as a white solid (0.083 g). MS electrospray (+ion) 399/401 (MH+). 1H NMR δ (DMSO-d6): 9.90 (1H, s), 7.41 (2H, m), 7.28 (3H, m), 7.11 (1H, s), 7.02 (1H, m), 4.83 (2H, s), 4.50 (2H, s), 4.14 (2H, t, J=5.9 Hz), 3.45 (2H, m), 3.25 (2H, m), 2.90 (2H, m), 2.18 (2H, m), 1.87-1.30 (6H, m).
Reaction SMILES: C1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10](=[O:19])[CH:9]([NH:20][C:21]([O:23]C3C=CC([N+]([O-])=O)=CC=3)=O)[N:8]=2)CCCCC1.C(N([CH2:38][CH3:39])CC)C.CN(C)C=O.[C:45]1([C:51]([NH:53][S:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([NH2:63])[CH:58]=2)(=[O:56])=[O:55])=[O:52])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CO>[CH2:39]1[CH2:38][CH:7]([C:9]2([NH:20][C:21]([NH:63][C:59]3[CH:60]=[CH:61][CH:62]=[C:57]([S:54]([NH:53][C:51]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[O:52])(=[O:56])=[O:55])[CH:58]=3)=[O:23])[N:8]=[CH:7][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10]2=[O:19])[CH2:13][CH2:12][CH2:17]1
Reactant: Nc1cccc(S(=O)(=O)NC(=O)c2ccccc2)c1
Reactant: CN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCCC2)c2ccccc21
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: CN1C(=O)C(NC(=O)Nc2cccc(S(=O)(=O)NC(=O)c3ccccc3)c2)(C2CCCCC2)N=Cc2ccccc21

Procedure:
The title compound was prepared in the same way as that described in Example 11, Step 4, using 5-cyclohexyl-1,3-dihydro-1-methyl-3(R,S)-[(4-nitrophenyloxycarbonyl)amino]-2H-1,4-benzodiaZepin-2-one (0.3 g, 0.69 mmol), triethylamine (96 μl, 0.69 mmol), dimethylformamide (6 ml) and 1-(phenylcarbonylaminosulphonyl)-3-aminobenzene (0.21 g, 0.76 mmol). After trituration with methanol, the compound (0.16 g, 41%) was afforded as a colourless solid. mp 200°-202° C. 1H NMR (360 MHz, D6 -DMSO) δ 0.91 (1H, m), 1.10-1.40 (3H, m), 1.42-1.69 (4H, m), 1.78 (1H, m), 1.92 (1H, m), 2.94 (1H, m), 3.32 (3H, s), 5.06 (1H, d, J=8.1 Hz), 7.36 (2H, m), 7.45-7.56 (6H, m), 7.62 (2H, m); 7.75 (1H, d, J=7.9 Hz), 7.84 (2H, m), 8.17 (1H, s), 9.42 (1H, s), 12.50 (1H, brs).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C[Si](Cl)(C)C.[CH3:17][CH2:18][O:19][CH2:20][CH3:21]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[C:6]1([CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[CH2:7][C:8]2=[O:11]
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: CCOCC
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: O=C1CC2(CCOCC2)c2ccc(Br)cc21
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-1-indanone (0.50 g, 2.35 mmol) in anhydrous THF (40 mL) under N2 atmosphere at −78° C. was added a solution of NHMDS (1 M in THF, 2.5 mL, 2.5 mmol) within 30 min, followed by TMSCl (0.281 g, 0.327 mL 2.59 mmol) after stirred 30 min. To this reaction mixture was added NHMDS (1 M in THF, 6.0 mL, 6.0 mmol) within 30 min at this temperature. The temperature was allowed to warm to −30 to −20° C., after stirred another 30 min, 2,2-eichlorodiethyl ether (336 mg, 0.275 mL, 2.35 mmol) was added. Then the reaction temperature was allowed to warm to room temperature without removing cooling bath, and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl, and extracted with EA two times. The combined organic phases were washed with 1 M HCl, H2O, brine successively, and dried over anhydrous Na2SO4, and filtered, and concentrated to give black oil. It was purified by flash chromatography on silica gel yield 103 mg of the desired product. MS ESI+ve m/z 281 (M+H)+.
Reaction SMILES: [C:1]([Si:5]([CH3:12])([CH3:11])[O:6][CH:7]([CH3:10])[CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:22]([O:26][C:27](=[O:30])[CH2:28]Br)([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C>[C:22]([O:26][C:27](=[O:30])[CH2:28][NH:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:12])[CH3:11])[CH3:10])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(CN)O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(CNCC(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 16 h

Procedure:
2-(tert-Butyl-dimethyl-silanyloxy)-propylamine (6.0 g, 31.6 mmol) was dissolved in DMF (60 mL). Diisopropylethylamine (5.5 mL, 31.6 mmol) and bromo-acetic acid tert-butyl ester (3.6 g, 18.6 mmol) was added. The reaction mixture was stirred at 50° C. for 16 h. The mixture was evaporated onto silica gel and and purified by column chromatography using a gradient, starting eluting with ethyl acetate/heptane 20:80 up to ethyl acetate/heptane 80:20. The product was isolated as an oil. Yield: 4.0 g, 71%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].CCN(CC)CC.[NH2:31][CH2:32][CH2:33][CH2:34][N:35]([CH3:43])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][CH2:32][CH2:33][CH2:34][N:35]([CH3:43])[C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Reactant: CN(CCCN)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(CCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
Combined 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (200 mg, 0.65 mmol) HATU (372 mg, 0.98 mmol), and Et3N (198 mg, 1.96 mmol) in DMF (3.0 mL). The mixture was stirred at room temperature for 0.5 hour, then tert-butyl (3-aminopropyl)(methyl)carbamate (147.39 mg, 0.79 mmol) was added. The mixture was stirred overnight at room temperature. The reaction mixture was purified by preparative HPLC to give tert-butyl (3-(6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinamido)propyl)(methyl)carbamate (150 mg, 48%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:5]([NH2:12])=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CO.[C:22]([O:25][CH2:26]C)(=[O:24])C.[C]=O>C(N(CC)CC)C>[CH3:26][O:25][C:22]([C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[N:6][C:5]([NH2:12])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:3]=1)=[O:24]
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1-c1ccc(Cl)cc1
Reactant: CCOC(C)=O
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1nc(-c2ccc(Cl)cc2)c(N)nc1C(F)(F)F

Procedure:
A mixture of 12.57 g 5-bromo-3-(4-chloro-phenyl)-6-trifluoromethyl-pyrazin-2-ylamine, 0.60 g palladium(II)chloride-dppf-dichloromethane complex, 75 ml methanol, 75 ml ethyl acetate and 10.0 ml triethylamine was heated to 110° C. in an autoclav under 70 bar of carbon monoxide for 20 h. The solvents were evaporated and the residue was purified by chromatography on silica gel with dichloromethane to yield 6.48 g of the title compound as off white solid. MS (M−H) at 330.1.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:4]=[CH:3]1.O=S(Cl)[Cl:13].[CH3:15]O>>[ClH:13].[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH3:15])=[O:9])[N:4]=[CH:3]1
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1c[nH]cn1
Agent: Cl
Product: COC(=O)Cc1c[nH]cn1

Procedure:
To a solution of 2-(1H-imidazol-4-yl)acetic acid hydrochloride (200 mg, 1.23 mmol) in methanol (5 ml) was added SOCl2 (145 mg, 1.23 mmol). The reaction mixture was concentrated after two hours to give the desired product. LC-MS: m/z (M+H)=141.1
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[NH2:16][C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1>ClCCl.CN(C=O)C>[CH3:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[O:9]
Reactant: Cc1cc[nH]c1C(=O)O
Reactant: Cc1ccccc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1NC(=O)c1[nH]ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
2.0 g (15.98 mmol) of 3-methyl-1H-pyrrole-2-carboxylic acid were dissolved in 50 mL of dichloromethane. 5.60 mL (63.9 mmol) of oxalyl chloride were added, followed by 5 drops of DMF. The reaction mixture was stirred at room temperature for 2 hours and then the solvents were evaporated. The black oil residue was dissolved in 50 mL of dichloromethane and 6.85 g (63.9 mmol) of o-toluidine were added dropwise. The reaction was stirred at room temperature for 1 hour and then the solvent was evaporated. The crude product was purified by flash chromatography (dichloromethane to dichloromethane/methanol 95:5) and then triturated in diisopropylether to give 2.97 g (87% yield) of the title compound as a brown solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[C:16]([OH:24])(=[O:23])[C:17]([CH2:19][C:20](O)=[O:21])=[CH2:18]>O>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([N:6]2[CH2:18][CH:17]([C:16]([OH:24])=[O:23])[CH2:19][C:20]2=[O:21])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: O
Product: O=C(O)C1CC(=O)N(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Temperature: 20 °C
Yield: 70.9 %

Procedure:
229 g (1 mole) of 3,5-bis-(trifluoromethyl)-aniline and 136.5 g (1.05 moles) of itaconic acid are stirred in 55 ml of water during 24 hours at 200° C in an autoclave. The reaction mixture is subsequently cooled to 20° C and 2 liters of cold water are added. Two liters of water are then evaporated, and the reaction mixture is again cooled to 20° C. The crystals that have precipitated are filtered off, dried, dissolved in 400 ml of diethyl ether and precipitated with 600 ml of n-hexane. There is obtained 242 g (71% of theory) of 1-(3,5-bis-trifluoromethylphenyl)-2-oxo-pyrrolidine-4-carboxylic acid; m.p. 108°-9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:18]=2)[C:15]([OH:17])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:19][O:20][C:21]([C:23]1([NH2:31])[CH2:28][CH2:27][CH:26]([CH2:29][CH3:30])[CH2:25][CH2:24]1)=[O:22]>>[CH3:19][O:20][C:21]([C:23]1([NH:31][C:15]([C:14]2[CH:13]=[N:12][CH:11]=[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=3)[CH:18]=2)=[O:17])[CH2:28][CH2:27][CH:26]([CH2:29][CH3:30])[CH2:25][CH2:24]1)=[O:22]
Reactant: COc1ccc(-c2cncc(C(=O)O)c2)cc1Cl
Reactant: CCC1CCC(N)(C(=O)OC)CC1
Product: CCC1CCC(NC(=O)c2cncc(-c3ccc(OC)c(Cl)c3)c2)(C(=O)OC)CC1

Procedure:
The title compound was synthesized from 5-(3-Chloro-4-methoxy-phenyl)-nicotinic acid and 1-Amino-4-ethyl-cyclohexanecarboxylic acid methyl ester in analogy to example 126, step 4.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[CH2:11]([Li])CCC.[CH3:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]=1[CH:28]=[O:29]>C1COCC1.CCCCCC>[CH3:11][O:9][C:8]([C:4]1[S:3][C:2]([CH2:1][CH:28]([OH:29])[C:18]2[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:20][O:21][C:17]=2[CH3:16])=[N:6][C:5]=1[CH3:7])=[O:10]
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: Cc1onc(-c2ccccc2)c1C=O
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1sc(CC(O)c2c(-c3ccccc3)noc2C)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a stirred solution of 2,4-dimethyl-thiazole-5-carboxylic acid (0.84 g, 5.34 mmol) in THF (50 mL) at −78° C. and under argon was added n-butyllithium (7.63 mL of a 1.40M solution in hexane, 10.7 mmol) dropwise. After 1 h, a solution of 5-methyl-3-phenyl-isoxazole-4-carbaldehyde (1.0 g, 5.34 mmol) in THF (50 mL) was added dropwise. After 3 h the reaction mixture was quenched with 10% aqueous citric acid (50 mL) then warmed to room temperature. The reaction mixture was extracted with ethyl acetate then the combined extracts were dried, filtered and concentrated. The resultant oil was redissolved in ethyl acetate, washed with water then dried, filtered and concentrated in vacuo. The resultant residue was dissolved in methanol (40 mL) and ether (20 mL) then (trimethylsilyl)diazomethane (4.0 mL of a 2M solution in ether, 8.0 mmol) was added dropwise. After 30 min, further (trimethylsilyl)diazomethane (4.0 mL of a 2M solution in ether, 8.0 mmol) was added. After 15 h, the reaction mixture was quenched with acetic acid (3 drops) then was concentrated and the residue redissolved in ethyl acetate and washed with NaOH (2 N). The organic phase was dried, filtered and concentrated then purified by chromatography (silica, 10 to 40% ethyl acetate in heptane) to give the title compound (500 mg, 26%) as a yellow foam. MS: m/e=359.0 [M]+.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[N-:6]([C:9]#[N:10])[C:7]#[N:8].[Na+].CN1CCCC1=O>CC(O)CC>[NH2:8][C:7]([NH:6][C:9]#[N:10])=[C:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#C[N-]C#N
Reactant: N#CCC#N
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCC(C)O
Product: N#CNC(N)=C(C#N)C#N
Temperature: 145 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a 250 ml flask is charged 6.6 gm (0.1 mole) of malononitrile, 8.9 gm (0.1 mole) of sodium dicyanamide and 40 ml of N-methylpyrrolidone. The stirred mixture is heated to 145° C. and held for one hour, then cooled to about room temperature. Then 150 ml of 2-butanol is added and the stirred mixture is cooled in an ice bath. The solids are filtered, washed with 2-butanol and dried. There is obtained 10.7 gm of 1-amino-1-cyanamido-2,2-dicyanoethylene, sodium salt, 82.5% pure, or a 57.0% yield.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3=[N:27][CH:28]=[CH:29][CH:30]=[C:25]3[N:24]([CH2:31][CH2:32][CH3:33])[C:23]2=[O:34])=[CH:18][CH:17]=1.[H-].[Na+]>CN(C=O)C.CO>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[O:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:26]3=[N:27][CH:28]=[CH:29][CH:30]=[C:25]3[N:24]([CH2:31][CH2:32][CH3:33])[C:23]2=[O:34])=[CH:20][CH:21]=1
Reactant: CCCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncccc21
Temperature: 180 °C
Yield: 50.4 %

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (320 mg) was added to a solution of 3-(4-hydroxyphenyl)-1-propyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (400 mg) and NaH (65.3 mg) in DMF (5 ml) at 100° C. The mixture was heated at 180° C. for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1-propyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg) as white crystals.
Reaction SMILES: [C:1]1([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18][N:17]([C:19]([C:21]4[CH:32]=[CH:31][C:24]([O:25][C@H:26]5[CH2:30][CH2:29][NH:28][CH2:27]5)=[CH:23][CH:22]=4)=[O:20])[CH2:16]3)[CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[CH3:40][N:41]([CH3:46])[S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[CH3:40][N:41]([CH3:46])[S:42]([N:28]1[CH2:29][CH2:30][C@H:26]([O:25][C:24]2[CH:31]=[CH:32][C:21]([C:19]([N:17]3[CH2:16][CH:15]([N:12]4[CH2:11][CH2:10][N:9]([C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[O:8])[CH2:14][CH2:13]4)[CH2:18]3)=[O:20])=[CH:22][CH:23]=2)[CH2:27]1)(=[O:44])=[O:43]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=C(c1ccccc1)N1CCN(C2CN(C(=O)c3ccc(O[C@H]4CCNC4)cc3)C2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)N1CC[C@H](Oc2ccc(C(=O)N3CC(N4CCN(C(=O)c5ccccc5)CC4)C3)cc2)C1
Reaction time: 3 h
Yield: 58 %

Procedure:
A solution of compound 33a (0.164 mmol) and Et3N (0.5 mL) in CH2Cl2 (2 mL) was treated with N,N-dimethylsulfamoyl chloride (26 uL, 0.246 mmol) at room temperature. The resulting mixture was stirred for 3 h, and the solvent was then removed under reduced pressure. The resultant residue was directly loaded onto a silica gel column and was purified by silica gel flash column chromatography, eluting with 5% MeOH/CH2Cl2 to give compound 439 (51.5 mg). 1H NMR (CDCl3): δ 7.61 (d, J=8.21 Hz, 2H), 7.36-7.46 (m, 5H), 6.86 (d, J=8.6 Hz, 2H), 4.98 (m, 1H), 4.31 (br. s., 1H), 4.11-4.26 (m, 2H), 4.05 (br. s., 1H), 3.87-3.96 (m, 1H), 3.84 (m, 1H), 3.70-3.79 (m, 1H), 3.66 (dd, J=11.4, 4.8 Hz, 1H), 3.39-3.58 (m, 4H), 3.21-3.26 (m, 1H), 2.82 (s, 6H), 2.42 (br. s., 4H), 2.19-2.29 (m, 2H); MS m/z (M+H+) 542.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.Cl[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=[O:16]>C(OCC)C>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([O:23][CH:20]2[CH2:19][CH2:18][N:17]([C:15](=[O:16])[CH2:14][NH:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]4)[CH2:22][CH2:21]2)=[CH:29][CH:28]=1
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Reactant: O=C(CCl)N1CCC(Oc2ccc(Cl)cc2)CC1
Solvent: CCOCC
Product: O=C1CCc2cc(NCC(=O)N3CCC(Oc4ccc(Cl)cc4)CC3)ccc2N1

Procedure:
The title compound is prepared from 6-amino-3,4-dihydro-quinolin-2-one and 2-chloro-1-[4-(4-chloro-phenoxy)-piperidin-1-yl]-ethanone (Example 233a) according to the method described in Example 206. Melting Point: 248-251° C. (diethylether)
Reaction SMILES: [NH2:1][C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([CH3:6])([OH:5])[CH3:4].[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14]>ClCCl>[CH3:4][C:3]1([CH3:6])[O:5][C:13](=[O:14])[NH:1][C@H:2]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(O)[C@@H](N)c1ccccc1
Solvent: ClCCl
Product: CC1(C)OC(=O)N[C@H]1c1ccccc1
Temperature: 25 °C

Procedure:
A solution of C2 (38.8 g, 235 mmol) in dichloromethane (1000 mL) was treated with carbonyldiimidazole (45.6 g, 281 mmol) and heated at reflux for 2 hours. The reaction mixture was cooled to 25° C., quenched with 1 N hydrochloric acid (560 mL), and extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate and concentrated, and the resultant residue was purified by trituration with 4:1 hexanes:ethyl acetate, followed by chromatography on silica gel (gradient: 9:1 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate) to provide C3 as a white solid. Yield: 24.7 g, 55%. MS (APCI) m/z 192.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 0.91 (3H, s), 1.58 (3H, s), 4.62 (1H, s), 5.53-5.60 (1H, br s), 7.20-7.39 (5H, m).
Reaction SMILES: [S:1]=[C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8](O)=O)[NH:3]1.[CH3:11][C:12]([C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])C=O)([CH3:14])[CH3:13].N1CCCCC1>C1(C)C=CC=CC=1.N1C=CC=CC=1>[OH:23][C:22]1[C:21]([C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:20][C:17](/[CH:8]=[CH:7]/[C:4]2[NH:3][C:2](=[S:1])[NH:6][N:5]=2)=[CH:16][C:15]=1[C:12]([CH3:14])([CH3:13])[CH3:11]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: O=C(O)Cc1n[nH]c(=S)[nH]1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(/C=C/c2n[nH]c(=S)[nH]2)cc(C(C)(C)C)c1O
Yield: 33 %

Procedure:
A solution of 2-(5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetic acid (prepared by the method described in Aust. J. Chem., 1979, 32, 161-5, Nowel W. Jacobsen, Bruce L. McCarthy, Stephanie Smith) (3.3 g, 0.021 mole) and 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzaldehyde (4.9 g, 0.021 mole) in a 2:1 mixture of toluene/pyridine (300 ml) is treated with piperidine (0.021 mole). The resulting mixture is stirred at reflux for 48 hours. The mixture is concentrated in vacuo and the residue dissolved in ether, the product is extracted from the organic phase with aqueous 1M NaOH. The combined aqueous layers are made acidic by treatment with aqueous 2M HCl, and the product extracted with a 1:1 mixture of ethyl acetate/ether. The organic layer is washed with saturated aqueous NaCl and dried over MgSO4. Filtration and concentration gives a solid which is triturated in hot isopropyl ether and filtered to provide 2.3 g (6.9 g theor., 33%) of desired (E)-2,4-dihydro-5-[2-[4-hydroxy-3,5-bis(1,1-dimethylethyl)phenyl]ethenyl]-3H-1,2,4-triazole-3-thione, mp 243° C.