Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:2]([N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[C:3]2[CH:4]=[CH:5][C:6]3[NH:12][C:11](=[O:13])[CH2:10][N:9]=[C:8]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:7]=3[CH:20]=2)=[CH:22][CH:23]=1
Reactant: O=C1CN=C(c2ccccc2)c2cc(C(Cl)c3ccc(Cl)cc3)ccc2N1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CN=C(c2ccccc2)c2cc(C(c3ccc(Cl)cc3)n3ccnc3)ccc2N1
Yield: 44.6 %

Procedure:
A mixture of intermediate (29) (0.0125 mol), 1H-imidazole (0.0375 mol) and K2CO3 (8.62 g) in acetonitrile (150 ml) was stirred and refluxed for 3 h. The mixture was cooled, filtered off and the filtrate was evaporated till dryness. The residue was taken up in DCM. The organic layer was washed with water, dried (MgSO4), filtered off and evaporated. The residue (5.7 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1) (15–40 μm). The pure fractions were collected and evaporated. The residue (2.71 g) was crystallized from DIPE, yielding 2.38 g (51%) of (±)-7-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, mp. 144° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2].C1N=CN([C:22]([N:24]2[CH:28]=N[CH:26]=[CH:25]2)=O)C=1.C[N:30]([CH:32]=O)C>>[ClH:14].[C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([NH:30][CH2:32][CH:5]2[CH:13]3[CH2:28][N:24]4[CH2:22][CH:6]2[CH2:7][CH:25]4[CH2:26]3)=[O:11])=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)C=O
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NCC1C2CC3CC1CN3C2
Product: Cl
Reaction time: 0.5 h
Yield: 54 %

Procedure:
4-Acetylamino-5-chloro-2-methoxybenzoic acid (235 mg, 0.965 mmol) and CDI (156 mg, 0.965 mmol) were dissolved in 5 ml of DMF and stirred for 0.5 hour. A solution of the amines of Example D (147 mg, 0.956 mmol) in 1 ml DMF was then added to the above solution. This mixture was stirred for 10 hours and concentrated to dryness. The residue was dissolved in CHCl3, washed successively with water and 10% K2CO3 and then dried over K2CO3, filtered and concentrated to dryness. The resulting solid was chromatographed with silica gel eluting with 15% MeOH (NH3)/CHCl3 to give a 51% (anti)/49%(syn) epimeric mixture of the title compound (196 mg, 54%). Conversion to the hydrochloride salt was accomplished by treatment with methanolic HCl.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][CH2:10][C:11]#[N:12].N1C=CC=CC=1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=1)[CH2:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:8][N:9]([CH2:10][C:11]#[N:12])[S:25]([CH2:24][C:23]1[CH:29]=[CH:30][CH:31]=[C:21]([C:20]([F:19])([F:32])[F:33])[CH:22]=1)(=[O:27])=[O:26]
Reactant: CNCC#N
Reactant: O=S(=O)(Cl)Cc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CN(CC#N)S(=O)(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
In this example 21 ml (0.15 mole) of triethylamine was added over a 5 minute period to a cooled solution containing 16 g (0.15 mole) of the hydrochloride salt of methylaminoacetonitrile in 150 ml of methylene chloride. The mixture was stirred at 20° C. for 15 minutes and then 7.9 g (0.1 mole) of pyridine was added. Then 25.9 g (0.1 mole) of 3-trifluoromethylbenzylsulfonylchloride dissolved in about 50 ml methylene chloride was added to the reaction mixture. The reaction mixture was maintained at 20° C. during the addition and then refluxed for three hours. The mixture was cooled to room temperature and washed once with 200 ml of water and then washed twice with 100 ml of aqueous 5 wt. % hydrochloric acid. The washed mixture was dried over magnesium sulfate and evaporated under vacuum affording 28.2 g of the title compound as a solid residue.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]1)[CH2:5][CH2:6]C)[CH2:2]C.BrCC#N.C([N:22]([CH2:26][CH:27]1[CH2:32][CH2:31]CCN1CC#N)CCC)CC>ClCCl.C(OCC)(=O)C>[CH2:1]([N:4]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:31][CH2:32][CH2:27][C:26]#[N:22])[CH2:5][CH3:6])[CH3:2]
Reactant: CCCN(CCC)CC1CCCCN1
Reactant: CCCN(CCC)CC1CCCCN1CC#N
Agent: N#CCBr
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCN(CC)CC1CCCCN1CCCC#N

Procedure:
from 2-[(dipropylamino)methyl]piperidine and 2-bromoacetonitrile, (±)-2-[2-[(dipropylamino)methyl]piperidin-1-yl]acetonitrile, RF 0.9 (Macherey-Nagel, PolygramRSIL G/UV254, pre-coated plastic sheets for TLC, eluant: dichloromethane/ethyl acetate 50:50 v/v).
Reaction SMILES: [CH2:1]1[O:8][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:9]([NH2:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]>CO>[CH2:9]([NH:18][CH2:1][CH:2]([OH:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:1][CH:2]([OH:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC1CO1
Reactant: NCCCCCCCCN
Solvent: CO
Product: CCCCCC(O)CNCCCCCCCCNCC(O)CCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-heptene oxide (52 g.) and 1,8-octanediamine (32.8 g.) and two recrystallizations of the resulting product from methanol gave N,N'-(1,8-octylene)-bis[2-hydroxyheptylamine] (I: R= CH3 (CH2)4, R' = H, X= (CH2)8, Z= H) (17.2 g., m.p. 128.0°-132.8° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[CH3:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:27])=[CH:24][CH:23]=1)(=[O:20])=[O:21]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(S(C)(=O)=O)cc4)cc3c2C1
Yield: 12.8 %

Procedure:
Beginning with 8.7 mg (0.038 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 17.0 mg (0.085 mMol) 4-methanesulfonylbenzoic acid, 2.0 mg (13%) of the title compound were recovered as a beige solid.
Reaction SMILES: O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)C(C)C)(C)C.[CH:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1.[C:39]([O:43][C:44]([NH:46][CH2:47][C:48](O)=[O:49])=[O:45])([CH3:42])([CH3:41])[CH3:40]>ClCCl>[CH2:31]([C:32]1[CH:33]=[CH:34][C:35]([NH:38][C:48](=[O:49])[CH2:47][NH:46][C:44]([O:43][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:45])=[CH:36][CH:37]=1)[C:28]1[CH:27]=[CH:26][CH:25]=[CH:30][CH:29]=1
Reactant: Nc1ccc(Cc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(Cc2ccccc2)cc1
Reaction time: 17.5 h
Yield: 83.9 %

Procedure:
Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (1.90 g) and N,N-diisopropylethyl-amine (1.5 mL) were added to a solution of 4-aminodiphenylmethane (0.52 g) and N-tert-butoxycarbonylglycine (0.50 g) in dichloromethane (30 mL) at 0° C. After stiriing at 0° C. for 10 min and at room temperature for 17.5 hr, the solvent was removed in vacuo. The residue was diluted with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium hydrogen carbonate, and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1, v/v) to afford the title compound (0.81 g) as a colorless powder: 1H NMR (400 MHz, CDCl3) δ 1.47 (s, 9H), 3.90 (d, 2H), 3.94 (s, 2H), 7.12-7.21 (m, 5H), 7.28 (d, 2H), 7.41 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:11][CH:10]=2)N)=[CH:4][CH:3]=1.CC([O-])=O.[Na+].CC(O)=O.[C:38]([S:42][CH2:43][C:44](=O)[CH2:45][C:46]([CH2:53][CH3:54])([CH2:51][CH3:52])[C:47]([O:49][CH3:50])=[O:48])([CH3:41])([CH3:40])[CH3:39]>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:9]3[C:14](=[CH:13][C:12]([O:15][CH2:16][C:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:18]=4)=[CH:11][CH:10]=3)[C:43]([S:42][C:38]([CH3:41])([CH3:40])[CH3:39])=[C:44]2[CH2:45][C:46]([CH2:53][CH3:54])([CH2:51][CH3:52])[C:47]([O:49][CH3:50])=[O:48])=[CH:4][CH:3]=1
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CCC(CC)(CC(=O)CSC(C)(C)C)C(=O)OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCC(CC)(Cc1c(SC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)OC
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-(4-chlorobenzyl)-1-[4-(quinolin-2-ylmethoxy)phenyl]hydrazine from Example 1A, Step D, (660 mg, 1.7 mmol) and anhydrous NaOAc (160 mg, 1.95 mmol) in toluene (3 mL) was added glacial HOAc (1.5 mL). After 30 minutes, a solution containing methyl 5-(t-butylthio)-2,2-diethyl-4-oxopentanoate from Step B (402 mg, 1.47 mmol) in toluene (1 mL) was added and the reaction mixture stirred for 24 hours at room temperature and for 48 hours at 65° C. The reaction was then diluted with EtOAc, washed with NH4OAc buffer (25% w/v) and dried over MgSO4. Filtration and concentration gave a viscous oil which was purified by flash chromatography on silica gel (eluant: EtOAc-hexane 15:85) to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][O:14][CH3:15])[CH2:10][CH2:9][C:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:7][C:6]=2[CH:23]=1.B([O-])([O-])O[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)C.O>[CH2:36]([O:35][CH2:34][CH2:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH2:12][CH2:13][O:14][CH3:15])[CH2:10][CH2:9][C:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:7][C:6]=3[CH:23]=2)=[CH:31][CH:30]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: COCCN1CCC(C(=O)OC(C)(C)C)=Cc2cc(Br)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC(C)(C)C)CCN3CCOC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
In toluene/ethanol/water (=10/1/1, 62.4 ml) was dissolved tert-butyl 7-bromo-1-(2-methoxyethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (1.8 g). To the solution were added 4-(2-butoxyethoxy)phenyl borate (1.68 g) and potassium carbonate (1.55 g), and the mixture was stirred for 30 minutes under argon atmosphere. To the mixture was added tetrakistriphenylphosphinpalladium (0.22 g), and the mixture was heated to reflux for 16 hours. After cooled to room temperature, the reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (ethyl acetate/ethanol=5/1) to give tert-butyl 7-[4-(2-butoxyethoxy)phenyl]-1-(2-methoxyethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (1.4 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[CH:18][CH:19]=[CH:20][C:21](OCC)=[O:22])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=[O:22])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=CC=Cc1cn(Cc2ccccc2)c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=CC=CC=Cc1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 26 h
Yield: 77.3 %

Procedure:
To a solution of ethyl 5-(1-benzylindol-3yl)-2,4-pentadienoate (1.5 g, 4.5 mmol) in 100 ml of diethyl of diethyl ether and 20 ml of tetrahydrofuran, stirred at 0° C. (ice bath), was added in portions 0.34 g (9 mmol) of LAH; the resulting mixture was stirred at room temperature for 26 hours, and worked up in manner similar to Example 13 to afford, after purifications by dry column chromatography (2:1, hexane:ethyl acetate), 1.2 g of the intermediate 2,4-pentadienol. This substance was dissolved in 250 ml of dichoromethane and 6 g of activated manganese dioxide was added. The suspension was stirred at room temperature for 6 hours. Manganese dioxide was removed by filtering through Celite® and washed thoroughly with a mixture of ethyl acetate and methylene chloride. The combined filtrate and washing were concentrated on a rotary evaporator to give 1 g of the product as an orange colored oil. This substance was used without purification in Example 15. NMR spectrum shows a singlet a 5.18 ppm and a doublet (J=7.5 Hz) at 9.48 ppm.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[NH:13][CH2:14][CH2:15][CH2:16][C:10]3=[N:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.O=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[C:1]1([C:7]2[N:12]=[C:11]3[N:13]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:14][CH2:15][CH2:16][C:10]3=[N:9][C:8]=2[C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccccc2)NCCC3)cc1
Reactant: CCOC(=O)CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Phenyl-2-p-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate F) (162 mg, 0.538 mmol) in dry DCE (1 ml) was treated with DIPEA (0.103 ml, 0.591 mmol) followed by ethyl 7-oxoheptanoate (185 mg, 1.075 mmol). The reaction mixture was stirred at RT for 10 minutes and sodium triacetoxyborohydride (570 mg, 2.69 mmol) was added. The resulting mixture was stirred at 60° C. for 16 hours. After cooling to RT, the mixture was slowly added to water (50 ml) and extracted with DCM (3×). The combined organic extracts were passed through a phase separating column and concentrated in vacuo. The resulting crude product was purified by chromatography on silica eluting with 0-10% EtOAc/iso-hexane to afford the title compound; LCMS; Rt 1.38 mins MS m/z 458 [M+H]+; Method 2minLC_v003
Reaction SMILES: [CH2:1]([N:8]([CH3:13])[CH2:9][CH2:10][NH:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:20]1([CH2:26][CH2:27]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Br-]>>[CH2:1]([N:8]([CH3:13])[CH2:9][CH2:10][N:11]([CH3:12])[CH2:27][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCc1ccccc1
Reactant: CNCCN(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Product: CN(CCc1ccccc1)CCN(C)Cc1ccccc1

Procedure:
A mixture of 0.900 gm N-benzyl-N,N'-dimethylethylenediamine, 1.10 gm powdered sodium carbonate and 0.75 ml of 2-phenylethylbromide is refluxed for 5 hours. An additional 0.25 ml of bromide is added during this time. The reaction mixture is then cooled and filtered. The filterate is concentrated in vacuo and the residue chromatographed on silica gel using an eluent of CH2Cl2 /CH3OH/NH4OH (97/3/0.3) to yield 0.875 gm of N-benzyl-N,N'-dimethyl-N'-(2-phenylethyl)ethylenediamine.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:18]=[CH:17][C:11]([CH:12]=[CH:13][C:14]([OH:16])=O)=[CH:10][CH:9]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C.[NH2:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1>CN(C)C=O>[OH:1][CH:2]([C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[CH:13][C:14](=[O:16])[NH:36][CH2:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[CH:17][CH:18]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: NCc1cccnc1
Reactant: COC(=O)CC(O)c1ccc(C=CC(=O)O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CC(O)c1ccc(C=CC(=O)NCc2cccnc2)cc1

Procedure:
Finally, 82 mg of 4-[1-hydroxy-2-(methoxycarbonyl)ethyl]cinnamic acid was dissolved in 37 μl 3-(aminomethyl)pyridine and 1 ml dimethylformamide, and then treated with 55 μl diethyl cyanophosphate and 50 μl triethylamine on ice for 1 hour to give methyl 3-hydroxy-3-[4-[2-[N-(3-pyridylmethyl)carbamoyl]ethenyl]phenyl]propionate of interest (17 mg, 15%) as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:37])[NH:7][C:8](=[O:36])[N:9]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.C([N:40](CC)CC)C.[CH2:45]([CH:47]([C:51](Cl)=[O:52])[C:48](Cl)=[O:49])[CH3:46].O>O1CCCC1>[CH2:45]([CH:47]([C:51]([NH2:40])=[O:52])[C:48]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:37])[NH:7][C:8](=[O:36])[N:9]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][CH:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:18][CH2:17]2)=[CH:4][CH:3]=1)=[O:49])[CH3:46]
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: Nc1ccc2c(=O)[nH]c(=O)n(CCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)c2c1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCC(C(N)=O)C(=O)Nc1ccc2c(=O)[nH]c(=O)n(CCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)c2c1
Yield: 80 %

Procedure:
7-Amino-2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazoline (700 mg) obtained in Example 39 was dissolved in tetrahydrofuran (10.0 ml), and triethylamine (0.24 ml) and ethyl malonyl chloride (0.20 ml) were added with stirring and cooling on ice. The reaction mixture was stirred at room temperature for 18. 5 hours and combined with water and extracted with ethyl acetate. After the extract was washed with water and dried (Na2SO4), the solvent was distilled off under reduced pressure to give the title compound (690 mg, 80%) as an amorphous.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH3:9])[NH2:2].C(O[CH:13]=[C:14]([C:17]#[N:18])[C:15]#[N:16])C>CO>[NH2:18][C:17]1[N:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH3:9])[N:2]=[CH:13][C:14]=1[C:15]#[N:16]
Reactant: CCOC=C(C#N)C#N
Reactant: Cc1cnccc1NN
Solvent: CO
Product: Cc1cnccc1-n1ncc(C#N)c1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Hydrazinyl-3-methylpyridine (CAS no. 114913-51-8) (700 mg, 5.68 mmol) was suspended in MeOH (30 mL) under nitrogen at −5° C. 2-(ethoxymethylene)malononitrile (694 mg, 5.68 mmol) was added portionwise over 2 mins and the mixture stirred at ˜0° C. for 0.5 hours then heated at reflux for 2 hours. The mixture was allowed to cool and was then evaporated under reduced pressure to afford the crude 5-amino-1-(3-methylpyridin-4-yl)pyrazole-4-carbonitrile which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 2.09 (3H, m), 7.07 (1H, d), 7.87 (2H, m), 7.98 (1H, d), 10.22 (1H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH3:11][O-:12].[Na+].[CH3:14][OH:15]>>[CH3:11][O:12][C:2]1[CH:7]=[C:6]([O:15][CH3:14])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: CO
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Product: COc1cc(OC)nc(SC)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 162.8 grams (0.832 mole) of 4,6-dichloro-2-methylthiopyrimidine in 325 mL of methanol was cooled to 15° C., and 419 mL (1.83 mole) of sodium methoxide (25% in methanol) was added dropwise at a rate to maintain the reaction mixture temperature below 20° C. Upon completion of the addition, which required 45 minutes, the reaction mixture was allowed to warm to ambient temperature where it was stirred for 18 hours. After this time the reaction mixture was concentrated under reduced pressure to a residual solid. The solid was dissolved in 850 mL of ethyl acetate. The solution was washed with one 500 mL portion and two 200 mL portions of water, and then with one 200 mL portion of an aqueous solution saturated with sodium chloride. The aqueous washes were combined and extracted with one 350 mL portion of ethyl acetate. The ethyl acetate extract was then washed with one 150 mL portion of an aqueous solution saturated with sodium chloride. The ethyl acetate layers and extracts were combined and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to yield 155.0 grams of 4,6-dimethoxy-2-methylthiopyrimidine, which solidified upon standing; m.p. 50°-52° C. The reaction was repeated several times.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:22])[C:8]4[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25](=[O:30])[CH2:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(N(C)C)=O>[CH3:23][O:24][C:25](=[O:30])[CH2:26][CH2:27][CH2:28][O:21][C:19]1[CH:18]=[CH:17][C:9]2[C:10]([CH3:16])([CH3:15])[C:11]3[NH:12][C:13]4[C:5]([C:6]=3[C:7](=[O:22])[C:8]=2[CH:20]=1)=[CH:4][CH:3]=[C:2]([Br:1])[CH:14]=4
Reactant: CC1(C)c2ccc(O)cc2C(=O)c2c1[nH]c1cc(Br)ccc21
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)CCCOc1ccc2c(c1)C(=O)c1c([nH]c3cc(Br)ccc13)C2(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Bromo-9-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound JJ2, 20 mg, 0.056 mmol), 4-bromo-butyric acid methyl ester (7.0 μl, 0.056 mmol) and cesium carbonate (36.6 mg, 0.112 mmol) were dissolved in DMA (0.09 ml), and then stirred at room temperature for 1 hr. Thereafter, 4-bromo-butyric acid methyl ester (7.0 μl, 0.056 mmol) was added thereto and the mixture was stirred at room temperature for 3 hr, followed by further stirring at 45° C. for 30 min. The reaction solution was added with water, extracted with diethyl ether and dried over anhydrous magnesium sulfate. After the concentration under reduced pressure, the resulting residues were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain 4-(3-bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl oxy)-butyric acid methyl ester. This compound was dissolved in MeOH (0.50 ml), added with aqueous solution of sodium hydroxide (6 mol/1), and then stirred at room temperature for 10 min. The reaction solution was added with hydrochloric acid (3 mol/1), extracted with diethyl ether, and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain white solid. This white solid was washed with methylene chloride to obtain the title compound (6.1 mg, 25%).