Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[C:5]1([N:15]=[C:16]=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1>O>[C:5]1([NH:15][C:16]([O:3][CH2:2][CH2:1][OH:4])=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: OCCO
Reactant: O=C=Nc1cccc2ccccc12
Solvent: O
Product: O=C(Nc1cccc2ccccc12)OCCO
Reaction time: 3 h

Procedure:
Ethylene glycol (3.0 g) was mixed with α-naphthyl isocyanate (8.5 g), and reaction was allowed to proceed at room temperature for 3 hours, then at 50° C. for 2 hours. The reaction mixture was poured into water, which was subjected to extraction with chloroform. The extract was concentrated and subjected to purification by means of a silica gel chromatography(silica gel 400 g, developing solvent:hexane-ethyl acetate, 1:2→1:3).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1.[F:12][C:13]1[C:21]([NH:22][S:23]([CH2:26][CH2:27][CH2:28][F:29])(=[O:25])=[O:24])=[CH:20][CH:19]=[C:18]([F:30])[C:14]=1[C:15](O)=[O:16].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:12][C:13]1[C:21]([NH:22][S:23]([CH2:26][CH2:27][CH2:28][F:29])(=[O:25])=[O:24])=[CH:20][CH:19]=[C:18]([F:30])[C:14]=1[C:15]([NH:11][C:8]1[CH:9]=[C:10]2[C:2]([CH3:1])=[N:3][NH:4][C:5]2=[N:6][CH:7]=1)=[O:16]
Reactant: O=C(O)c1c(F)ccc(NS(=O)(=O)CCCF)c1F
Reactant: Cc1n[nH]c2ncc(N)cc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1n[nH]c2ncc(NC(=O)c3c(F)ccc(NS(=O)(=O)CCCF)c3F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.5 %

Procedure:
3-Methyl-1H-pyrazolo[3,4-b]pyridin-5-amine (0.100 g, 0.675 mmol, Example 4, Step B), 2,6-difluoro-3-(3-fluoropropylsulfonamido)benzoic acid (0.211 g, 0.709 mmol), EDCI (0.136 g, 0.709 mmol) and HOBt (0.091 g, 0.675 mmol) were dissolved in DMF (1.9 mL) and stirred at room temperature for 16 hours. The reaction mixture was purified by reverse phase HPLC to give 2,6-difluoro-3-(3-fluoropropylsulfonamido)-N-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide (0.085 g, 29%) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 13.22 (s, 1H), 11.05 (s, 1H), 9.93 (br s, 1H), 8.60-8.59 (m, 1H), 8.55-8.54 (m, 1H), 7.59-7.53 (m, 1H), 7.30-7.25 (m, 1H), 4.62 (t, 1H), 4.50 (t, 1H), 3.26-3.23 (m, 2H), 2.20-2.07 (m, 2H); m/z (ES-MS) 428.1 (100.0%) [M+1].
Reaction SMILES: [N:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[S:3][C:2]=1[C:10]1([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[CH3:25][C:26](OC(C)=O)=[O:27]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:26]([N:6]1[CH2:7][CH2:8][C:9]2[N:1]=[C:2]([C:10]3([C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=4)[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[S:3][C:4]=2[CH2:5]1)(=[O:27])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(C2(c3nc4c(s3)CNCC4)CCOCC2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)N1CCc2nc(C3(c4ccc(C(=O)O)cc4)CCOCC3)sc2C1

Procedure:
4-[4-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-tetrahydro-pyran-4-yl]-benzoic acid (40 mg, 0.116 mmol) in pyridine, catalytic amount of 4-dimethylaminopyridine (DMAP), and excess Ac2O were mixed together at room temperature. After the reaction was complete, the mixture was evaporated, washed with water, and extracted with EtOAc. The organic phase was dried and evaporated to give 4-[4-(5-acetyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-tetrahydro-pyran-4-yl]-benzoic acid. Similar HATU coupling procedure from Example 9 was followed to obtain the title compound. MS found for C26H28N4O3S as (M+H)+ 477.58. 1H NMR (400 MHz, dmso-d6): δ: 9.53 (s, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.51 (t, J=8.4 Hz, 2H), 7.10 (d, J=7.2 Hz, 1H), 6.92 (t, J=7.6 Hz, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.54 (t, J=7.6 Hz, 1H), 4.84 (s, 2H), 4.61-4.57 (m, 2H), 3.69-3.57 (m, 6H), 2.80-2.29 (m, 6H), 2.05-1.98 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([CH3:19])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.[CH:21]([N-]C(C)C)(C)C.[Li+].CI.Cl>O1CCCC1>[CH3:1][O:2][C:3](=[O:20])[C:4]([CH3:21])([CH3:19])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:8][CH2:7]1
Reactant: COC(=O)C(C)CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(C)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2-methyl-3-(N-Boc-piperidine-4-yl)-propionic acid methyl ester (789 mg, 2.77 mmol) from above was dissolved in dry tetrahydrofuran (2 mL) and cooled to −78° C. To this solution was added lithium diisopropylamide (5.5 mmol, prepared from diisopropylamine and n-butyl lithium). The mixture was stirred at −78° C. for 1 hr and methyl iodide (0.7 mL, 11.24 mmol) was added. The mixture was stirred at −78° C. for 2 hrs until complete consumption of the starting material. The mixture was treated with hydrochloric acid (1N, 10 mL) and extracted with ether. The organic layer was washed with brine and dried over sodium sulfate. After evaporation of the solvents, the residue was purified using flash chromatography (eluting with hexanes and ethyl acetate) to give 2,2-dimethyl-3-(N-Boc-piperidine-4-yl)-propionic acid methyl ester as a colorless oil that slowly turned into a solid (598 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-nitro-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-nitro-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]2)=[O:9])[CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:42][CH2:43][C:44]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[F:52])=[O:45]>C(N(CC)CC)C.C(Cl)Cl>[F:52][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[C:44](=[O:45])[CH2:43][NH:42][C:16]([CH:13]1[CH2:12][CH2:11][N:10]([C:8]([O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:9])[CH2:15][CH2:14]1)=[O:18]
Reactant: O=C(O)C1CCN(C(=O)Oc2cccnc2)CC1
Reactant: NCC(=O)c1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)C1CCN(C(=O)Oc2cccnc2)CC1)c1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To a mixture of 1-[(pyridin-3-yloxy)carbonyl]piperidine-4-carboxylic acid (500 mg) and DCM (10 mL) were added HOBt (297 mg) and WSC hydrochloride (498 mg), followed by stirring at room temperature for 30 minutes. Then, 2-amino-1-(2-fluorophenyl)ethanone hydrochloride (417 mg) and triethylamine (0.31 mL) were added thereto, followed by stirring at room temperature overnight. The reaction liquid was purified directly by silica gel column chromatography (chloroform/methanol=99/1 to 95/5) to obtain pyridin-3-yl 4-{[2-(2-fluorophenyl)-2-oxoethyl]carbamoyl}piperidine-1-carboxylate (423 mg) as a colorless solid.
Reaction SMILES: [CH3:1][NH2:2].[O:3]=[C:4]1[C:10]2[CH:11]=[CH:12][C:13]([CH:15]([CH3:19])[C:16](Cl)=[O:17])=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]1=2>C(Cl)Cl>[O:3]=[C:4]1[C:10]2[CH:11]=[CH:12][C:13]([CH:15]([CH3:19])[C:16]([NH:2][CH3:1])=[O:17])=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]1=2
Reactant: CN
Reactant: CC(C(=O)Cl)c1ccc2c(c1)CCc1ccccc1C2=O
Solvent: ClCCl
Product: CNC(=O)C(C)c1ccc2c(c1)CCc1ccccc1C2=O

Procedure:
A 2.6N solution of methylamine in methylene chloride (250 cc.) is added at 0°C. and over the course of 30 minutes to a solution of 2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionyl chloride (10 g.) in methylene chloride (100 cc.). The reaction mixture is concentrated, and the residue taken up in distilled water (100 cc.) and benzene (300 cc.). The organic layer is decanted, dried over anhydrous sodium sulphate and evaporated at 60°C. under reduced pressure (20 mm.Hg). The product obtained is recrystallised from di-isopropyl ether (100 cc.) to give 2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)-N-methylpropionamide (5.8 g.) melting at 140°C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]1([CH2:12][CH:13]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:14](OC)=[O:15])[CH:11]=[N:10][CH:9]=[N:8]1.CO>C(OCC)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH:13]([CH2:12][N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)[CH2:14][OH:15])=[CH:19][CH:20]=1
Reactant: COC(=O)C(Cn1cncn1)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Product: OCC(Cn1cncn1)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
1.3 g of LiAlH4 is suspended in 170 ml of anhydrous diethyl ether under N2 atmosphere. Within one hour, 8 g of methyl α-(1H-1,2,4-triazol-1-ylmethyl)-4-chlorophenylacetate is introduced. The reaction is exothermic, and proceeds with solvent reflux. At the end of heat evolution, 10 ml of methanol in 50 ml of diethyl ether is added to destroy the excess of hydride.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:18]=2)[C:10](=[O:27])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][CH2:30][CH2:31]Br>>[CH2:1]([N:8]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:18]=2)[C:10](=[O:27])[N:9]1[CH2:31][CH2:30][O:29][CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCBr
Reactant: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]n(Cc3ccccc3)c2=O)cn1
Product: COCCn1c(=O)n(-c2cnn(Cc3c(C)noc3C)c2)c(=O)n1Cc1ccccc1
Yield: 20 %

Procedure:
Prepared as in example 10-91 from 1-benzyl-4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,2,4-triazolidine-3,5-dione (example 10-91a) and 2-bromoethyl methyl ether. Yield: 20%. MS M+H calculated 425.19. Found 425.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.06 μM.
Reaction SMILES: [Cl:1]C1C=CC2C3=C(C4CCCCC4)C4C=CC(C(OC(C)(C)C)=O)=CC=4N3CC(C(OC)=O)=CC=2C=1.Cl[C:38]1[CH:39]=[CH:40][C:41]([CH:47]=[O:48])=[C:42]([B:44]([OH:46])[OH:45])[CH:43]=1>>[Cl:1][C:39]1[CH:38]=[CH:43][C:42]([B:44]([OH:46])[OH:45])=[C:41]([CH:47]=[O:48])[CH:40]=1
Reactant: O=Cc1ccc(Cl)cc1B(O)O
Reactant: COC(=O)C1=Cc2cc(Cl)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2C1
Product: O=Cc1cc(Cl)ccc1B(O)O
Yield: 70 %

Procedure:
The title compound 24a was synthesized following the 2-step procedure reported for the synthesis of 10-tert-butyl 6-methyl 3-chloro-13-cyclohexyl-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate 21a, using 5-chloro-2-formylphenylboronic acid in the first step, instead of 4-chloro-2-formylphenylboronic acid 34a, and was obtained with an overall yield of 70% as a yellowish solid; m/z 507 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[CH:18][CH:17]=1.[H][H]>[Ni].C1COCC1.CO>[NH2:12][C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[CH:20][CH:21]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2
Reactant: [H][H]
Reactant: CC(C)(C#N)c1ccc(Nc2c([N+](=O)[O-])cnc3ccc(Br)cc23)cc1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(Nc2c(N)cnc3ccc(Br)cc23)cc1

Procedure:
2-(4-(6-Bromo-3-nitroquinolin-4-ylamino)phenyl)-2-methylpropane nitrile (Compound of Preparation C, 16 g, 42 mmol) was hydrogenated using Raney-Ni (7 g), THF-MeOH [(1:1), 250 mL] under 25 psi of hydrogen for 1 hour at RT. After completion of the reaction, the catalyst was filtered-off and the filtrate was evaporated to dryness to obtain the title compound. Yield: 13 g (88%); 1H NMR (DMSO-d6, 300 MHz): δ 8.609 (s, 1H), 7.908 (s, 1H), 7.829-7.836 (d, 1H, J=2.1 Hz), 7.744-7.773 (d, 1H, J=8.7 Hz), 7.425-7.462 (dd, 1H, J=9 Hz, 2.1 Hz), 7.236-7.265 (d, 2H, J=8.7 Hz), 6.511-6.540 (d, 2H, J=8.7 Hz), 5.448 (s, 2H), 1.600 (s, 6H); MS: m/z 381 (M+).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7](=O)[CH2:8][NH:9][C:10](=O)[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[S:36][C:10]([C:11]3[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=3)=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)s1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)s2)s1
Yield: 50.8 %

Procedure:
In a manner similar to Example 1, the reaction of N-[2-(5-methylthienyl)-2-oxoethyl]-3,5-bis(trifluoromethyl)benzamide (4.0 g, 0.01 mole) in toluene (100 ml) with a suspension of Lawesson's Reagent (2.0 g, 0.005 mole) in toluene (100 ml) yielded 1.0 g of 5-(5-methylthien-2-yl)-2-[3,5-bis(trifluoromethyl)phenyl]thiazole as a solid, m.p. 119.5°-121° C.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:35])[C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](OC2C=CC([N+]([O-])=O)=CC=2)=[O:24])=[CH:18][CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=[CH2:3].[NH2:36][C@@H:37]([CH2:41][CH2:42][NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:38]([OH:40])=[O:39]>ClCCl>[CH2:1]([O:4][C:5](=[O:35])[C@@H:6]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([NH:36][C@@H:37]([CH2:41][CH2:42][NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:38]([OH:40])=[O:39])=[O:24])=[CH:18][CH:17]=1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)OC(=O)NCC[C@H](N)C(=O)O
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CCNC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Temperature: 75 °C

Procedure:
7.50 g (15.4 mmol) of the compound from example 1A was dissolved in 150 ml dichloromethane. 3.36 g (15.4 mmol) (2S)-2-Amino-4-[(tert-butoxycarbonyl)amino]butanoic acid was added. The reaction mixture was split into 10 portions. The portions were heated for 30 min in a sealed tube at 75° C. in a microwave synthesizer. The combined reaction mixture was extracted with approx. 100 ml saturated ammonium chloride solution. The aqueous phase was twice back extracted with approx. 50 ml dichloromethane each. The combined organic phases were extracted with approx. 50 ml brine and dried over sodium sulfate. The solvent was removed under reduced pressure. The raw product was dissolved in dichloromethane and chromatographed over approx. 1 l silica gel. Solvents used were dicloromethane/ethyl acetate 4/1, dichloromethane/methanol 10/1 to dichloromethane/methanol 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 8.70 g (10.8 mmol, 70% of theory) of the desired product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([NH2:7])=[O:6].[CH3:8][N:9]([CH3:14])[CH2:10][CH2:11][CH2:12]N.N>>[CH3:8][N:9]([CH3:14])[CH2:10][CH2:11][CH2:12][NH:7][C:5](=[O:6])[CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCC(N)=O
Reactant: CN(C)CCCN
Agent: N
Product: COCCC(=O)NCCCN(C)C

Procedure:
103.1 g (1.0 mole) of 3-methoxypropionamide are heated with 107.3 g (1.05 mole) of 3-dimethylaminopropylamine for 6 hours in a temperature range of 145°-170° C. until the evolution of ammonia is complete. In the subsequent distillation in a high vacuum 176 g (0.93 mole=93.5% of the theoretical yield) of a colorless liquid are obtained having Bp0.1 of 97°-99° C.
Reaction SMILES: CI.[CH3:3][NH:4][C:5]([C:7]1[NH:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:6].[C:23]([O-])([O-])=O.[Cs+].[Cs+]>N1C=CC=CC=1>[CH3:3][NH:4][C:5]([C:7]1[N:15]([CH3:23])[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:6]
Reactant: CNC(=O)c1[nH]c2cccnc2c1Sc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: c1ccncc1
Product: CNC(=O)c1c(Sc2ccccc2)c2ncccc2n1C
Yield: 20.3 %

Procedure:
Add methyl iodide (20 mg, 0.164 mmol) at r.t. to a mixture of 3-phenylsulfanyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid methylamide (Ia-33, 47 mg, 0.166 mmol), Cs2CO3 (65 mg, 0.2 mmol) and pyridine (1.5 mL). Heat the reaction at 60° C. in a sealed vessel for 3 hrs. Add additional methyl iodide (20 mg) and moniter the progress on the reaction by chromatography. When complete, cool the mixture, concentrate to dryness and extract into ethyl acetate from brine. Separate the organic phase and concentrate. Purify the residue by flash chromatography twice (SiO2, 3 gm, elute with MeOH 0-4% in DCM; and SiO2, 1 gm, elute with heptane:DCM, 1:1) to provide title compound (10 mg) as a white solid, 1H NMR (CDCl3) and LC-MS (m/e=297) were consistent for the title compound structure.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]3[O:29][C:28](=[O:30])[CH:27]=[CH:26][C:25]=3[CH:31]=2)[C:3]1=[O:32].[CH3:33][C:34]1[CH:35]=[C:36]([N:40]=[C:41]=[O:42])[CH:37]=[CH:38][CH:39]=1>C(Cl)Cl>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]3[O:29][C:28](=[O:30])[CH:27]=[CH:26][C:25]=3[CH:31]=2)[C:3](=[O:32])[CH:2]([NH:1][C:41]([NH:40][C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([CH3:33])[CH:35]=2)=[O:42])[N:8]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2N(Cc2ccc3oc(=O)ccc3c2)C1=O
Solvent: ClCCl
Product: Cc1cccc(NC(=O)NC2N=C(c3ccccc3F)c3ccccc3N(Cc3ccc4oc(=O)ccc4c3)C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
To a solution of (3RS)-3-amino-2,3-dihydro-5-(2-fluorophenyl)-1-(2-oxo-2H-1-benzopyran-6-yl)methyl-1H-1,4-benzodiazepin-2-one (214 mg) in dry methylene chloride (20 ml) was added dropwise a solution of 3-methylphenyl isocyanate (73 mg) in dry methylene chloride (10 ml) under nitrogen atmosphere at cooling in an ice-bath. The mixture was stirred under the same temperature for 1 hour and at ambient temperature overnight. The resultant precipitates were collected by filtration to afford a crude product. The crude product was purified by column chromatography on silica gel with eluents of chloroform and a mixture of chloroform and ethyl acetate to afford N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-oxo-2H-1-benzopyran-6-yl)methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea as a colorless crystalline solid (200 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:28][C@@:26]3([CH3:27])[C@@H:22]([CH2:23][CH2:24][C:25]3=O)[C@H:21]3[C:12]2=[C:13]2[C:18]([CH2:19][CH2:20]3)=[CH:17][C:16](=[O:30])[CH2:15][CH2:14]2)=[CH:7][CH:6]=1.[Cl:31]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:31][C:17]1[C:16](=[O:30])[CH2:15][CH2:14][C:13]2[C:18]=1[CH2:19][CH2:20][C@@H:21]1[C:12]=2[C@@H:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:10][CH:9]=2)[CH2:28][C@@:26]2([CH3:27])[C@H:22]1[CH2:23][CH2:24][CH2:25]2
Reactant: C[C@]12C[C@H](c3ccc(CCCO)cc3)C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CCC2=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@]12CCC[C@H]1[C@@H]1CCC3=C(Cl)C(=O)CCC3=C1[C@@H](c1ccc(CCCO)cc1)C2
Yield: 74.7 %

Procedure:
To a solution of 11.9 g of 11β-[4-(3-hydroxypropyl)phenyl]-estra-4.9-diene -3,17-dione prepared to preparation 1 in 100 ml of DMF, under inert atmosphere and at 60° C., 4.93 g of N-chloro succinimide is added and stirred for 10 mn at this temperature. It is poured into water, drawn off, washed, dried, evaporated under reduced pressure until 16.2 g of raw expected product is obtained that is purified by chromatography by eluting with the compound CH2Cl2/Acetone 85/15. 9.34 g of pure expected product is obtained.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].S(Cl)(Cl)=O.[CH2:17](O)[CH3:18]>>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH2:17][CH3:18])=[O:7]
Reactant: CCO
Reactant: O=C(O)C=Cc1ccccc1F
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C=Cc1ccccc1F
Yield: 96 %

Procedure:
A solution of 2-fluorocinnamic acid (48.4 g, 0.29 mol, Aldrich) and thionyl chloride (5 mL) in ethanol (650 mL) was heated to reflux for 48 h. The mixture was concentrated in vacuo. The residue was taken up in ethyl acetate, washed successively with a 5% aqueous sodium bicarbonate solution, water and brine, and dried (Na2SO4). Filtration and concentration gave 54.25 g (96%) of crude ethyl 2-fluorocinnamate. This material was used without further purification.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1.[NH3:26]>C(O)C>[NH2:26][C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O
Reactant: N
Solvent: CCO
Product: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(N)nc32)c(=O)[nH]c1=O

Procedure:
The product from example 44 step (viii) (0.05 g) was heated with 0.88 ammonia (2 ml) and ethanol (1 ml) in a sealed tube at 100° C. for 24 h. The volatiles were removed under reduced pressure and the residue triturated with ethyl acetate and methanol mixtures to leave the title product as a yellow solid.
Reaction SMILES: [N:1]1[N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]2=[C:3]([C:10]([OH:12])=O)[CH:2]=1.[NH2:13][C@@H:14]([CH3:30])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1>>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:3]3[CH:2]=[N:1][N:5]4[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=34)=[O:12])[CH3:30])[N:17]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cnn2c1CCCC2
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cnn2c1CCCC2
Yield: 55.5 %

Procedure:
The title compound was prepared as described in Example 34(d), starting from 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylic acid (0.127 g, 0.767 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2 g, 0.767 mmol). The product was purified by flash-chromatography. Yield 55.5%. 1H-NMR (400 MHz; DMSO-d6): δ 1.12 (d, 3H), 1.66-1.75 (m, 2H), 1.85-1.95 (m, 2H), 2.87 (t, 2H), 4.02 (t, 2H), 4.22-4.23 (m, 2H), 4.32-4.42 (m, 1H), 6.94 (d, 1H), 7.72 (d, 1H), 7.80 (d, 1H), 7.83 (s, 1H), 7.91 (dd, 1H), 7.97 (d, 1H), 8.06 (d,
Reaction SMILES: [CH3:1][C:2]([CH3:28])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:27])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:26])=[CH:11]/[CH2:12][CH2:13][C:14]1([CH3:25])[O:19][C:18]2[CH:20]=[CH:21][C:22]([OH:24])=[CH:23][C:17]=2[CH2:16][CH2:15]1.[CH3:29]CCCCC.C(OC(=O)C)C>>[CH3:29][C:20]1[C:18]2[O:19][C@@:14]([CH2:13][CH2:12]/[CH:11]=[C:10](/[CH2:9][CH2:8]/[CH:7]=[C:6](/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:28])[CH3:1])\[CH3:27])\[CH3:26])([CH3:25])[CH2:15][CH2:16][C:17]=2[CH:23]=[C:22]([OH:24])[CH:21]=1
Reactant: CCCCCC
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC1(C)CCc2cc(O)ccc2O1
Solvent: CCOC(C)=O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC[C@]1(C)CCc2cc(O)cc(C)c2O1

Procedure:
Tocotrienol isomers were derived from tocotrienol rich fraction of palm oil received from First Tech International Ltd., Hong Kong and was fractionated using silica gel column chromatography with n-hexane/ethylacetate (gradient elution) as a mobile phase to yield pure δ-tocotrienol.