Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5]1[C:22](=[O:23])[CH:21]=[CH:20][C@@:19]2([CH3:24])[C:6]=1[CH2:7][CH2:8][C@@H:9]1[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]1[CH2:11][CH2:12][C:13]2=[O:25])[C:2]([CH3:4])=[O:3].[Br:26]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:26][C@H:7]1[C:6]2[C@:19]([CH3:24])([CH:20]=[CH:21][C:22](=[O:23])[C:5]=2[NH:1][C:2]([CH3:4])=[O:3])[C@@H:18]2[C@H:9]([C@H:10]3[C@@:14]([CH2:16][CH2:17]2)([CH3:15])[C:13](=[O:25])[CH2:12][CH2:11]3)[CH2:8]1
Reactant: CC(=O)NC1=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)C=CC1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)NC1=C2[C@H](Br)C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)C=CC1=O
Yield: 90 %

Procedure:
To a solution of 4-acetamino-androsta-1,4-diene-3,17-dione (3.404 g, 10 mmol) in CCl4 (250 ml) were added N-bromosuccinimide (2.850 g, 16 mmol) and benzoyl peroxide (0.121 g, 0.5 mmol). The solution was heated under reflux for 1 h and then filtered to remove any insoluble material. The filtrate was washed with 5% NaHCO3 solution and with water and the organic phase evaporated to dryness under reduced pressure. The residue was triturated with a small amount of 95% EtOH to give mixture of crude 6α- and 6α-bromoacetamino-androsta-1,4-diene-3,17-dione in 90% yield (3.780 g), which was used in the following fluorination reaction without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[CH:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH:26]([CH2:28][C:29]([O:31]CC)=[O:30])[CH2:25][CH2:24][C:23]=3[CH:34]=2)=[O:17])[CH2:10][CH2:9]1.C(O)C.[OH-].[Na+]>C(O)(=O)C>[NH:8]1[CH2:9][CH2:10][CH:11]([CH:14]=[CH:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH:26]([CH2:28][C:29]([OH:31])=[O:30])[CH2:25][CH2:24][C:23]=3[CH:34]=2)=[O:17])[CH2:12][CH2:13]1
Reactant: CCOC(=O)CC1CCc2cc(NC(=O)C=CC3CCNCC3)ccc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: O=C(O)CC1CCc2cc(NC(=O)C=CC3CCNCC3)ccc2O1

Procedure:
0.1 g (0.2 mmol) of the ester from Example 77 were stirred overnight at room temperature in a mixture 2.5 ml ethanol and 0.35 ml 2 N aqueous sodium hydroxide solution. The reaction mixture was cooled with ice and brought to pH 5.5 with 2 N acetic acid. The precipitate of the title acid was filtered with suction, washed with a small amount of cold water, and dried at 50° C. in vacuo. Yield: 42 mg (59%) of beige crystals, m.p. 175-178° C.
Reaction SMILES: [O:1]1[C:5](=[O:6])[NH:4][C:3](=[O:7])[NH:2]1.[CH:8]([N:11]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:12](Cl)=[O:13])([CH3:10])[CH3:9]>CN(C)C1C=CN=CC=1>[F:21][C:18]1[CH:17]=[CH:16][C:15]([N:11]([CH:8]([CH3:10])[CH3:9])[C:12]([N:2]2[C:3](=[O:7])[NH:4][C:5](=[O:6])[O:1]2)=[O:13])=[CH:20][CH:19]=1
Reactant: O=c1[nH]oc(=O)[nH]1
Reactant: CC(C)N(C(=O)Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Product: CC(C)N(C(=O)n1oc(=O)[nH]c1=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 57.6 %

Procedure:
A 1 L three neck round bottom flask equipped with nitrogen inlet, thermometer and water condenser was charged with dioxanes (400 mL), 1,2,4-oxadiazole-3,5-dione (30 g 0.29 moles, prepared according to Srivastava, P. and Robins, R., J. Med. Chem. 1981, 24, 1172-1177), 4-dimethylaminopyridine (36 g, 0.29 mole), and N-isopropyl-4-flourophenylcarbamoyl chloride (63 g, 0.29 moles) at room temperature. The yellow mixture was heated at reflux for 4 hours. When no starting material was detected by thin layer chromatography, heat was tuned off and mixture was cooled to room temperature. The solvent was removed under reduced pressure and the resulting solids were suspended in ethyl acetate. The mixture was washed with 1N HCl, and the aqueous layer was extracted twice with ethyl acetate. The combined organic solutions were washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The product was crystallized from chlorobutane and hexanes, and filtered to give 47 g (57%) of the title compound as a white solid melting at 94-95° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([N+:19]([O-])=O)=[CH:14][CH:15]=2)[CH2:10]1)[CH3:8])=[O:5])[CH3:2].O.O.[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:19][C:13]1[CH:12]=[C:11]2[C:16]([CH2:17][CH2:18][N:9]([CH:7]([CH3:8])[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10]2)=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC(C)N1CCc2ccc([N+](=O)[O-])cc2C1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(C)N1CCc2ccc(N)cc2C1
Yield: 93.3 %

Procedure:
0.43 g of 2-[2-(ethoxycarbonyl)-1-methylethyl]-7-nitro-1,2,3,4-tetrahydroisoquinoline was dissolved in 10 ml of ethanol, and 1.23 g of tin chloride dihydrate was added to the solution. The solution was heated under reflux for 30 minutes to allow for the reaction to take place. The resulting solution was made basic by adding saturated aqueous solution of sodium bicarbonate, and the insoluble content was separated by using celite. The solution was extracted with ethyl acetate, washed with saturated aqueous solution of sodium chloride, and dried with anhydrous sodium sulfate. After separating the desiccant by filtration, the residue was concentrated under reduced pressure to obtain 0.36 g of 7-amino-2-[2-(ethoxycarbonyl)-1-methylethyl]-1,2,3,4-tetrahydroisoquinoline, which was a brown oily product (yield: 93%).
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:14]=[CH:15][C:16]2[S:20][C:19]3[CH:21]=[CH:22][C:23]([N:25]4[C:37]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[C:31]5[C:26]4=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:24][C:18]=3[C:17]=2[CH:38]=1.C[O:40][B:41](OC)[O:42]C.Cl>O1CCCC1>[CH:36]1[C:37]2[N:25]([C:23]3[CH:22]=[CH:21][C:19]4[S:20][C:16]5[CH:15]=[CH:14][C:13]([B:41]([OH:42])[OH:40])=[CH:38][C:17]=5[C:18]=4[CH:24]=3)[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]=2[CH:33]=[CH:34][CH:35]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc2sc3ccc(-n4c5ccccc5c5ccccc54)cc3c2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc2sc3ccc(-n4c5ccccc5c5ccccc54)cc3c2c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 69.7 %

Procedure:
An excess of 1.6M n-BuLi in hexane (30 mL, 48 mmol) was added to a solution of 9-(8-bromodibenzo[b,d]thiophen-2-yl)-9H-carbazole (18.6 g, 43.4 mmol) in 500 ml dry tetrahydrofuran at −78° C. under N2. The reaction mixture was then maintained at 0° C. for 1 h before cooling to −78° C. Trimethylborate (5.9 g, 56 mmol) was added dropwise, the solution was then warmed slowly to room temperature and stirred for 24 h. 2N HCl (100 ml) was added and then the mixture was stirred for a further 1 h. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuum, and the residue was crystallized from n-hexane to give 8-(9H-carbazol-9-yl)dibenzo[b,d]thiophen-2-ylboronic acid 11.9 g (63%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[N-:15]=[C:16]=[S:17].[NH4+].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[NH:24][CH2:25][CH3:26]>CC(C)=O.CN(C=O)C>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([N:24]([C:16]2[S:17][C:2]3[N:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4](=[O:6])[N:15]=2)[CH2:25][CH3:26])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: CCNc1ccc(OC)c(OC)c1
Reactant: O=C(O)c1cccnc1Cl
Reactant: [N-]=C=S
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: O=S(Cl)Cl
Product: CCN(c1ccc(OC)c(OC)c1)c1nc(=O)c2cccnc2s1
Yield: 89.7 %

Procedure:
The reaction procedure of Example 85 was followed except that 1.733 g (11 mmol) of 2-chloronicotinic acid, 15 ml of thionyl chloride, two droplets of DMF, 880 mg of ammonium isothiocyanate, 15 ml of acetone, 1.993 g of 3,4-dimethoxy-N-ethylaniline and 10 ml of acetone were used. The product was then recrystallized from ethanol to obtain 3.388 g of 2-[N-(3,4-dimethoxyphenyl)-N-ethylaminoj-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[NH2:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[C:15]([CH3:21])([CH3:20])[CH2:14]1.CCN(C(C)C)C(C)C>C(O)(C)C>[OH:19][C@H:16]1[CH2:17][CH2:18][C@@H:13]([NH:12][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)[CH2:14][C:15]1([CH3:21])[CH3:20]
Reactant: CC1(C)C[C@H](N)CC[C@@H]1O
Reactant: CSc1ncc(C#N)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CSc1ncc(C#N)c(N[C@@H]2CC[C@H](O)C(C)(C)C2)n1
Temperature: 100 °C
Yield: 71.7 %

Procedure:
A mixture of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (2.15 g, 11.6 mmol)), (1S,4R)-4-amino-2,2-dimethylcyclohexanol (1.51 g, 10.5 mmol) and DIEA (2.72 mg, 21.1 mmol) in isopropanol (30 mL) was heated at 100° C. for 3 h. After removal of the organic solvent under reduced pressure, the residue was treated with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give a crude product, which was purified by silica gel column chromatography (15% ethyl acetate in petroleum) to afford the desired compound as a pale yellow solid (2.2 g, 7.53 mmol, 72% yield). MS (ESI) m/z 293.2 [M+H]+.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.C(N1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[CH3:22])C1=S)C=C>ClCCl>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]([CH3:22])=[C:15]([NH:11][CH2:12][CH2:13][CH2:14][NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[CH:20]=1
Reactant: NC1CCC1
Reactant: C=CCN1CCCN(c2cc(Cl)ccc2C)C1=S
Solvent: ClCCl
Product: Cc1ccc(Cl)cc1NCCCNC1CCC1
Yield: 58.5 %

Procedure:
To neat cyclobutylamine (10.0 mL) was added the hydrobromide salt of Example 8, Step B in two equal portions (2×4.3 g) 15 minutes apart at ambient temperature. The mixture was heated at reflux under nitrogen for 30 minutes, then cooled and partitioned between dichloromethane and 1N sodium hydroxide The aqueous layer was extracted with dichloromethane, the combined extracts were dried over sodium sulfate and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with a solvent gradient (from 98:2 dichloromethane-methanol to 80:20 dichloromethane-methanol containing 0.2% ammonium hydroxide) gave the title compound (3.7 g, 58.5%) as a brown solid, which was used as such in the next step.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH2:17][CH3:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:39][C:36]1[CH:35]=[CH:34][C:33]([CH:26]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[N:27]2[CH2:28][CH2:29][N:30]([CH2:14][CH2:13][CH2:12][C:11]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[C:9]([CH2:16][CH2:17][CH3:18])[CH:10]=3)[CH2:31][CH2:32]2)=[CH:38][CH:37]=1
Reactant: CCCc1cc(CCC=O)n(-c2ccccc2)n1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)n(-c2ccccc2)n1

Procedure:
157 mg (92%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (75 mg, 0.310 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (89 mg, 0.310 mmol), DIPEA (0.081 mL, 0.465 mmol) and NaBH(OAc)3 (197 mg, 0.930 mmol).
Reaction SMILES: [CH3:1][CH:2]([CH:6]([CH3:10])[C:7](=[O:9])[CH3:8])[C:3](=O)[CH3:4].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:4][C:3]1[O:9][C:7]([CH3:8])=[C:6]([CH3:10])[C:2]=1[CH3:1]
Reactant: CC(=O)C(C)C(C)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Cc1oc(C)c(C)c1C
Yield: 19.4 %

Procedure:
A solution of 3,4-dimethylhexane-2,5-dione (3.00 g, 21.1 mmol) and p-toluenesulfonic acid (401 mg, 2.11 mmol) in benzene (30 mL) was heated to reflux in a Dean-Stark trap overnight. The reaction mixture was distilled at atmospheric pressure to remove the excess benzene. The remaining mixture was transferred to a smaller flask and distilled at atmospheric pressure. The fraction that came over between 80–100° C. was collected to give 509 mg (19%) of compound 219A as a light yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[S:11][C:12]([C:15]([NH:17][C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])=[O:16])=[CH:13][N:14]=2)[CH:3]=1.[CH2:26]([O:28][C:29]([CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:30])[CH3:27]>CCO>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:18]=1[NH:17][C:15]([C:12]1[S:11][C:10]([NH:9][C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([N:35]3[CH2:34][CH2:33][N:32]([CH2:31][C:29]([O:28][CH2:26][CH3:27])=[O:30])[CH2:37][CH2:36]3)[CH:3]=2)=[N:14][CH:13]=1)=[O:16]
Reactant: Cc1nc(Cl)cc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)n1
Reactant: CCOC(=O)CN1CCNCC1
Solvent: CCO
Product: CCOC(=O)CN1CCN(c2cc(Nc3ncc(C(=O)Nc4c(C)cccc4Cl)s3)nc(C)n2)CC1
Temperature: 150 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A mixture of 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (1) (0.20 g, 0.51 mmol) and 1-(ethoxycarbonylmethyl)piperazine (3) (0.17 g, 1.01 mmol) in 4 mL of EtOH was heated with a CEM Discover® microwave at 250 W, Pmax 150° C. for 45 min. The resulting mixture was treated with EtOH (6 mL) and then stirred at rt for 1 h. The solid was collected on a filter to give 0.24 g of ethyl 2-(4-(6-(5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-ylamino)-2-methylpyrimidin-4-yl)piperazin-1-yl)acetate (4) (89% yield). HPLC>99% pure (Rt 2.517 min); LC/MS (ES+) 530/532 (M+H, 100); 1H NMR (DMSO-d6) δ 11.48 (s, 1H), 9.86 (s, 1H), 8.22 (s, 1H), 7.40 (m, 1H), 7.28 (m, 2H), 6.06 (s, 1H), 4.10 (q, J=7.1 Hz, 2H), 3.53 (s, 4H ??), 3.29 (s, 2H), 2.59 (t, J=4.6 Hz, 4H), 2.41 (s, 3H), 2.24 (s, 3H), 1.20 (t, J=7.1 Hz, 3H); Anal. Calcd for C24H28ClN7O3S: C, 54.38; H, 5.32; Cl, 6.69; N, 18.50; S, 6.05. Found: C, 54.24; H, 5.16; Cl, 6.80; N, 18.59; S, 6.09.
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][CH2:8][CH:9]1[CH2:11][O:10]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[CH3:22])[NH2:18]>CC#N>[C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][CH2:8][CH:9]([OH:10])[CH2:11][NH:18][C:17]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:15]([F:14])[CH:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N)cc1F
Reactant: CC(C)(C)[Si](C)(C)OCCC1CO1
Solvent: CC#N
Product: Cc1ccc(NCC(O)CCO[Si](C)(C)C(C)(C)C)cc1F
Temperature: 50 °C
Reaction time: 5 h
Yield: 94.3 %

Procedure:
LiClO4 (6.31 g, 60 mmol) was added to a solution of (RS)-tert-butyl-dimethyl-(2-oxiranyl-ethoxy)-silane (4 g, 20 mmol, prepared according to Heterocycles (1987), 25(1), 329-32) in MeCN (60 mL). 3-Fluoro-4-methylaniline (2.28 g, 18 mmol) was added and the mixture was stirred at 50° C. for 5 h. The solvent was removed under reduced pressure and the residue was purified by CC (DCM/MeOH/NH4OH 1000:25:2) to afford the title intermediate as brown oil (5.56 g, 86%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][N:15]2[CH:20]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:21]([O:23][CH3:24])=[O:22])=[O:9])([CH3:6])([CH3:5])[CH3:4].[F:32][CH2:33][CH2:34]I>CN(C=O)C>[C:3]([O:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][N:15]2[C:20]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)([CH2:34][CH2:33][F:32])[C:21]([O:23][CH3:24])=[O:22])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Reactant: FCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCF)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (60% dispersion in mineral oil) (22 mg, 0.55 mmol) in anhydrous DMF (3 mL) under nitrogen atmosphere was added methyl 2-(4-(tert-butoxycarbonylamino)-1H-indol-1-yl)-2-(4-chlorophenyl)acetate (207 mg, 0.5 mmol), as described in Example 2 step B, in anhydrous DMF (2 mL) and the mixture was then stirred at 0° C. for 1 h. To this mixture was added 1-fluoro-2-iodoethane (17.4 mg, 1 mmol), and the mixture was then stirred at room temperature for 4 h. The volatile was evaporated. The residue was purified by silica gel chromatography eluting with PE/EA (10/1 to 3/1, v/v) to afford the title compound as a white solid. LC/MS m/z=405.1[M+H]+.
Reaction SMILES: C([NH:3][C:4]1[CH:38]=[CH:37][CH:36]=[CH:35][C:5]=1[C:6]([NH:8][CH2:9]CN1CCC(NC2N(CC3C=CC(F)=CC=3)C3C=CC=CC=3N=2)CC1)=[O:7])C.C(=O)([O-])[O-:40].[Na+].[Na+].C([Cl:49])(=O)OC.O>ClCCl>[ClH:49].[ClH:49].[NH:3]1[C:4]2[C:5](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:6](=[O:7])[NH:8][C:9]1=[O:40]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cl
Reactant: CCNc1ccccc1C(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cl
Product: O=c1[nH]c(=O)c2ccccc2[nH]1
Reaction time: 8 h

Procedure:
To a stirred mixture of 4 parts of 2-(ethylamino)-N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]benzamide, 1.06 parts of sodium carbonate and 65 parts of dichloromethane was added dropwise a solution of 2 parts of methyl carbonochloridate in dichloromethane. Upon completion, stirring was continued overnight at reflux temperature. Water was added and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in acetonitrile and 2-propanol. The salt was filtered off and dried, yielding 1.8 parts of 1-ethyl-3-[2-[4-[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2yl]amino]-1-piperidinyl]ethyl]-2,4-(1H,3H)-quinazolinedione dihydrochloride; mp. +260° C. (compound 125).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([O:7][CH2:8][C@@H:9]([CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[O:10][CH3:11])=[O:6].[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl-:1].[CH3:11][O:10][C@H:9]([CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:8][O:7][C:5]([NH:4][CH2:3][CH2:2][N+:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:6]
Reactant: CCCCCCCCCCCCCCCCCCOC[C@H](COC(=O)NCCCl)OC
Reactant: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOC[C@H](COC(=O)NCC[n+]1ccccc1)OC
Product: [Cl-]
Temperature: 80 °C

Procedure:
A solution of 0.035 g of (R)-1-O-[(2-chloroethyl)carbamoyl]-2-O-methyl-3-O-octadecylglycerine is treated with 5 ml of pyridine and heated at 80° C. for 3 days. The solution is evaporated and the residue is treated with toluene by azeotropic distillation. The residue is recrystallized from acetone. There is obtained 1-[2-[1-[(R)-2-methoxy-3-(octadecyloxy)propoxy]formamido]ethyl]pyridinium chloride of melting point 65° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21]3[CH:20]=[CH:19][C:18]([CH:22]=[C:23]([C:38]#[N:39])[C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=4)=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1.[C-:40]#[N:41].[Na+].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>CN(C)C=O.O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:21]3[CH:20]=[CH:19][C:18]([C:22]([C:40]#[N:41])=[C:23]([C:38]#[N:39])[C:24]4[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:25]=4)=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2c3ccccc3c3cc(C=C(C#N)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)ccc32)cc1
Reactant: [C-]#N
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Pb+4]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-n2c3ccccc3c3cc(C(C#N)=C(C#N)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)ccc32)cc1
Reaction time: 0.17 h
Yield: 19.2 %

Procedure:
0.50 g (0.93 mmol) of N-(4-methoxyphenyl)-3-(2-cyano-2-(3,5-bis(trifluoromethyl) phenyl)ethenyl)carbazole and 5 ml of N,N-dimethylformamide as solvent were placed in a 200 ml four-necked flask with a mechanical stirrer and bulb-shaped cooler. To this was added an aqueous solution prepared from 0.05 g (1.00 mmol) of sodium cyanide and 0.5 ml of water, which was stirred for 10 minutes. Further, 0.44 g (1.00 mmol) of lead tetraacetate was added. The resultant product was subjected to the reaction for 30 minutes. After the reaction was completed, 20 ml of chloroform was added. To the resultant solution was added 20 ml of water. The resultant liquid was washed in a separatory funnel. To the washed liquid was added sodium sulfate, which was left to stand for 30 minutes and dehydrated. The dehydrated solution was concentrated in an evaporator and dried under vacuum to obtain a vermilion solid. The vermilion solid was recrystallized in the presence of ethanol to obtain 0.10 g of an orange crystal. The yield of the synthesized orange crystal was 19%, and its melting point was 170-172° C. The IR chart is shown in FIG. 21.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1.[H-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19]>CN(C)C=O>[CH2:19]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: Oc1ccc(Cl)cc1C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Cl)cc1C1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 106.1 %

Procedure:
To a solution of 4-chloro-2-cyclohexylphenol (23.00 g, 0.109 mol) in N,N-dimethylformamide (600 mL) was added sodium hydride (4.56 g, 0.114 mol, 60 wt. %) followed by allyl bromide (14.51 g, 0.120 mol) and the reaction mixture was allowed to stir at room temperature for 5 h. The solvent was removed in vacuo and the residue diluted with water (500 mL) and extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with water (500 mL), saturated aqueous sodium chloride (500 mL), dried (magnesium sulfate), and the solvent removed in vacuo to give 29.0 g of 1-(allyloxy)-4-chloro-2-cyclohexylbenzene as a brown oil. Treatment of the allyl ether in refluxing mesitylene generally according to the procedure described for Intermediate 8 provided 18.0 g of 2-allyl-4-chloro-6-cyclohexylphenol. Treatment of the phenol (6.5 g, 0.026 mol) with 3-chloroperoxybenzoic acid (9.88 g, 0.045 mol, 77%) followed by potassium carbonate (10.00 g, 0.072 mol) generally according to the procedure described for Intermediate 9 afforded 4.6 g (67%) of (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methanol as a white solid. mp 67-69° C.; Anal. calcd. for C15H19ClO2: C, 67.54; H, 7.18. Found: C, 67.81; H, 6.98.