Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]3[C:14](=[O:17])[O:15][CH2:16][C:12]=3[CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N:20]1([C:25]2[N:30]=[CH:29][C:28]([CH2:31][CH:32]=O)=[CH:27][CH:26]=2)[CH:24]=[N:23][N:22]=[N:21]1>>[N:20]1([C:25]2[N:30]=[CH:29][C:28]([CH2:31][CH2:32][N:5]3[CH2:6][CH2:7][N:2]([CH2:8][CH2:9][C:10]4[CH:11]=[C:12]5[C:13](=[CH:18][CH:19]=4)[C:14](=[O:17])[O:15][CH2:16]5)[CH2:3][CH2:4]3)=[CH:27][CH:26]=2)[CH:24]=[N:23][N:22]=[N:21]1
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Reactant: O=CCc1ccc(-n2cnnn2)nc1
Agent: Cl
Product: O=C1OCc2cc(CCN3CCN(CCc4ccc(-n5cnnn5)nc4)CC3)ccc21

Procedure:
5-[2-[4-[2-[6-(Tetrazol-1-yl)-3-pyridyl]ethyl]piperazin-1-yl]ethyl]-3H-isobenzofuran-1-one was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetaldehyde. LC-MS (IE, m/z): 392.0 [(M+1)+−28]. (0.91 μM)
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:19]([F:20])=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[C:12]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])[N:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+].O.Cl>CO>[F:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[NH:21][C:12]1[N:11]=[C:10]([N:7]2[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]2)[C:19]([F:20])=[CH:18][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1cc(F)c(N2CCN(C(C)=O)CC2)nc1Nc1ccc(F)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(F)c(N2CCNCC2)nc1Nc1ccc(F)cc1F
Yield: 98.1 %

Procedure:
In 3.9 ml of methanol was suspended 130 mg of methyl 6-(4-acetyl-1-piperazinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinate, and 3.33 ml of 2N aqueous sodium hydroxide solution was added thereto, after which the resulting mixture was subjected to reaction under reflux for 2 hours. To the reaction mixture was added 2 ml of water, and the pH thereof was adjusted to 8.5 with 1N hydrochloric acid, after which the crystals thus deposited were collected by filtration and washed with 2 ml of water to obtain 110 mg (yield 98.2%) of 2-(2,4-difluorophenylamino)-5-fluoro-6-(1-piperazinyl)nicotinic acid having a melting point of 279°-281° C.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]([CH3:22])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:23]1([NH2:26])[CH2:25][CH2:24]1>C(O)C.CCCCCC>[F:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]([CH3:22])[C:3]=1[C:4]([C:6](=[CH:12][NH:26][CH:23]1[CH2:25][CH2:24]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: NC1CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(F)c(F)c1C
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)cc(F)c(F)c1C
Temperature: 5 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a solution of 8.3 g (26 mmol) of ethyl 2-(2,4,5-trifluoro-6-methylbenzoyl)-3-ethoxyacrylate in 30 mL of absolute ethanol at 5° C. was added 1.64 g (29 mmol) of cyclopropylamine. The reaction mixture was stirred at 5° C. for 90 minutes and at room temperature for 2 hours. The solution was concentrated to give a brown oil which was dissolved in hexane and reconcentrated to give a tan solid. Recrystallization from hexane gave 7.2 g of colorless crystals, mp 69°-72° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[F:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26](=O)[CH2:27]Br>O>[F:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]1[N:12]=[C:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=2)[S:13][CH:27]=1
Reactant: O=C(CBr)c1ccccc1F
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Solvent: O
Product: O=C(O)c1cc(-c2nc(-c3ccccc3F)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 18 %

Procedure:
4-[4-(2-Fluoro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (46 mg, 18%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-fluorophenacyl bromide (available from Matrix Scientific) using the procedure described for the preparation of Example 18 except that the entire 4 mL of water was added at the beginning of the hydrolysis step rather than being added in two portions. 1H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J=1.8 Hz, 1H), 8.12-8.30 (m, 4H), 7.61-7.80 (m, 2H), 7.34-7.50 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[F:21][C:22]([F:32])([F:31])[C:23](N1CCOCC1)=[O:24].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:5]([C:23](=[O:24])[C:22]([F:32])([F:31])[F:21])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cl)n1
Reactant: O=C(N1CCOCC1)C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1nc(Cl)ccc1C(=O)C(F)(F)F
Temperature: -50 °C
Reaction time: 2 h

Procedure:
8 g (35 mmol) of tert-butyl (6-chloropyridin-2-yl)carbamate (Example 105A) are introduced into 100 ml of THF and cooled to −50° C. 55 ml (87 mmol) of butyllithium (1.6N) are added dropwise. After the dropwise addition is complete, the reaction is slowly warmed to −10° C. and kept at 0° C. for 2 h. It is then cooled again to −40° C., and 12.8 g (70 mmol) of 4-(trifluoroacetyl)morpholine (Example 35A), dissolved in 4 ml of THF, are added. The reaction solution is stirred at −40° C. for 1 h and then, at −40° C., poured into 1 l of ethyl acetate and 350 ml of ammonium chloride solution and extracted. The organic phase is separated off, dried over magnesium sulphate and concentrated in a rotary evaporator. The reaction mixture is chromatographed on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). 9 g (79% of theory) of the product are obtained as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[B:14](OC)([O:17]C)[O:15]C.Cl>C1(C)C=CC=CC=1.CCCCCC.O1CCCC1>[F:1][C:2]1[C:3]([F:8])=[CH:4][CH:5]=[CH:6][C:7]=1[B:14]([OH:17])[OH:15]
Reactant: COB(OC)OC
Reactant: Fc1ccccc1F
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1cccc(F)c1F
Temperature: -60 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
First, 100 g of 1,2-difluorobenzene and 350 ml of dehydrated tetrahydrofuran were put in an argon-replaced 2 flask, and cooled to −60° C. Then, 700 ml of a hexane solution containing n-butyllithium at a concentration of 1.6 mol/l was dropped into the resultant mixture while being stirred for two hours, and further stirred keeping the same temperature for another two hours. Subsequently, 175 g of trimethyl borate was dropped and stirred keeping the same temperature for one hour. The resultant mixture was left to gradually resume room temperature, stirred for eight hours, and again cooled to 0° C. The resultant reaction solution was poured into dilute hydrochloric acid to acidify the reaction solution. Toluene was then added, and the resultant toluene layer was washed with a saturated brine and dried with sodium sulfate. The solvent was then distilled off. The crystallized residue was immersed in a heated hexane solution and washed, to obtain 80.8 g of 2,3-difluorophenylboronic acid. The purity of the resultant compound was 99.5% as measured by HPLC.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25](O)=[O:26])[C:19](=[O:28])[CH:18]=[CH:17]2>>[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]([NH:7][C:4]1[S:5][CH:6]=[C:2]([Br:1])[C:3]=1[C:8]1[N:12]=[CH:11][NH:10][N:9]=1)=[O:26])[C:19](=[O:28])[CH:18]=[CH:17]2
Reactant: Nc1scc(Br)c1-c1nc[nH]n1
Reactant: O=C(O)Cn1c(=O)ccc2cc(Br)ccc21
Product: O=C(Cn1c(=O)ccc2cc(Br)ccc21)Nc1scc(Br)c1-c1nc[nH]n1

Procedure:
The title compound was prepared from 4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-amine (55 mg, 224 umol) and 2-(6-bromo-2-oxoquinolin-1(2H)-yl)acetic acid (85 mg, 301 umol) according to protocol A. HPLC purification gave 2-(6-bromo-2-oxoquinolin-1(2H)-yl)-N-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)acetamide. Method [7] retention time 5.41 min by HPLC (M+=508, 510, and 512). 1H NMR (300 MHz, CDCl3) δ 7.80 (m, 2H), 7.70 (s, 1H), 7.63 (dd, J=9.0 and 2.4 Hz, 1H), 7.19 (d, J=9.0 Hz, 1H), 6.94 (m, 2H), 5.31 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:3]=1.[CH2:21]([CH2:23][NH2:24])[OH:22].CCN(C(C)C)C(C)C>CCCCO>[O:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:24][CH2:23][CH2:21][OH:22])[CH:3]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: NCCO
Reactant: Clc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: OCCNc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Temperature: 200 °C
Yield: 77 %

Procedure:
78 mg of 6-chloro-N-(4-morpholinophenyl)pyrimidin-4-amine, 33 mg of ethanolamine and 70 mg of DIPEA were dissolved in 2 mL of n-BuOH and the mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. Progress of the reaction was monitored by TLC. Upon termination of the reaction n-BuOH. was evaporated off and the evaporation residue obtained was subjected to crystallization from n-BuOH-EtOH solvent mixture. 2-(6-(4-Morpholinophenylamino)pyrimidin-4-ylamino)ethan-1-ol was obtained in the form of a colorless solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH:19]=[C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[S:28][C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[CH:14]([O:17][CH:18]([CH3:20])[CH3:19])([CH3:15])[CH3:13].[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH:19]=[C:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:27]5[S:28][C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N1CC=C(c2cc3cc(C4CCNCC4)oc3cn2)CC1
Reactant: FC(F)(F)c1nnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)OC(C)C
Product: CS(=O)(=O)N1CC=C(c2cc3cc(C4CCN(c5nnc(C(F)(F)F)s5)CC4)oc3cn2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-furo[2,3-c]pyridine (HCl salt, 70 mg), 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole (35 mg), K2CO3 (55 mg), and dimethyl sulfoxide (3 mL) is stirred at 60° C. overnight. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na2SO4), and concentrated. The residue is triturated with methanol and then with diisopropylether to give the title compound. LC (method 1): tR=0.94 min; Mass spectrum (ESI+): m/z=514 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:21]=[CH:20][C:10]([CH2:11][N:12]3[CH:16]=[C:15]([C:17]([OH:19])=O)[N:14]=[CH:13]3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[C:22]([O:26][C:27](=[O:39])[NH:28][C:29]1[CH:34]=[C:33]([CH3:35])[C:32]([CH2:36][NH2:37])=[C:31]([CH3:38])[N:30]=1)([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:22]([O:26][C:27](=[O:39])[NH:28][C:29]1[CH:34]=[C:33]([CH3:35])[C:32]([CH2:36][NH:37][C:17]([C:15]2[N:14]=[CH:13][N:12]([CH2:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:21][CH:20]=3)[CH:16]=2)=[O:19])=[C:31]([CH3:38])[N:30]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Reactant: O=C(O)c1cn(Cc2ccc(Cn3cccn3)cc2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn(Cc2ccc(Cn3cccn3)cc2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(4-Pyrazol-1-ylmethyl-benzyl)-1H-imidazole-4-carboxylic acid (0.67 g, 2.4 mmol), (5-Aminomethyl-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (0.61 g, 2.4 mmol), HATU (1.8 g, 4.8 mmol) and DIPEA (1.3 mL, 7.2 mmol) in 10 mL DMF was stirred at room temperature for 16 h. The mixture was evaporated and the residue was partitioned between ethyl acetate and 1 N aq. HCl. The organic layer was dried over MgSO4 and evaporated in vacuo. The crude product was purified by preparative HPLC (Waters Sunfire Prep C18 PBD 5 um, 30×100 mm, 5 to 100% ACN and 0.1% TFA, flow 40 ml/min). LCMS (method A) RtA=1.418 min; [M+H]+=516.1.
Reaction SMILES: Cl.C(OC1C([Cl:16])=CC=CC=1C1(OC)CCN(CCC2(O)CCCCC2)CC1)C1C=CC=CC=1.[CH2:34]([O:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]([C:59]2([OH:65])[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]2)[C:49]([N:51]2[CH2:56][CH2:55][CH:54]([O:57][CH3:58])[CH2:53][CH2:52]2)=O)=[CH:44][C:43]=1[Cl:66])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[ClH:16].[CH2:34]([O:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]([C:59]2([OH:65])[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]2)[CH2:49][N:51]2[CH2:52][CH2:53][CH:54]([O:57][CH3:58])[CH2:55][CH2:56]2)=[CH:44][C:43]=1[Cl:66])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COC1CCN(C(=O)C(c2ccc(OCc3ccccc3)c(Cl)c2)C2(O)CCCCC2)CC1
Reactant: COC1(c2cccc(Cl)c2OCc2ccccc2)CCN(CCC2(O)CCCCC2)CC1
Agent: Cl
Product: COC1CCN(CC(c2ccc(OCc3ccccc3)c(Cl)c2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 1, step 2, 1-[1-[4-(benzyloxy-3-chlorophenyl]-2-(4-methoxypiperidin-1-yl)ethyl]cyclohexanol hydrochloride was prepared from 1-[1-[4-(benzyloxy)-3-chlorophenyl]-2-(4-methoxypiperidin-1-yl)-2-oxoethyl]cyclohexanol HRMS: calcd for C27H36ClNO3+H, 458.24620; found (ESI, [M+H]+), 458.2443.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[N:6]2[N:11]=[C:12]([S:14][CH3:15])[N:13]=[C:5]2[N:4]=1)[CH3:2].C(O)(=[O:18])C.OO.[OH2:22]>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH3:15][S:14]([C:12]1[N:13]=[C:5]2[N:4]=[C:3]([CH2:1][CH3:2])[CH:8]=[C:7]([CH2:9][CH3:10])[N:6]2[N:11]=1)(=[O:18])=[O:22]
Reactant: CC(=O)O
Reactant: O
Reactant: CCc1cc(CC)n2nc(SC)nc2n1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CCc1cc(CC)n2nc(S(C)(=O)=O)nc2n1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
A mixture of 5,7-diethyl-2-(methylsulfanyl)-[1,2,4]triazolo[1,5-a]pyrimidine (11.0 g, 49.5 mmol), sodium tungstate dihydrate (490 mg, 1.49 mmol), and glacial acetic acid (90 mL) was added to a 1 L RBF with a magnetic stirring bar. The flask was cooled to ˜10° C. using ice and water bath. A solution of 35% Hydrogen peroxide in water (12.7 mL, 148.6 mmol) was slowly added drop-wise. The mixture was stirred at room temperature for 10 minutes, then at 60° C. for 40 minutes. Progress of the reaction was monitored by analytical HPLC with UV detection at 215 nm. The starting material eluted with retention time of 4.7 min, and the product eluted with retention time of 3.8 min. The reaction was cooled to room temperature and a solution of sodium sulfite (3.0 g Na2SO3 in 20 mL water) (˜4 mL) was added to the mixture until negative to peroxide test strip, and allowed to stir at room temperature overnight. The reaction was concentrated to ˜15 mL and partitioned using ethyl acetate (300 mL) and water (30 mL). The aqueous layer was extracted with ethyl acetate (2×75 mL). The combined organic layers were washed with saturated aqueous NaCl (30 mL), dried (Na2SO4), filtered, and concentrated to afford the title compound as a white powder (12.2 g, 97% yield).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.C([Sn](CCCC)(CCCC)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)CCC.N1C=CC=C(B(O)O)C=1.ClC1C(=O)[C:40](C#N)=[C:41](C#N)[C:42](=[O:45])[C:43]=1Cl.N1C2C(=CC=CC=2)C=CC=1>>[OH:45][C:42]1[CH:43]=[C:19]2[C:14](=[CH:40][CH:41]=1)[N:15]=[CH:16][CH:17]=[CH:18]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: OB(O)c1cccnc1
Solvent: c1ccc2ncccc2c1
Product: Oc1ccc2ncccc2c1

Procedure:
A trifluoromethanesulfonate derivative may be produced by reacting a 7-benzyloxy-4-chloroquinoline derivative with a suitable reducing agent, for example, hydrogen gas/palladium hydroxide to give an alcohol (step (i) above) and then reacting the alcohol with trifluoromethanesulfonic anhydride (step (ii) above) to give a trifluoromethanesulfonate derivative. A quinoline derivative may be produced by reacting the trifluoromethanesulfonate derivative with an alkyltin reagent, for example, tri-n-butyl-(2-pyridyl)-tin or an alkylboronic acid reagent, for example, 3-pyridylboronic acid in the presence of a suitable transition metal catalyst, for example, tetrakis triphenylphosphine palladium (step (iii) above) and reacting the resultant compound with a suitable oxidizing agent, for example, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, to give a quinoline derivative (step (iv) above). Next, a 6-hydroxyquinoline derivative may be produced by reacting the quinoline derivative with a suitable reagent, for example, boron tribromide (step (v) above). The contemplated compound may be produced by reacting the 6-hydroxyquinoline derivative with a 4-chloroquinoline derivative or a corresponding quinazolone derivative in a suitable solvent, for example, o-dichlorobenzene, or in the absence of a solvent, for example, at 120 to 180° C. (step (vi) above).
Reaction SMILES: [CH3:1][C:2]([CH:10]([CH3:17])[CH2:11][CH:12]=[C:13]([CH3:16])[CH2:14][CH3:15])=[CH:3][CH2:4]C(OCC)=O.[H-].C[O:20]CCO[Al+]OCCOC.[Na+].[H-].O.CCOCC>C1C=CC=CC=1>[CH3:1][C:2]([CH:10]([CH3:17])[CH2:11][CH:12]=[C:13]([CH3:16])[CH2:14][CH3:15])=[CH:3][CH2:4][OH:20]
Reactant: COCCO[Al+]OCCOC
Reactant: CCOC(=O)CC=C(C)C(C)CC=C(C)CC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCC(C)=CCC(C)C(C)=CCO
Temperature: 40 °C
Reaction time: 2 h

Procedure:
157 g. of ethyl 3,4,7-trimethyl-2,6-nonadienecarboxylate are dissolved in 300 ml. of benzene and added dropwise while cooling with ice to a solution of 370 g. of 70% sodium bis-(methoxyethoxy)-aluminum hydride in benzene. The mixture is then stirred at 40° C. for 2 hours and subsequently worked up with water/ether as described earlier. The 3,4,7-trimethyl-2,6-nonadien-1-ol obtained boils at 79°-84° C./0.09 mmHg.
Reaction SMILES: [O:1]=[C:2]([NH:18][CH:19]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[C:20]([F:23])([F:22])[F:21])/[CH:3]=[CH:4]/[C:5]1[CH:13]=[CH:12][C:8](C(O)=O)=[C:7](C(F)(F)F)[CH:6]=1.C([N:36](CC)CC)C.[Cl:41][C:42]1[N:50]=[CH:49][CH:48]=[CH:47][C:43]=1[C:44](Cl)=[O:45]>ClC(Cl)Cl.ClCCl>[Cl:41][C:42]1[N:50]=[CH:49][CH:48]=[CH:47][C:43]=1[C:44]([NH:36][C:7]1[CH:8]=[CH:12][CH:13]=[C:5](/[CH:4]=[CH:3]/[C:2](=[O:1])[NH:18][CH:19]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:6]=1)=[O:45]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: O=C(/C=C/c1ccc(C(=O)O)c(C(F)(F)F)c1)NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(/C=C/c1cccc(NC(=O)c2cccnc2Cl)c1)NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
100 mg (0.25 mmol) of (2E)-3-(3-aminophenyl)-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]-ethyl}acrylamide from Example 3, Stage 2 and 33.8 mg (0.33 mmol) of triethylamine were initially charged in 1 ml of trichloromethane, and a solution of 49.8 mg (0.33 mmol) of 2-chloronicotinoyl chloride in 1 ml of trichloromethane was added. The reaction solution was stirred at room temperature for 18 hours, then diluted with dichloromethane, washed three times with water and dried over sodium sulphate. The solvent was distilled off under reduced pressure and the residue purified by preparative HPLC (solvent=water (A)+acetonitrile (B), gradient=40 min, from 10% B to 100% B, flow=18 ml/min).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[C:18](=[O:24])[CH2:17][C@@:16]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH:13]=[CH2:14])[CH2:3]1.C(=O)(O)[O-].[K+].O.[CH2:32]([OH:34])[CH3:33]>>[CH2:32]([O:34][CH2:14][CH2:13][C:12](=[O:15])[C@@H:11]1[C@:16]2([CH3:25])[C@H:8]([C@H:7]3[C@H:19]([C:18](=[O:24])[CH2:17]2)[C@:20]2([CH3:23])[C@H:4]([CH2:3][C@H:2]([OH:1])[CH2:22][CH2:21]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1)[CH3:33]
Reactant: C=CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: CCO
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: CCOCCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
3α-Hydroxy-21-methylene-5α-pregnane11,20 -dione (250 mg) was dissolved in ethanol (50 ml) and potassium bicarbonate solution (10%; 3 ml) added to the refluxing solution. After 3/4 hour the mixture was poured into water, and extracted into ether. The extract was washed with water, dried (Na2SO4) and evaporated to a white solid (190 mg) which was recrystallised from ether to give title compound (120 mg) m.p. 126°-129.5° C [α]D + 87.5° (c, 1.03).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].CCCCCC>CN(C=O)C.C(OCC)(=O)C>[Si:18]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: O=Cc1ccc(OCCO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 49.9 %

Procedure:
To 4-(2-hydroxyethoxy)benzaldehyde (commercial, 0.5 g, 3 mmol) dissolved in DMF (10 mL) is added imidazole (0.4 g, 6 mmol) and tert-butyldimethylsilylchloride (0.53 g, 3.5 mmol). Reaction mixture is stirred for 20 h. at room temperature. TLC analysis (hexane:ethyl acetate,7:3) shows small amounts of unreacted starting material. Additional tert-butyldimethylsilylchloride (0.25 g, 1 mmol) is added and stirring continued for 16 h. The reaction is quenched with saturated aqueous ammonium chloride (20 mL) and diluted further with ethyl ether (20 mL). Aqueous layer is separated and extracted thrice with ether (10 mL). Combined organics dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel using a gradient of 2% to 5% ethyl acetate in hexanes to provide 0.42 g of the title compound.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].Cl[CH2:6][C:7]([C:9](=[N:15][O:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[O:4]1[C:7]([C:9](=[N:15][O:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][S:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Reactant: OCCS
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=NOC)C1=CSCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 798.4 %

Procedure:
To a stirred solution of 2-mercaptoethanol (7.8 g.) and ethyl 2-(2-chloroacetyl)-2-methoxyiminoacetate (2.08 g.) in dry chloroform (200 ml.) was added a solution of triethylamine (11 g.) in dry chloroform (30 ml.) at 20° C., and stirred at the same temperature for 3 hours. The resultant solution was washed with 10% hydrochloric acid twice, a saturated aqueous solution of sodium hydroxide twice and water twice in turn, and dried over magnesium sulfate. The solution was concentrated in vacuo at 40° C., and the residue was dissolved in dry toluene (200 ml.). After adding p-toluenesulfonic acid (3 g.) to the solution, the solution was heated under reflux for 30 minutes while removing the produced water. The resultant solution was allowed to cool at room temperature and treated with activated charcoal, and then ethyl acetate (150 ml.) was added thereto. The solution was washed with a saturated aqueous solution of sodium bicarbonate and water twice in turn dried over magnesium sulfate, and then concentrated in vacuo at 40° C. to give ethyl 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetate (mixture of syn isomer and anti isomer, 18.5 g.), yellow oil.