Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH2:7])=[CH:2]1.[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([N:16]([CH3:21])[C:17](=[O:20])[CH:18]=[CH2:19])=[CH:11][N:10]=1.C(N(CC)CC)C>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4].C(Cl)Cl>[Cl:8][C:9]1[N:10]=[C:11]2[C:12]([N:16]([CH3:21])[C:17](=[O:20])[CH2:18][CH2:19][N:7]2[CH2:6][C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[CH:13][N:14]=1
Reactant: C=CC(=O)N(C)c1cnc(Cl)nc1Cl
Reactant: NCc1ccoc1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)CCN(Cc2ccoc2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.3 %

Procedure:
3-Furylmethylamine (Maybridge; 175 mg, 1.8 mmol), N-(2,4-dichloropyrimidin-5-yl)-N-methyl-prop-2-enamide (Intermediate 113; 347 mg, 1.5 mmol), Triethylamine (420 μL, 3 mmol), Titanium Tetra-ethoxide (157 μL, 0.75 mmol) and DCM (5 mL) were combined and stirred at room temp for 1 hr, heated at 40° C. overnight then cooled to room temperature. The reaction mixture was washed with water then gravity filtered through a PTFE cup, the aqueous layer containing the titanium emulsion was washed with further DCM (3×10 mL) and the combined organic solutions gravity filtered through a PTFE cup and solvents evaporated. The residue was dissolved in DCM and purified by chromatographic separation on silica eluting with a shallow gradient (25 column volumes) of 10-50% Ethyl Acetate/iso-hexane. Product containing fractions were combined and evaporated to give the title compound as a yellow gum (67 mg, 15%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH:22]=O)[CH:10]=2)=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:26]=[C:27]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:28]=[CH:29][C:30]=1[Cl:31].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:24][C:25]1[CH:26]=[C:27]([N:32]2[CH2:37][CH2:36][N:35]([CH2:22][CH2:21][CH2:20][C:11]3[CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:13]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:12]=3)[CH2:34][CH2:33]2)[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: COc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)c(Cl)c4)CC3)nn2-c2ccccc2)cc1

Procedure:
104 mg (76%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (75 mg, 0.245 mmol), 1-(3,4-dichlorophenyl)piperazine (57 mg, 0.245 mmol), DIPEA (0.064 mL, 0.368 mmol) and NaBH(OAc)3 (156 mg, 0.735 mmol).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:20])[O:19][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:18])([CH3:17])[CH2:8]3.[N-:21]=[N+:22]=[N-:23].[Na+]>C(OCC)(=O)C.CCCCCC>[N:21]([CH2:2][C:3]1([CH3:20])[O:19][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:18])([CH3:17])[CH2:8]3)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2c(c3c1NC(=O)C(C)(C)C3)OC(C)(CBr)C2
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc2c(c3c1NC(=O)C(C)(C)C3)OC(C)(CN=[N+]=[N-])C2
Yield: 81.1 %

Procedure:
Using 2-bromomethyl-2,5,8,8-tetramethyl-2,3,6,7,8,9-hexahydrofuro[2,3-f]quinoline-7-one (1.28 g, 3.78 mmol) and sodium azide (1.96 g, 30.1 mmol), the procedure of Example 300 was followed (reaction, post-treatment, and recrystallization from ethyl acetate-hexane) to obtain 921 mg of the title compound as colorless needles (81%).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([O:23][C@@:9]2([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12][C@@H:13]3[C@H:8]2[CH2:7][CH2:6][N:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1ccc(F)cc1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-fluoro-benzoic acid to yield (3aR,4S,7aR)-methyl 4-(4-fluorobenzoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester eliminated ion); RT=4.093 min; HPLC Method III
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-].[Cl:10]C(Cl)(Cl)C(Cl)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:10][CH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc[n+]([O-])c1C
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cccnc1CCl

Procedure:
A solution of 15 g of 2,3-dimethylpyridine 1-oxide in 75 ml of chloroform was boiled at reflux and treated as rapidly as possible with 37 ml of trichloroacetyl chloride (the acid chloride was added through the reflux condenser). The reaction mixture was heated under reflux for 2.5 hours, subsequently poured into a mixture of ice and sodium bicarbonate and the resulting solution was washed several times with methylene chloride. The organic phase was dried with sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel with methylene chloride, the medium pressure flash chromatography method being used and the pressure being produced with nitrogen gas. The 2-chloromethyl-3-methylpyridine obtained was processed directly.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:31])C(=O)C1.O>CN(C=O)C>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[C:9]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:10][CH:11]=[C:12]([Br:31])[C:13]=1[F:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1c(F)cccc1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1c(OCc2ccccc2)ccc(Br)c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2-benzyloxy-6-fluorophenyl)-carbamic acid tert-butyl ester (2.35 g, 7.41 mmol) in DMF (20 mL) at 0° C. is added NBS (1.45 g, 8.15 mmol). The mixture is stirred at 0° C. for 30 min., and then at RT for 18 h. It is then poured into water, extracted with EtOAc, washed with water and brine, and dried with MgSO4. The solvent is removed to give the title compound and it is used in the next step.
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1>C(O)C.O1CCCC1>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[CH2:24][CH2:23][C:12]1[CH:13]=[C:14]([OH:15])[C:9](=[O:8])[NH:10][N:11]=1
Reactant: Fc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c(F)c1
Solvent: CCO
Solvent: C1CCOC1
Product: O=c1[nH]nc(CCc2ccc(F)cc2F)cc1O
Yield: 26 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(2,4-difluorophenyl)ethynyl]pyridazine (Intermediate 21) except that the reaction was carried out in a mixture of ethanol and tetrahydrofuran (1:1). The crude material was purified by reverse phase chromatography (25 g C18) cartridge eluting with 5-100% acetonitrile/water with acidic modifier and the appropriate fractions combined to give a yellow solid. This was recrystallised from ethanol to give a white solid (yield=26%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[O:8]([C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[O:8]([C:15]1[CH:16]=[CH:17][C:18]([O:1][C@@H:2]2[CH2:6][CH2:5][NH:4][C:3]2=[O:7])=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1NCC[C@@H]1O
Reactant: Oc1ccc(Oc2ccccc2)cc1
Product: O=C1NCC[C@H]1Oc1ccc(Oc2ccccc2)cc1

Procedure:
Typical Procedure 3 was followed. Reaction of (S)-3-hydroxy-pyrrolidin-2-one with 4-(phenoxy)-phenol provided the title compound. MS ESI+: m/z=270 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:23])=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+].CO>>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:13]2[S:14][C:8]3[C:7]([OH:23])=[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])[N:11]=[CH:10][C:9]=3[N:12]=2)=[CH:16][CH:17]=1)#[N:22]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2nc(-c3ccc(C#N)cc3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(-c2nc3cnc(C(=O)NCC(=O)O)c(O)c3s2)cc1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
A mixture of 2-(4-cyano-phenyl)-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (111 mg, 0.34 mmole) and glycine (512 mg, 6.82 mmole) in 0.5 M sodium methoxide/methanol (13 ml, 6.48 mmole) was refluxed for 45 h before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (35 ml) and extracted with methyl tert-butyl ether (2×25 ml). The remaining aqueous layer was acidified to pH=3 with 1N HCl (9 ml). The suspension was extracted with chloroform/isopropanol (3:1, 35 ml). The organic suspension was concentrated, washed with water and dried in vacuo to give the title compound as a brown solid (52 mg). 1H NMR (DMSO-d6, 200 MHz): δ=9.52 (t, 1H), 8.90 (s, 1H), 8.30 (d, 1H, J=8.2 Hz), 8.04 (d, 1H, J=8.2 Hz), 4.00 (d, 2H, J=5.8 Hz); MS: (+) m/z 355.22 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([CH2:16]O)=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.[C-:18]#[N:19].[K+]>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([CH2:16][C:18]#[N:19])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1
Reactant: OCc1cnn2c(-c3cccnc3)ccnc12
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1cnn2c(-c3cccnc3)ccnc12
Temperature: 100 °C

Procedure:
A mixture of 0.01 mole of 7-(3-pyridyl)pyrazolo-[1,5-a]pyrimidine-3-methanol and 0.025 mole of potassium cyanide in N,N-dimethylformamide is heated at 100° C. for 16 hours. The solvent is removed and water is added to the residue to give 7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-acetonitrile. A mixture of 0.001 mole of the preceding compound in a 1:1 mixture of acetic acid and concentrated hydrochloric acid is heated at reflux temperature for 16 hours. The solvent is removed to give 7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-acetic acid. The preceding compound is heated at 180° C. to give the product of the example.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[S:16]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 3 h
Yield: 97.9 %

Procedure:
(S)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (3.5 g, 16.59 mmol) was dissolved in CH2Cl2 (60 ml), and then TsCl (3.8 g, 19.91 mmol), Et3N (3.47 ml, 24.87 mmol), and DMAP (0.21 g, 1.66 mmol) were added, followed by at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was extracted with H2O, MC, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (EA:Hex=1:5), to give (S)-tert-butyl 3-((tosyloxy)methyl)piperidine-1-carboxylate (6 g, 97%).
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[K+].Br[CH2:26][CH2:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30].C(OCC)(=O)C>O1CCCC1>[O:12]=[C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][CH2:10][N:9]1[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30]
Reactant: O=C1NCCC1(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)CCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)CCCN1CCC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3,3-diphenylpyrrolidin-2-one (2.00 g, 8.43 mmol; Example 1A) in tetrahydrofuran (10 mL) was added potassium 2-methylpropan-2-olate (9.27 mL, 9.27 mmol). After stirring for 30 minutes, the reaction was a suspension so the reaction was heated to 40° C. The reaction was cooled to ambient temperature, and then tert-butyl 4-bromobutanoate (2.068 g, 9.27 mmol) as a solution in tetrahydrofuran (3 mL) was added. The reaction was stirred for 3 hours, then poured into ethyl acetate/1 N HCl (1:1, 300 mL). The organic layer was separated, washed with brine (100 mL), dried over magnesium sulfate and concentrated. The residue was loaded onto a GraceResolv™ 40 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 40% ethyl acetate/hexanes (Flow=40 mL/minute) over 30 minutes. The product was dissolved in 5 mL of dichloromethane then 5 mL of trifluoroacetic acid was added. After stirring for 3 hours, the reaction was concentrated to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.36-7.22 (m, 10H), 3.45 (m, 4H), 2.79 (t, J=6.5, 2H), 2.31 (t, J=7.1, 2H), 1.89 (p, J=7.0, 2H); MS (ESI+) m/z 324.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:14])=[C:7]([C:11]([OH:13])=O)[S:8][C:9]=1[CH3:10])[CH:2]([CH3:4])[CH3:3].[OH:15][C:16]1[C:25]([CH3:26])=[CH:24][C:19]([C:20]([NH:22]O)=[NH:21])=[CH:18][C:17]=1[CH2:27][CH3:28]>>[CH2:27]([C:17]1[CH:18]=[C:19]([C:20]2[N:22]=[C:11]([C:7]3[S:8][C:9]([CH3:10])=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:6]=3[CH3:14])[O:13][N:21]=2)[CH:24]=[C:25]([CH3:26])[C:16]=1[OH:15])[CH3:28]
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Reactant: Cc1sc(C(=O)O)c(C)c1CC(C)C
Product: CCc1cc(-c2noc(-c3sc(C)c(CC(C)C)c3C)n2)cc(C)c1O

Procedure:
2-Ethyl-4-[5-(4-isobutyl-3,5-dimethyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol is prepared in analogy to Example 21 starting from 4-isobutyl-3,5-dimethyl-thiophene-2-carboxylic acid and 4,N-dihydroxy-3-ethyl-5-methyl-benzamidine; LC-MS: tR=1.20 min, [M+1]=371.04.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]1([C:15]2[NH:19][N:18]=[C:17]([NH2:20])[CH:16]=2)[CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:20][C:17]2[CH:16]=[C:15]([CH:12]3[CH2:14][CH2:13]3)[NH:19][N:18]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.6 %

Procedure:
A mixture of 2,4-dichloro-5-nitropyrimidine (2 g) and 5-cyclopropyl-1H-pyrazol-3-amine (2 g) in acetonitrile (20 mL) with diisopropylethylamine (2 mL) was stirred at room temperature for 24 hours, The resulting mixture was concentrated, and the resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to afford 2.1 g desired product. MS (electrospray): 281 (M+1) for C10H9ClN6O2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[CH2:16]O.P(Br)(Br)[Br:19].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[C:10]1([CH2:9][O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:16][Br:19])[CH:4]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrP(Br)Br
Reactant: OCc1cc(OCc2ccccc2)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Clc1ccc(OCc2ccccc2)cc1CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.6 %

Procedure:
To a solution of 4-chloro-3-(hydroxymethyl)phenol (for as preparation see Intermediate 12) (3.3 g, 20.8 mmol) in ethanol (30 ml) was added 2 M sodium hydroxide (10 ml, 20 mmol). To the mixture was added dropwise a solution of benzyl bromide (2.48 ml, 20.8 mmol, Aldrich) in ethanol (30 ml). The reaction was stirred under nitrogen overnight at ambient temperature. The ethanol was removed in vacuo to leave a cream solid and the residue partitioned between water (80 ml) and dichloromethane (60 ml). The phases were separated and the aqueous phase extracted with dichloromethane (40 ml). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (40 ml) and the solvent removed in vacuo to leave a white solid (4.6 g). The sample was loaded in dichloromethane and purified on silica (2×100 g) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give {2-chloro-5-[(phenylmethyl)oxy]phenyl}methanol as a clear oil (4.12 g). To a solution of {2-chloro-5-[(phenylmethyl)oxy]phenyl}methanol (1.22 g, 4.91 mmol) in DCM (25 ml) at −10 to −15° C., under nitrogen, was added a solution of phosphorus tribromide (0.463 ml, 4.91 mmol, Aldrich) in DCM (10 ml) dropwise. The solution was allowed to warm to ambient temperature and stirred for 3 h under nitrogen. To the reaction mixture in an ice-bath was added dropwise saturated aqueous sodium hydrogen carbonate (15 ml). The mixture was diluted with water (80 ml) and DCM (100 ml). The phases were separated and the aqueous phase washed with DCM (60 ml). The combined organic extracts were washed with water (50 ml). The organic extract was dried (MgSO4), filtered and the solvent removed in vacuo to give 3-(bromomethyl)-4-chlorophenyl phenylmethyl ether as a colourless gum (1.11 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:4][N:3]=1.[CH3:17][NH:18][CH3:19]>>[CH3:17][N:18]([CH3:19])[C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2ccc(Cl)nc2)OC1(C)C
Reactant: CNC
Product: CN(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
The title compound was prepared according to the procedures of intermediate 8 except using 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and dimethyl amine.
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15](/[C:16](=[N:28]/[OH:29])/[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C=C1C2[C@](C)(CCC(=[O:49])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1>>[OH:29]/[N:28]=[C:16]1/[C@@H:15]2[C@@H:25]([C@:23]3([CH3:24])[CH:18]([CH2:17]/1)[CH2:19][C:20](=[O:49])[CH2:21][CH2:22]3)[CH2:26][CH2:27][C@@:4]1([CH3:5])[C@H:6]2[CH2:7][CH2:8][C:3]1=[O:12]
Reactant: C[C@]12CCCCC1C/C(=N\O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Product: C[C@]12CCC(=O)CC1C/C(=N\O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 50 %

Procedure:
The title compound II-at was prepared in 50% yield from 3,3:17,17-bis(ethylendioxy)-7-(E)-hydroxyiminoandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography (SiO2, n-hexane/EtOAc 6/4). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS: δ 10.37 (1H, s), 2.99 (1H, m), 2.58-0.67 (19H, m), 1.12 (3H, s), 0.82 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)=O.[F:20][C:21]([F:29])([F:28])[C:22](=[O:27])[CH2:23][C:24](=O)[CH3:25]>C(O)(=O)C.S(=O)(=O)(O)O>[Cl:19][C:14]1[CH:13]=[C:12]([C:10]2[C:23]([C:22](=[O:27])[C:21]([F:29])([F:28])[F:20])=[C:24]([CH3:25])[N:1]=[C:2]3[S:6][C:5]4[CH2:7][CH2:8][CH2:9][C:4]=4[C:3]=23)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: Nc1sc2c(c1C(=O)c1ccc(Cl)c(Cl)c1)CCC2
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2ccc(Cl)c(Cl)c2)c1C(=O)C(F)(F)F)CCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 13.1 %

Procedure:
To a stirred solution of 50 mg (0.16 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-(3,4-dichloro-phenyl)-methanone in 2 ml acetic acid was added 0.020 ml (0.17 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 10:1) afforded 9 mg (14%) 1-[4-(3,4-dichloro-phenyl)-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-2,2,2-trifluoro-ethanone as a yellow solid. ES-MS m/e (%): 430 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([N:25]=[C:26]=[S:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:26]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[S:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: S=C=NCc1ccccc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=S)NCc4ccccc4)cc23)CC1
Yield: 68.6 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 14.63 mg (0.098 mMol) benzyl isothiocyanate, 17.0 mg (86%) of the title compound were recovered.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH2:25]>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccc2)n1
Reactant: COc1ccc(C)c(N)c1
Product: COc1ccc(C)c(Nc2cc(C(F)(F)F)nc(-c3ccccc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-phenyl-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 5-methoxy-2-methylaniline (40 mg, 0.290 mmol) similar to Example 77 and isolated as a tan oil (33 mg, 48%). 1H NMR (CDCl3): 8.46-8.42 (m, 2H), 7.50-7.46 (m, 3H), 7.22 (d, J=8.4 Hz, 1H), 7.01 (d, J=2.4 Hz, 1H), 6.92 (s, 1H), 6.80 (dd, J=2.6, 8.6 Hz, 1H), 6.61 (s, 1H), 3.81 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[CH2:32]([CH2:34][NH2:35])[OH:33]>>[CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:35][CH2:34][CH2:32][OH:33])=[O:25])[C:6]1=[O:29]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Reactant: NCCO
Product: CN(C)C(=O)Cn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those those described in Example 9 and was purified by recrystallization from DMSO and MeOH. The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.53 (1H, br), 8.14 (1H, s), 7.26 (3H, m), 7.10 (2H, t, J=9 Hz), 4.92 (2H, s), 4.74 (1H, br t), 3.99 (2H, s), 3.45 (2H, m), 3.27 (2H, m), 3.08 (3H,), 2.78 (3H, s); HRMS calcd for C22H23FN4O5+H+: 443.1731. Found: 443.1738.