Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[C:24](Cl)(=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][C:24](=[O:33])[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)NC(Cc2ccc(C(F)(F)F)cc2)C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (200 mg, 0.57 mmol) in ethyl acetate (5 ml) were added 4-anisoyl chloride (146 mg, 0.86 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to give the title compound (185 mg, 72%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:18]=[CH:17][N:16]=[N:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[N:15]1[CH:14]=[CH:13][C:18]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH2:1])=[CH:4][CH:5]=2)=[CH:17][N:16]=1
Reactant: NCc1ccc(B(O)O)cc1
Reactant: Brc1ccnnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: NCc1ccc(-c2ccnnc2)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a sealed tube was added 4-(aminomethyl)phenylboronic acid 1-1 (1.87 g, 10 mmol), 4-bromopyridazine 1-2 (1.58 g, 10 mmol), Pd(PPh3)4 (230 mg, 0.2 mmol), saturated Na2CO3 (15 mL), ethanol (15 mL) and toluene (45 mL). The reaction was heated to 110° C. and stirred for 2 hours. The reaction was cooled down to room temperature. The solvent was removed by rotary evaporation. The residue was dissolved in 10% methanol in DCM. The salt was removed by filtration. The filtrate was dried. The crude product was purified by silica-gel flash chromatography, eluted with 10% methanol in DCM to give (4-(pyridazin-4-yl)phenyl)methanamine 1-3 as off-white solid. MS m/z 186.2 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19]3)[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: ClCCCCn1ccc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C1=C(c2ccccc2)CCN(CCCCn2ccc3ccccc32)C1
Temperature: 90 °C
Yield: 57.8 %

Procedure:
A mixture of 4.8 g (30 mmol) of 4-phenyl-1,2,3,6-tetrahydropyridine, 6.22 g of 1-(4-chlorobutyl)indole and 8.3 g of potassium carbonate in 100 ml of dimethylformamide is heated at 90° C. for 3 hours. Evaporation to dryness is then carried out at reduced pressure, the residue is redissolved in chloroform and washing is carried out repeatedly with water. The organic phase is dried with anhydrous sodium sulfate and evaporation is carried out at reduced pressure, a crude product being obtained which is purified by chromatography on silica gel. 5.7 g (17.3 mmol) of 1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]indole are obtained.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([C:15]([O:17][CH3:18])=[O:16])[C:9]2[CH:10]=[N:11][NH:12][C:13]=2[CH:14]=1)([O-:5])=[O:4].Br[CH:20]([CH3:22])[CH3:21].IC>CS(C)=O.CN(C)C=O>[CH3:21][CH:20]([N:12]1[C:13]2[CH:14]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[C:8]([C:15]([O:17][CH3:18])=[O:16])[C:9]=2[CH:10]=[N:11]1)[CH3:22]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2[nH]ncc12
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CS(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])cc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (1.142 g, 45.2 mmol) was added to N,N-Dimethylformamide (DMF) (100 mL) which was cooled in a ice water bath. A DMSO solution (20 mL) of methyl 6-nitro-1H-indazole-4-carboxylate (5 g, 22.61 mmol) was then added dropwise. After 15 minutes was added 2-bromopropane (4.25 mL, 45.2 mmol) dropwise and the contents were stirred at room temperature for 16 hours. Next added iodomethane (2.83 mL, 45.2 mmol) and let stir at room temperature for 3 hours followed by heating at 50° C. for 3 hours. The solvent was removed in vacuo. The residue was purified via silica gel chromatography (eluent: 0% to 25% EtOAc:Hex) to afford the product as 1.39 g (23%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.07 (s, 3H), 8.61-8.63 (m, 1H), 8.64 (s, 1H), 8.73 (d, J=2.02 Hz, 1H); LCMS(ES) [M+H]+264.0
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]([CH2:19][OH:20])([CH2:17][OH:18])[CH2:15][CH2:14][C:13]1=[O:21].[CH3:22][CH2:23][C:24](=O)[CH2:25][CH3:26].C([BH3-])#N.[Na+].CO>ClCCl.C(O)(=O)C>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[CH:4][C:3]([N:12]2[C:16]([CH2:17][OH:18])([CH2:19][OH:20])[CH2:15][CH2:14][C:13]2=[O:21])=[C:2]([NH:1][CH:24]([CH2:25][CH3:26])[CH2:23][CH3:22])[CH:7]=1)=[O:9]
Reactant: CCC(=O)CC
Reactant: COC(=O)c1ccc(N2C(=O)CCC2(CO)CO)c(N)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CCC(CC)Nc1cc(C(=O)OC)ccc1N1C(=O)CCC1(CO)CO
Reaction time: 12 h
Yield: 84.7 %

Procedure:
A solution of 1-(2-amino-4-methoxycarbonylphenyl)-5,5-bis-hydroxymethylpyrrolidin-2-one (0.1 g, 0.34 mmol) from Example 6 in 1 mL of dichloromethane and 0.5 mL of acetic acid was treated with 3-pentanone (0.2 g, 2.3 mmol) and sodium cyanoborohydride (0.075 g, 1.2 mmol). The resulting mixture was stirred at ambient temperature for 6 h after which time additional 3-pentanone (0.2 g, 2.3 mmol), sodium cyanoborohydride (0.075 g, 1.2 mmol) and methanol (0.5 mL) were added and stirring continued for 12 h. A third portion of 3-pentanone (0.3. g, 3.4 mmol) and sodium cyanoborohydride (0.15 g, 2.3 mmol) was added and the stirring continued for an additional 16 h. The reaction mixture was quenched with 10 mL of a saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried and concentrated. The residue was purified by chromatography (silica gel; 5% ethanol in ether) to give 0.105 g (82%) of 1-[4-methoxycarbonyl-2-(3-pentylamino)phenyl]-5,5-bis-(hydroxymethyl)pyrrolidin-2-one as a white solid, mp 183-185° C.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:21])[CH2:6][CH2:5]1.[C:22]1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(N(CC)CC)C>COC(OC)(C)C.C(OCC)(=O)C>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9](=[CH:10][CH2:11]2)[CH:8]=[C:7]([O:21][CH3:22])[CH2:6][CH2:5]1
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: COC(C)(C)OC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC1=CC2=CC[C@@H]3[C@H]([C@@H](F)C[C@]4(C)C(=O)CC[C@@H]34)[C@H]2CC1

Procedure:
7.8 g of 11β-fluoro-estr-4-ene-3,17-dione is stirred in 40 ml of 2,2-dimethoxypropane with 780 mg of pyridinium-toluene4-sulfonate for 5 hours at 80° C. Then, 1.5 ml of triethylamine is added, it is diluted with ethyl acetate and washed with saturated sodium chloride solution. After crystallization from methanol, 5.3 g of 11β-fluoro-3-methoxy-estra-3,5-dien-17-one with a melting point of 173° C. is obtained.
Reaction SMILES: [CH:1]1([C:7]2([OH:20])[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:21]1([Mg]Cl)CCCCC1.C1C2C(=O)C3C(=CC=CC=3)C=2C=CC=1>>[CH3:21][C:5]1[CH:6]=[C:1]([C:7]2([OH:20])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:2]=[CH:3][CH:4]=1
Reactant: OC1(C2CCCCC2)c2ccccc2-c2ccccc21
Reactant: Cl[Mg]C1CCCCC1
Agent: O=C1c2ccccc2-c2ccccc21
Product: Cc1cccc(C2(O)c3ccccc3-c3ccccc32)c1

Procedure:
9-Cyclohexyl-9H-fluoren-9-ol: from cyclohexylmagnesium chloride and 9-fluorenone;
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=O)(C)(C)C.Cl.[CH3:18][O:19][C:20](=[O:23])[CH2:21][NH2:22].Cl.CN([CH2:28][CH2:29][CH2:30]N=C=NCC)C.CC[N:38](CC)CC>CCOC(C)=O.C(CC(C)(C)C)(C)C>[CH3:18][O:19][C:20](=[O:23])[CH2:21][NH2:22].[CH2:18]([O:19][C:20]([NH:38][C:14](=[O:16])[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]1)=[O:23])[CH2:30][CH2:29][CH3:28]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: COC(=O)CN
Agent: Cl
Solvent: CC(C)CC(C)(C)C
Solvent: CCOC(C)=O
Product: CCCCOC(=O)NC(=O)C1CCCCN1

Procedure:
1-(tertButoxycarbonyl)-2-piperidinecarboxylic acid (11.46 g, 1.2 eq), glycine methyl ester hydrochloride (9.42 g), 1-(dimethylaminopropyl)-3-(ethyl)carbodiimide hydrochloride (8.00 g, 1.0 eq) and Et3N (16.3 mL) were reacted as described in Example 1 to give 5.6 g of the title compound as a colorless crystallinesolid: mp 118.5-119.5° C. (EtOAc/isooctane 1:3);
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)(=[O:3])[CH3:2].[H-].[Na+].[C:15](OCC)(=[O:17])[CH3:16]>>[NH:8]1[C:9]2[C:5](=[C:4]([C:1](=[O:3])[CH2:2][C:15](=[O:17])[CH3:16])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: CCOC(C)=O
Reactant: CC(=O)c1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Product: CC(=O)CC(=O)c1cccc2[nH]ccc12

Procedure:
4-Acetylindole (0.101 g) was refluxed in 5 mL of ethyl acetate. Sodium hydride (0.20 g, 60% oil dispersion) was added in portions to the refluxing solution until thin layer chromatography analysis showed complete consumption of the starting material. The reaction mixture was quenched with water and acidified to pH 3. The ethyl acetate layer was dried (magnesium sulfate) and concentrated to give a crude product. The crude material was chromatographed on silica gel, eluting with hexane/ethyl acetate to give 1-(1H-indol-4-yl)-1,3-butanedione (0.104 g), a compound of formula (11), m.p. 104°-105° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:13]1[N:17]2[CH:18]=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[N:21][C:16]2=[N:15][CH:14]=1)CCC>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]1[N:17]2[CH:18]=[CH:19][C:20]([C:22]([F:23])([F:24])[F:25])=[N:21][C:16]2=[N:15][CH:14]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Clc1ccccn1
Product: FC(F)(F)c1ccn2c(-c3ccccn3)cnc2n1
Yield: 26.8 %

Procedure:
2-Chloropyridine (361 μl, 3.78 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.89 mmol) by the method of Example 1 to give 3-(pyridin-2-yl)-7-trifluoromethyl-imidazo[1,2-α]pyrimidine (134 mg) as a white solid: δH (400 MHz, CDCl3) 7.24-7.30 (1H, m), 7.33 (1H, d, J 7.0), 7.82-7.84 (2H, m), 8.51 (1H, s), 8.68-8.70 (1H, m), 10.54 (1H, d, J 7.0); m/z (ES+) 265 (M++H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.C[Si]([N:27]=[C:28]=[S:29])(C)C>C1C=CC=CC=1.O>[CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([C:28](=[S:29])[NH2:27])[C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnc2c1CCCC2
Reactant: C[Si](C)(C)N=C=S
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: O
Solvent: CCCCCC
Product: Cc1ccnc2c1CCCC2C(N)=S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-methyl-5,6,7,8-tetrahydroquinoline (5.83 g., 0.04 mole) in dry benzene (40 ml.) was cooled to 0° and to the stirred solution was added dropwise a 15% w/w solution of butyl lithium in hexane (17.5 ml., 0.04 mole) under an atmosphere of nitrogen. The red reaction mixture was stirred at 0° for a further 30 minutes. Trimethylsilylisothiocyanate (5.6 ml., 0.04 mole) was then added dropwise, maintaining the temperature at 0°. After an additional 30 minutes, the solution of 4-methyl-5,6,7,8-tetrahydroquinoline-8-(N-lithio-N-trimethylsilyl)thiocarboxamide was allowed to warm to room temperature and diluted with water (40 ml.) causing hydrolysis to 4-methyl-5,6,7,8-tetrahydroquinoline-8-(N-trimethylsilyl) thiocarboxamide and subsequent hydrolysis to the title compound. The pH was adjusted to 2.0 by addition of conc. HCl and the benzene layer separated and discarded. The aqueous phase was adjusted to pH 10.0 by adding anhydrous Na2CO3 and extracted with CHCl3 (3 × 40 ml.). The CHCl3 solution was then dried (MgSO4), filtered and evaporated (reduced pressure) to afford an oil (5.77 g.). Addition of ether caused crystallisation of the title compound as colourless needles. Filtration afforded 0.69 g. of base which was converted to the hydrochloride by dissolving in a minimum of EtOH, adding EtOH/HCl until just acid followed by ether to induce crystallisation. Filtration provided the title compound hydrochloride as colourless needles, (0.64 g.), m.p. 213° C. Analysis: Found: C, 54.95; H, 6.40; N, 11.52. C11H14N2S.HCl requires C, 54.42; H, 6.23; N, 11.54%.
Reaction SMILES: [CH3:1][C@@H:2]([NH:13][CH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.Cl.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1.N1C=CC=CC=1>C(O)C>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][N:30]=[C:17]2[CH2:18][CH2:19][CH:14]([NH:13][C@H:2]([CH3:1])[CH2:3][C:4]3[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=3)[CH2:15][CH2:16]2)=[CH:25][CH:24]=1
Reactant: C[C@H](Cc1ccc([N+](=O)[O-])cc1)NC1CCC(=O)CC1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: C[C@H](Cc1ccc([N+](=O)[O-])cc1)NC1CCC(=NNc2ccc(Br)cc2)CC1
Temperature: 80 °C
Yield: 83.6 %

Procedure:
To a solution of 22.3 gm (85.01 mMol) N-((R)-(+)-a-methyl-(4-nitrophenyl)ethyl)-4-aminocyclohexanone in 375 mL ethanol were added 19.0 gm (85.0 mMol) 4-bromophenylhydrazine hydrochloride and 6.73 gm (85.1 mMol) pyridine. The reaction mixture was heated to 80° C. for 48 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane and the organic solution was washed sequentially with aqueous potassium carbonate and saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure to give 31.66 gm (86%) N-((R)-(+)-a-methyl-(4-nitrophenyl)ethyl)-4-aminocyclohexanone 4-bromophenylhydrazone as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][C:7]=1[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl.[I:38]I>C1C=CC=CC=1.S([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][I:38])=[CH:8][C:7]=1[CH3:14]
Reactant: II
Reactant: COC(=O)CCc1ccc(CO)cc1C
Agent: O=S([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: COC(=O)CCc1ccc(CI)cc1C
Temperature: 25 °C

Procedure:
A mixture of 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionic acid methyl ester (0.62 g, 2.98 mmol), triphenyl phosphine (0.86 g, 3.27 mmol) and dichloromethane (10 mL) is stirred at room temperature. A solution of iodine (0.83 g, 3.27 mmol) in benzene (5 mL) is added and the black mixture is stirred at room temperature 2 hr. The brown mixture is diluted with 10% aqueous sodium hydrogen sulfite (5 mL) and the resulting clear mixture is washed with ethyl acetate (3×50 mL). The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified via silica chromatography eluting with 9:1 hexanes:ethyl acetate to afford the title compound as a crystalline ivory solid, 0.689, 72%. MS M++1 319. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: CS(C)=O.[C:5]([N:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1)([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].C(N(CC)CC)C>C(Cl)Cl>[C:5]([N:15]1[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]1)([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Yield: 73403.4 %

Procedure:
To a cooled solution (-78° C.) of oxalyl chloride (freshly distilled, 18.2 mL, 0.21 mol, 1.5 eq) in methylene chloride (1400 mL) under nitrogen was added freshly distilled dimethylsulfoxide (29.6 mL, 0.42 mol, 3.0 eq). The solution was stirred for 10 min after which a methylene chloride solution (150 mL) of 1-carbobenzyloxypiperidin-4-ol (described in example 87b) (32.76 g, 0.139 mmol) was added via cannula transfer. The solution was maintained at -78° C. for 30 min Triethylamine (116 mL, 0.83 mol, 6.0 eq) was added and the reaction warmed to room temperature over 1.5 h. Once at room temperature, the reaction was quenched with 3N HCl (400 mL). The organic phase was washed with 3N HCl (2×400 mL), 2.5N NaOH (2×400 mL) and saturated brine (1×400 mL). The methylene chloride phase was dried over anhydrous magnesium sulfate, filtered over 100 g of silica gel, and reduced to an oil. The procedure resulted in 23.8 g (73%) of the title compound which did not require any additional purification. 1H NMR (CDCl3, 300 MHz) 7.34 (m, 5H), 5.18 (s, 2H), 3.80 (t, J=6.2 Hz, 4H), 2.46 (br t, 4H) MS (CI, CH4) m/z 234 (M+1,39), 262 (M+29,10), 91 (100).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>CCOCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: OCCCCCCCCCCCBr
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCCCCCCCCCBr)cc1

Procedure:
A solution of 30 g. 11-bromoundecyl alcohol and 25.0 g. 4-toluenesulfonyl chloride in 250 ml. dry ether is cooled with stirring in an ice-water bath. To this is added dropwise 13.2 g. triethylamine in 50 ml. ether. After addition, the solution is stirred in the cold for 1 hour and filtered. The ether is washed with 100 ml. 10% hydrochloric acid solution, 100 ml. brine, dried and evaporated to yield the title compound as an oily solid.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C:51]4([C:56]([O:58][CH3:59])=[O:57])[CH2:55][CH2:54][CH2:53][CH2:52]4)[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[CH2:60]([C:65]1[CH:73]=[CH:72][C:68]([C:69](Cl)=[O:70])=[CH:67][CH:66]=1)[CH2:61][CH2:62][CH2:63][CH3:64]>>[O:50]=[C:47]1[C:48]2[C:44](=[CH:43][CH:42]=[C:41]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:69](=[O:70])[C:68]4[CH:72]=[CH:73][C:65]([CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])=[CH:66][CH:67]=4)=[CH:40][CH:39]=3)[CH:49]=2)[CH2:45][N:46]1[C:51]1([C:56]([O:58][CH3:59])=[O:57])[CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: COC(=O)C1(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)CCCC1
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N(C3(C(=O)OC)CCCC3)C4)cc2)cc1
Yield: 85 %

Procedure:
The compound of example 536 was prepared analogous to compound of example 97 by reaction of compound of example 527 with 4-(n-pentyl)benzoyl chloride.
Reaction SMILES: CN(P(N(C)C)N(C)C)C.Br[C:12](Br)([F:14])[F:13].O=[C:17]([CH3:31])[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>COCCOCCOC>[F:13][C:12]([F:14])=[C:17]([CH3:31])[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: CC(=O)CCCC(=O)OCc1ccccc1
Reactant: FC(F)(Br)Br
Agent: CN(C)P(N(C)C)N(C)C
Solvent: COCCOCCOC
Product: CC(CCCC(=O)OCc1ccccc1)=C(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
27.85 g Tris(dimethylamino)phosphine was added dropwise to a solution of 17.90 g dibromodifluoromethane in 130 ml diglyme, maintained under a nitrogen atmosphere and ice bath cooling. After stirring for one hour on the ice bath, 8.82 g benzyl 5-oxohexanoate in 70 ml diglyme was added slowly, dropwise. The ice bath was then removed and the reaction mixture stirred for 3 hours at room temperature, allowed to stand overnight, poured into 200 ml ice water and extracted with ether. The ether phase was washed twice with water, dried over sodium sulphate, filtered and concentrated in a rotary evaporator. The residue was distilled under reduced pressure.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([CH3:33])([CH3:32])[C:30]#[N:31])[CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:36]>C(=O)([O-])[O-].[Na+].[Na+]>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([CH3:32])([CH3:33])[C:30]([NH2:31])=[O:36])[CH2:25][CH2:24]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCN(C(C)(C)C#N)CC4)cc2OCC3)n(C(C)C)n1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCN(C(C)(C)C(N)=O)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 9 %

Procedure:
To 2-{4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1.3a-diaza-benzo[e]azulen-8-yl]-piperidin-1-yl}-2-methyl-propionitrile (140 mg, 0.31 mmol) was added concentrated sulfuric acid (1.75 mL). The mixture was stirred at RT for 3.5 hours before the reaction was diluted with ice and neutralised with sodium carbonate. The aqueous mixture was extracted with 10% MeOH in DCM (×5) before the organic phase was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2, gradient 0-10% MeOH in DCM). The material was triturated with diethyl ether before being purified by reverse phase HPLC (C18, gradient 20-70% MeOH/0.1% formic acid in water/0.1% formic acid). The resultant residue was taken up into MeOH (1.2 mL) and treated with 0.2 M HCl in diethyl ether. The solution was concentrated in vacuo affording 289 (14 mg, 0.03 mmol, 9%). LCMS: RT=2.65 min, [M+H]+=478. 1H NMR δ (ppm) (DMSO-d6): 9.50 (1 H, m), 8.33 (1 H, d, J=8.29 Hz), 7.97 (1 H, s), 7.93 (1 H, s), 7.86 (1 H, s), 7.02 (1 H, dd, J=8.36, 1.75 Hz), 6.87 (1 H, d, J=1.71 Hz), 5.78-5.71 (1 H, m), 4.50-4.44 (4 H, m), 3.19-3.04 (2 H, m), 2.91-2.80 (1 H, m), 2.25 (3 H, s), 2.12 (2 H, d, J=13.49 Hz), 1.98 (2 H, d, J=13.54 Hz), 1.51 (6 H, s), 1.43 (6 H, d, J=6.59 Hz). 2H obscured by solvent.