Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:29]([Cl:30])=[CH:28][C:5]([O:6][C:7]2[C:12]([C:13]([N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH:25]4[CH2:27][CH2:26]4)[CH2:17][CH2:16]3)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([Cl:31])[CH:3]=1.CO.[C:34]([O:37][CH2:38]C)(=[O:36])C>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:38][O:37][C:34](=[O:36])[C:2]1[CH:3]=[C:4]([Cl:31])[C:5]([O:6][C:7]2[C:12]([C:13]([N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH:25]4[CH2:27][CH2:26]4)[CH2:17][CH2:16]3)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:28][C:29]=1[Cl:30]
Reactant: O=C(c1cccnc1Oc1cc(Cl)c(Br)cc1Cl)N1CCN(C2CC2)c2ccccc21
Reactant: CCOC(C)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Product: COC(=O)c1cc(Cl)c(Oc2ncccc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 100 °C
Reaction time: 20 h
Yield: 52 %

Procedure:
To a solution of [2-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone (100 mg, 0.19 mmol, 1.0 equiv; Example 163) in a 1:1 mixture of methanol and ethyl acetate (4 mL) was added 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride (10.1 mg, 0.012 mmol, 0.064 equiv; [CAS RN 95464-05-4]) and the reaction mixture stirred under an atmosphere of carbon monoxide (70 bar) at 100° C. for 20 h. The crude reaction mixture was filtered over Celite® and purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate to afford 50 mg (52%) of the title compound as a off-white solid. MS (ISN): 498.3 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:10][CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[CH3:17][S:14]([CH2:13][CH2:12][CH2:11][CH2:10][C:5]1([C:3]([OH:4])=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:15])=[O:16]
Reactant: COC(=O)C1(CCCCS(C)(=O)=O)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)CCCCC1(C(=O)O)CCCC1
Temperature: 52.5 °C
Reaction time: 15 h
Yield: 92.3 %

Procedure:
To a solution of 1-[4-(methylsulfonyl)butyl]cyclopentanecarboxylic acid methyl ester (18.8 mmol, 4.94 g) in a mixture of THF (38 mL) and methanol (38 mL) was added 1 N sodium hydroxide (38 mL) and the mixture was heated to 50-55° C. After 15 h, TLC analysis of the reaction mixture indicated the absence of starting material and the mixture was allowed to cool to room temperature. The solvent was removed under vacuum and the residue was diluted with water (100 mL) and extracted with diethyl ether (2×50 mL) to remove any neutral impurities. Then, the basic aqueous layer was acidified with 1 N hydrochloric acid and the product was extracted with ethyl acetate (2×75 mL). The combined extracts were washed with brine, dried (MgSO4), filtered and the solution was concentrated in vacuo. The residual material was dried under high vacuum to afford 4.31 g (92%) of 1-[4-(methylsulfonyl)butyl]cyclopentane carboxylic acid as a low melting colorless solid. LR MS (C11H20O4S): 249 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][CH2:16][CH2:17]O)[C:13]2[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:20][CH:21]=[CH:22][C:12]=2[N:11]=1.CS(Cl)(=O)=O>N1C=CC=CC=1.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2=[N:11][C:12]3[C:13](=[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:20]=[CH:21][CH:22]=3)[N:14]2[CH2:15][CH2:16][CH2:17]1
Reactant: CCN(CC)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCN(CC)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Yield: 85.6 %

Procedure:
To a solution of 3-[2-[(2,4-dichlorophenyl)amino]-7-(diethylamino)-1H-benzimidazol-1-yl]propan-1-ol (Reference Example 29; 35.7 mg, 0.0876 mmol) in pyridine (1 mL) was added methanesulfonyl chloride (0.0339 mL, 0.438 mmol) at 0° C. After the resultant mixture was stirred at room temperature for 2 hr, the mixture was diluted with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a solid (29.2 mg, 0.0750 mmol, 86%). Analytically pure material was obtained by recrystallization from ethyl acetate/n-hexane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:19]#[N:20].[K+]>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH:17]([OH:18])[C:19]#[N:20])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCc1ccc(OCc2ccccc2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(O)CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
A solution of 3-(4-(benzyloxy)phenyl)propanal (S49, 700 mg, 3.07 mmol, 1 equiv) in THF (13 mL) and H2O (18 mL) was treated with KCN (2.30 g, 35.3 mmol, 11.5 equiv). After stirring for 50 h at 25° C., the reaction was quenched with H2O and extracted with ether. The organic layer was washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated to afford S50 (755 mg, 2.96 mmol, 96%) as a white solid: 1H NMR (CDCl3, 400 MHz) 7.47-7.33 (m, 5H), 7.14 (d, 2H, J=8.8 Hz), 6.95 (d, 2H, J=8.8 Hz), 5.06 (s, 2H), 4.39 (t, 1H, J=6.9 Hz), 2.82-2.77 (m, 2H), 2.17-2.10 (m, 2H); 13C NMR (CDCl3, 100 MHz) 157.3, 136.9, 131.9, 129.4, 128.5, 127.9, 127.4, 119.9, 115.0, 70.0, 60.2, 36.6, 29.7; IR (film) νmax 3444, 2927, 2865, 2250, 1611, 1583, 1514, 1454, 1382, 1246, 1177, 1079, 1024, 912, 830, 738, 695 cm−1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8](=[O:17])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH:18]1[C:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=2)=[CH:22][CH:21]=[C:20]([N:34]=[C:35]=[O:36])[CH:19]=1>C1(C)C=CC=CC=1>[N:31]([C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:23]2[CH:18]=[CH:19][C:20]([NH:34][C:35]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8](=[O:17])[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:10])=[O:36])=[CH:21][CH:22]=2)=[CH:26][CH:27]=1)=[C:32]=[O:33]
Reactant: O=C(OCCOCCO)C(=O)c1ccccc1
Reactant: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(Cc2ccc(NC(=O)OCCOCCOC(=O)C(=O)c3ccccc3)cc2)cc1
Temperature: 110 °C
Reaction time: 19 h

Procedure:
Under argon gas, 2.14 g of the phenylglyoxylic acid (2-hydroxyethoxy)ethyl ester from Example 1 and 2.24 g of 4,4′-diphenylmethane diisocyanate (Desmodur VL, Bayer) in 15 g of toluene are placed as the initial charge in a 50 ml multi-necked flask and refluxed at 110° C. After 19 hours, the solution is cooled and the toluene is concentrated using a rotary evaporator. The residue is dried under a high vacuum for two hours. 4.6 g of a viscous, slightly brownish oil are obtained. The conversion and the composition of the product mixture are verified by 1H-NMR spectrum and IR spectrum (NCO bands).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH-](CC)CC)C.[Li+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 79 %

Procedure:
To a solution of 2-(S)-(toluene-4-sulfonyloxymethyl)-pyrrolidine- 1-carboxylic acid tert-butyl ester (compound (4), 1.77 g, 4.99 mmol) in 5 mL of THF at 0° C. was added dropwise 15 mL (15 mmol) of a 1 M THF solution of lithium triethylborohydride. After 15 hours, the reaction was quenched by addition of 7.39 mL of water. The reaction was diluted with 35 mL of chloroform, and poured into a separatory funnel. The mixture was diluted with dichloromethane and washed with saturated aqueous NaCl solution. The organic phase then was dried over sodium sulfate. The mixture was concentrated in vacuo and purified by flash chromatography on silica gel, eluting with 1:3 ethyl acetate/hexane to give pure product as a clear oil (0.73 g, 79% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].I[CH2:11][CH3:12].C(N(CC)CC)C>C(#N)C>[CH2:11]([S:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH3:12]
Reactant: CCI
Reactant: Fc1ccc(S)c(F)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCSc1ccc(F)cc1F
Temperature: 80 °C

Procedure:
To thick-walled, reaction pressure tube was added 2,4-difluorobenzenethiol (1500 mg, 10.26 mmol), iodoethane (1.095 mL, 13.34 mmol), acetonitrile (20 mL), and triethylamine (1.860 mL, 13.34 mmol). The vessel was capped and heated at 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. Methylene chloride was added and the mixture was washed with water three times. The organic layer was concentrated to provide crude 4-(ethylthio)-1,3-difluorobenzene which was used without further purification. To this material (1700 mg, 9.76 mmol) in acetic acid (10 mL) was added hydrogen peroxide (30% in H2O, 4.7 mL, 48.8 mmol). The mixture was refluxed for 2 hours. After cooling to room temperature, the reaction mixture was added to methylene chloride and washed with water three times. The organic layer was dried with sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography (silica gel, 0-100% ethyl acetate/hexane) to give 1-(ethylsulfinyl)-2,4-difluorobenzene (1.2 g, 6.31 mmol) as white oil. 1H NMR (CDCl3, 500 MHz) δ 7.69-7.86 (m, 1H), 7.03-7.17 (m, 1H), 6.80-6.94 (m, 1H), 3.05 (dd, J=13.75, 7.15 Hz, 1H), 2.83 (dd, J=13.75, 7.15 Hz, 1H), 1.22 (t, J=7.42 Hz, 3H); MS (ESI) 191.1 (M+H). To a solution of 1-(ethylsulfinyl)-2,4-difluorobenzene (1100 mg, 5.78 mmol) in 2-propanol (10 mL) was added water (10 mL) and OXONE® (4622 mg, 7.52 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was then filtered and the filtrate was concentrated. The resulting crude material was dissolved in ethyl acetate and was washed with saturated aqueous sodium chloride twice. The organic layer was dried with sodium sulfate, filtered, and concentrated. The residue obtained was then purified by flash chromatography (silica gel, 0-100% ethyl acetate/hexane) to give Intermediate 9 (600 mg, 50% yield) as a white oil. 1H NMR (CDCl3, 500 MHz) δ 7.90-8.02 (1H, m), 6.90-7.12 (2H, m), 3.30 (2H, q, J=7.3 Hz), 1.30 (3H, t, J=7.4 Hz); MS (ESI) 207.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[C:26]([CH3:27])=[N:25][C:24]2[C:19](=[CH:20][C:21]([F:29])=[C:22]([F:28])[CH:23]=2)[N:18]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:17]1[C:26]([CH3:27])=[N:25][C:24]2[C:19](=[CH:20][C:21]([F:29])=[C:22]([F:28])[CH:23]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2cc(F)c(F)cc2nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Solvent: CN(C)C=O
Product: Cc1nc2cc(F)c(F)cc2nc1NC[C@@H]1CCCCN1C(=O)OC(C)(C)C
Temperature: 90 °C

Procedure:
(S)-2-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.14 g), and 2-chloro-6,7-difluoro-3-methylquinoxaline Teng et al PCT Int. Appl (2000), WO00/42026A1 20000720 (1.14 g) were dissolved in DMF (2 ml) and heated to 90° C. for 3 days under an atmosphere of argon. After cooling, the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated brine, dried and evaporated. The residue was chromatographed over silica gel, eluting with a gradient of 10 to 50% ethyl acetate in hexane. The title compound was obtained as a pink foam (0.524 g), MH+ 393.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[CH2:22]([O:15][C:14]([C:9]1[N:10]([CH3:13])[N:11]=[N:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:16])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cn1nnc(-c2ccc(Br)cc2)c1C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nnc(-c2ccc(Br)cc2)c1C(=O)OCc1ccccc1
Reaction time: 15 h
Yield: 99.8 %

Procedure:
To a suspension of 5-(4-bromophenyl)-3-methyl-3H-[1,2,3]triazole-4-carboxylic acid (209 mg, 0.74 mmol) and sodium bicarbonate (187 mg, 2.22 mmol) in DMF (10 mL) was added an excess of benzyl bromide (380 mg, 264 μL, 2.22 mmol) at room temperature under nitrogen atmosphere. The resulting colorless reaction mixture was stirred for 15 h at which time LC/MS and TLC analysis indicated the absence of starting material. The mixture was diluted with water and extracted with ethyl acetate (2×70 mL). The combined extracts were washed with brine solution and dried over anhydrous MgSO4. Filtration and concentration gave the crude colorless oil which was purified using an ISCO (40 g) column chromatography eluting with ethyl acetate in hexanes (0-60%). The desired fractions were collected and the solvent was removed under vacuum to isolate the 5-(4-bromophenyl)-3-methyl-3H-[1,2,3]triazole-4-carboxylic acid benzyl ester as a viscous oil (275 mg, 99% yield). LC/MS calcd. for C17H14BrN3O2 (m/e) 373, obsd. 373.8 [M+H, ES+].
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12](O)=[O:13])[CH:5]=[N:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].ClC(OCC(C)C)=O.CN1CCOCC1.Cl.[NH2:45][CH2:46][C:47]([NH2:49])=[O:48]>CC(N(C)C)=O.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH:45][CH2:46][C:47]([NH2:49])=[O:48])=[O:13])[CH:5]=[N:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: NCC(N)=O
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
To a cooled (0° C.) solution of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (from Step 3) (0.25 g, 0.61 mmol) in DMA (2 mL) was added isobutyl chloroformate (0.96 mL stock solution prepared 0.1 mL in 0.9 mL DCM, 0.74 mmol) and 4-methylmorpholine (0.88 mL stock solution prepared 0.1 mL in 0.9 mL DMA, 0.80 mmol). Stirred at 0° C. for 5 min, ambient temperature for 30 min. Added NMM (0.1 mL, 0.92 mmol), glycineamide HCl (0.10 g, 0.92 mmol), and DMAP (0.01 g, 0.06 mmol) and stirred at ambient temperature for 1.5 h. Removed DMA under reduced pressure. Purified crude product by preparatory HPLC using a 10–90% CH3CN/H2O (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z=463) were combined and concentrated to approximately 20 mL under reduced pressure. Added 5% NaHCO3 (20 mL) and extracted with DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as an off-white solid (77 mg, 27%). 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.96 (m, 1H), 7.80 (s, 1H), 7.61 (m, 1H), 7.54 (m, 1H), 7.01 (m, 2H), 5.60 (m, 2H), 4.01 (s, 2H), 2.20 (s, 3H). ESHRMS m/z 463.0990 (M+H calculated for C21H18ClF2N4O4 requires 463.0979).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:28]=[CH:27][C:7]2[C:8]3[CH:9]=[CH:10][CH:11]([CH:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19]4)[O:12][C:13]=3[C:14]([F:17])=[C:15]([F:16])[C:6]=2[CH:5]=1)[CH3:2]>C1COCC1.[Pd]>[CH2:1]([O:3][C:4]1[CH:28]=[CH:27][C:7]2[C:8]3[CH2:9][CH2:10][CH:11]([CH:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19]4)[O:12][C:13]=3[C:14]([F:17])=[C:15]([F:16])[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCCC1CCC(C2C=Cc3c(c(F)c(F)c4cc(OCC)ccc34)O2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCc3c(c(F)c(F)c4cc(OCC)ccc34)O2)CC1

Procedure:
5.1 g (13.1 mmol) of 8-ethoxy-5,6-difluoro-3-(4-propylcyclohexyl)-3H-benzo[f]chromene are hydrogenated at atmospheric pressure in THF and in the presence of Pd/C (5% of Pd). The reaction solution is filtered, and the filtrate is evaporated to dryness. The residue is recrystallised from ethyl acetate, giving 8-ethoxy-5,6-difluoro-3-(4-propylcyclohexyl)-2,3-dihydro-1H-benzo[f]chromene as a colourless solid (m.p. 158° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:6](O)=O)[CH3:2].C=O.N1CCCCC1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:22])[C:5](=[CH2:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[CH3:2]
Reactant: CCOC(=O)C(CCCCCCCC1CCCCC1)C(=O)O
Agent: C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: C=C(CCCCCCCC1CCCCC1)C(=O)OCC

Procedure:
9.2 g of 9-cyclohexyl-2-methylenenonanoic acid ethyl ester, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: 95:5 petroleum ether/ethyl acetate), are obtained by the procedure described in Example (1b) from 16.2 g of (7-cyclohexylheptyl)-malonic acid ethyl ester, 1.86 g of paraformaldehyde, 11.5 ml of pyridine and 0.6 ml of piperidine.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]([NH:21][CH:22]([CH3:27])[CH:23]=[C:24](Cl)Cl)=[O:20])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.C(OCC)(=[O:31])C>CN1CCCC1=O>[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[O:20][C:23]([CH2:24][OH:31])=[C:22]([CH3:27])[N:21]=2)=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(C)=O
Reactant: CC(C=C(Cl)Cl)NC(=O)c1nn(Cc2ccccc2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nc(-c2nn(Cc3ccccc3)c3ccccc23)oc1CO
Temperature: 55 °C
Yield: 77 %

Procedure:
80 μl of NaOH, 1M, were added to 15 mg of 3-(1-benzylindazole-3-carboxamido)-1,1-dichlorobut-1-ene (40 μmol) in 20 μl of N-methylpyrrolidone under argon and the mixture was heated at 55° C. for 1 hour. It was cooled and 0.8 ml of water and 8 ml of ethyl acetate were added. The organic phase was concentrated and the residue was purified by preparative TLC (SiO2). 9.9 mg (77%) of 2-(1-benzylindazol-3-yl)-5-hydroxymethyl-4-methyl-oxazole were obtained (melting point 127-129° C.).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[N:28][C:29]([C:32]3[CH:33]=[N:34][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:36][CH:37]=3)=[N:30][CH:31]=2)=[C:22]([F:45])[C:21]=1[F:46])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[F:45][C:22]1[C:21]([F:46])=[C:20]([OH:19])[CH:25]=[CH:24][C:23]=1[C:26]1[CH:31]=[N:30][C:29]([C:32]2[CH:33]=[N:34][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:36][CH:37]=2)=[N:28][CH:27]=1
Reactant: [H][H]
Reactant: CCCCCCOc1ccc(-c2ncc(-c3ccc(OCc4ccccc4)c(F)c3F)cn2)cn1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(-c2ncc(-c3ccc(O)c(F)c3F)cn2)cn1
Yield: 74.1 %

Procedure:
1.5 g of 10 percent palladium/charcoal and 0.1 g of 4-toluenesulfonic acid are added to a solution of 14 mmol of 5-(4-benzyloxy-2,3-difluorophenyl)-2-(6-hexyloxypyridin-3-yl)pyrimidine in 200 ml of THF. The mixture is stirred at 50° C. under hydrogen in a suitable apparatus until the take-up of hydrogen is complete, the catalyst is filtered off, and the solvent is removed in vacuo. Purification by recrystallization from acetonitrile gives 4.0 g (73%) of a colorless solid, m.p. 150-155° C.
Reaction SMILES: [CH2:1]([C:9]1[NH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(OC)(O[CH3:21])(=O)=O>C(O)=O>[CH3:21][N:10]1[C:11]([N+:14]([O-:16])=[O:15])=[CH:12][N:13]=[C:9]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ncc([N+](=O)[O-])[nH]1
Reactant: COS(=O)(=O)OC
Solvent: O=CO
Product: CCCCCCCCc1ncc([N+](=O)[O-])n1C
Yield: 66 %

Procedure:
225 parts of 2-octyl-5-nitroimidazole is boiled under reflux with 500 parts of formic acid and 126 parts of dimethyl sulfate for 4 hours, the formic acid is distilled off in vacuo and 500 parts of water is added to the residue. The unreacted 2-octyl-5-nitroimidazole (72 parts) is separated and the aqueous phase is adjusted with aqueous ammonia solution to pH 10 so that the 1-methyl-2-octyl-5-nitroimidazole separates as an oily substance. The crude product is dissolved in ether and saturated with hydrogen chloride while cooling. 123 parts of 1-methyl-2-octyl-5-nitroimidazole having a melting point of 141° C. is obtained and this is equivalent to a yield of 66% of theory based on the 2-octyl-5-nitroimidazole reacted.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=3)[CH2:13][CH2:12]2)[CH:5]=1.[OH-].[Na+]>C1COCC1.CO>[C:23]([C:19]1[CH:18]=[C:17]([N:14]2[CH2:13][CH2:12][N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:25])=[O:2])[CH2:16][CH2:15]2)[CH:22]=[CH:21][CH:20]=1)#[N:24]
Reactant: COC(=O)c1cccc(CN2CCN(c3cccc(C#N)c3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cccc(N2CCN(Cc3cccc(C(=O)O)c3)CC2)c1
Reaction time: 8 h

Procedure:
Dissolve 3-[4-(3-cyano-phenyl)-piperazin-1-ylmethyl]-benzoic acid methyl ester into 10 mL of 1:1 THF/MeOH and add 2 mL of 15% NaOH. Stir the mixture overnight and concentrate to dryness. Dissolve the residue in 5% HCl and apply to Dowex column. Rinse the resin with 2×20 mL H2O, 2×20 mL MeOH and 2×20 mL of dichloromethane. Liberate the basic residues by washing the resin with 3×20 mL of 10% NH3/MeOH to give 0.26 g 3-[4-(3-cyano-phenyl)-piperazin-1-ylmethyl]-benzoic acid as a white solid. 1H NMR indicates some contamination with starting amine. The crude intermediate is carried on without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]([N:16]3[CH2:19][CH:18]([O:20][C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH2:17]3)=[O:15])=[N:11][N:10]=2)=[CH:5][CH:4]=1.Cl.[CH3:30][C:31]1([OH:38])[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.[Na].C([O-])(O)=O.[Na+]>ClCCl>[OH:38][C:31]1([CH3:30])[CH2:37][CH2:36][CH2:35][N:34]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH:18]3[CH2:19][N:16]([C:14]([C:12]4[O:13][C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)=[N:10][N:11]=4)=[O:15])[CH2:17]3)=[CH:28][CH:27]=2)[CH2:33][CH2:32]1
Reactant: CC1(O)CCCNCC1
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4)C3)o2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CCCC(C)(O)CC5)cc4)C3)o2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Intermediate 55A (0.10 g, 0.26 mmol), 4-methylazepan-4-ol hydrochloride (0.057 g, 0.34 mmol, see Helvetica Chimica Acta, 45, 1823-32, (1962)) and TEA (0.146 mL, 1.05 mmol) were mixed in dichloromethane (4 mL). The mixture was stirred at RT for 1 h and then sodium triacetoxyhydroborate (0.112 g, 0.53 mmol) was added and the mixture was stirred at RT overnight. Aqueous NaHCO3 (sat., 3 mL) and dichloromethane (3 mL) were added and the mixture was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by preparative reverse-phase HPLC at pH 10 to give 83 mg (64%). 1H NMR (600 MHz, DMSO) δ 1.11 (s, 3H), 1.35-1.8 (m, 7H), 2.31-2.65 (m, 3H), 3.51 (s, 2H), 3.88 (s, 3H), 4.07-4.12 (m, 1H), 4.51-4.66 (m, 2H), 5.06-5.18 (m, 2H), 6.85 (d, 2H), 7.16-7.3 (m, 4H), 8-8.06 (m, 2H), LC-purity: 92%.