Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:50])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([C:30]3[CH:34]=[C:33]([C:35]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[NH:36])[S:32][C:31]=3[S:45][CH3:46])(=[O:29])=[O:28])[CH:22]=2)=[C:16]([N+:47]([O-])=O)[CH:15]=1)=[O:12])[CH3:2].[NH4+].[Cl-]>CCO.[Fe]>[CH2:1]([O:3][C:4](=[O:50])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([C:30]3[CH:34]=[C:33]([C:35]([NH:37][C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])=[NH:36])[S:32][C:31]=3[S:45][CH3:46])(=[O:29])=[O:28])[CH:22]=2)=[C:16]([NH2:47])[CH:15]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)CCCCCNC(=O)Nc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)CCCCCNC(=O)Nc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(N)c1
Yield: 99.7 %

Procedure:
6-(3-{3′-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-2-nitro-biphenyl-4-yl}-ureido)-hexanoic acid ethyl ester (74 mg, 98.9 μmol, Example 278: step b) in EtOH (5 mL) was reduced as in Example 20: step c using Fe (28 mg, 0.50 mmol) and aqueous NH4Cl solution (50 mg, 0.93 mmol, 10 mL). The solvents were removed from the filtrate in vacuo. The crude was diluted in EtOAc and washed with water and brine. The organic layer was dried over magnesium sulfate. The solvents were removed in vacuo to yield the title compound as a brown oil (70.8 mg, quantitative). ESI-MS (m/z): Calcd. for C33H43N5O7S3: 718.2 (M+1); found: 718.1.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([O:26][C:27]4[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:28]=4[F:36])=[CH:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[O:37][CH3:38])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C=O>C(Cl)Cl>[F:36][C:28]1[CH:29]=[C:30]([N+:33]([O-:35])=[O:34])[CH:31]=[CH:32][C:27]=1[O:26][C:20]1[C:19]2[C:24](=[CH:25][C:16]([O:15][CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)=[C:17]([O:37][CH3:38])[CH:18]=2)[N:23]=[CH:22][CH:21]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CCN(C)CC1
Reaction time: 1.5 h
Yield: 93.7 %

Procedure:
To a solution of 4-[4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester (305 mg, 0.58 mmol) in CH2Cl2 (1 mL) was added 0.4 mL of TFA. The reaction mixture was stirred for 1.5 h and the solvents were removed under reduced pressure. The crude product was treated with NaBH(OAc)3 (381 mg, 1.80 mmol) and formaldehyde (0.5 mL, 37% in H2O). The stirring was continued for 12 h. The reaction was quenched with sat. aqueous NaHCO3. 15% NaOH was added until PH=14. The product was extracted with EtOAc. Removal of the solvent in vacuo gave the crude product, 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinoline, (240 mg, 93%), which was used directly in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:23][C:24]1[C:25]([O:30]C)=[N:26][CH:27]=[CH:28][CH:29]=1.C(O)C.Cl.C(=O)([O-])O.[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:20])([CH3:21])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:23][C:24]1[C:25]([OH:30])=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ncccc1Cn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@@H]1CC[C@@]2(C)C1(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1cccnc1O
Temperature: 75 °C
Reaction time: 0.67 h
Yield: 75 %

Procedure:
A mixture of (4R,7S)-2-(2,4-difluoro-phenyl)-1-(2-methoxy-pyridin-3-ylmethyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Example 113; 149 mg, 0.35 mmol), ethanol (440 μL) and concentrated aqueous hydrochloric acid (440 μL) was heated at 75° C. overnight, and then at ˜100° C. for 40 min. Water (10 mL) was added and the mixture was neutralized to pH 7-8 by the dropwise addition of saturated aqueous sodium hydrogen carbonate solution. The resulting mixture was extracted with dichloromethane (2×25 mL). The combined organic layers were washed with brine (10 mL), dried (magnesium sulfate), filtered, evaporated, purified using a Biotage 40S system, eluting with 3-4% methanol/dichcloromethane, and then dried in a vacuum overn for 3 days to give (4R,7S)-2-(2,4-difluoro-phenyl)-1-(2-hydroxy-pyridin-3-ylmethyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (108 mg, 75%) as an off-white solid. APCI(+)-MS (M+H) 412.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:9](=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12].N1C=CN=C1.[OH-].[Na+]>CN(C=O)C.C1CCCCC1.CC(=O)OCC>[Si:1]([O:12][C:11]1[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=1[CH:9]=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Agent: c1c[nH]cn1
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1C=O
Temperature: 25 °C

Procedure:
13.58 g (90.07 mmol) of t-butyidimethylsilyl chloride (TBDMSCl) were added to a solution of 10.00 g (81.89 mmol) of salicylaldehyde and 6.13 g (90.07 mmol) of imidazole in 82 ml of DMF. The mixture was stirred at room temperature and the reaction was monitored by thin-layer chromatography (cyclohexane/EA 10:1). 1 N NaOH was added, and the mixture was extracted with petroleum ether. The combined organic phases were dried over Na2SO4, the solvent was removed and the product was purified chromatographically (silica gel, cyclohexane/EA 10:1). This gave 16.94 g (87.5%) of a clear liquid.
Reaction SMILES: C([O:8][C:9](=[O:34])[CH2:10][C@@H:11]([NH:16][C:17](=[O:33])[CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:12][N:13]([CH3:15])[CH3:14])C1C=CC=CC=1.CN(C)C[C@H](NC(=O)CCCCCCCCOC1C=CC=CC=1F)CC(O)=O>>[CH3:15][N:13]([CH3:14])[CH2:12][C@H:11]([NH:16][C:17](=[O:33])[CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:10][C:9]([OH:34])=[O:8]
Reactant: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCOCCCCCc1ccccc1
Agent: CN(C)C[C@@H](CC(=O)O)NC(=O)CCCCCCCCOc1ccccc1F
Product: CN(C)C[C@@H](CC(=O)O)NC(=O)CCCOCCCCCc1ccccc1

Procedure:
Hydrogenation of (R)-4-dimethylamino-3-[4-(5-phenyl-pentyloxy)-butyrylamino]-butyric acid benzyl ester in analogy with example 1, step 4 produced (R)-4-dimethylamino-3-[9-(2-fluoro-phenoxy)-nonanoylamino]-butyric acid. White solid, m/e=379.5 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[C:12]([N+:14]([O-])=O)[CH3:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.O>C1COCC1>[CH3:13][CH:12]([CH2:11][C:6]1[C:5]2[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1)[NH2:14]
Reactant: CC(=Cc1c[nH]c2cc(F)ccc12)[N+](=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(N)Cc1c[nH]c2cc(F)ccc12
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 92.2 %

Procedure:
α-Methyl-6-fluorotryptamine was prepared by the dropwise addition of an anhydrous THF solution of 6-fluoro-3-(2-nitropropenyl)-1H-indole (560 mg, 2.54 mmol) to a stirred mixture of LiAIH4 (480 mg, 12.7 mmol) in THF (40 mL) at 0° C. The reaction slurry was allowed to stir under N2 from 0° C. to ambient room temperature over 3.5 hours. The reaction solution was again cooled to 0° C. prior to the dropwise addition of H2O to quench excess LiAIH4. The reaction suspension was filtered through a pad of Celite to remove Al salts. The filtrate was concentrated under reduced pressure, diluted with EtOAc (200 mL), washed with NaCl (50 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure to provide 450 mg of α-methyl-6-fluorotryptamine as a viscous oil; 1H NMR (CDCl3) δ 8.30 (1H, br s), 7.52 (1H, m), 6.98-7.04 (2H, m), 6.87 (1H, t), 3.29 (1H, m), 2.87 (1H, dd), 2.64 (1H, q), 1.25 (3H, d); MS (ESI): 193 (MH+); TLC (SiO2 plate, 100% DCM) Rf=0.1.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.[N:29]1([CH2:34][CH2:35][NH2:36])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:36][CH2:35][CH2:34][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: NCCN1CCCC1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)NCCN4CCCC4)cc3C)cc12

Procedure:
4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methyl-N-(2-(pyrrolidin-1-yl)ethyl)benzamide was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116/Step 2) and 2-(pyrrolidin-1-yl)ethanamine following the procedures described for Example 117. 1H NMR (CDCl3): δ 8.58 (s, 1H), 8.38 (s, 1H), 8.07 (d, 1H), 7.64 (s, 1H), 7.51-7.55 (m, 2H), 7.12-7.20 (m, 2H), 6.26 (br, 2H), 3.61 (dd, 2H), 3.05-3.12 (m, 4H), 2.81 (t, 2H), 2.69 (br, 4H), 2.50 (s, 3H), 2.33 (s, 3H), 1.83-1.85 (m, 4H). LRMS [M+H]=468.3
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:12]=[N:13][CH:14]=[N:15][CH:16]=1>O1CCCC1.CO.[Pd]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)[CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1-c1cncnc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(N)cc1-c1cncnc1
Yield: 99.7 %

Procedure:
A suspension of 5-(2-methyl-5-nitrophenyl)pyrimidine (0.431 g) in tetrahydrofuran (4 ml) and methanol (4 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 129 mg) under hydrogen atmosphere for 2 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 5-(5-amino-2-methylphenyl)pyrimidine (370 mg, 99.7%).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][N:5]=[C:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[N:3]=1.[CH3:23][O:24][CH:25]([O:28][CH3:29])[CH2:26][NH2:27].C(N(CC)C(C)C)(C)C>O1CCOCC1>[CH3:23][O:24][CH:25]([O:28][CH3:29])[CH2:26][NH:27][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][N:5]=[C:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[N:3]=1
Reactant: COC(CN)OC
Reactant: COC(=O)Cc1cnc(Cc2ccc([N+](=O)[O-])cc2)nc1Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cnc(Cc2ccc([N+](=O)[O-])cc2)nc1NCC(OC)OC
Temperature: 85 °C
Reaction time: 24 h
Yield: 73.6 %

Procedure:
To a solution of methyl [4-chloro-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (2.70 g, 8.39 mmol) and aminoacetoaldehyde dimethyl acetal (1.83 mL, 16.78 mmol) in dioxane (40 mL) was added N,N-diisopropylethylamine (1.46 mL, 8.39 mmol). The mixture was stirred at 85° C. for 1 day. After cooling to room temperature, the reaction was quenched with water, and extracted with ethyl acetate. The extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica-gel, (ethyl acetate) to give methyl [4-[(2,2-dimethoxyethyl)amino]-2-(4-nitrobenzyl)-pyrimidin-5-yl]acetate (2.41 g, 74%) as brown oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.S(=O)(=O)(O)O.[Br:23]([O-])(=O)=O.[K+].[OH-].[Na+]>O>[Br:23][C:9]1[CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:3][C:2]([F:1])([F:16])[F:17]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: FC(F)(F)Oc1ccc(-c2ccncc2)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: FC(F)(F)Oc1ccc(-c2ccncc2)cc1Br
Temperature: 80 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
4-[4-(Trifluoromethoxy)phenyl]pyridine (500 mg, 2.1 mmol) was suspended in water (2 ml) and conc. sulphuric acid (2 ml). The suspension was heated to 80° C. and potassium bromate (386 mg, 2.31 mmol) was added in portions over 2 hours. The reaction was stirred at 80° C. for a further 2 hours, allowed to cool to ambient temperature and then poured onto ice. The solution was basified with 4N sodium hydroxide solution, extracted with ethyl acetate (2×30 ml) and the combined organic layers were washed with water. The solution was dried over sodium sulphate and the solvent was removed in vacuo giving an oil (467 mg) which was used without further purification. 1H NMR (250 MHz, CDCl3) δ8.70 (2H, br s), 7.92-7.91 (1H, d, J=2.2 Hz), 7.62-7.58 (1H, dd, J=8.5 Hz and 2.2 Hz), and 7.47-7.41 (3H, m), m/z (ES+) 318, 320 (M+1).
Reaction SMILES: [FH:1].N[C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.N([O-])=O.[Na+]>>[Cl:10][C:4]1[C:3]([F:1])=[CH:8][C:7]([Cl:9])=[CH:6][N:5]=1
Reactant: F
Reactant: Nc1cc(Cl)cnc1Cl
Agent: O=N[O-]
Agent: [Na+]
Product: Fc1cc(Cl)cnc1Cl
Reaction time: 1.5 h

Procedure:
To 450 ml (22.5 mol) of hydrogen fluoride in a stainless steel reaction vessel are added at a temperature of -5° to -1°, 163 g (1.0 mol) of 3-amino-2,5-dichloropyridine. Then there are added while stirring at the same temperature 82.8 g (1.2 mol) of sodium nitrite into the solution. The reaction mixture is stirred for 1.5 hours at -5° to -1°, then the temperature is slowly raised to +60° C. After the evolution of gas has ceased, the hydrogen fluoride is distilled off and the residue is taken up in methylene chloride. Ice/water is then added thereto and the cold mixture is neutralized with concentrated ammonium hydroxide solution. The organic phase separated and the water phase is extracted three times with methylene chloride. The organic phases are washed with water, dried over magnesium sulfate, filtered through silicagel and evaporated. Thus, 141.5 g (85% of the theory) of 2,5-dichloro-3-fluoropyridine are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:35]([C:37]1([CH2:45]O)[CH2:42][O:41]C(C)(C)[O:39][CH2:38]1)[CH3:36].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O.ClCCl.CC(C)=O>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:45][C:37]([CH2:35][CH3:36])([CH2:42][OH:41])[CH2:38][OH:39])=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCC1(CO)COC(C)(C)OC1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCC(CO)(CO)COc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
To a solution of 4-hydroxybenzophenone (2.00 g; 10.1 mmol), triphenylphosphine (4.234 g; 16.1 mmol) and (5-ethyl-2,2-dimethyl-1,3-dioxan-5-yl)methanol (2.813 g; 16.14 mmol) in anhydrous tetrahydrofuran (50 mL) at 0° C. was added diisopropyl azodicarboxylate (3.264 g; 16.14 mmol) dropwise over 10 min. The reaction mixture was stirred for 16 h at ambient temperature. TLC (eluent dichloromethane/acetone 10:1) confirmed ca 50° A) conversion. The reaction was warmed to 35-40° C. for 12 h and the conversion was monitored until ca 95° A) of 4-hydroxybenzophenone had reacted. The bright orange reaction mixture was evaporated to dryness, dissolved in dichloromethane and passed through a plug of silica. The eluent was again evaporated to dryness, redissolved in methanol (80 mL) and 1M HCl (22 mL) was added. The colourless reaction mixture was stirred for 1 h at ambient temperature, complete ketal cleavage was confirmed by TLC (eluent hexane/2-butanone 1:1). The methanol was evaporated to leave an aqueous residue. Water (150 mL) was added and the mixture was extracted with ethyl acetate (2×100 mL). The organic phase was separated, dried, evaporated and the oily crude product was purified by chromatography (eluent hexane/2-butanone 2:1→1:1). This provided the desired 2-(4-benzoylphenoxymethyl)-2-ethylpropane-1,3-diol (2.11 g; 66%) as a viscous colourless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([O:23][CH3:24])[CH:17]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]([C:28]1[N:29]=[CH:30][C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)=[N:32][CH:33]=1)#[N:27]>CN(C=O)C>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:35]([NH:34][C:31]2[CH:30]=[N:29][C:28]([C:26]#[N:27])=[CH:33][N:32]=2)=[O:36])=[C:18]([O:23][CH3:24])[CH:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1cnc(NC(=O)Oc2ccccc2)cn1
Reactant: COc1cc(CN(Cc2ccccc2)C(=O)OC(C)(C)C)ccc1N
Solvent: CN(C)C=O
Product: COc1cc(CN(Cc2ccccc2)C(=O)OC(C)(C)C)ccc1NC(=O)Nc1cnc(C#N)cn1
Temperature: 80 °C
Yield: 67.3 %

Procedure:
(4-Amino-3-methoxy-benzyl)-benzyl-carbamic acid tert-butyl ester (0.25 g, 0.73 mmol) and phenyl 5-cyanopyrazin-2-ylcarbamate (0.21 g 0.87 mmol) (Example 10) were dissolved in DMF (2.5 mL) and heated at 80° C. for 2 hours. The mixture was allowed to cool to room temperature then partitioned between water (15 mL) and EtOAc (25 mL). The separated aqueous layer was extracted with EtOAC (25 ml), and then the combined organic extracts were washed with water (15 mL), brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography on neutral silica gel using 15-25% EtOAc in hexane to afford the title compound (0.24 g, 67%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[C:15]([Cl:16])=[C:14]([CH2:17][CH3:18])[N:13]=[CH:12][N:11]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C:27](=[O:34])[CH2:28][N:29]1[CH:33]=[N:32][CH:31]=[N:30]1>C1COCC1>[Cl:9][C:10]1[C:15]([Cl:16])=[C:14]([CH:17]([CH3:18])[C:27]([C:21]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=2[F:19])([OH:34])[CH2:28][N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)[N:13]=[CH:12][N:11]=1
Reactant: CCc1ncnc(Cl)c1Cl
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(c1ncnc(Cl)c1Cl)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.17 h

Procedure:
To a solution of LDA (13.6 mmol) in THF (50 ml) (prepared by a similar method to that used in Example 1) at -70° C. was added dropwise 4,5-dichloro-6-ethylpyrimidine (the product of part (ii)) (2.37 g, 13.3 mmol) and the resulting solution was stirred at this temperature for 10 minutes. A solution of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (2.97 g, 13.3 mmol) in THF (50 ml) was added to the reaction mixture at such a rate so as to maintain the reaction temperature below -50° C. After stirring at -70° C. for 1 hour and at -50° C. for a further 1 hour the reaction was quenched by the addition of 10% aqueous acetic acid (11 ml).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:11][C:12]([S:15][CH3:16])=[N:13][N:14]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].[I:19]I>CN(C=O)C>[I:19][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]3[S:11][C:12]([S:15][CH3:16])=[N:13][N:14]=3)[CH:5]=2)[NH:1][CH:2]=1
Reactant: II
Reactant: CSc1nnc(-c2ccc3[nH]ccc3c2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CSc1nnc(-c2ccc3[nH]cc(I)c3c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a solution of 2-(1H-indol-5-yl)-5-(methylthio)-1,3,4-thiadiazole (18.5 g, 74.8 mmol) in DMF (190 mL) was added KOH (16.2 g, 299 mmol) followed by I2 (38 g, 149.7 mmol). The reaction was stirred at RT for 2 h, and was quenched with 10% aq sodium bisulphate solution. The resulting precipitate was filtered and washed with H2O to give 2-(3-iodo-1H-indol-5-yl)-5-(methylthio)-1,3,4-thiadiazole (21 g, 75%). MS (ESI, pos. ion) m/z: 373.8 (M+1). 1HNMR (DMSO-d6, 300 MHz): 2.8 (s, 3H), 7.5 (d, 1H), 7.7 (m, 2H), 12.0 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=O)=[CH:16][CH:15]=3)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([CH2:29]C#N)=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]4=[N:20][O:22][C:32]([C:23]5[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=5)=[C:16]4[CH:15]=3)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(CC#N)cc1
Reactant: COc1ccc(-n2nccc2-c2ccc([N+](=O)[O-])cc2)cc1
Product: COc1ccc(-n2nccc2-c2ccc3noc(-c4ccc(C)cc4)c3c2)cc1

Procedure:
The title compound, light green solid (32 mg, 25%), MS (ISP) m/z=382.3 [(M+H)+], mp 159° C., was prepared in accordance with the general method of example 1 from 1-(4-methoxy-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate G) (100 mg, 353 μmol) and commercially available 2-(p-tolyl)-acetonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]([C:15]([NH2:17])=O)=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O>>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]([C:15]#[N:17])=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[CH:3]=1
Reactant: NC(=O)c1sc2ccc(Br)cc2c1-c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1sc2ccc(Br)cc2c1-c1ccccc1

Procedure:
Reflux 2.1 g. 5-bromo-3-phenylbenzo [b ]thiophene-2-carboxamide (0.0063 mole) together with 10 ml. of phosphorus oxychloride for 11/2 hours and then carefully pour onto ice water. Filter off the white precipitate. Dry. Recrystallize the title compound from methanol; m.p. 145°-146°.
Reaction SMILES: C([O:8][C@H:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C@@H:17]([OH:20])[CH2:18][CH3:19])[CH3:10])C1C=CC=CC=1.C(OCC)(=O)C.CCCCCC>C(O)C.[Pd]>[CH3:10][C@H:9]([OH:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C@@H:17]([OH:20])[CH2:18][CH3:19]
Reactant: CC[C@H](O)CCCCCC[C@H](C)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC[C@H](O)CCCCCC[C@H](C)O
Reaction time: 12 h
Yield: 91.4 %

Procedure:
To a solution of 1.95 g (7 mmol) (2S,9S)-2-benzyloxyundecane-9-ol in 30 ml ethanol was added 20 mg Pd/C-catalyst. Hydrogenation was carried out over a period of 12 h at a pressure of 40 atm. After completion of the reaction, the catalyst was filtered off over silica, and the solution was concentrated in vacuo. Flash chromatography (ethyl acetate:hexane 1:1) yielded 1.2 g (6.4 mmol, 92%) (2S,9S)-undecane-2,9-diol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:12][C:13]([O:15]CC)=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:12][C:13]([OH:15])=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC1(c2cccc(Br)c2)COC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC1(c2cccc(Br)c2)COC1
Temperature: 0 °C
Yield: 105.2 %

Procedure:
Ethyl 2-[3-(3-bromophenyl)oxetan-3-yl]acetate (1.5 g, 4.513 mmol) was dissolved in MeOH (25 mL) and cooled to 0° C. NaOH (9.026 mL of 1 M, 9.026 mmol) was added and the reaction allowed to warm to rt overnight. The solvent was removed under reduced pressure and the solution neutralised with 2 eq of HCl (1M soln, 9.026 mL) and extracted with ethyl acetate. The combined organics were washed with brine, dried over MgSO4, filtered and the solvent removed under reduced pressure to give 2-[3-(3-bromophenyl)oxetan-3-yl]acetic acid as a viscous yellow oil (1.287 g, 95%).