Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][C:10]=2[N:11]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[CH2:21][CH2:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:19][C:20]3[CH2:21][CH2:22][C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: ClCC1=Cc2ccccc2CC1
Reactant: Nc1nc2c(s1)CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1nc2c(s1)CCN(CC1=Cc3ccccc3CC1)CC2
Yield: 29 %

Procedure:
Prepared from 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine, potassium carbonate and 3-chloromethyl-1,2-dihydronaphthalene (prepared from 1,2-dihydronaphthalene, paraformaldehyde and concentrated hydrochloric acid) in anhydrous dimethylformamide for 2 hours at 50° C. Yield: 29% of theory, Melting point: 158°-160° C. (ethyl acetate).
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].F[B-](F)(F)F.[F:10][S:11]([F:23])([F:22])([F:21])([F:20])[C:12]1[CH:17]=[CH:16][C:15]([N+]#N)=[CH:14][CH:13]=1>CC#N>[F:10][S:11]([F:20])([F:21])([F:22])([F:23])[C:12]1[CH:13]=[CH:14][C:15]([S:1][C:2]#[N:3])=[CH:16][CH:17]=1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: N#C[S-]
Agent: F[B-](F)(F)F
Agent: [NH4+]
Solvent: CC#N
Product: N#CSc1ccc(S(F)(F)(F)(F)F)cc1

Procedure:
A solution of ammonium thiocyanate (7.3 mg, 0.096 mmol) and 1 (10.1 mg, 0.0318 mmol) in 0.29 g of MeCN was heated at 70° C. for 0.5 h. After cooling, the mixture was filtered through SiO2 with CH2Cl2 and the solvent was evaporated to give a pale yellow oil, whose purification by SiO2 column chromatography with 9:1 hexane/CH2Cl2 furnished pure 25c as colorless crystals (2.6 mg, 31%); m.p. 67.2-68.2° C. IR (ATR): {tilde over (v)}=3103, 2162, 1585, 1479, 1402, 1105, 1082, 837 cm-1. MS (GC, EI): m/z=261 [M+], 242 [M+-F], 153, 133. 1H NMR (500 MHz, CDCl3): δ=7.84 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H) ppm. 13C NMR (125 MHz, CDCl3): δ=154.0 (C), 129.6 (C), 128.7 (2CH), 127.8 (2CH), 108.6 (C) ppm. 19F NMR (470 MHz, CDCl3): δ=82.5 (quint, J=151 Hz, 1 F), 62.9 (d, J=151 Hz, 4 F) ppm.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[CH:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=2)=[CH:20][CH:19]=1)=[O:17]
Reactant: CC(C)(C)OC(=O)Nc1cc(I)ccn1
Reactant: O=Cc1ccc(B(O)O)cc1
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: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cc(-c2ccc(C=O)cc2)ccn1

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.08 mmol, 0.05 equiv) was added to a deoxygenated mixture of tert-butyl 4-iodopyridin-2-ylcarbamate (1-1, 0.500 g, 1.56 mmol, 1 equiv), 4-formylphenyl boronic acid (351 mg, 2.34 mmol, 1.50 equiv), and aqueous saturated sodium carbonate solution (2.0 M, 2.3 mL, 4.7 mmol, 3.0 equiv) in dioxane (15 mL), and the resulting mixture was heated at reflux for 18 h. The reaction mixture was cooled then concentrated. The residue was partitioned between half-saturated aqueous NaCl solution (100 mL) and EtOAc (100 mL). The organic layer was dried over sodium sulfate, and concentrated to give tert-butyl 4-(4-formylphenyl)pyridin-2-ylcarbamate (2-1) as an off-white solid. LRMS m/z (M+H) Calcd: 242.2 (minus t-Bu), 199.2 (minus Boc); found 243.0 and 199.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[NH2:21][CH2:22][C:23]1[NH:24][C:25](=[O:32])[C:26]2[CH2:31][CH2:30][CH2:29][C:27]=2[N:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:21][CH2:22][C:23]3[NH:24][C:25](=[O:32])[C:26]4[CH2:31][CH2:30][CH2:29][C:27]=4[N:28]=3)=[O:18])[CH2:13][CH2:14]2)=[O:8])=[CH:19][CH:20]=1
Reactant: NCc1nc2c(c(=O)[nH]1)CCC2
Reactant: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Product: COc1ccc(C(=O)C2CCN(CC(=O)NCc3nc4c(c(=O)[nH]3)CCC4)CC2)cc1
Yield: 21.1 %

Procedure:
The title compound (70 mg) was prepared following the general procedure of Example 1 from 2-(4-(4-methoxybenzoyl)piperidin-1-yl)acetic acid (307 mg, 0.78 mmol, 70% purity) and 2-(aminomethyl)-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one (128 mg, 0.78 mmol). 1H NMR (400 MHz, CDC3) δ 10.58 (br. s., 1H), 8.06 (br. s., 1H), 7.95 (d, J=9.1 Hz, 2H), 6.98 (d, J=9.1 Hz, 2H), 4.41 (d, J=6.1 Hz, 2H), 3.90 (s, 3H), 3.28 (br. s., 3H), 3.02 (br. s., 2H), 2.70-2.95 (m, 4H), 2.43 (br. s., 2H), 2.09 (dq, J=7.8, 7.7 Hz, 2H), 1.91 (br. s., 4H). HRMS calculated for C23H28N4O4 425.2189. found (ESI, [M+H]+), 425.2180. Retention time=4.65 min.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5][CH:4]=1.[CH2:24]1[O:36][C:27]([CH3:35])([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:26][CH2:25]1.[H-].[Na+]>O1CCCC1>[CH3:35][C:27]1([CH2:28][CH:29]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5][CH:4]=2)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:26][CH2:25][CH2:24][O:36]1
Reactant: CCCCCCCCCCCCCCOc1ccc(CBr)cc1
Reactant: CCOC(=O)CCC1(C)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(CC(CC2(C)OCCO2)C(=O)OCC)cc1
Reaction time: 18 h
Yield: 52.3 %

Procedure:
A mixture of about 33 g of 1-(bromomethyl)-4-(tetradecyloxy)benzene, about 16.2 g of ethyl levulinate ethylene ketal, about 4.54 g of about 50% sodium hydride and about 350 ml of tetrahydrofuran was refluxed with stirring, under argon for about 18 hours and then filtered through celite. The solvent was removed and the residue was dissolved in ether. The ether solution was washed with aqueous monobasic sodium phosphate, dried and the solvent removed. The residue was subjected to high performance liquid chromatography (HPLC), using the system hexane:ethyl acetate (about 9:1), giving about 22.1 g of the desired title compound as a light yellow oil).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:13]([Cl:25])=[CH:14][C:15]([Cl:24])=[C:16]([CH:23]=2)[O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[CH3:26][NH:27][CH3:28].N1C=CC=N1.C(OCC)(=O)C>O1CCCC1>[CH3:26][N:27]([CH3:28])[C:19](=[O:20])[CH:18]([O:17][C:16]1[CH:23]=[C:12]([C:3]2[C:2]([Cl:1])=[C:6]([O:7][CH:8]([F:10])[F:9])[N:5]([CH3:11])[N:4]=2)[C:13]([Cl:25])=[CH:14][C:15]=1[Cl:24])[CH3:22]
Reactant: CNC
Reactant: CC(Oc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl)C(=O)Cl
Agent: c1cn[nH]c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(Oc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl)C(=O)N(C)C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
A solution of 2-[5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole-3-yl)-2,4-dichlorophenoxy]propionyl chloride (0.80 g, 1.78 mmoles) in 20 ml anhydrous tetrahydrofuran was added dropwise to a solution of 50% dimethylamine (0.32 g, 3.56 mmoles) in 20 ml tetrahydrofuran at room temperature to react the pyrazole derivative with dimethylamine. After the addition was finished, the reaction was continued further for 1 hour. Then ethyl acetate was added to the reaction product solution, and the mixture was washed with water. The separated organic layer was dehydrated, concentrated under reduced pressure, and purified by silica gel chromatography, giving crystals (0.24 g) of the title compound, m.p. 148.9° C., yield 27%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([O:11]S(C=C)(=O)=O)=[C:4]([CH3:17])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C(O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([CH3:17])[CH:3]=1
Reactant: C=CS(=O)(=O)Oc1cc([N+](=O)[O-])c(Cl)cc1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cc(Cl)c([N+](=O)[O-])cc1O
Yield: 101.3 %

Procedure:
A solution of compound 106 (27.8 g, 100 mmol) and potassium carbonate (27.6 g, 200 mmol) in ethanol water 1/1 (600 ml) was refluxed for one hour. Citric acid (5%) was added and the mixture was extracted three times with DCM. The organic phase was dried with sodium sulphate and evaporated under reduced pressure which gave the title compound (19 g, 100%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CCN(CCCO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCN2CCN(C)CC2)cc1

Procedure:
4-Toluenesulphonyl chloride (3.2 g) was added to a stirred mixture of 1-(3-hydroxypropyl)-4-methylpiperazine (2.4 g), triethylamine (4.6 ml) and methylene chloride (60 ml) and the resultant mixture was stirred at ambient temperature for 2 hours. The solution was washed in turn with a saturated aqueous sodium bicarbonate solution and with water and filtered through phase separating paper. The organic filtrate was evaporated to give 3-(4-methylpiperazin-1-yl)propyl 4-toluenesulphonate as an oil which crystallised on standing (3.7 g); Mass Spectrum: M+H+ 313.
Reaction SMILES: [OH:1][CH:2]([CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:3][O:4][NH2:5].[CH2:13]([N:19]=[C:20]=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(Cl)(Cl)Cl>[CH2:13]([NH:19][C:20]([NH:5][O:4][CH2:3][CH:2]([OH:1])[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: NOCC(O)CN1CCCCC1
Reactant: CCCCCCN=C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCNC(=O)NOCC(O)CN1CCCCC1

Procedure:
O-(2-hydroxy-3-piperidino-propyl)-hydroxylamine (1,85 g, 0,011 mol) was dissolved in 30 ml chloroform and 1,17 ml (0,011 mol) n-hexyl-isocyanate was added while stirring. After 3 hours the reaction mixture was evaporated and purified by column chromatography. The oil thus obtained crystallizes slowly in refrigerator and rubbing the crystals in petroleum ether a white material was obtained.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:29]([CH3:30])=[C:28]([C:31]([NH2:33])=O)[N:27]([CH3:34])[N:26]=4)=[CH:21][C:20]=3[CH3:35])=[C:6]([N:10]3[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>O>[CH:1]1([C:4]2[C:5]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:29]([CH3:30])=[C:28]([C:31]#[N:33])[N:27]([CH3:34])[N:26]=4)=[CH:21][C:20]=3[CH3:35])=[C:6]([N:10]3[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(-c2nn(C)c(C(N)=O)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Solvent: O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2nn(C)c(C#N)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Reaction time: 2 h

Procedure:
At room temperature, to the mixture of 1-{3-cyclopropyl-2-[2-methyl-4-(5-aminocarbonyl-1,4-dimethyl-1H-pyrazol-3-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (Present compound 49) 0.8 g and pyridine 10 ml was added phosphorus oxychloride 0.58 g and was stirred for two hours. To the resulting mixture was added water 40 ml and precipitates were filtrated. The precipitates were washed with water and dried under reduced pressure to give 1-{3-cyclopropyl-2-[2-methyl-4-(5-cyano-1,4-dimethyl-1H-pyrazol-3-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (hereinafter, referred to as “Present compound 50”) 0.6 g.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([NH:13][CH:14]([CH3:16])[CH3:15])[N:4]=1)[CH3:2].[CH:17]1([SH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(N(CC)CC)C>[CH2:1]([C:3]1[N:8]=[C:7]([S:23][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([NH:13][CH:14]([CH3:16])[CH3:15])[N:4]=1)[CH3:2]
Reactant: CCc1nc(Cl)c([N+](=O)[O-])c(NC(C)C)n1
Reactant: SC1CCCCC1
Solvent: CCN(CC)CC
Product: CCc1nc(NC(C)C)c([N+](=O)[O-])c(SC2CCCCC2)n1
Yield: 74.8 %

Procedure:
12.1 g (50 m-moles) of 2-ethyl-4-chloro-5-nitro-6-isopropylamino-pyrimidine (vide Ex. 9a) are reacted with 7.0 g (60 m-moles) of cyclohexylmercaptan and 6.1 g (60 m-moles) of triethylamine to yield 12.0 g of 2-ethyl-4-cyclohexylthio-5-nitro-6-isopropylamino-pyrimidine of m.p. 69°-71° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1.[NH3:22]>CCO>[F:1][C:2]([F:21])([F:20])[CH2:3][N:4]=[C:5]([NH2:22])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1
Reactant: N#CCCCSc1cccc(NC(=S)NCC(F)(F)F)n1
Reactant: N
Solvent: CCO
Product: N#CCCCSc1cccc(NC(N)=NCC(F)(F)F)n1

Procedure:
A mixture of 4-[2-(3-[2,2,2-trifluoroethyl]thioureido)pyrid-6-ylthio]butyronitrile (29 g.), yellow mercuric oxide (29 g.) and a saturated solution of ammonia in EtOH (100 ml.) was stirred at room temperature for 24 hours and then filtered. The filtrate was evaporated to dryness and the residue triturated with petroleum ether (b.p. 60°-80°) and collected to give 4-[2-(2-[2,2,2-trifluoroethyl]guanidino)pyrid-6-ylthio]butyronitrile (24 g.), m.p. 89°-91°.
Reaction SMILES: C(OC1C=C[C:15]2[C:11](=[C:12]([C:31]3[CH:36]=[CH:35][C:34]([O:37]C)=CC=3)[C:13]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)(C(OC)=O)[CH:14]=2)C=1)C1C=CC=CC=1.C[CH2:40][O:41][C:42]([CH3:44])=O>CCO.[Pd]>[OH:37][C:34]1[CH:35]=[C:36]2[C:14](=[CH:15][CH:11]=1)[CH:13]([C:22]1[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=1)[CH:12]([C:29]([O:28][CH3:25])=[O:30])[CH:31]2[C:11]1[CH:15]=[CH:44][C:42]([O:41][CH3:40])=[CH:13][CH:12]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)C1(c2ccc3c(c2)OCO3)C=c2ccc(OCc3ccccc3)cc2=C1c1ccc(OC)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C1C(c2ccc3c(c2)OCO3)c2ccc(O)cc2C1c1ccc(OC)cc1
Reaction time: 20 h
Yield: 89 %

Procedure:
To a degassed solution of methyl(RS)-5-benzyloxy-3-(4-methoxyphenyl)-2-(3,4-methylenedioxyphenyl)indene-2-carboxylate (6.60 g, 13.0 mmol) in EtOAc (25 ml) and EtOH (175 ml) was added 5% palladium on activated carbon (0.6 g). The resulting suspension was shaken on a Parr hydrogenator at 60 psi H2 for 20 h, at which time NMR analysis of the reaction mixture indicated that the reaction was incomplete. The catalyst was removed by filtration through a pad of Celite, and fresh 5% palladium on activated carbon (0.6 g) was added. The mixture was shaken on a Parr hydrogenator at 60 psi H2 for an additional 48 h. The catalyst was removed by filtration through a pad of Gelite, and the filtrate was concentrated under reduced pressure. The residue was crystallized from EtOAc/hexanes to afford the title compound (4.83 g, 89%); m.p. 187°-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[Mg].[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:16](=[O:17])[O:15][CH2:14]2.[Cl-].[NH4+]>CCOCC.O1CCCC1>[OH:15][CH2:14][C:13]1[CH:12]=[C:11]([Br:10])[CH:20]=[CH:19][C:18]=1[C:16]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:17]
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: Clc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(c1ccc(Cl)cc1)c1ccc(Br)cc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
A Grignard-solution prepared from 220 grams (1.15 mol) of p-chlorobromobenzene and 29 grams of magnesium turnings (1.2 mol) in 1500 milliliters of dry ether was added dropwise in the course of one hour to a suspension of 213 grams of 5-bromphthalide (1 mol) in 1500 milliliters of dry tetrahydrofuran. The temperature was not allowed to rise over 10 degrees Centigrade. After the addition was completed the reaction mixture was stirred for three hours at room temperature. The mixture was then poured into 2 liters of icewater and 100 milliliters of saturated aqueous ammonium chloride were added. The etherphase was separated and the water-tetrahydrofuranphase extracted once with 500 milliliters of ether. The etherphase was washed with water, dried over anhydrous magnesiumsulphate, filtered and evaporated in vacuum to yield 320 grams of 2-hydroxymethyl-4-bromo-4'-chloro-benzophenone in the form of a yellow oil which was not purified further but used directly in the next step. The 320 grams of oil were dissolved in 200 milliliters of dry tetrahydrofuran and added dropwise to a great excess of N,N-dimethylaminopropyl magnesium chloride in tetrahydrofuran under gentle reflux. After completed addition the mixture was refluxed over night. The reaction mixture was then poured into 5 liters of icewater and 200 milliliters of saturated aqueous ammonium chloride solution added. The mixture was extracted with a total of 2500 milliliters of ether. The etherphase was then extracted with 20% aqueous acetic acid to acid reaction, whereupon the acetic acid solution was made alkaline with 10 N sodiumhydroxide solution. After cooling, the oil, which separated out, was extracted twice with 500 milliliters of ether. The combined ether extracts were dried over anhydrous potassium carbonate, treated with active carbon and evaporated in vacuum. The remaining oil consists of somewhat impure (4-bromo-2-(hydroxymethyl)phenyl)-(4-chlorophenyl)-(3-dimethylaminopropyl)methanol which was used in the next step without further purification. Yield: 219 grams.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:5]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([CH:29]3[CH2:31][CH2:30]3)=[CH:21][CH:20]=2)[C:6]([S:9][C:10]2([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12][CH2:11]2)=[N:7][N:8]=1>C1COCC1.CO>[Br:3][C:4]1[N:5]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([CH:29]3[CH2:31][CH2:30]3)=[CH:21][CH:20]=2)[C:6]([S:9][C:10]2([C:14]([OH:16])=[O:15])[CH2:11][CH2:12][CH2:13]2)=[N:7][N:8]=1
Reactant: CCOC(=O)C1(Sc2nnc(Br)n2-c2ccc(C3CC3)c3ccccc23)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(Sc2nnc(Br)n2-c2ccc(C3CC3)c3ccccc23)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Lithium hydroxide solution (1M aqueous, 0.387 mL, 0.387 mmol, 3 eq) was added to a solution of ethyl 1-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)cyclobutanecarboxylate (61 mg, 0.129 mmol) in THF/methanol (2/1, 3 mL) and the mixture stirred at room temperature for 18 h. The mixture was acidified with HCL (1N aqueous, 0.645 mL, 0.645 mmol, 5 eq), concentrated, water (10 mL) added and extracted with diethyl ether (2×15 mL). The combined organic extracts were dried over calcium chloride and concentrated to give 1-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)cyclobutanecarboxylic acid as an off-white solid (43 mg, 75%).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17].[CH2:19]([CH:23]1[CH2:29][CH:28]2[NH:30][CH:25]([CH2:26][CH2:27]2)[CH2:24]1)[CH2:20][CH2:21][CH3:22]>CCCCCCC.CCOC(C)=O>[CH2:19]([CH:23]1[CH2:24][CH:25]2[N:30]([CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]3[C:10]4[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=4[O:8][CH2:7][C:6]3=[O:17])[CH:28]([CH2:27][CH2:26]2)[CH2:29]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCC1CC2CCC(C1)N2
Reactant: COc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccc(OC)cc21
Yield: 67.8 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one (111MF36) (0.239 g, 0.66 mmol) and 3-Butyl-8-aza-bicyclo[3.2.1]octane (0.100 g, 0.60 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF40) (0.163 g, 61%). 1H NMR (CDCl3) d 6.88 (d, J=8.8 Hz, 1H), 6.85 (d, J=2.8 Hz, 1H), 6.49 (dd, J=8.8 Hz, J=2.8 Hz, 1H), 4.61-4.47 (m, 2H), 4.01-3.99 (m, 2H), 3.77 (s, 3H), 3.17-3.04 (m, 2.35-2.29 (m, 1H), 2.14-1.79 (m, 3H), 1.57-1.13 (m, 6H), 0.88 (m, 3H); 13C NMR (CDCl3) d 165.4, 155.6, 139.8, 129.8, 117.1, 107.0, 103.8, 68.0, 61.6, 60.2, 58.1, 56.0, 45.4, 38.5, 38.4, 36.9, 31.6, 29.4, 28.2, 27.3, 26.5, 23.9, 14.3; HPLC-MS (ammonium acetate) [M+H]+=401.3.
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1)([O-])=O.Cl>C(O)C>[NH2:3][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:14])[CH3:13])=[CH:8][CH:7]=1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1ccc(N)cc1
Yield: 78.7 %

Procedure:
Under nitrogen, 2.85 g (75 mmol) sodium borohydride, 500 mg (0.9 mmol) cobalt (II) phthalocyanine and 1.65 g (10 mmol) p-nitro acetophenone are agitated in 50 ml ethanol for 48 hours at 20° C. The reaction mixture is acidified with 5N hydrochloric acid, cooling with ice, and the blue precipitate is centrifuged which is washed with methanol. The centrifugate collected is concentrated and the residue separated into water and ether. The water phase is alkalized with sodium hydroxide and extraction is accomplished with ether. The ether phase is dried with sodium sulfate and concentrated, leaving behind 1.08 g (79%) α-(p-aminophenyl)-ethanol.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8](O)[CH2:9][CH2:10][CH3:11])=[CH:6][CH:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:3]=1.O=S(Cl)[Cl:25]>C(Cl)Cl>[Cl:25][CH:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[CH:5][CH:6]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCC(O)c1ccc(-c2cccc(C(F)(F)F)c2)nc1C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCC(Cl)c1ccc(-c2cccc(C(F)(F)F)c2)nc1C

Procedure:
0.276 g (0.892 mmol) of the above prepared [rac]-1-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-butan-1-ol was dissolved in 4.3 ml of CH2Cl2 and treated dropwise at 0° C. with 0.13 ml (2 eq.) of SOCl2. The reaction mixture was kept at 0° C. for 5 Min. and at RT for 30 Min. Pouring onto crashed ice/NaHCO3, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents yielded 0.289 g of pure title compound as light yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:8]([NH:19][S@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])([CH3:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CCCCCC.Cl[C:38]([O:40][CH3:41])=[O:39].[Cl-].[NH4+]>C1COCC1>[CH3:15][C:14]([CH3:17])([Si:11]([CH3:13])([CH3:12])[O:10][CH2:9][C@:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:38]([O:40][CH3:41])=[O:39])([CH3:18])[NH:19][S@@:20](=[O:21])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:16]
Reactant: CC(C)(C)[S@](=O)N[C@@](C)(CO[Si](C)(C)C(C)(C)C)c1cccc(Br)c1
Reactant: COC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1cccc([C@](C)(CO[Si](C)(C)C(C)(C)C)N[S@@](=O)C(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
To a solution of 403 mg of (S)—N-[(2R)-2-(3-bromophenyl)-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl]-2-methylpropane-2-sulfinamide in 4 ml of THF was added 1.4 ml of a 1.63 M n-butyllithium/hexane solution at −78° C., followed by stirring for 30 minutes, and then 283 μl of methyl chloroformate was added dropwise thereto, followed by stirring for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 280 mg of methyl 3-[(6R,8S)-2,2,3,3,6,9,9-heptamethyl-8-oxo-4-oxa-8λ4-thia-7-aza-3-siladecan-6-yl]benzoate.