Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:18]2[O:17][C:16]([CH3:20])([CH3:19])[CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)[NH2:5].[F:21][C:22]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:23]=1[C:24]([N:26]=[C:27]=[O:28])=[O:25]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:27]([NH:26][C:24](=[O:25])[C:23]2[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:22]=2[F:21])=[O:28])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:18]2[O:17][C:16]([CH3:20])([CH3:19])[CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: CC1(C)Cc2cccc(Oc3ccc(N)cc3Cl)c2O1
Solvent: Cc1ccccc1
Product: CC1(C)Cc2cccc(Oc3ccc(NC(=O)NC(=O)c4c(F)cccc4F)cc3Cl)c2O1
Temperature: 70 °C
Yield: 83.2 %

Procedure:
Solution containing 4.0 g (13.8 m moles) of 3-chloro-4-(2,3-dihydro-2,2-dimethyl-7-benzofuranyloxy)aniline in 45 ml of toluene was placed under an atmosphere of nitrogen and heated to 70° C. To this was added 3.79 g (20 m moles) of 2,6-difluorobenzoyl isocyanate in 5 ml of toluene via an addition funnel. The resulting mixture was heated for 45 min. and then cooled to room temperature. The mixture was further cooled below 0° C. in a freezer and then filtered. The collected solid was washed with cold toluene. This was dried under vacuum to afford 5.43 g of the desired product as a white solid, mp 171° C. NMR (DMSO-d6): δ1.40 (s, 6H), 3.05 (s, 2H), 6.3-8.0 (m, 10H), 10.20 (broad s, 1H), 11.47 (broad s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.Cl.[N:11]1([CH2:16][CH2:17][C:18](O)=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:18](=[O:19])[CH2:17][CH2:16][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1
Reactant: O=C(O)CCN1CCCC1
Reactant: NNc1ccc(F)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCN1CCCC1)NNc1ccc(F)cn1
Reaction time: 18 h

Procedure:
5-fluoro-2-hydrazinopyridine (285 mg, 2.24 mmol) and 3-(pyrrolidin-1-yl)propanoic acid hydrochloride (400 mg, 2.24 mmol) were dissolved in DMF (15 mL). EDC (516 mg, 2.69 mmol), HOBt (30.0 mg, 0.22 mmol) and triethylamine (374 μL, 2.69 mmol) were added and the reaction stirred for 18 h. The mixture was loaded onto an SCX-2 cartridge, which was washed with MeOH then with 2M NH3 in MeOH. The basic fractions were evaporated in vacuo then purified by FCC using 0-10% [2M NH3 in MeOH] in DCM to give the title compound contaminated with several impurities (400 mg). The product was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:35]2[CH:40]=[CH:39][C:38](Br)=[CH:37][CH:36]=2)([CH:14]([O:23][C:24]2[NH:28][C:27]3[CH:29]=[C:30]([Cl:34])[C:31]([Cl:33])=[CH:32][C:26]=3[N:25]=2)[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:42]([C:44]1[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=1)#[N:43].C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=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.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:35]2[CH:40]=[CH:39][C:38]([C:48]3[CH:47]=[CH:46][CH:45]=[C:44]([C:42]#[N:43])[CH:49]=3)=[CH:37][CH:36]=2)([CH:14]([O:23][C:24]2[NH:28][C:27]3[CH:29]=[C:30]([Cl:34])[C:31]([Cl:33])=[CH:32][C:26]=3[N:25]=2)[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)cc2)(C(COCC[Si](C)(C)C)Oc2nc3cc(Cl)c(Cl)cc3[nH]2)CC1
Reactant: N#Cc1cccc(B(O)O)c1
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: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cccc(C#N)c3)cc2)(C(COCC[Si](C)(C)C)Oc2nc3cc(Cl)c(Cl)cc3[nH]2)CC1
Temperature: 80 °C
Yield: 79.5 %

Procedure:
A mixture of 0.105 g of 4-(4-bromo-phenyl)-4-[5,6-dichloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester 51 (0.144 mmol, 1 eq), 0.024 g of 3-cyanophenyl boronic acid (0.16 mmol, 1.1 eq), and 0.034 g of Pd(PPh3)4 (0.03 mmol, 20 mol %) was mixed with 3 mL of toluene, 2 mL of ethanol and 1 mL of 2M aqueous Na2CO3 and then heated at 80° C. for 20 h while stirring. The reaction was allowed to cool to room temperature, diluted with 25 mL of ethyl acetate and washed with 25 mL of saturated brine. The organic extracts were dried over Na2SO4, filtered and concentrated by rotary evaporation to give the crude product which was purified by flash column chromatography eluting with a gradient of 5-20% ethyl acetate in hexane to give 0.081 g of 4-(3′-cyano-biphenyl-4-yl)-4-[5,6-dichloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester 52 as a pale foam: 1H NMR (300 MHz, CDCl3): δ 7.82-7.76 (m, 2H), 7.59-7.48 (m, 7H), 7.13-7.10 (m, 1H), 5.17 (s, 2H), 4.53 (s, 2H), 3.85-3.80 (br. d, 2H), 3.41-3.36 (t, 2H), 3.18-3.10 (t, 2H), 2.36-2.3 (d, 2H), 2.00-1.96 (t, 2H), 1.44 (s, 9H), 0.83-0.77 (t, 2H), 0.10 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][C:38]([O:40][CH3:41])=[O:39]>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:9][CH:10]=1
Reactant: COC(=O)CBr
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(O)cc3)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)cc1
Temperature: 25 °C
Yield: 101.6 %

Procedure:
150 mg of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol (described later, produced in Intermediate Production Example 1) was dissolved in 1.0 ml of N,N-dimethylformamide, and to this was added 51 mg of anhydrous potassium carbonate, and 50 mg of methyl bromoacetate was added with stirring at room temperature, then, the mixtures was stirred for 2 hours at 60° C. The reaction solution was cooled to room temperature, then, the reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 167 mg of methyl [4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate [Compound 1-11 of the present invention].
Reaction SMILES: [NH2:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:23]([N:27]=[C:28]=[S:29])([CH3:26])([CH3:25])[CH3:24].[N-]=C=S>C(O)C.CCOCC>[CH2:16]([O:15][C:13]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][C@@H:2]([NH:1][C:28]([NH:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[S:29])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:14])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)N=C=S
Reactant: CCOC(=O)[C@H](N)CCCCNC(=O)OCc1ccccc1
Agent: [N-]=C=S
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)[C@@H](CCCCNC(=O)OCc1ccccc1)NC(=S)NC(C)(C)C
Temperature: 80 °C

Procedure:
The process is performed as in Example 2, starting with 7.4 g of ethyl (2R)-2-amino-6-{[(benzyloxy)carbonyl]-amino}hexanoate with 5 cm3 of tert-butyl isothiocyanate in 200 cm3 of anhydrous ethanol at a temperature in the region of 20° C. for 20 hours. The reaction is completed by addition of a further 1 cm3 of isothiocyanate and heating for 2 hours at a temperature in the region of 80° C. The reaction medium is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained is taken up in ether and concentrated again under the above conditions. 13 g of ethyl (2R)-6-{[(benzyloxy)carbonyl]amino}-2-{[(tert-butylamino)carbothioyl]amino}hexanoate are obtained in the form of a colorless oil. (αD20=−12.5±0.5 at a concentration of 0.5% in methanol).
Reaction SMILES: Br[C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)O1>>[O:34]=[S:30]1(=[O:33])[CH2:31][CH2:32][N:27]([C:24]2[CH:25]=[CH:26][C:21]([C:2]3[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=3)=[CH:22][CH:23]=2)[CH2:28][CH2:29]1
Reactant: NC(=O)c1cc(Br)sc1[N+](=O)[O-]
Reactant: CC1(C)OB(c2ccc(N3CCS(=O)(=O)CC3)cc2)OC1(C)C
Product: NC(=O)c1cc(-c2ccc(N3CCS(=O)(=O)CC3)cc2)sc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 5-bromo-2-nitrothiophene-3-carboxamide (Intermediate 10 Step 4) (300 mg, 1.20 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]thiomorpholine 1,1-dioxide (403 mg, 1.20 mmol) according to the general procedure described in Intermediate 10 Step 5.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.[I:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[I:11][C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:10][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc2ccncc2[nH]1
Solvent: ClC(Cl)Cl
Product: Cc1[nH]c2cnccc2c1I
Reaction time: 2 h
Yield: 91.3 %

Procedure:
2-Methyl-1H-pyrrolo[2,3-c]pyridine (100 mg, 0.76 mmol) was dissolved in CHCl3 (5 mL), N-iodosuccinimide (179 mg, 0.79 mmol) was added and the reaction mixture was stirred for 2 h. The reaction mixture was quenched with 1 M aq sodium thiosulphate (5 mL) and the CHCl3 was removed in vacuo. The reaction mixture was partitioned between sat aq NaHCO3 (40 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (40 mL) and the combined organic fractions were washed with sat aq NaHCO3 (50 mL) and brine (50 mL), dried (MgSO4) and concentrated in vacuo to give the title compound as a cream solid (179 mg, 92%). LCMS (ES+): 258.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]2[C:3]=1[CH2:4][C:5]1[NH:6][C:7]3[C:12]([C:13]=12)=[CH:11][CH:10]=[CH:9][CH:8]=3.[BH3-]C#N.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH3:1][C:2]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]2[C:3]=1[CH2:4][C@@H:5]1[C@H:13]2[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1
Reactant: COc1cc(C)c2c(c1)-c1c([nH]c3ccccc13)C2
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C)c2c(c1)[C@@H]1c3ccccc3N[C@@H]1C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of 0.74 g of (0.00296 mol) of 5,6-dihydro-7-methyl-9-methoxyindeno[2,1-b]indole in 25 ml of acetic acid was added 0.93 g (0.0148 mol) of NaCNBH3 in portions during 5 minutes. The mixture was stirred for 3 hours at room temperature, whereafter it was diluted with water and then stirred for another hour. The resulting mixture was alkalinized with NaOH-solution (10M) to pH9, and was then extracted twice with ether. The combined organic phases were washed twice with aqueous NaCl-solution and dried (Na2SO4). After evaporation the residue was purified by chromatography on silica using methylene chloride as eluant. This gave 0.61 g (24%) of the expected product. M.p. 104° C. 1H NMR (CDCl3): 2.2 (3H,s), 3.0-3.4 (2H,dd), 3.4-3.5 (1H,bs), 3.75 (3H,s), 4.65-4.80 (2H,m), 6.4-7.4 (6H,m)--thereof 6.45 (1H,dd), 6.75 (1H,dd).
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[C:35]([C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36]>>[C:35]([C:39]1[CH:40]=[CH:41][C:42]([C:43]([N:19]([CH2:18][C:17]2[CH:33]=[CH:34][C:14]([C:13]#[C:12][C:9]3[CH:8]=[CH:7][C:6]([CH2:2][CH2:3][CH2:4][CH3:5])=[CH:11][CH:10]=3)=[CH:15][CH:16]=2)[C:20]2[CH:32]=[CH:31][C:23]3[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=3[CH:21]=2)=[O:44])=[CH:46][CH:47]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: Cl
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)c3ccc(C(C)(C)C)cc3)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1

Procedure:
The titled compound was prepared following the procedure J using 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one hydrochloride and 4-tert-butylbenzoyl chloride as a colorless oil (76%). 1H NMR (CDCl3, 300 MHz) δ 7.65 (d, J=2.3 Hz, 1H), 7.46 (m, 4H), 7.30-7.16 (m, 8H), 7.01 (dd, J=8.7, 2.3 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H), 5.14 (s, 2H), 2.64 (t, J=7.7 Hz, 2H), 1.68 (s, 6H), 1.62 (m, 2H), 1.38 (m, 2H), 1.25 (s, 9H), 0.95 (t, J=7.2 Hz, 3H). HPLC, Rt: 6.12 min (Purity: 97%).
Reaction SMILES: C[Si](Cl)(C)C.Cl[C:7]([F:18])([F:17])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[O:9].[I:19]I.O>C(#N)C.[Zn]>[F:17][C:7]([F:18])([I:19])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[O:9]
Reactant: II
Reactant: Cc1ccccc1C(=O)C(F)(F)Cl
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: O
Solvent: CC#N
Product: Cc1ccccc1C(=O)C(F)(F)I
Temperature: 55 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
To a suspension of zinc (1.6 g) in acetonitrile (40 mL) were added trimethylsilyl chloride (3.1 mL) and 2-chloro-2,2-difluoro-1-(2-methylphenyl)ethanone (4.0 g), and the mixture was stirred at 55° C. for 3 hr. The reaction mixture was allowed to cool to room temperature, iodine (3.5 g) was added, and the mixture was further stirred for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with aqueous sodium hydrogen sulfite solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane) to give the title compound as a yellow oil (yield 2.6 g, 46%).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Cl>C(O)C>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][S:1][C:2]1[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=1
Reactant: ClCc1ccccc1Cl
Reactant: FC(F)(F)c1nnc(S)s1
Solvent: CCO
Solvent: CCN(CC)CC
Product: FC(F)(F)c1nnc(SCc2ccccc2Cl)s1
Yield: 64.4 %

Procedure:
9.3 g (0.05 mole) of 2-mercapto-5-trifluoromethyl-1,3,4-thiadiazole, 5.1 g (0.05 mole) of triethylamine and 8.1 g (0.05 mole) of o-chlorobenzyl chloride in 80 ml of absolute ethanol were stirred for 2 hours under nitrogen at 50° C and then poured onto ice. The precipitate was filtered off and purified by low temperature crystallization from petroleum ether. 10 g (64% of theory) of 2-(o-chlorobenzylthio)-5-trifluoromethyl-1,3,4-thiadiazole of melting point 36°-37° C were obtained. A solution of 9.8 g (0.048 mole) of m-chloroperbenzoic acid (85% pure) in 85 ml of methylene chloride was added dropwise to 5 g (0.016 mole) of the above compound in 10 ml of methylene chloride. The mixture was stirred for 4.5 hours under reflux and then mixed successively with a solution of 6.4 g of sodium sulfite in a little water, followed by a solution of 2.7 g of sodium carbonate in a little water, and stirred thoroughly for 15 minutes. The organic phase, after concentration and recrystallization from cyclo-hexane/ethyl acetate, gave colorless crystals. 4.8 g (87% of theory) of 2-(o-chlorobenzylsulfonyl)-5-trifluoromethyl-1,3,4-thiadiazole of melting point 103° C were obtained.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:38])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:36])(=[O:35])[NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=3[CH3:34])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:37])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:33][C:29]1[C:28]([CH3:34])=[C:27]([NH:26][S:25]([C:22]2[CH:21]=[CH:20][C:19]([C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([F:37])[CH:14]=4)[CH:9]=[C:8]([CH2:7][C:6]([OH:38])=[O:5])[C:17]=3[CH3:18])=[CH:24][CH:23]=2)(=[O:36])=[O:35])[CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)Nc3cccc(Cl)c3C)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1c(Cl)cccc1NS(=O)(=O)c1ccc(-c2c(C)c(CC(=O)O)cc3ccc(F)cc23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.3 %

Procedure:
Lithium hydroxide monohydrate (0.017 g, 0.39 mmol) was added to a stirred solution of {4-[4-(3-chloro-2-methyl-phenylsulfamoyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.050 g, 0.10 mmol) in a 3:1 mixture of THF—H2O mixture (5 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane afforded {4-[4-(3-chloro-2-methyl-phenylsulfamoyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (0.039 g, 80%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.46 (br. s, 1 H), 9.95 (br. s, 1 H), 8.01 (dd, J=8.80, 6.40 Hz, 1 H), 7.90 (s, 1 H), 7.77 (d, J=7.80 Hz, 2 H), 7.32-7.46 (m, 4 H), 7.18 (t, J=7.80 Hz, 1 H), 7.03 (d, J=7.80 Hz, 1 H), 6.63 (dd, J=11.00, 2.40 Hz, 1 H), 3.85 (s, 2 H), 2.07 (s, 3 H), 2.06 (s, 3 H). MS calcd. for C26H20ClFNO4S [(M−H)−] 496, obsd. 496.3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[C:22]([C:23](=[O:32])[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:21]([NH:33][CH2:34][CH:35]3[CH2:42][CH2:41][C:38]4([CH2:40][CH2:39]4)[CH2:37][CH2:36]3)[N:20]=[C:19]([C:43]#[N:44])[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:25]([NH:24][C:23]([C:22]1[C:17]([O:16][CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:18][C:19]([C:43]#[N:44])=[N:20][C:21]=1[NH:33][CH2:34][CH:35]1[CH2:36][CH2:37][C:38]2([CH2:39][CH2:40]2)[CH2:41][CH2:42]1)=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2nc(C#N)nc(NCC3CCC4(CC3)CC4)c2C(=O)NCc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1nc(NCC2CCC3(CC2)CC3)c(C(=O)NCc2ccccc2)c(OCCC2CCNCC2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(2-{5-benzylcarbamoyl-2-cyano-6-[(spiro[2.5]oct-6-ylmethyl)amino]-pyrimidin-4-yloxy}ethyl)piperidine-1-carboxylic acid tert-butyl ester (0.68 mmol) in CH2Cl2 (10 mL) is added TFA (2 mL) at 0° C. After stirring for 2 h at 0° C. under N2 atmosphere, the mixture is concentrated and dried in vacuo to give 2-cyano-4-(2-piperidin-4-yl-ethoxy)-6-[(spiro[2.5]oct-6-ylmethyl)amino]pyrimidine-5-carboxylic acid benzyl amide as a yellow solid. 1H-NMR (CDCl3), δ 0.17-0.30 (4H, m), 0.89-0.93 (2H, m), 1.00-1.11 (2H, m), 1.14-1.24 (2H, m), 1.29-1.38 (1H, m), 1.51-1.81 (9H, m), 2.41-2.48 (2H, m), 2.99-3.02 (2H, m), 3.42 (2H, t), 4.45 (2H, t), 4.56 (2H, d), 7.29-7.39 (5H, m), 8.17 (1H, t), 10.16 (1H, t).
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][C:8]1[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:34]([C:36]1[CH:57]=[CH:56][C:39]([CH2:40][CH:41]([CH:54]=O)[CH2:42][CH2:43][C:44]2[CH:53]=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][CH:45]=2)=[CH:38][CH:37]=1)#[N:35].O>CCCCCC.C1COCC1>[C:34]([C:36]1[CH:37]=[CH:38][C:39]([CH2:40][CH:41](/[CH:54]=[CH:10]/[C:9]2[CH:30]=[CH:31][CH:32]=[CH:33][C:8]=2[OH:7])[CH2:42][CH2:43][C:44]2[CH:45]=[CH:46][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:52][CH:53]=2)=[CH:56][CH:57]=1)#[N:35]
Reactant: COC(=O)c1ccc(CCC(C=O)Cc2ccc(C#N)cc2)cc1
Reactant: Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.5 %

Procedure:
5.91 ml (9.45 mmol) of a 1.6 M solution of n-butyllithium in hexane are slowly added to a solution of 1820 mg (4.05 mmol) of (2-hydroxybenzyl)triphenylphosphonium bromide in 10 ml of anhydrous THF at 0° C. Then, at this temperature, 1085 mg (3.38 mmol) of methyl 4-[3-(4-cyanobenzyl)-4-oxobutyl]benzoate from Example 74A, dissolved in. 10 ml of THF, are slowly metered in. After warming to room temperature, the reaction solution is stirred for 12 hours and then some water is added and the mixture is concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1→2:1). 1150 mg (2.79 mmol, 83% yield) of a colorless solid are obtained.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][CH:23]=[C:15]([O:14][C:13]([F:12])([F:24])[F:25])[CH:16]=3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cccc(OC(F)(F)F)c1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 3-trifluoromethoxybenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.96 (d, J=13 Hz, 2H), 2.12 (s, 1H), 2.31 (d, J=13 Hz, 2H), 2.40 (s, 2H), 3.50 (s, 2H), 3.60 (s, 4H), 4.40 (s, 1H), 7.45-7.51 (m, 1H), 7.56-7.62 (m, 1H), 7.74 (s, 1H), 7.82-7.87 (m, 1H); MS (APCI/NH3) m/z 341 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.[CH2:14]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1.[Pt]=O.C(O)C>[CH2:14]([N:17]([CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10]1)[CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16]
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: CCCNCCC
Agent: O=[Pt]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCO
Product: CCCN(CCC)C1CCc2ccc(OC)cc2C1
Yield: 69.8 %

Procedure:
7-Methoxy-2-tetralone (35.1 g, 0.20 mole) was dissolved in dry benzene (1000 ml) and put in a 2000 ml three neck-flask. To this solution was added dipropylamine (109 ml, 0.80 mole) and p-toluenesulfonic acid monohydrate (34 g, 0.2 mole). This mixture was refluxed under nitrogen with continuous water removal for 48 hr. The benzene was replaced by ethanol (600 ml, anhydrous) and the solution was hydrogenated in a 2 liter pressure bottle over platinum oxide (1.0 g) under 2 atmospheres of pressure at room temperature for 2.5 hr. The solution was filtered through cellulose powder and concentrated. Benzene was added to the filtrate. The organic solution was basified with 10% sodium hydroxide, washed with water and extracted with 5% hydrochloric acid. The aqueous solution was basified with 10% sodium hydroxide and extracted with diethyl ether. The organic extract was dried and evaporated to give a brown liquid (36.5 g) of N,N-dipropyl-7-methoxy-1,2,3,4-tetrahydro-2-naphthylamine. A sample was purified by chromatography through a column of silica gel using 2% methanol-chloroform mixture as eluant. The hydrochloride salt was prepared and crystallized from methanol and diethyl ether: mp 152-157° C., and Anal. Calcd for C17H28NOCl.1/2H2O:C, 66.53%;H, 9.45%;N, 4.56%; and Found:C, 66.39%;H, 9.40%;N, 4.39%.