Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)#[N:27]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][N:16]([C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([C:26]#[N:27])=[CH:29][CH:30]=3)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C(=O)c1ccc(C#N)cc1)CC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
The synthesis of the starting material, 3-tert-butoxycarbonyl-3,9-diaza-spiro[5.5]undecane, was accomplished as described in U.S. Pat. No. 5,451,578. This mateial (1.45 g) was dissolved in CH2Cl2 (25 mL) and cooled to 0° C. under an argon atmosphere. To this solution was added triethylamine (1.67 mL) and 4-dimethylaminopyridine (70 mg) followed by 4-cyanobenzoyl chloride (1.04 g). The mixture was stirred overnight as it warmed to rt. It was cooled to 0° C., and ice cold 1 M HCl (30 mL) was carefully added. The resulting mixture was washed with EtOAc (3×30 mL). Then washing the EtOAc with saturated NaHCO3 and brine followed by drying with MgSO4 and evaporation of the solvent under reduced pressure afforded the title compound (1.62 g, 74%) as a yellow foam. Chromatography on silica gel with hexanes/ethyl acetate (2:1) as eluant gave pure compound.
Reaction SMILES: C([O:8][C:9]1[N:24]=[C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[C:29]([O:34][CH3:35])[CH:28]=3)[C:22]([CH2:36][CH3:37])=[C:21]([O:38]CC2C=CC=CC=2)[C:10]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[CH2:36]([C:22]1[C:21]([OH:38])=[C:10]([C:11]([OH:13])=[O:12])[C:9](=[O:8])[NH:24][C:23]=1[C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[C:29]([O:34][CH3:35])[CH:28]=2)[CH3:37]
Reactant: CCc1c(-c2cc3ccc(OC)cc3[nH]2)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1c(-c2cc3ccc(OC)cc3[nH]2)[nH]c(=O)c(C(=O)O)c1O
Reaction time: 8 h
Yield: 34.3 %

Procedure:
The intermediate obtained in Step 4 (170 mg, 0.24 mmol) was dissolved in a mixed solvent of MeOH (0.5 mL) and ethyl acetate (2.0 mL) and hydrogenated with 10% Pd on charcoal (50 mg) using a balloon at room temperature. LC/MS showed complete conversion was achieved overnight. The catalyst was filtered over Celite and washed with 5% MeOH in DCM. The filtrate was concentrated to dryness and the residue was triturated with DCM and dried to provide the title compound as a pale yellow powder (27 mg) in 34% yield.
Reaction SMILES: COC1C=C2[C@@:13]34[C@@H:17]5[CH2:18][C@H:19]6C(CN5[CH2:15][CH2:14]3)=CC[O:25][C@H:21]3[CH2:22][C:23](=[O:24])N([C@H]4[C@@H:20]63)C2=CC=1OC.C[C@@]12[C@H]3CC[C@]4(C)[C@@H](C(CO)=O)CC[C@H]4[C@@H]3CC[C@@H]1CC(=[O:35])CC2.Cl.[C:55]([O:58][CH2:59]C)(=[O:57])[CH3:56]>>[C:55]([CH2:56][CH2:15][CH2:14][CH2:13][CH2:17][CH2:18][CH:19]1[C:20](=[O:35])[C@H:21]([OH:25])[CH2:22][C:23]1=[O:24])([O:58][CH3:59])=[O:57]
Reactant: CCOC(C)=O
Reactant: C[C@]12CCC(=O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CO)CC[C@@H]12
Reactant: COc1cc2c(cc1OC)[C@@]13CCN4CC5=CCO[C@H]6CC(=O)N2[C@H]1[C@H]6[C@H]5C[C@H]43
Agent: Cl
Product: COC(=O)CCCCCCC1C(=O)C[C@@H](O)C1=O
Reaction time: 0.03 h

Procedure:
The resolved brucine-hydroxydione salt (2.2 g) was dissolved in ethyl acetate (30 ml). To this solution 30 ml of 0.25 N HCl was added and the heterogeneous mixture was stirred very vigorously for 2 minutes. upon standing two layers formed and were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers from the two extractions were combined and were washed with water and saturated brine solution and were dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 2-(6'-carbomethoxyhexyl)-4(R)-hydroxy-cyclopentane-1,3-dione as a white crystalline solid (780 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:7])[S:5][CH:6]=1.[CH3:8][Si:9]([C:12]#[CH:13])([CH3:11])[CH3:10].C(N(CC)CC)C>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.C(#N)C>[CH3:8][Si:9]([CH3:11])([CH3:10])[C:12]#[C:13][C:2]1[CH:3]=[C:4]([CH3:7])[S:5][CH:6]=1
Reactant: Cc1cc(Br)cs1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C#C[Si](C)(C)C)cs1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 4-bromo-2-methylthiophene (1.00 g), trimethylsilyl acetylene (1.17 mL), bis(triphenylphosphine) palladium(II) dichloride (119 mg), copper(I) iodide (65 mg), triethylamine (1.57 mL), and acetonitrile (15 mL) was stirred at 80° C. for 4 hours under an argon atmosphere. The reaction mixture was left to be cooled and filtrated through a Celite (registered trademark) pad. To the filtrate was added saturated brine, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (605 mg). 1H-NMR (CDCl3) δ ppm: 0.23 (9H, s), 2.44 (3H, d, J=1.0 Hz), 6.75-6.80 (1H, m), 7.21-7.25 (1H, m).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.Cl.Cl.[NH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH2:23])[N:17]=2)[N:15]=1.C(N(CC)CC)C>CN(C)C=O.O1CCCC1>[NH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][C:2]([O:4][CH2:5][CH3:6])=[O:3])[N:17]=2)[N:15]=1
Reactant: CCOC(=O)Cl
Reactant: NCc1cccc(-c2csc(N)n2)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)NCc1cccc(-c2csc(N)n2)n1
Reaction time: 1 h
Yield: 133.9 %

Procedure:
Ethyl chloroformate (3.7 g) was added slowly to a suspension of 2-amino-4-(6-aminomethylpyridin-2-yl)thiazole trihydrochloride (8.9 g) and triethylamine (11.4 g) in N,N-dimethylformamide (80 ml) and tetrahydrofuran (80 ml) with cooling on an ice bath. The mixture was stirred with cooling for 1.5 hours and then at room temperature for 1 hours. The solvent was removed under reduced pressure. The residue was dissolved in water (300 ml). The mixture was alkalized with a saturated aqueous potassium carbonate solution and then was extracted with a mixture of ethyl acetate (500 ml) and tetrahydrofuran (100 ml). The extract was dried over magnesium sulfate and then was evaporated to afford 2-amino-4-(6-ethoxycarbonylaminomethylpyridin-2-yl)thiazole (10.51 g).
Reaction SMILES: C([O:4][C:5]1[C:9]([CH3:10])=[N:8][N:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:6]=1)(=O)C.[OH-].[Na+]>CO.O>[F:17][C:14]1[CH:13]=[CH:12][C:11]([N:7]2[NH:6][C:5](=[O:4])[C:9]([CH3:10])=[N:8]2)=[CH:16][CH:15]=1
Reactant: CC(=O)Oc1nn(-c2ccc(F)cc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nn(-c2ccc(F)cc2)[nH]c1=O

Procedure:
2-(4-Fluorophenyl)-5-methyl-2H-1,2,3-triazol-4-yl acetate (i.e. the product of Step B, 7.8 g, 33 mmol) was suspended in methanol (150 mL). A solution of sodium hydroxide (7 M, 22 mL, 140 mmol) was added over several minutes with stirring during which time the mixture became homogeneous and then stirred at 23° C. for 18 h. The reaction was concentrated under reduced pressure to remove excess methanol. The remaining residue was diluted with water (200 mL) and washed with hexanes. The aqueous layer was acidified with concentrated hydrochloric acid during which time a thick creamy precipitate formed. The mixture was diluted with water and stirred for 30 min. The precipitate was filtered and washed well with water. The moist solid was dissolved in ethyl acetate, dried (MgSO4) and concentrated under reduced pressure to afford the title compound (6.1 g) as a beige solid. The title compound was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:6][O:7][C:8]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:27])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:35](Cl)(=[O:39])[O:36][CH2:37][CH3:38].C(OCC)(=O)C>ClCCl>[CH2:37]([O:36][C:35](=[O:39])[NH:1][CH2:2][C:3]1([CH2:6][O:7][C:8]2[C:9]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C:22]4=[O:27])=[CH:10][CH:11]=[C:12]([O:16][CH3:17])[C:13]=2[O:14][CH3:15])[CH2:4][CH2:5]1)[CH3:38]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)CC2)c1OC
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)NCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OC)CC1

Procedure:
To a stirring solution of 4-[2-(1-Aminomethyl-cyclopropylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 182) (110 mg, 0.272 mmol) in dichloromethane (10 mL), were added triethylamine (0.082 g, 0.811 mmol) and ethyl carbonochloridate (59 mg, 0.544 mmol) and the resultant reaction mixture was subjected to the conditions used in the preparation of Compound 183 and Purification by column chromatography (silica gel, 0-25% ethyl acetate in pet ether) to afford the title compound as a solid.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:6][C:7]1[N:12]=[C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([F:23])=[CH:15][CH:14]=2)[CH:10]=[C:9]([CH:24]([CH3:26])[CH3:25])[N:8]=1)[CH3:5].[CH3:28][NH2:29]>>[CH:24]([C:9]1[N:8]=[C:7]([NH:6][CH:4]([CH3:5])[C:3]([NH:29][CH3:28])=[O:2])[N:12]=[C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([F:23])=[CH:15][CH:14]=2)[CH:10]=1)([CH3:26])[CH3:25]
Reactant: CN
Reactant: COC(=O)C(C)Nc1nc(-c2ccc(F)c3ccccc23)cc(C(C)C)n1
Product: CNC(=O)C(C)Nc1nc(-c2ccc(F)c3ccccc23)cc(C(C)C)n1

Procedure:
2-[6-Isopropyl-4-(4-fluoronaphth-1-yl)pyrimidin-2-ylamino]-propionic acid methyl ester was dissolved in ethanolic methyl amine solution (33%) and sonicated in a Branson ultrasonic bath for 3 hours. The solution was evaporated to dryness and taken up in methanol. Sufficient water was added to cause crystallization. The impure reaction product was further purified by silica gel column chromatography, eluting with methylene chloride/methanol and recrystallized from methanol/water to give 2-[6-isopropyl-4-(4-fluoronaphth-1-yl)pyrimidin-2-ylamino]-N-methyl-propionamide, m.p. 141.1°-142.0° C.
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[CH2:19]([SnH:23]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].[Cl:32][C:33]1[CH:38]=[C:37](Cl)[N:36]=[C:35]([CH3:40])[N:34]=1>C1COCC1>[Cl:32][C:33]1[CH:38]=[C:37]([Sn:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:28][CH2:29][CH2:30][CH3:31])[N:36]=[C:35]([CH3:40])[N:34]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cc(Cl)nc(C)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium solution, 1.6 M in hexane (0.184 mL, 2.200 mmol, Aldrich, St. Louis, Mo.) was added to a solution of diisopropylamine (0.314 mL, 2.200 mmol) in THF (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min. Tributyltin hydride (0.527 mL, 2.000 mmol, Aldrich, St. Louis, Mo.) was added dropwisely. The solution was stirred at 0° C. for 15 min. The mixture was cooled down to −78° C., 4,6-dichloro-2-methylpyrimidine (326 mg, 2.000 mmol, Aldrich, St. Louis, Mo.) in THF (2 mL) was then added and the mixture was stirred at −78° C. for 8 h. The mixture was quenched by saturated aqueous KF (4 mL), and extracted with EtOAc (30 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give 4-chloro-2-methyl-6-(tributylstannyl)pyrimidine as a light-yellow oil. The crude material was used directly in the next step without purification.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12](I)=[CH:13][C:8]=2[C:7](=[O:15])[N:6]([CH3:16])[C:5]2[CH:17]=[CH:18][CH:19]=[N:20][C:4]1=2)[CH3:2].[CH:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)=[CH2:22].C(N(CC)CC)C.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>CN(C)C=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12](/[CH:22]=[CH:21]/[C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[CH:13][C:8]=2[C:7](=[O:15])[N:6]([CH3:16])[C:5]2[CH:17]=[CH:18][CH:19]=[N:20][C:4]1=2)[CH3:2]
Reactant: CCN1c2ncc(I)cc2C(=O)N(C)c2cccnc21
Reactant: C=Cc1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCN1c2ncc(/C=C/c3ccncc3)cc2C(=O)N(C)c2cccnc21
Temperature: 125 °C
Yield: 73.6 %

Procedure:
A mixture containing 5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]-diazepin-6-one (0.7 g, 1.9 mmol), 4-vinylpyridine (0.3 mL, 2.9 mmol), bis(triphenylphosphine)palladium(II) chloride (60 mg, 0.09 mmol), triethylamine (1.8 mL, 12.8 mmol), and 1 crystal of 2,6-di-tert-butyl-4-methylphenol in 4 mL of N,N-dimethylformamide was heated at 125° C. under argon for 3 hours. The reaction mixture was then cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (magnesium sulfate), and concentrated to give a yellow oil. Purification by flash chromatography, eluting with ethyl acetate/hexanes, and recrystallization (ethyl acetate/hexanes) provided the 0.5 g of the title compound as yellow crystals, m.p. 150° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:15]=[N:14][C:13]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.C([O-])(=[O:23])C.[NH4+].C[CH2:27][O:28][C:29]([CH3:31])=[O:30]>C(Cl)Cl.C[N+]([O-])=O>[CH3:27][O:28][C:29](=[O:30])[C:31]([C:9]1[C:8]2[C:12](=[C:13]([N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)[N:14]=[CH:15][C:7]=2[O:6][CH3:5])[NH:11][CH:10]=1)=[O:23]
Reactant: CC(=O)[O-]
Reactant: CCOC(C)=O
Reactant: COc1cnc(-n2cncn2)c2[nH]ccc12
Agent: [Al+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: COC(=O)C(=O)c1c[nH]c2c(-n3cncn3)ncc(OC)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
To a mixture of AlCl3 (0.665 g, 5.0 mmol) in 4 mL of CH2Cl2-MeNO2 (4:1) was added 4-methoxy-7-(1,2,4-triazol-1-yl)-6-azaindole (0.108 g, 0.50 mmol) as a solid. To the resulting solution was added methyl oxalyl chloride (0.185 mL, 2.0 mmol) dropwise and then the mixture was stirred at room temperature for 16 h. The reaction mixture was then carefully poured into 20% aqueous ammonium acetate and EtOAc were added. The resulting emulsion was filtered and the residue was washed with additional EtOAc. The organic phase was washed (brine), dried (Na2SO4) and evaporated, and the residue was triturated with MeOH to give 4-methoxy-7-(1,2,4-triazol-1-yl)-6-azaindol-3-yl-oxoacetic acid methyl ester (0.069 g, 46%) as a yellow solid: MS m/e 300 (M−H)−. This material (0.069 g, 0.229 mmol) was taken up in 3 mL of MeOH, 1M K2CO3 (0.9 mL, 0.9 mmol) was added and the mixture was stirred at room temperature for 20 h. The solution was then diluted with an equal volume of water and concentrated in vacuo. The resulting aqueous solution was cooled at 0° C. and acidified to pH 1-2 with 6N HCl. This gave a bright yellow precipitate which was filtered, washed with cold 0.1N HCl and then with ether. The wet solid was suspended in ether with sonication and then it was filtered and dried in vacuo to give the title compound (0.049 g, 75%) as a yellow powder:
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:11]1([OH:21])[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1.[C:22](=[O:24])=[O:23].Cl>C1COCC1.O>[OH:21][C:11]1([C:7]2[S:6][CH:10]=[C:9]([C:22]([OH:24])=[O:23])[N:8]=2)[CH2:12][CH2:13][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:19][CH2:20]1
Reactant: O=C=O
Reactant: OC1(c2nccs2)CCC2(CC1)OCCO2
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1csc(C2(O)CCC3(CC2)OCCO3)n1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A solution of n-butyllithium (17.1 mL of 1.6 M solution in hexane, 27.35 mmol) was added to 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (3.00 g, 12.43 mmol) in THF (50 mL) at −78° C. with stirring under N2. After being stirred at −78° C. for 1 h, dry ice (10 g, 227 mmol) was added to the lithiated compound solution and stirred for 2 h at −78° C. Water was added and the solution was warmed to room temperature. The mixture was then treated with 1N HCl to pH 3 to 4 and extracted with EtOAc (3×). The combined organic layers were washed with saturated NaCl solution, dried (MgSO4), and concentrated and chromatographed (EtOAc to 1% AcOH/EAOAc) to give 3.23 g of 2-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-1,3-thiazole-4-carboxylic acid. MS (EI) calcd: (M+H)+=286.1; found: 286.0.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[C:19]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:18]=[CH:17][C:16]=2[O:25][CH3:26])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO[CH:32]1[CH2:36][CH2:35][CH:34](OC)O1.C(O)(=O)C>O>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[C:19]([S:21]([N:22]3[CH:32]=[CH:36][CH:35]=[CH:34]3)(=[O:23])=[O:24])[CH:18]=[CH:17][C:16]=2[O:25][CH3:26])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: COC1CCC(OC)O1
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)n2cccc2)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 88.6 %

Procedure:
A mixture of N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-5-sulfamoyl-benzamide (442 mg, 1 mmol), 2,5-dimethoxytetrahydrofuran (159 mg, 1.2 mmol) and acetic acid (5 mL) was refluxed for 2 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporating the solvent under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=3:2) to give the title compound (436.5 mg, 88.6%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([OH:33])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[C:20]([CH3:30])=[C:19]([C:31]([NH:34][C@@H:35]4[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:37][CH2:36]4)=[O:33])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c7) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless foam.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[CH2:30][C:31](O)=[O:32])[CH2:27]2.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[CH2:30][C:31]([N:12]1[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]1)=[O:32])[CH2:27]2
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: O=C(O)CC1C2CC3CC(C2)CC1C3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1C3CC4CC(C3)CC1C4)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine 0.69 ml was added in a methylene chloride 20 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 0.78 g (4.1 mill), and stirred at 0° C. for 30 min. 2-adamantyl acetic acid 0.80 g (4.1 mill) and WSC 1.11 g (5.79 mill) were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 23 hours. The reaction mixture was washed with saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (1S)-3-(2-adamantylacetyl)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 50 ml solution of lithium aluminum hydride 0.47 g (12 mill) and refluxed for 2 hours. The reaction mixture was cooled, added water and filtered the insoluble material. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform:acetone=10:1-5:1) to obtain the product.
Reaction SMILES: [C:1]([CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])#[N:2].[C:20]([Cl:23])(=[O:22])[CH3:21].[CH2:24](O)C>>[ClH:23].[CH2:20]([O:22][C:1]([CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:18])([F:17])[F:19])[CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:24])=[O:7])=[NH:2])[CH3:21]
Reactant: CCO
Reactant: CC(=O)Cl
Reactant: COC(=O)CCC(C#N)c1ccccc1C(F)(F)F
Product: CCOC(=N)C(CCC(=O)OCC)c1ccccc1C(F)(F)F
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methyl 4-cyano-4-(2-trifluoromethylphenyl)butanoate (200 mg) was dissolved in ethanol (1.03 mL), and acetyl chloride (838 μl) was added at 0° C. The mixture was heated to room temperature and the reaction was initiated. After stirring for 24 hours, concentration under reduced pressure gave a crude product of the title compound as an oil (300 mg).
Reaction SMILES: [I:1][C:2]1[C:8]([Br:9])=[CH:7][C:6]([Br:10])=[CH:5][C:3]=1[NH2:4].[CH2:11]([C:18](=O)[C:19]([O-:21])=[O:20])[C:12]1C=CC=C[CH:13]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].[C:30]1([CH3:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:36]([O:21][C:19](=[O:20])[CH:18]([NH:4][C:3]1[CH:5]=[C:6]([Br:10])[CH:7]=[C:8]([Br:9])[C:2]=1[I:1])[CH2:11][CH:12]=[CH2:13])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1cc(Br)cc(Br)c1I
Reactant: Cc1ccccc1
Reactant: O=C([O-])C(=O)Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: C=CCC(Nc1cc(Br)cc(Br)c1I)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-iodo-3,5-dibromoaniline (1.1 g) in dry toluene (20 ml) were added benzylglyoxylate (0.530 g) and Na2SO4 (1 g). The mixture was refluxed overnight. After filtration the resulting solution was concentrated under vacuum to a brown oil, which was then taken up with dry dichloromethane (20 ml). After cooling to -78°, TiCl4 (0.318 ml) was slowly added with a syringe and stirring continued for 5 min. The solution was then allowed to warm to room temperature over 30 min by removing the dry ice/acetone bath, then cooled again to -78° and tributylallyltin (0.98 ml) added. After 1 hour the reaction was stopped by pouring it into a saturated solution of NH4Cl (80 ml). The aqueous phase was extracted with EA (2×100 ml) and the combined organic fractions washed with HCl (3 N, 2×30 ml) and brine (50 ml) and dried. Final purification by column chromatography (CH/EA 8/2) gave the title compound (0.6 g) as a yellow oil.