Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.[NH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:17][C@H:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: Brc1ccc2c(cnn2C2CCCCO2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2ccc3c(cnn3C3CCCCO3)c2)C1
Temperature: 55 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
A 500 mL round bottom flask with a stirbar was charged with 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (28.0 g, 0.0996 mol, 1.00 eq), (S)-3-amino-Boc-piperidine (21.75 g, 0.109 mol, 1.09 eq), tris(dibenzylideneacetone)dipalladium (4.75 g, 5.18 mmol, 0.052 eq), racemic BINAP (7.44 g, 12.0 mmol, 0.12 eq), and sodium tert-butoxide (28.7 g, 0.299 mol, 3.00 eq). The flask containing the solids was then evacuated and back-filled with nitrogen three times to degas. Pyridine (200 mL) was then added, and the flask was again purged three times with vacuum and nitrogen. The dark greenish mixture was then stirred at 55° C. overnight under a nitrogen atmosphere. In the morning, the reaction was cooled to room temperature, diluted with 250 mL EtOAc, washed three times with 250 mL portions of 10% NaHSO4, and the organic phase was evaporated. The residue was dissolved in toluene and loaded onto a silica column that had been packed with heptane. The column was washed with 5 column volumes of heptane, after which the desired product was eluted with EtOAc/heptane, to provide the title compound as a pale yellow foam (2.4 g, 81%).
Reaction SMILES: [C:1]([N:4]1[CH:9]([CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][S:12]2(=[O:18])=[O:17])[CH2:8][N:7]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:6](=[O:27])[CH2:5]1)(=[O:3])[CH3:2].[C:28](OCC)(=[O:34])[C:29](OCC)=[O:30].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>CN(C=O)C>[O:17]=[S:12]1(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[CH2:10][CH:9]1[N:4]2[C:1](=[O:3])[CH:2]=[C:28]([OH:34])[C:29]([OH:30])=[C:5]2[C:6](=[O:27])[N:7]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:8]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)CC1CN1CCCCS1(=O)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1c2c(O)c(O)cc(=O)n2C(CN2CCCCS2(=O)=O)CN1Cc1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 4-acetyl-5-[(1,1-dioxido-1,2-thiazinan-2-yl)methyl]-1-(4-fluorobenzyl)-piperazin-2-one (75 mg, 0.19 mmol) and diethyl oxalate (29 μL, 0.21 mmol) in DMF (3 mL) under an atmosphere of nitrogen, a solution of sodium bis(trimethylsilyl)amide in THF (1M, 0.21 mL, 0.21 mmol) was added over a period of 0.5 h and stirred at the temperature for 30 min. Then additional sodium bis(trimethylsilyl)amide in THF (1M, 0.21 mL, 0.21 mmol) was added over a period of 0.5 h and stirred at the temperature for 1 h. The product mixture was concentrated under vacuum, and the residue partitioned between aqueous HCl and ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: Cl.Cl.Cl.[N:4]1([CH2:10][CH2:11][NH:12][C:13](=[O:22])[CH:14]=[CH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:23]1([CH:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[C:33]1([CH:29]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:30]([N:7]2[CH2:8][CH2:9][N:4]([CH2:10][CH2:11][NH:12][C:13](=[O:22])[CH:14]=[CH:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH2:5][CH2:6]2)=[O:31])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: O=C(C=Cc1cccnc1)NCCN1CCNCC1
Agent: Cl
Solvent: ClCCl
Product: O=C(C=Cc1cccnc1)NCCN1CCN(C(=O)C(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
8.0 g (22.6 mmol) N-[2-(piperazin-1-yl)-ethyl]-3-pyridin-3-yl-acrylic amide trihydrochloride (substance 317 as a trihydrochloride) and 13 ml (92.7 mmol) TEA are present in 100 ml absolute dichloromethane and cooled to ca. 0° C. under moisture exclusion. 6.3 g (24.9 mmol) diphenylacetyl chloride (90%) are dissolved in 70 ml absolute dichloromethane and added dropwise. The mixture is stirred overnight at RT without further cooling. Subsequently, 200 ml dichloromethane are added and the batch is washed three times each with 100 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is crystallized twice from 40 ml and 30 ml acetonitrile. Beige coloured crystals of MP. 1740° C. yield 4.6 g (44%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:5]=[C:4](Cl)[CH:3]=1.B([C:27]1[CH:28]=[CH:29][C:30]([O:36][CH3:37])=[C:31]([CH:35]=1)[C:32]([OH:34])=[O:33])(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:5]=[C:4]([C:27]2[CH:28]=[CH:29][C:30]([O:36][CH3:37])=[C:31]([CH:35]=2)[C:32]([OH:34])=[O:33])[CH:3]=1
Reactant: N#Cc1c(Cl)cc(Cl)nc1-c1ccc(Oc2ccccc2)cc1
Reactant: COc1ccc(B(O)O)cc1C(=O)O
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(Cl)c(C#N)c(-c3ccc(Oc4ccccc4)cc3)n2)cc1C(=O)O
Temperature: 85 °C
Yield: 98 %

Procedure:
A mixture of 4,6-dichloro-2-(4-phenoxyphenyl)nicotinonitrile (41.2 mg, 0.121 mmol, from Step 3 of Example 152), 5-borono-2-methoxybenzoic acid (18.9 mg, 0.096 mmol), palladium(II) acetate (4 mg, 0.018 mmol), potassium phosphate (125.8 mg, 0.593 mmol) and 1,1′-bis(di-t-butylphosphino)ferrocene (8.3 mg, 0.017 mmol) in N,N-dimethylformamide (0.5 mL) was pumped and backfilled with nitrogen twice. The reaction vial was then sealed and heated to 85° C. for 3 h. The crude material was poured into a mixture of ethyl acetate (20 mL) and diluted HCl (1 mmol, 5 mL). The aqueous pH was tested as pH 5. The ethyl acetate phase was concentrated and purified by reverse phase HPLC (Sunfire S10 30×250 mm column), eluting with 80-100% solvent B (10% methanol-90% water-0.1% TFA) in solvent A (90% methanol-10% water-0.1% TFA), to give impure 5-(4-chloro-5-cyano-6-(4-phenoxyphenyl)pyridin-2-yl)-2-methoxybenzoic acid (43 mg). This material was taken to next reaction without further purification. MS (ES+) m/z: 457 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7](C(OC(C)(C)C)=O)[C:6]=2[CH:5]=[C:4]([C:19]([O:21]C)=[O:20])[CH:3]=1.[F:23][C:24]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]2[C:25]=1[CH:26](O)[CH2:27][CH2:28][O:29]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH-].[Li+]>C1(C)C=CC=CC=1.O1CCCC1>[F:23][C:24]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]2[C:25]=1[CH:26]([O:1][C:2]1[C:10]3[N:9]=[C:8]([CH3:11])[NH:7][C:6]=3[CH:5]=[C:4]([C:19]([OH:21])=[O:20])[CH:3]=1)[CH2:27][CH2:28][O:29]2
Reactant: OC1CCOc2cc(F)cc(F)c21
Reactant: COC(=O)c1cc(O)c2nc(C)n(C(=O)OC(C)(C)C)c2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)O)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
To a stirred mixture of 1-(1,1-dimethylethyl) 6-methyl 4-hydroxy-2-methyl-1H-benzimidazole-1,6-dicarboxylate (1.33 g, 4.34 mmol, STEP 3 in Example 4), (+)-5,7-difluoro-3,4-dihydro-2H-chromen-4-ol (1.82 g, 9.79 mmol, STEP 8 in Example 2) and triphenylphosphine (2.28 g, 8.69 mmol) in toluene (50 mL) was added diisopropyl azodicarboxylate (DIAD) (1.76 g, 8.70 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes and concentrated in vacuum. The residue was dissolved in methanol (20 mL) and tetrahydrofuran (5 mL), and to the mixture was added 4M lithium hydroxide aqueous solution (18.0 mL, 90.0 mmol) at room temperature. After stirring for 1 hour at 80° C., the reaction mixture was concentrated in vacuum. The residue was dissolved with water (200 mL), acidified with 2M hydrochloric acid aqueous solution (50 mL), and extracted with ethyl acetate (200 mL×3). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography on silica gel (gradient elution from ethyl acetate only to ethyl acetate:methanol with 1 wt % of acetic acid=3:1) to afford the title compound as a white solid (1.15 g, 73%, >99% ee).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].C(O)C[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CCCCO.CCCCO.CCCCO.CCCCO.[Ti].C(O)C>[Si:5]([CH2:4][CH2:3][CH2:2][SH:1])([O:12][CH2:13][CH2:14][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])([O:6][CH2:7][CH2:8][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[O:9][CH2:10][CH2:11][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: CCO[Si](CCCS)(OCC)OCC
Agent: [Ti]
Solvent: CCO
Solvent: CCCCO
Product: CCCCCCCCCCCCCCCCO[Si](CCCS)(OCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCC
Temperature: 105 °C

Procedure:
2002.6 g of 3-mercaptopropyl(triethoxy)silane are mixed with 6108.5 g of hexadecanol as well as with 2 g of tetrabutyl orthotitanate and heated at 95-115° C. for 360 minutes in a 10 liter flask in a distillation apparatus. Ethanol formed in the transesterification is distilled off in vacuo at 15-600 mbar. After cooling, 7022 g of a colourless, solid product are obtained. As can be shown by 1H-NMR and 29Si-NMR, 92% of the EtO—Si groups are replaced by R—O—Si. In the transesterification more than 80 mole % of the ethanol-free compound [(C16H33O)3Si—C3H6—SH is formed, as can be shown for example by 1H-NMR and 29Si-NMR.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:19]=[CH:18][C:12]([C:13](OCC)=[O:14])=[CH:11][CH:10]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.O>[F:8][C:9]1[CH:19]=[CH:18][C:12]([C:13](=[O:14])[CH2:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][N:3]=2)=[CH:11][CH:10]=1
Reactant: Cc1ccncn1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1ccncn1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a stirred solution of 4-methylpyrimidine (20.64 g, 0.22 mol) and ethyl 4-fluorobenzoate (36.9 g, 0.22 mol) in dry THF (100 mL) at 0° C. under nitrogen was added lithium bis(trimethylsilyl)amide (1M in THF, 440 mL, 0.44 mol) over a 2 h period. A white precipitate deposited during the addition and this suspension was stirred at room temperature overnight. The reaction was diluted with 100 mL of water and filtered. The filtrate was washed with water (3×) and dried. The solution was diluted with ethyl acetate (100 mL) and the organic phase separated. The aqueous phase was further extracted with ethyl acetate (100 mL). Organic phases were dried (MgSO4) and concentrated and combined with the filtrate to give a combined yield of 47 g (98%) of product. 1H NMR (CDCl3) exists as a 2:1 mixture of enol:keto tautomers: 6 enol form: 5.95 (s, 1H), 6.92 (dd, J=1.2, 5.7 Hz, 1H), 7.06–7.14 (m, 2H), 7.83 (dd, J=5.4, 8.7 Hz, 2H), 8.40 (d, J=5.7 Hz, 1H), 8.8 (s, 1H); keto form: 4.42 (s, 2H), 7.12–7.18 (m, 2H), 7.34 (d, J=4.2 Hz, 1H), 8.06 (dd, J=5.3, 8.8 Hz, 2H), 8.67 (d, J=5.1 Hz, 1H), 9.16 (s, 1H); APESI-MS m/z 215 (M−1)−.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]2[C:5]([CH2:6][CH2:7][CH:8]3[C:12](O)([C:13]4[O:17][N:16]=[C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[C:14]=4[C:24]([F:27])([F:26])[F:25])[O:11][N:10]=[C:9]32)=[CH:4][C:3]=1[C:31]([O:33][CH3:34])=[O:32].N1C=CC=CC=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:30]=[C:29]2[C:5]([CH2:6][CH2:7][C:8]3[C:9]2=[N:10][O:11][C:12]=3[C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:14]=2[C:24]([F:27])([F:26])[F:25])=[CH:4][C:3]=1[C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)c1cc2c(cc1F)C1=NOC(O)(c3onc(-c4ccccc4)c3C(F)(F)F)C1CC2
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2c(cc1F)-c1noc(-c3onc(-c4ccccc4)c3C(F)(F)F)c1CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
To a stirred suspension of methyl 8-fluoro-3-hydroxy-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-3,3a,4,5-tetrahydronaphtho[1,2-c]isoxazole-7-carboxylate (Preparation 67B, 0.055 g, 0.115 mmol) in anhydrous toluene (1.0 mL) at room temperature was added pyridine (0.2 mL) followed by thionyl chloride (0.014 mL, 0.196 mmol). The reaction mixture was stirred at room temperature for 15 min. and then at 80° C. for 15 min. The reaction mixture was cooled to room temperature and concentrated. The solid residue was partitioned between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The dichloromethane extract was collected and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded methyl 8-fluoro-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carboxylate [0.050 g, 0.109 mmol, 94%] as an off white solid product. The product had an HPLC ret. time=3.28 min. (condition B). LC/MS M+1=459.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][OH:6].CO[C:18](OC)([CH3:20])[CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][O:6][C:18]([CH3:20])([CH3:19])[N:7]1[C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])=[O:15]
Reactant: COC(C)(C)OC
Reactant: COC(=O)C(CO)NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (34) in CH2Cl2, stirring under nitrogen at 0° C., was added 2,2-dimethoxypropane (29.5 mL, 237.9 mmol) and p-toluene sulfonic acid monohydrate (9.050 g, 47.58 mmol). The mixture was removed from the ice bath after 15 minutes and stirred at room temperature for 1.5 hours. The reaction mixture was poured into 50 mL of saturated NaHCO3 (aq) and extracted with diethyl ether (3×50). The organic layer was extracted with NaHCO3 and brine, then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on SiO2 (1:1 EtOAc/Hexanes) to yield 7.659 g (62%, 3 steps) of a clear liquid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:19]=[CH:18][C:10]2[N:11]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[N:12]=[N:13][C:9]=2[C:8]=1[Cl:20])(=O)=O.[OH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)(O)[O-].[Na+]>O1CCOCC1.O.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.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.[Pd]>[Cl:20][C:8]1[C:9]2[N:13]=[N:12][N:11]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:10]=2[CH:18]=[CH:19][C:7]=1[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][OH:23])=[CH:26][CH:27]=1
Reactant: O=S(=O)(Oc1ccc2c(nnn2CC2CC2)c1Cl)C(F)(F)F
Reactant: OCc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: OCc1ccc(-c2ccc3c(nnn3CC3CC3)c2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Chloro-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl trifluoromethanesulfonate (1.1 g, 3.1 mmol) was dissolved in a mixture of 1,4-dioxane and water (15 mL:3.0 mL) and treated with [4-(hydroxymethyl)phenyl]boronic acid (0.70 g, 4.6 mmol), potassium phosphate (2.0 g, 9.2 mmol) and palladium(0) tetrakis(triphenylphosphine) (0.18 g, 0.15 mmol). The mixture was placed into a preheated oil bath at 90° C. for 1 hour. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (150 mL, aqueous saturated) and extracted with ethyl acetate (2×250 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100:0 to 0:100; hexane:ethyl acetate) to afford the titled compound.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[F:14])=O)C.[CH3:16][NH:17][C:18]([NH2:20])=[S:19].N12CCCN=C1CCCCC2.CS(O)(=O)=O>C1(C)C=CC=CC=1.O>[F:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:20]=[C:18]([SH:19])[N:17]([CH3:16])[C:4](=[O:3])[CH:5]=1
Reactant: CNC(N)=S
Reactant: CCOC(=O)CC(=O)c1ccncc1F
Agent: CS(=O)(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1c(S)nc(-c2ccncc2F)cc1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A suspension of 3-(3-fluoropyridin-4-yl)-3-oxo-propionic acid ethyl ester (60.3 g, 286 mmol), N-methylthiourea (88 g, 976 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (48 g, 315 mmol) in toluene (600 ml) was heated at 100° C. for 5 hour. After addition of water (2000 ml) and methanesulfonic acid (30.3 g, 315 mmol) at room temperature and stirring for one hour, resulting precipitate was collected by filtration and dried to afford 6-(3-fluoropyridin-4-yl)-2-mercapto-3-methyl-3H-pyrimidin-4-one (46.3 g, 195 mmol, 68%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:15]3[C:11]([S:12][C:13]([C:19]([N:21]4[CH2:44][C@H:43]([F:45])[CH2:42][C@H:22]4[C:23]([N:25]4[CH2:32][C:29]5([CH2:31][CH2:30]5)[N:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:27][C@@H:26]4[CH2:40][OH:41])=[O:24])=[O:20])=[C:14]3[CH:16]([CH3:18])[CH3:17])=[N:10][C@:9]2([C:47]2[CH:48]=[N:49][C:50]([Cl:53])=[CH:51][CH:52]=2)[CH3:46])=[CH:4][C:3]=1[F:54].C(O)(=[O:57])C.C(O)(=O)C.IC1C=CC=CC=1.CC1(C)N([O])C(C)(C)CCC1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O>[C:36]([O:35][C:33]([N:28]1[CH2:27][C@H:26]([C:40]([OH:57])=[O:41])[N:25]([C:23](=[O:24])[C@@H:22]2[CH2:42][C@@H:43]([F:45])[CH2:44][N:21]2[C:19]([C:13]2[S:12][C:11]3=[N:10][C@:9]([C:47]4[CH:48]=[N:49][C:50]([Cl:53])=[CH:51][CH:52]=4)([CH3:46])[C@@H:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:54])[CH:4]=4)[N:15]3[C:14]=2[CH:16]([CH3:17])[CH3:18])=[O:20])[CH2:32][C:29]21[CH2:31][CH2:30]2)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(=O)O
Reactant: CC(C)C1=C(C(=O)N2C[C@H](F)C[C@H]2C(=O)N2CC3(CC3)N(C(=O)OC(C)(C)C)C[C@@H]2CO)SC2=N[C@@](C)(c3ccc(Cl)nc3)[C@@H](c3ccc(Cl)c(F)c3)N21
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: Ic1ccccc1
Product: CC(C)C1=C(C(=O)N2C[C@H](F)C[C@H]2C(=O)N2CC3(CC3)N(C(=O)OC(C)(C)C)C[C@@H]2C(=O)O)SC2=N[C@@](C)(c3ccc(Cl)nc3)[C@@H](c3ccc(Cl)c(F)c3)N21
Temperature: 25 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
The compound (100 mg, 0.12 mmol) obtained in Step 2 above was dissolved in a mixed solvent of acetonitrile (1.5 ml) and water (1.5 ml), iodobenzene diacetate (88 mg, 0.26 mmol) and 2,2,6,6-tetramethylpiperidine 1-oxyl (20 mg, 0.12 mmol) were added and the resulting mixture was stirred at room temperature for 4 hours. Aqueous sodium thiosulfate solution (4 ml) was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel chromatography [chloroform:methanol=40:1→10:1 (v/v)] to give the title compound (58 mg, 59%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ncn2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.5 %

Procedure:
To a solution of 4,6-dichloro-pyrimidine (8.9 g, 59.7 mmol) and triethylamine (11 mL, 78.9 mmol) in 90 mL of DCM at 0° C., was added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.89 g, 24.4 mmol). The mixture was stirred at room temperature for 3 days, concentrated under vacuum and purified by flash chromatography (eluent: 0 to 50% EtOAc in hexane with 0.1% triethylamine) to afford 3.09 g (40%) of 17a.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[S:9](=O)(=[O:12])([OH:11])[OH:10]>C(Cl)CCl>[Br:1][C:2]1[CH:7]=[C:6]([S:9]([OH:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[Br:8]
Reactant: O=S(=O)(O)O
Reactant: Brc1ccccc1Br
Solvent: ClCCCl
Product: O=S(=O)(O)c1ccc(Br)c(Br)c1
Reaction time: 2 h

Procedure:
Next, There was furnished a 300-ml four-necked flask equipped with a stirrer, condenser, and thermometer, which was charged with 90 g of 1,2-ethylene dichloride and 45 g (0.19 mol) of 1,2-dibromobenzene. While moderately passing nitrogen gas, 53.5 g (0.2 0 mol) of 30% fuming sulfuric acid was added dropwise, and react ion was effected at 70° C. for 2 hours. The reaction solution was cooled, followed by filtration and drying, obtaining 57 g of crude 3,4-dibromobenzenesulfonic acid.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[CH3:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[OH:14].P(=O)(O)(O)O.O>ClC1C=CC=CC=1Cl.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[OH:14][C:8]1[CH:9]=[C:10]2[C:11](=[C:12]([CH3:13])[C:7]=1[CH3:6])[CH2:1][CH2:2][C:3]2([CH3:5])[CH3:4]
Reactant: C=CC(=C)C
Reactant: Cc1cccc(O)c1C
Agent: O=P(O)(O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: Clc1ccccc1Cl
Solvent: O
Product: Cc1c(O)cc2c(c1C)CCC2(C)C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
449 g of isoprene, stabilised with 1.3 g of phenothiazine, were added dropwise in the course of 7 hours to a solution of 732 g of 2,3-dimethyl-phenol, 76.5 g of 85% strength phosphoric acid and 6 ml of water in 1.44 liters of o-dichlorobenzene at 150° C. To complete the reaction, stirring of the mixture was continued overnight at 150° C. The acid phase was separated off and the organic phase was washed until neutral. Fractional distillation gave 526 g of 5-hydroxy-3,3,6,7-tetramethyl-indan; boiling point: 165°-167° C./15 mm Hg; melting point: 117°-118° C. ##STR7##