Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[S:24][C:23]2[C:18](=[N:19][CH:20]=[CH:21][C:22]=2[O:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:35][C:36]3[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=3[F:43])=[O:34])=[C:28]([F:44])[CH:27]=2)[CH:17]=1)=[O:15])[C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:79]([NH2:81])[CH3:80].Cl>O1CCCC1.O>[CH2:79]([NH:81][C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]1[S:24][C:23]2[C:18](=[N:19][CH:20]=[CH:21][C:22]=2[O:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:35][C:36]3[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=3[F:43])=[O:34])=[C:28]([F:44])[CH:27]=2)[CH:17]=1)=[O:15])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:45])[CH3:80]
Reactant: CCN
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)O)sc34)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1
Temperature: 60 °C

Procedure:
To a stirred suspension of (2S)-5-tert-butoxy-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoic acid (100 mg, 0.16 mmol) in 10 ml of anhydrous tetrahydrofuran were added HATU (73 mg, 0.19 mmol) and N,N-diisopropylethylamine (62 mg, 0.48 mmol). The mixture was heated at 60° C. for 10 minutes, followed by addition of 2M ethylamine solution in THF (0.25 ml, 0.50 mmol). The mixture was heated at 60° C. for another 5 minutes, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3˜5% methanol in chloroform to give tert-butyl (4S)-5-(ethylamino)-4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoate as white solid. Yield: 73 mg, 70%.
Reaction SMILES: C([CH:3]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])[CH2:4][NH:5][C:6](=[O:12])OC(C)(C)C)C.Cl.[C:22](OC(=O)C)(=O)[CH3:23].CO.[CH:31](Cl)(Cl)Cl>>[CH2:22]([C:19]1[C:14]([NH:13][CH2:3][CH2:4][NH:5][C:6](=[O:12])[CH3:31])=[C:15]([OH:20])[CH:16]=[CH:17][CH:18]=1)[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: ClC(Cl)Cl
Reactant: CCC(CNC(=O)OC(C)(C)C)Nc1ccccc1O
Agent: Cl
Solvent: CO
Product: CCc1cccc(O)c1NCCNC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Degassed ethyl acetate (75 ml) was added to 5.5 g (19.6 mmol) 2-(ethyl)(2-hydroxyphenyl)aminoethylcarbamic acid, 1,1-dimethylethyl ester (6). To this was added 50 ml of 3N HCl and the reaction was stirred at ambient temperature overnight. TLC analysis was done using 30% EtOAc/hexanes. The reaction mixture was tranferred to a separatory funnel and extracted with 2×40 ml 1N HCl. The pooled aqueous layers were placed on the rotary evaporator and the volatiles removed. Water was added (about 50 ml) and removed by rotary evaporation, 2 cycles. The resulting oil was frozen in dry ice and placed under vacuum, then allowed to warm naturally to remove all volatiles. The resulting crispy material (7) was used without further purification, and kept free of air and moisture. Dry pyridine (75 ml) was added to the isolate by cannula. The flask was swirled to dissolve the material. Acetic anhydride (1.2 eq.) was added via syringe and the reaction was stirred under argon at ambient temperature. TLC analysis was performed with 10% methanol/chloroform. At the completion of the reaction, the pyridine was removed by rotary evaporation and the residue treated with 100 ml of 10% NaOH by stirring overnight under argon. The reaction was adjusted to pH 9 with 1N HCl and extracted with 4×75 ml ethyl acetate. The combined organic layers were washed with water, then brine (once each), pre-dried with Na2SO4, then dried overnight with MgSO4. The solution was collected by filtration and the volatiles were removed by rotary evaporation. The material was purified by flash chromatography on silica: loaded with 5% methanol/chloroform; eluted with 150 ml each of 3.3, 6.6, and 9.9% solvent as above to give 3-(ethyl)(2-acetylaminoethyl)aminophenol (8). Yield was 4.2 g (96%).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[C:4]1/[C:5]2[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:6]=2[O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]/1=2.[N+:23]([C:26]1[CH:34]=[CH:33][C:29]2[N:30]=[CH:31][NH:32][C:28]=2[CH:27]=1)([O-:25])=[O:24]>>[N+:23]([C:26]1[CH:34]=[CH:33][C:29]2[N:30]=[CH:31][N:32]([CH2:2]/[CH:3]=[C:4]3/[C:5]4[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:6]=4[O:7][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]/3=4)[C:28]=2[CH:27]=1)([O-:25])=[O:24]
Reactant: COC(=O)c1ccc2c(c1)/C(=C/CCl)c1ccccc1CO2
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Product: COC(=O)c1ccc2c(c1)/C(=C/Cn1cnc3ccc([N+](=O)[O-])cc31)c1ccccc1CO2

Procedure:
Compound h, 2.0 g, and 5.2 g of 5-nitrobenzimidazole were treated in a manner similar to Example 23 to give a 1:1 mixture of Compounds E-55a and E-56a. The mixture was separated and purified by silica gel column chromatography (eluting solvent, hexane:ethyl acetate:triethylamine=10:10:1) to give 1.1 g of methyl (E)-11-[2-(5-nitro-1-benzimidazolyl)ethylidene]-6,11-dihydiodibenz[b,e]oxepin-2-carboxylate (Compound E-55a) and 0.7 g of methyl (E)-11-[2-(6-nitro-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound E-56a).
Reaction SMILES: [CH3:1][C:2](Br)([CH3:17])[C:3]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>C(#N)C>[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:26][CH2:27][N:28]([CH2:1][CH:2]([CH3:17])[C:3]([C:5]3[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: COC(=O)COc1ccc(C(=O)C(C)(C)Br)cc1
Solvent: CC#N
Product: COC(=O)COc1ccc(C(=O)C(C)CN2CCN(c3ccncc3)CC2)cc1

Procedure:
A stirred mixture of methyl 4-(2,2-dimethylbromoacetyl)-phenoxyacetate (3.15 g), and 1-(4-pyridyl)piperazine (3.26 g) in acetonitrile (200 ml) was heated at reflux temperature for 4 days. The solvent was removed in vacuo and the residue partioned between dichloromethane/water. The organic phase was dried (MgSO4), evaporated and then purified by flash chromatography on silica, eluting with 2 to 5% v/v methanol/dichloromethane. Further purification by flash chromatography on neutral alumina, eluting with dichloromethane, gave the title compound, 350 mg, as a clear oil: NMR (d6DMSO) δ 8.12 (2H, d), 7.98 (2H, d), 7.04 (2H, d), 6.75 (2H, d), 4.92 (2H, s), 3.86 (1H,m), 3.71 (3H, s), 3.19 (.4H, t), 2.70 (1H, q), 2.49 (DMSO+4H), 2.36 (1H, q), 1.09 (3H, s), trace of dichloromethane; m/e 398 (H+H)+ ; calculated for C22H27N3O4.0.1 CH2Cl2 : C, 65.3; H, 6.7; N, 10.3. found: C, 65.1; H, 6.9; N, 10.1%.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([C:10]([O:12]C)=[O:11])=[CH:9][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[K+:22].[K+].O>CO>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([C:10]([O-:12])=[O:11])=[CH:9][C:5]=2[CH:4]=1.[K+:22]
Reactant: COC(=O)c1cc2cc(C(F)(F)F)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C([O-])c1cc2cc(C(F)(F)F)ccc2s1
Temperature: 80 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
A mixture of 5.00 g of methyl 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 2.93 g of potassium carbonate, 20 ml of water and 60 ml of methanol was stirred at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was recrystallized from water to obtain 3.74 g of potassium 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (hereinafter referred to as “the present compound 6”).
Reaction SMILES: N(C1C=CC=C(OC(F)(F)F)C=1)=C=O.[Cl:15][C:16]1[CH:17]=[C:18]([N:26]2[CH2:31][CH2:30][N:29]([C@H:32]([CH2:38][O:39][CH3:40])[CH2:33][CH2:34][C:35](O)=[O:36])[C:28](=[O:41])[C@@H:27]2[CH3:42])[CH:19]=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23].[CH2:43]1[C:45]2([CH2:50][CH2:49][NH:48][CH2:47][C@H:46]2[OH:51])[CH2:44]1>CCCCCCC.C(O)(C)C>[ClH:15].[CH2:21]1[C:20]2([CH2:19][CH2:18][NH:26][CH2:27][C@H:28]2[OH:41])[CH2:22]1.[Cl:15][C:16]1[CH:17]=[C:18]([N:26]2[CH2:31][CH2:30][N:29]([C@H:32]([CH2:38][O:39][CH3:40])[CH2:33][CH2:34][C:35]([N:48]3[CH2:49][CH2:50][C:45]4([CH2:43][CH2:44]4)[C@H:46]([OH:51])[CH2:47]3)=[O:36])[C:28](=[O:41])[C@@H:27]2[CH3:42])[CH:19]=[CH:20][C:21]=1[C:22]([F:24])([F:25])[F:23]
Reactant: COC[C@H](CCC(=O)O)N1CCN(c2ccc(C(F)(F)F)c(Cl)c2)[C@@H](C)C1=O
Agent: O=C=Nc1cccc(OC(F)(F)F)c1
Agent: O[C@@H]1CNCCC12CC2
Solvent: CCCCCCC
Solvent: CC(C)O
Product: COC[C@H](CCC(=O)N1CCC2(CC2)[C@H](O)C1)N1CCN(c2ccc(C(F)(F)F)c(Cl)c2)[C@@H](C)C1=O
Product: Cl

Procedure:
In analogy to intermediate 15, (S)-4-[(S)-4-(3-chloro-4-trifluoromethyl-phenyl)-3-methyl-2-oxo-piperazin-1-yl]-5-methoxy-pentanoic acid (61% ds) (intermediate 45) and 1.1 eq. of (S)-6-aza-spiro[2.5]octan-4-ol; hydrochloride (intermediate 2) gave after flash chromatography (SiO2, n-heptane/isopropanol 1:1) the titled compound in 30% yield (90% ds) as off-white waxy solid. MS: 532.22 (MH+, 1Cl).
Reaction SMILES: [N+](C1C=CC(C(O[C@@H:11]2[O:31][C@H:30]([CH2:32][O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@@H:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:12]2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)=CC=1)([O-])=O.[Cl:43][C:44]1[NH:45][C:46]2[C:52]([Cl:53])=[C:51]([Cl:54])[C:50]([Cl:55])=[CH:49][C:47]=2[N:48]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(Cl)Cl.CC#N.CCOC(C)=O>[CH2:14]([O:13][C@@H:12]1[C@H:21]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@H:30]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:31][C@H:11]1[N:48]1[C:47]2[CH:49]=[C:50]([Cl:55])[C:51]([Cl:54])=[C:52]([Cl:53])[C:46]=2[N:45]=[C:44]1[Cl:43])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Clc1nc2cc(Cl)c(Cl)c(Cl)c2[nH]1
Reactant: O=C(O[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Clc1cc2c(nc(Cl)n2[C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c(Cl)c1Cl
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 45 %

Procedure:
For the preparation of 1-O-chloro-2,3,5-tri-O-benzyl-D-ribofuranose, HCl gas was allowed to pass through a solution of 1-O-p-nitrobenzoyl-2,3,5-tri-O-benzyl-β-D-ribofuranose (1.479 g, 2.6 mmol) in 10 mL of dry CH2Cl2 at 0° C. for 15 min. The resulting suspension was quickly filtered and the filtrate was evaporated. The residue was coevaporated with dry MeCN and then dissolved in 5 mL of dry MeCN for immediate use in the subsequent glycosylation reaction. To a mixture of 13 (0.512 g, 2 mmol) in 10 mL of dry MeCN, was added 0.5 mL (2 mmol) of BSA. The reaction mixture was stirred at 75° C. for 20 min. This solution was treated with the above MeCN solution of the blocked carbohydrate and 0.464 mL (2.4 mmol) of TMSOTf at 70° C. for 20 min. The reaction mixture was cooled and diluted with EtOAc (50 mL). The EtOAc solution was washed with sat. NaHCO3 solution (50 mL×2), sat. NaCl solution (50 mL), dried (Na2SO4), and evaporated. The residue was chromatographed on a silica column (1.9×38 cm, eluted with hexane, 10%, 15% EtOAc/hexane). Evaporation of fractions 30-37 (15 mL per fraction) gave 0.593 g (45%) of 91a as a colorless syrup. MS: (EI) m/e 658.0780 (2%, M+ =658.0774). 1H NMR (DMSO-d6): d 7.93 (s, 1, 7-H), 7.35, 6.92 (2×m, 15, 3×PhCH2), 5.99 (d, 1, 1'-H, J1'-2' =8.0 Hz), 4.72, 4.58, 4.35 (3×m, 9, 2'-H, 3'-H, 4'-H, and 3×PhCH2), 3.76 (dd, 1, 5'-H, J4'-5' =2.0 Hz, J5'-5' =11.0 Hz), 3.65 (dd, 1, 5"-H, J4'-5" =2.5 Hz). 13C NMR (DMSO-d6): d 142.00 (C2), 138.40 (C3a), 137.81, 137.44, 136.74 (3×PhCH2), 131.34 (C7a), 128.08, 128.03, 127.59, 127.40, 127.32, 127.28, 126.97 (3×PhCH2 and C4), 124.64, 122.52 (C5 and C6), 112.65 (C7), 87.46 (C1'), 83.03, 77.08, 74.92 (C2', C3', and C4'), 72.43, 71.44, 71.28 (3×PhCH2), 69.22 (C5').
Reaction SMILES: N[C:2]([CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)=O.F[B-](F)(F)F.C([O+](CC)CC)C.[NH2:27][C:28]1[C:29]([NH:37][C@H:38]2[CH2:43][CH2:42][C@H:41]([CH2:44][C:45]#[N:46])[CH2:40][CH2:39]2)=[C:30]2[S:36][CH:35]=[CH:34][C:31]2=[N:32][CH:33]=1>O1CCCC1.C(O)C.CCOC(C)=O>[C:45]([CH2:44][C@H:41]1[CH2:40][CH2:39][C@H:38]([N:37]2[C:29]3=[C:30]4[S:36][CH:35]=[CH:34][C:31]4=[N:32][CH:33]=[C:28]3[N:27]=[C:2]2[CH:4]2[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:5]2)[CH2:43][CH2:42]1)#[N:46]
Reactant: N#CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Reactant: CC(C)(C)OC(=O)N1CC(C(N)=O)C1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(c2nc3cnc4ccsc4c3n2[C@H]2CC[C@H](CC#N)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 3-(aminocarbonyl)azetidine-1-carboxylate (156 mg, 0.779 mmol) and triethyloxonium tetrafluoroborate (280 mg, 1.5 mmol) in tetrahydrofuran (0.4 mL) was stirred at room temperature for 1 h and then concentrated. A mixture of {trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acetonitrile (39 mg, 0.14 mmol) and the above made reagent in ethanol (0.70 mL) was heated at reflux for 2 h. The mixture was cooled to room temperature, diluted with EtOAc, washed with sat. NaHCO3 solution, dried over MgSO4, concentrated and purified on silica gel column (0-5% MeOH in methylene chloride) to give the desired product. LCMS calculated for C24H30N5O2S (M+H)+: m/z=452.2. Found: 452.1.
Reaction SMILES: [Cl:1][C:2]1[S:17][C:5]2[C:6]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[O:7][CH2:8][C:9]([F:11])([F:10])[C:4]=2[CH:3]=1.[Cl:18][C:19]1[C:20]([N:25]2[CH:29]=[C:28]([CH:30]=O)[C:27]([CH3:32])=[N:26]2)=[N:21][CH:22]=[CH:23][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C.ClCCl>[Cl:1][C:2]1[S:17][C:5]2[C:6]3([O:7][CH2:8][C:9]([F:11])([F:10])[C:4]=2[CH:3]=1)[CH2:12][CH2:13][N:14]([CH2:30][C:28]1[C:27]([CH3:32])=[N:26][N:25]([C:20]2[C:19]([Cl:18])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:29]=1)[CH2:15][CH2:16]3
Reactant: FC1(F)COC2(CCNCC2)c2sc(Cl)cc21
Reactant: Cc1nn(-c2ncccc2Cl)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1nn(-c2ncccc2Cl)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To a solution of 2′-chloro-4′,4′-difluoro-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran] (0.2 g, 0.71 mmol) in 1,2-dichloroethane (5 mL) are added 1-(3-chloro-2-pyridyl)-3-methyl-pyrazole-4-carbaldehyde (0.19 g, 0.86 mmol) and a few drops of acetic acid. The reaction mixture is stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.315 g, 1.43 mmol) is added and stirred at room temperature for 14 hours. After completion, the reaction mixture is diluted with dichloromethane and washed with saturated sodium bicarbonate solution and brine. The organic phase is dried over sodium sulfate and concentrated in vacuo. The crude mixture is purified by HPLC to yield 0.195 g (56%) of 2-chloro-1′-[[1-(3-chloro-2-pyridyl)-3-methyl-pyrazol-4-yl]methyl]-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]. MS (m/z): 485 (M+1).
Reaction SMILES: [BH4-].[Na+].CO.[C:5]([C:7]1[C:15]2[S:14][C:13]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])=[N:12][C:11]=2[CH:10]=[CH:9][C:8]=1[O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([NH:30]C(=O)C(F)(F)F)[CH:24]=1)#[N:6]>C(O)C>[NH2:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[F:29])[O:22][C:8]1[CH:9]=[CH:10][C:11]2[N:12]=[C:13]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21]3)=[O:18])[S:14][C:15]=2[C:7]=1[C:5]#[N:6]
Reactant: N#Cc1c(Oc2ccc(F)c(NC(=O)C(F)(F)F)c2)ccc2nc(NC(=O)C3CC3)sc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: N#Cc1c(Oc2ccc(F)c(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of sodium borohydride (586 mg, 15.5 mmol) in ethanol (7 mL) was added dropwise methanol (3 ml). To this suspension was added N-(7-cyano-6-{4-fluoro-3-[(trifluoroacetyl)amino]phenoxy}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide (360 mg, 0.775 mmol). The reaction mixture was stirred at 60° C. for 1 hr, cooled to room temperature, and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (100 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=80/20→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (194 mg, 68%) as a white powder.
Reaction SMILES: [CH3:1][Si:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(Cl)[Cl:3].[OH2:11]>CCOCC>[CH3:1][Si:2]([Cl:3])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[O:11][Si:2]([Cl:3])([CH3:1])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[Si](Cl)(Cl)c1ccccc1
Reactant: O
Solvent: CCOCC
Product: C[Si](Cl)(O[Si](C)(Cl)c1ccccc1)c1ccccc1
Yield: 33.5 %

Procedure:
Methylphenyl dichlorosilane (765 g; 4.0 mol.) and the same amount of diethyl ether were introduced into a four-necked flask of 2 liters volume equipped with a stirring machine, a reflux condenser, a thermometer and a dropping funnel, followed by stirring the mixture, dropwise adding 36 g (2.0 mol.) of water through the dropping funnel over five hours under nitrogen atmosphere, and then refluxing the mixture for an additional three hours. After refluxing the mixture, ether was distilled off and the starting material, methylphenyl dichlorosilane (184 g; 0.96 mol.) was recovered by distilling the reaction mixture in vacuo to obtain 220 g (0.67 mol.) of 1,3-dimethyl-1,3-diphenyl dichlorodisiloxane. Boiling Point=135°-138° C. /2 mmHg.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[C:7]([O:10][C:11]1[C:19]([O:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14])(=[O:9])[CH3:8]>ClCCCl>[C:7]([O:10][C:11]1[C:19]([O:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([N:15]=[C:2]=[O:3])=[O:14])(=[O:9])[CH3:8]
Reactant: CC(=O)Oc1cccc(C(N)=O)c1OC(C)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: CC(=O)Oc1cccc(C(=O)N=C=O)c1OC(C)=O

Procedure:
Oxalyl chloride (5.3 g) was added to a solution of 2,3-diacetoxybenzamide (4.0 g) in 1,2-dichloroethane (40 ml) while stirring under cooling. The mixture was gradually heated to a reflux temperature and allowed to react under reflux for 10 hours. Then, the solvent and excess oxalyl chloride were distilled off under reduced pressure to give 2,3-diacetoxybenzoyl isocyanate, which was dissolved in dried dichloromethane (40 ml) for the subsequent reaction.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13]Cl)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[N:16]1(C(OC(C)(C)C)=O)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[I-].[Na+].C(N(CC)CC)C.FC(F)(F)C(O)=O>O1CCCC1>[C:1]([NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 71.3 %

Procedure:
N-tert-Butyl-3-(chloromethyl)benzamide (14.71 g, 65.2 mmol), tert-butyl piperazine-1-carboxylate (12.14 g, 65.2 mmol), sodium iodide (1.95 g, 13.0 mmol), triethylamine (27.3 mL, 195.5 mmol) and tetrahydrofuran (125 mL) were stirred together at room temperature for 18 hours. The reaction was then concentrated under vacuum and the residue dissolved in ethyl acetate. The organic mixture was washed consecutively with saturated aqueous sodium hydrogen carbonate solution, water (×2) and brine then concentrated under vacuum. The residue was dissolved in dichloromethane (100 mL), treated with trifluoroacetic acid (25.0 mL, 326.0 mmol) and stirred at 60° C. for 2.5 hours. The reaction was concentrated under vacuum and purified by strong cation exchange (SCX) chromatography, eluting macroporous polystyrene sulfonic acid with 2M ammonia in methanol. The resulting solution was concentrated under vacuum to give the title compound (12.8 g) as a white solid.
Reaction SMILES: [CH3:1][C@@:2]([S:23]([CH3:26])(=[O:25])=[O:24])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)=[CH:10][CH:9]=1)[C:3]([OH:5])=O.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[O:33][NH2:34].BrC1C=CC(CCC(C)(S(C)(=O)=O)C(NOC2CCCCO2)=O)=CC=1>>[CH3:1][C@@:2]([S:23]([CH3:26])(=[O:24])=[O:25])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([B:14]2[O:15][C:16]([CH3:21])([CH3:22])[C:17]([CH3:20])([CH3:19])[O:18]2)=[CH:10][CH:9]=1)[C:3]([NH:34][O:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][O:27]1)=[O:5]
Reactant: CC1(C)OB(c2ccc(CC[C@](C)(C(=O)O)S(C)(=O)=O)cc2)OC1(C)C
Reactant: NOC1CCCCO1
Agent: CC(CCc1ccc(Br)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Product: CC1(C)OB(c2ccc(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)cc2)OC1(C)C
Yield: 77.5 %

Procedure:
The title compound (7.2 g, 77%) was prepared from (2R)-2-methyl-2-(methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanoic acid (7.4 g, 19.3 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (3.3 g, 28 mmol) by a procedure analogous to that described for (+/−)-4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide as in Preparation 3 step C. LCMS m/z 480.8 (M−1).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[C:17]([F:29])=[CH:18][C:19]([CH3:28])=[C:20]([CH:27]=1)[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([NH:15][C:16]1[C:17]([F:29])=[CH:18][C:19]([CH3:28])=[C:20]([CH:27]=1)[C:21]([O:23][CH:24]([CH3:25])[CH3:26])=[O:22])=[O:14]
Reactant: CC1=C(C(=O)O)SCCO1
Reactant: Cc1cc(F)c(N)cc1C(=O)OC(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC1=C(C(=O)Nc2cc(C(=O)OC(C)C)c(C)cc2F)SCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
Thionyl chloride (4.7 g, 0.040 mole was added to a stirred mixture of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid (6.0 g, 0.037 mole) and methylene chloride (50 ml). The mixture was stirred overnight at room temperature, then evaporated under reduced Pressure. The solid residue, crude 5,6-dihydro-2-methyl-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride (50 ml) and the chilled solution treated dropwise over about 1 hour with a solution of 1-methylethyl 5-amino-4-fluoro-2-methylbenzoate (7.9 g, 0.037 mole) and triethylamine (3.9 g, 0.039 mole) in methylene chloride (50 ml). The reaction mixture was left stirring overnight at room temperature and worked up by washing in sequence with water (50 ml), dilute hydrochloric acid (3.5%, 50 ml), water (50 ml), dilute sodium hydroxide (2%, 25 ml) and water (50 ml). Evaporation of the solvent left a solid residue. Recrystallization from 100% ethanol (60 ml) gave yellow-tan crystals, m.p. 119°-122° C. (7.6 g, 57% yield).