Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@@H:9]([NH2:15])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)=[O:4].[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@@H:9]([NH:15][C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1ccc2c(c1)SCC[C@@H]2N
Product: COC(=O)c1ccc2c(c1)SCC[C@@H]2NC(=O)OCc1ccccc1

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 4 using (S)-4-aminothiochromane-7-carboxylic acid methyl ester (3.80 g) and benzyloxycarbonyl chloride (3.65 ml), the objective (S)-4-(benzyloxycarbonylamino)thiochromane-7-carboxylic acid methyl ester (5.02 g) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)(=[O:27])=[O:26]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1c(S(=O)(=O)N2CCOCC2)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reaction time: 4 h

Procedure:
To a solution of ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate (149 mg, 0.322 mmol) in 5 mL of dichloromethane at 0° C. was added triethylamine (0.050 mL, 0.39 mmol), followed by morpholine (0.040 mL, 0.48 mmol). After four hours, the mixture was concentrated in vacuo to give the crude titled product. ESI+MS: 513.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1.[CH3:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:32]4[CH:31]=[CH:30][CH:29]=[C:28]([CH3:27])[CH:33]=4)=[CH:19][CH:18]=3)=[O:24])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(I)cc3)cc2s1
Reactant: Cc1cccc(B(O)O)c1
Product: Cc1cccc(-c2ccc(C(=O)Nc3ccc4nc(N(C)CCN(C)C)sc4c3)cc2)c1

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using N-{2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-4-iodo-benzamide (0.10 g, 0.21 mmol) and 3-methyl-phenyl boronic acid (0.037 g, 0.27 mmol) to afford 0.048 g (51%). LC/MS, Retention time=4.96 min; (m/z): calcd for C2H26N4OS (M+H)+: 445.6; found: 445.0.
Reaction SMILES: [N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:26][C:27]1[CH:32]=[N:31][CH:30]=[C:29](Cl)[N:28]=1>CN1C(=O)CCC1.C(=O)(O)[O-].[Na+]>[Cl:26][C:27]1[N:28]=[C:29]([N:10]2[CH2:11][CH2:12][CH:7]([CH:4]3[CH2:5][CH2:6][N:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][CH2:3]3)[CH2:8][CH2:9]2)[CH:30]=[N:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cncc(Cl)n3)CC2)CC1
Reaction time: 8 h

Procedure:
The tert-butyl 4,4′-bipiperidine-1-carboxylate (100 mg, 0.45 mmol) and cesium carbonate (364 mg, 1.1 mmol) were slurried in NMP (0.75 ml) and the 2,6-dichloropyrazine (67 mg, 0.45 mmol) added. The mixture was stirred at 70 C overnight. The slurry was diluted with 15% saturated sodium bicarbonate:water (40 ml) and extracted with DCM (3×25 ml). The combined organic fraction was washed with 4:1 water:saturated sodium bicarbonate (2×), brine, dried over magnesium sulfate, filtered, and the volatiles removed in vac. The crude material was purified by chromatography on silica gel with 20% acetone:hexanes to yield the title compound.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]1([C:25]2[N:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([C:25]2[N:26]=[CH:27][C:28]([NH:31][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:29][N:30]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: Nc1cnc(N2CCOCC2)nc1
Product: O=C(Nc1cnc(N2CCOCC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a procedure similar to example 1 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2-morpholin-4-yl-pyrimidin-5-yl)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 2-morpholin-4-yl-pyrimidin-5-ylamine. LCMS calcd for C19H16F3N5O3 (m/e) 419, obsd 420 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@H:17]([OH:36])[C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:21]=2)[NH2:19])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37](N1C=CN=C1)(N1C=CN=C1)=[O:38]>C1(C)C=CC=CC=1>[CH2:29]([O:28][C:22]1[CH:21]=[C:20]([C@@H:18]2[C@H:17]([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[O:36][C:37](=[O:38])[NH:19]2)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1ccc([C@@H](N)[C@@H](O)c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Product: COc1ccc([C@H]2NC(=O)O[C@H]2c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1

Procedure:
Mixture: 1.0 g (2.06 mmol) of rel-(1S,2R)-1,2-bis(3'-benzyloxy-4'-methoxyphenyl)-2-aminoethanol, 334 mg (2.05 mmol) of carbonyldiimidazole, 20 ml of toluene.
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:51]2[N:52]=[C:53]([NH:56]C(OC(C)(C)C)=O)[S:54][CH:55]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][NH:42]C(OC(C)(C)C)=O)[C:38]([CH3:50])=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:42][CH2:41][C:39]1[C:38]([CH3:50])=[N:37][N:36]([CH2:35][C@@H:27]2[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([OH:16])=[O:14])[CH2:19][CH2:18]3)/[C:51]3[N:52]=[C:53]([NH2:56])[S:54][CH:55]=3)[C:29](=[O:30])[N:28]2[S:31]([OH:34])(=[O:32])=[O:33])[N:40]=1
Reactant: Cc1nn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)nc1CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: Cc1nn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)nc1CN
Yield: 59.5 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (155 mg, 0.170 mmol), DCM (1.70 mL), anisole (37 μL, 0.34 mmol) anf TFA (0.787 mL, 10.2 mmol). The crude material was purified by reverse phase preparative HPLC (XSELECT C18, 5μ, 30×100 mm, ACN—H2O w/0.1% formic acid buffer, 60 mL/min), affording the title compound (55 mg, 57%) as an off-white solid. LCMS: Rt=0.49 min, m/z=544.1 (M+1) Method 2m_acidic_polar. 1H NMR (400 MHz, D2O) δ 7.04 (s, 1H), 5.46 (d, J=5.6 Hz, 1H), 4.91-4.84 (m, 1H), 4.84-4.76 (m, 1H), 4.62-4.56 (m, 1H assumed; obscured by solvent residual peak), 4.13 (s, 2H), 2.16 (s, 3H), 1.32-1.18 (m, 2H), 1.18-1.00 (m, 2H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]1[C:16]([Br:28])=[CH:17][C:18]2[C:23](=[O:24])[O:22][C:21]([CH3:26])(C)[O:20][C:19]=2[CH:27]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[CH2:7]([O:14][C:15]1[C:16]([Br:28])=[CH:17][C:18]([C:23]([O:22][CH3:1])=[O:24])=[C:19]([O:20][CH2:21][CH3:26])[CH:27]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC1(C)OC(=O)c2cc(Br)c(OCc3ccccc3)cc2O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCOc1cc(OCc2ccccc2)c(Br)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
Potassium carbonate (7.57 g) was added to a mixture of 7-(benzyloxy)-6-bromo-2,2-dimethyl-4H-1,3-benzodioxin-4-one (9.95 g) and methanol (50 mL), and the resultant mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and then, the solvent was distilled off under reduced pressure. Iodoethane (3.29 mL) was added to a DMF (50 mL) suspension of the obtained residue and potassium carbonate (7.57 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was allowed to cool to room temperature, and then, water was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (9.80 g).
Reaction SMILES: [CH3:1][N:2]([CH:10]([C:12]1[CH:13]=[N:14][C:15]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:16][CH:17]=1)[CH3:11])C(=O)OC(C)(C)C.C(OC(=O)C)C.[ClH:30]>>[ClH:30].[CH3:1][NH:2][CH:10]([C:12]1[CH:13]=[N:14][C:15]([O:18][CH2:19][C:20]([F:22])([F:23])[F:21])=[CH:16][CH:17]=1)[CH3:11]
Reactant: CC(c1ccc(OCC(F)(F)F)nc1)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNC(C)c1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42 %

Procedure:
tert-butyl methyl(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)carbamate (198 mg, 0.59 mmol, Step-2, single enantiomer) is dissolved in 4M hydrochloric acid ethyl acetate solution (3 mL). The mixture is stirred at room temperature for 1.5 hours. After concentration under reduced pressure, the residue is crystallized from n-hexane to give 68 mg (42% yield) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:4](C)([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C)C)[C:5](OCC)=O)(=[O:3])[CH3:2].[OH-].[Na+].Cl>CO.O>[OH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:4]([CH3:5])[C:1](=[O:3])[CH3:2]
Reactant: CCOC(=O)C(C)(CCCCCCO[Si](C)(C)C(C)(C)C)C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)C(C)CCCCCCO
Temperature: 50 °C
Yield: 65.5 %

Procedure:
Ethyl 2-acetyl-8-(tert-butyldimethylsilyloxy)-2-methyloctanoate (13.5 g, 37.65 mmol) was dissolved in 10 mL CH3OH to which 5 g NaOH in 50 mL water was then added. The mixture was then heated to 50° C. overnight. The volume of the reaction mixture was reduced to about 50 mL under reduced pressure and acidified to pH 1 by the addition of 2 M HCl. This resulting mixture was heated to 60° C. for 5 hours. After cooling to room temperature the product was extracted into EtOAc. Concentration gave a yellow oil that was subjected to silica gel chromatography affording a colorless oil (4.25 g, 65.5%). 1H-NMR (300 MHz, CDCl3): δ 3.60 (t, 2H) 2.46 (m, 1H), 2.09 (s, 3H), 1.54 (m, 4H), 1.30 (m, 6H), 1.04 (d, 3H) ppm; MS m/z calculated for C10H20O2 (M+H): 173.2. Found 173.1 (M+H, ESI+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C)C=O>[CH2:11]([O:10][C:6]1[CH:5]=[C:4]([Br:3])[CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cccc(OCc2ccccc2)c1

Procedure:
25.43 g (0.64 mol) of a 60% strength by weight sodium hydride dispersion in mineral oil are added in portions at room temperature to 100 g (0.58 mol) of commercially available 3-bromophenol in 600 ml of dimethylformamide, the mixture is stirred for a further half an hour, and 66.5 ml (0.58 mol) of commercially available benzyl chloride are added dropwise. The mixture is stirred at room temperature for 1 hour, 11 of water is added, and the solid which precipitates is filtered off, washed with water and recrystallized from 600 ml of isopropanol, giving 108 g of 3-benzyloxybromobenzene. ##STR12##
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][OH:12].[OH-].[Na+].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.ClCCl>O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:12][CH2:11][CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: OCCc1nc2ccccc2o1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: BrCCCCCCOCCc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 2-benzoxazoleethanol (1.46 g), 50% sodium hydroxide (3 ml), 1,6-dibromohexane (3 ml), TAB (100 mg) and dichloromethane (2 ml) was vigorously stirred at room temperature for 22 h, diluted with water (15 ml) and extracted with ether (40 ml). The organic phase was washed with brine (10 ml), dried and evaporated in vacuo. The residual oil was purified by FCC. Elution with hexane and hexane-ether (19:1) followed by hexane-ether (2:1) and ether gave the title compound as a pale yellow oil (1.60 g) which solidified on refrigeration.
Reaction SMILES: C(O[C:4]([C@H:6]1[C@@H:11]([N:12]([C:21](=[O:35])[CH2:22][C:23]2[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[S:25](=[O:34])(=[O:33])[N:24]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]2[CH2:36][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])C.[O-]CC.[Na+].Cl>C(O)C>[O:34]=[S:25]1(=[O:33])[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:23]([C:22]2[C:21](=[O:35])[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C@@H:11]3[C@H:6]([C:4]=2[OH:5])[C@@H:7]2[CH2:36][C@H:10]3[CH2:9][CH2:8]2)[NH:24]1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2ccccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1C(C2=Nc3ccccc3S(=O)(=O)N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
The crude (1S,2R,3S,4R)-3-[[2-(1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(4-fluoro-benzyl)-amino]-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester was dissolved in ethanol (8 mL), and a 21 wt. % solution of sodium ethoxide in ethanol (1.6 mL, 4.2 mmol) was added into the above solution. The mixture was stirred at 60° C. for 4 h and allowed to cool down to 25° C. The mixture was poured into 0.5 M aqueous hydrochloric acid solution (100 mL). The product started to precipitate and was collected by vacuum filtration. The precipitate was purified by flash column chromatography (Teledyne Isco RediSep column; 100% ethyl acetate) to afford the desired product, (1R,2S,7R,8S)-5-(1,1-dioxo-1,2-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.242 g, 0.517 mmol, 62.1% over two steps), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.16-1.22 (2H, m), 1.40-1.60 (4H, m), 2.51 (1H, bs), 2.64 (1H, d, J=2.1 Hz), 3.03 (1H, d, J=8.0 Hz), 3.54 (1H, d, J=9.3 Hz), 4.42 (1H, d, J=15.6 Hz), 4.97 (1H, d, J=15.7 Hz), 7.15 (2H, t, J=8.8 Hz), 7.33 (2H, dd, J1=8.0 Hz, J2=5.9 Hz), 7.45-7.53 (2H, m), 7.67-7.71 (1H, m), 7.85 (1H, d, J=7.9 Hz). LC-MS (ESI) calcd for C24H22FN3O4S 467.13. found 468.2 [M+H+]. Anal. calcd for C24H22FN3O4S: C, 61.66; H, 4.74; N, 8.99; found C, 61.96; H, 4.88; N, 8.99.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([N:11](CC2C=CC(OC)=CC=2)[CH3:12])[CH2:8][CH2:7][C@@H:6]1[N:22]1[CH2:26][CH2:25][C@H:24]([NH:27]C(=O)OCC2C=CC=CC=2)[C:23]1=[O:38])(=[O:3])[CH3:2]>CO.O[Pd]O>[NH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C@H:6]2[CH2:7][CH2:8][C@@H:9]([NH:11][CH3:12])[CH2:10][C@H:5]2[NH:4][C:1](=[O:3])[CH3:2])[C:23]1=[O:38]
Reactant: COc1ccc(CN(C)[C@@H]2CC[C@H](N3CC[C@H](NC(=O)OCc4ccccc4)C3=O)[C@H](NC(C)=O)C2)cc1
Agent: O[Pd]O
Solvent: CO
Product: CN[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](NC(C)=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
A sample of benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-((4-methoxybenzyl)(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (25.0 g, 47.8 mmol) was dissolved in MeOH. The flask was charged with dihydroxypalladium (6 g, 8.54 mmol), evacuated, and back filled with hydrogen from a hydrogen balloon. The mixture was stirred at RT overnight and then filtered (3×80 mL isopropanol washes). The residue was concentrated under high vacuum to dryness. The residue was dried azeotropically with iso-propanol (4×150 mL) under reduced pressure to afford N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(methylamino)cyclohexyl)acetamide (12.5 g, 46.6 mmol, 97% yield). LC/MS found [M+H]+=269.
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[C:25]([N:29]=[C:30]=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:30]([NH:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1
Reactant: Cc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Reactant: CC(C)(C)N=C=O
Agent: Cl
Product: Cc1ccc(C(OC2CN(C(=O)NC(C)(C)C)C2)c2ccccc2C(F)(F)F)cc1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4′-methylbenzhydryloxy]azetidine hydrochloride (151) (0.56 mmol) and tert-butyl isocyanate (0.56 mmol) using the procedure described for compound (10). The desired product was obtained as a colourless glass which gave a white solid on scratching (232 mg, 98%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH2:27][CH3:28])[N:25]=[CH:24][CH:23]=2)=[C:12]([F:29])[C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C>ClCCl.FC(F)(F)C(O)=O>[CH2:27]([N:26]1[C:22]([C@@H:18]2[CH2:19][CH2:20][CH2:21][C@H:17]2[O:16][C:13]2[CH:14]=[CH:15][C:10]([S:7]([NH:6][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][N:32]=3)(=[O:8])=[O:9])=[C:11]([F:30])[C:12]=2[F:29])=[CH:23][CH:24]=[N:25]1)[CH3:28]
Reactant: CCn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)c(F)c1F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1nccc1[C@@H]1CCC[C@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1F
Reaction time: 1 h

Procedure:
To a solution of the N-(2,4-dimethoxybenzyl)-4-{[(1S,2R)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (77.2 g, 129 mmol) prepared in Example 118b and triethylsilane (23 mL) in dichloromethane (230 mL), trifluoroacetic acid (230 mL) was added at room temperature, and the reaction solution was stirred for 1 hour. The reaction solution was concentrated, and the residue was purified with silica gel chromatography (ethyl acetate/methanol=9:1) to yield the title compound as a colorless solid. A suspension of this title compound in ethyl acetate (200 mL) was further irradiated with ultrasonic wave for 20 minutes. The suspension was filtered, and crystals collected by filtration were washed with ethyl acetate and dried at 40° C. for 24 hours to yield the title compound (44.4 g, 77%) as colorless crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:45])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[C:24]([NH:27][C:28]([CH:30]4[CH2:34][CH2:33][CH2:32][N:31]4[C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:36])=[O:29])[S:25][CH:26]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCCC(NC(=O)C2C=CC(C3N=C(NC(C4CCCN4C(OCC4C=CC=CC=4)=O)=O)SC=3)=CC=2)C1)=O)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[CH2:38]([O:37][C:35]([N:31]1[CH2:32][CH2:33][CH2:34][CH:30]1[C:28](=[O:29])[NH:27][C:24]1[S:25][CH:26]=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:15](=[O:45])[NH:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:17][CH:18]=2)[N:23]=1)=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(-c3csc(NC(=O)C4CCCN4C(=O)OCc4ccccc4)n3)cc2)CC1
Agent: CC(C)(C)OC(=O)N1CCCC(NC(=O)c2ccc(-c3csc(NC(=O)C4CCCN4C(=O)OCc4ccccc4)n3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CCNCC1)c1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 25 °C

Procedure:
4-(4-{2-[(1-Benzyloxycarbonyl-pyrrolidine-2-carbonyl)-amino]-thiazol-4-yl}-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester (Compound 5336 Example 336 100 mg, 0.16 mmol) was dissolved in 4 mL of 1:1 solution of CH2Cl2/TFA and stirred for 1.5 at room temperature. The reaction mixture was evaporated under reduced pressure to give pure desired product. MS: 534.2(M+H+); H1 NMR (MeOH-d4): δ(ppm) (HCl salt) 7.99 (m, 4H), 7.28 (m, 3H), 7.12 (d, 1H), 7.00 (d, 2H), 5.02 (m, 2H), 4.56 (m, 2H), 4.19 (m, 1H), 3.69 (m, 1H), 3.55 (m, 4H), 3.17 (t, 2H), 2.16 (m, 1H), 2.11 (m, 4H), 1.92 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:34][C:35]1[O:39][C:38](B(O)O)=[CH:37][CH:36]=1>COCCOC.O.C(OCC)(=O)C.C.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>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:38]4[O:39][C:35]([CH3:34])=[CH:36][CH:37]=4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: Cc1ccc(B(O)O)o1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccc(C)o2)cc1

Procedure:
4-Bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (32.96 g, 72.5 mmol) was suspended in 1,2-dimethoxyethane (300 ml) and treated with sodium carbonate (38.4 g, 363 mmol) dissolved in water (150 ml). (5-Methyl-2-furanyl)boronic acid (13.7 g, 109 mmol) and bis(triphenylphosphine)palladium(II) chloride (108 mg, 0.15 mmol) were added and the mixture was heated at reflux for 1.5 hours. The mixture was cooled and diluted with ethyl acetate, charcoal added and the mixture was stirred with charcoal for 45 minutes. The mixture was filtered through celite, the filtrate separated and washed with saturated sodium bicarbonate solution, water (×3), brine, dried over anhydrous sodium sulfate and concentrated to a crude solid, titrated with pentane and filtered. The combined residues were purified by flash chromatography (Biotage Flash 75+L, dichloromethane to 1:10 2M ammonia in methanol: dichloromethane) followed by trituration with pentane to give the title compound (E247). MS (ES+) m/e 456 [M+H]+.