Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:23](=[O:27])[C:24]([NH2:26])=[O:25])=[C:9]([CH3:22])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].CCOC(C)=O>CO>[NH2:26][C:24](=[O:25])[C:23]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:28])=[O:2])[N:10]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:9]=1[CH3:22])=[O:27]
Reactant: COC(=O)COc1cccc2c1c(C(=O)C(N)=O)c(C)n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
A mixture of 660 mg (1.7 mmol) of ((3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid methyl ester and 10 mL of 1N NaOH in 30 mL of methanol was heated to maintain reflux for 1 hour, cooled to room temperature and stirred for 0.5 hour. The mixture was concentrated at reduced pressure and the residue taken up in EtOAc/water. The aqueous layer was separated, made acidic to pH 2-3 with 1N HCl and extracted with EtOAc. On concentrating the EtOAc solution, 431 mg (69% yield) of ((3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid crystallized, melting at 218-220° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[OH2:13]>C(O)(=O)C.C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:12])[O:11][C:7](=[O:13])[NH:8][C:9]=2[CH:10]=1
Reactant: O
Reactant: O=C1Nc2cc(I)ccc2C1=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=c1[nH]c2cc(I)ccc2c(=O)o1
Temperature: 80 °C
Yield: 81.8 %

Procedure:
To a stirred warm (80° C.) solution of 6-iodo-1H-indole-2,3dione (3.0 g, 11 mM) in acetic acid (10 mL) and acetic anhydride (10 mL) was added in small portions chromium trioxide (1.83 g, 18.3 mM) while maintaining the temperature of the reaction mixture at 80°-90° C. The reaction mixture was then heated at 80° C. for 10 min, cooled and poured into water. The resulting mixture was filtered and the collected solids dried to provide the title compound as a yellow solid (2.6 g, 81.8%); MS(CI): 290 (M+H).
Reaction SMILES: [NH:1]1[C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=[CH:3][C:2]1=[O:10].COCCOC.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)(=O)C>C1COCC1>[OH:8][CH2:7][C:6]1[NH:1][C:2](=[O:10])[CH:3]=[CH:4][CH:5]=1
Reactant: O=C(O)c1cccc(=O)[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: COCCOC
Product: O=c1cccc(CO)[nH]1
Temperature: 0 °C
Yield: 31.7 %

Procedure:
1H-Pyridin-2-one-6-carboxylic acid (2.51 g, 18 mmol) was suspended in dry THF (30 ml) and 1,2-dimethoxyethane (10 ml) under argon. Lithium aluminium hydride (1.0 M in diethyl ether) (30 ml, 30 mmol) was added and the mixture heated to reflux. After 67 h heating was stopped, the mixture cooled to 0° C. and acetic acid (7 ml) added. The solvent was removed in vacuo and the residue purified by flash column chromatography on silica gel, eluting with 20–30% methanol in dichloromethane, to give the title compound as tan needles (0.714 g, 32%); δH (400 MHz; CD3OD) 4.47 (2H, s), 6.38 (1H, d, J 6.8), 6.41 (1H, d, J 9.2), 7.56 (1H, dd, J 6.8, 9.2); m/z (ES+) 126 (100%, [MH]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[C:5]([C:12]#[N:13])=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]([CH:31]2[CH2:33][CH2:32]2)CC2C=CC(OC)=CC=2)[C:18]2=[N:34][CH:35]=[C:36]([C:37]#[N:38])[N:17]2[N:16]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[C:5]([C:12]#[N:13])=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([NH:21][CH:31]2[CH2:33][CH2:32]2)[C:18]2=[N:34][CH:35]=[C:36]([C:37]#[N:38])[N:17]2[N:16]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)c(CCCO)cc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: COc1ccccc1
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)cc1CCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
2-((2-chloro-5-cyano-4-(3-hydroxypropyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (30 mg, 0.057 mmol) was taken up in DCE (0.6 mL) and anisole (0.031 mL, 0.284 mmol) was added, followed by TFA (0.175 mli, 2.268 mmol). The reaction was stirred at room temperature overnight. LCMS indicates formation of the TFA ester. The solvent was removed in vacuo and the material dissolved in 2N NH3 in MeOH. The solution was stirred at room temperature for 30 min. The solvent was removed in vacuo and the material was triturated with Et2O to remove the anisole. The material was purified by preparative HPLC to provide 2-((2-chloro-5-cyano-4-(3-hydroxypropyl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (6.2 mg).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.BrC[CH2:28][CH2:29][C:30]1[O:34][N:33]=[C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[N:31]=1>>[ClH:19].[C:35]([C:32]1[N:31]=[C:30]([CH2:29][CH2:28][CH2:21][S:20][C:15]2[C:12]3[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=3[CH:18]=[CH:17][C:16]=2[Cl:19])[O:34][N:33]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: CC(C)(C)c1noc(CCCBr)n1
Product: CC(C)(C)c1noc(CCCSc2c(Cl)ccc3c2CCNCC3)n1
Product: Cl

Procedure:
Use a method similar to the Example 387, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 5-(3-bromopropyl)-3-tert-butyl-[1,2,4]oxadiazole to give, after deprotection using a method similar to the General Procedure 1-4, the title compound as a white solid. MS (APCI+) m/z 380 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH3:10][NH:11][CH3:12]>C(O)C>[NH2:1][C:2]1[C:7]([N:11]([CH3:12])[CH3:10])=[N:6][C:5]([Br:9])=[CH:4][N:3]=1
Reactant: CNC
Reactant: Nc1ncc(Br)nc1Br
Solvent: CCO
Product: CN(C)c1nc(Br)cnc1N

Procedure:
2-Amino-3,5-dibromopyrazine (1.0 g) was dissolved in a solution of dimethylamine in ethanol (33% v/v; 20 ml) and the solution was heated under reflux for 18 hours. Volatile material was removed by evaporation and the residue was purified by elution with dichloromethane through a silica gel Mega Bond Elut column to give 2-amino-5-bromo-3-dimethylaminopyrazine (0.67 g); 1H NMR (d6 -DMSO): 2.75 (s, 6H), 6.1-6.2 (br s, 2H), 7.6 (s, 1H); mass spectrum (+ve CI): 217 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C@@H:16]([C:22]([N:24]1[CH2:47][CH2:46][CH2:45][C@H:25]1[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=1[N:40]1[CH:44]=[N:43][N:42]=[N:41]1)=[O:27])=[O:23])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=O)(C)(C)C>C(Cl)Cl>[CH3:19][C:18]([CH3:21])([CH3:20])[CH2:17][C@H:16]([C:22]([N:24]1[CH2:47][CH2:46][CH2:45][C@H:25]1[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[CH:32][C:31]=1[N:40]1[CH:44]=[N:43][N:42]=[N:41]1)=[O:27])=[O:23])[NH2:15]
Reactant: CC(C)(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCc1cc(C(F)(F)F)ccc1-n1cnnn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C[C@@H](N)C(=O)N1CCC[C@H]1C(=O)NCc1cc(C(F)(F)F)ccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TFA (1 mL) was added to a solution of N-(tert-butoxycarbonyl)-4-methyl-D-leucyl-N-[2-(1H-tetraazol-1-yl)-5-(trifluoromethyl)benzyl]-L-prolinamide (32 mg, 0.06 mmol) in dry CH2Cl2 (3 mL). The solution was stirred at room temperature for 30 min and was then concentrated in vacuo. The title compound was isolated by reverse phase HPLC as a white foam. 1H NMR (400 MHz, CD3OD)): δ 9.62 (s, 1H), 8.03 (s, 1H), 7.89 (dd, J=1.5, 8.2 Hz, 1H), 7.74 (d, J=8.3 Hz, 1H), 4.42 (d, J=15.6 Hz, 1H), 4.35 (d, J=15.6 Hz, 1H), 4.30 (dd, J=3.7, 8.6 Hz, 1H), 4.17 (apparent t, J=6.4 Hz, 1H), 3.83–3.78 (m, 1H), 3.62–3.56 (m, 1H), 2.25–2.18 (m, 1H), 2.15–1.85 (m, 4H), 1.64 (dd, J=6.8, 14.8 Hz, 1H), 1.01 (s, 9H). HRMS (ESI, M+H): 468.2324 (found); 468.2335 (calculated).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=[C:21]([C:22]([OH:24])=O)[C:4]=2[N:3]=1.C[N:32](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=[C:21]([C:22]([NH2:32])=[O:24])[C:4]=2[N:3]=1
Reactant: CN(C)C=O
Reactant: Cc1nc2c(C(=O)O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1nc2c(C(N)=O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of 2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carboxylic acid, prepared as described in Example 20 (100 mg) in DCM (20 mL) was added a drop of DMF. The solution was then cooled to 0° C. and then Oxalyl chloride (64 mg) was then added. The mixture was stirred at room temperature for 30 min. The solvent was removed in-vacuo to afford a white solid that used directly in the next step. To the solid dissolved in dry DCM (20 mL) was bubbled in NH3 at 0° C. for 5 min. The mixture was then concentrated in-vacuo to afford the desired product as a white solid (79 mg, 79%). 1H NMR (300 MHz, DMSO-d6): δ ppm 2.47 (s, 3H), 3.05 (t, 4H, J=4.5 Hz), 3.69 (t, 4H, J=4.5 Hz), 6.05 (s, 2H), 6.35 (d, 1H, J=7.5 Hz), 7.23 (s, 1H), 7.34 (t, 1H, J=7.5 Hz), 7.53 (s, 1H), 7.60-7.74 (m, 3H), 7.86 (d, 1H, J=7.5 Hz), 8.01 (d, 1H, J=9.0 Hz), 8.24 (d, 1H, J=9.0 Hz), 9.22 (s, 1H); LC-MS: m/e=401 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([OH:15])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[CH3:31][C:32]([Si:35](Cl)([CH3:37])[CH3:36])([CH3:34])[CH3:33]>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([O:15][Si:35]([C:32]([CH3:34])([CH3:33])[CH3:31])([CH3:37])[CH3:36])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1O
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 76 %

Procedure:
To a solution of (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate (1.0 equiv.) in dichloromethane (0.1 M solution) was added imidazole (1.1 equiv.), DMAP (0.1 equiv.), and TBDMSCl (1.1 equiv.) sequentially. The reaction mixture was stirred at room temperature for 20 h. After worked up with dichloromethane, the crude material was purified by silica column chromatography (10% to 20% EtOAc in hexanes) yielding (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4-(tert-butyldimethylsilyloxy)piperidine-1-carboxylate (76%). LCMS (m/z): 365.2 [(M-Boc)H+]; LC Rt=6.05 min.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(#N)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:20]2[CH2:19][CH2:18][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:22][CH2:21]2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)cc2)CC1
Temperature: 80 °C
Yield: 23.4 %

Procedure:
A mixture of 4-fluorobenzonitrile (3.6 g) and N-tert-butyloxycarbonylpiperazine (5.58 g) in acetonitrile (60 mL) was heated at 80° C. for 72 hours. The reaction mixture was then cooled to room temperature and then treated with a mixture of sodium bicarbonate solution and ethyl acetate (300 mL, 1:1, v/v). The organic phase was separated and then evaporated. The residue was subjected to chromatography on silica gel eluting with a mixtures of heptane and ethyl acetate (from 3:7 to 1:1, v/v) to give the title compound (2 g) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:37]>CCCCCCC>[NH2:37][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCCCCCC
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)s1
Temperature: 20 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
In 1 gal pressure reactor, a mixture of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (120 g) prepared in accordance with Step C, above, and ammonium hydroxide (28-30%, 2.4 L, 20 vol) was heated in the sealed pressure reactor to 98-103° C. and stirred at this temperature for 2 hours. The reaction was cooled slowly to room temperature (20° C.) and stirred overnight. The solids were filtered and washed with minimum amount of the mother liquor and dried under vacuum. The solids were added to a mixture of EtOAc (15 vol)/water (2 vol) and heated to complete dissolution at 60-70° C. and the aqueous layer was removed and discarded. The EtOAC layer was charged with water (1 vol) and neutralized with aq. HCl to ˜pH 5.4-5.5. and added water (1 vol). The aqueous layer was removed and discarded at 60-70° C. The organic layer was washed with water (1 vol) at 60-70° C. and the aqueous layer was removed and discarded. The organic layer was filtered at 60° C. and concentrated to 3 volumes. EtOAc (6 vol) was charged into the mixture and heated and stirred at 72° C. for 10 min, then cooled to 20° C. and stirred overnight. EtOAc was removed via vacuum distillation to concentrate the reaction mixture to ˜3 volumes. The reaction mixture was maintained at ˜65-70° C. for ˜30 mins. Product crystals having the same crystal form as those prepared in Example 58b (and preparable by the procedure of Example 58b), above, in heptanes slurry were charged. Heptane (9 vol) was slowly added at 65-70° C. The slurry was stirred at 65-70° C. for 2-3 hours and then cooled slowly to 0-5° C. The product was filtered, washed with EtOAc/heptane (3/1 v/v, 4 vol) and dried at 45° C. under vacuum to obtain N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (102.3 g, 88%).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:20])=[C:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1.CCOC(C)=O>CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:20])=[C:4]([N:12]([CH2:37][C:36]2[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH:5]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)Nc1cc(OC(F)F)cc(Br)c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(OC(F)F)cc(Br)c2Cl)cc1
Reaction time: 8 h
Yield: 72.9 %

Procedure:
tert-Butyl (3-bromo-2-chloro-5-(difluoromethoxy)phenyl)carbamate (2.78 g, 7.46 mmol) was dissolved in DMF (37.3 ml) at room temperature. NaHMDS (8.95 ml, 8.95 mmol) was added drop wise and the reaction mixture was stirred for 30 min before the addition of 4-methoxybenzyl chloride (1.321 ml, 9.70 mmol). The reaction was allowed to stir overnight. EtOAc (250 mL) was added and the organic layer was washed with 10% LiCl solution (2×, dried over Na2SO4 and concentrated. Column chromatography (120 g SiO2, 0 to 10% EtOAc-hexane gradient elution) afforded tert-butyl (3-bromo-2-chloro-5-(difluoromethoxy)phenyl)(4-methoxybenzyl)carbamate as a clear oil (2.68 g)
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([O:10]CC)=O.[NH2:21][CH2:22][C:23]([OH:25])=[O:24].[O-]CC.[Na+].Cl>CN(C=O)C.O>[OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:10]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2c(-c3cccs3)noc2c1O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CNC(=O)c1ncc2c(-c3cccs3)noc2c1O
Temperature: 25 °C
Yield: 75.8 %

Procedure:
Ethyl 7-hydroxy-3-(thiophen-2-yl)isoxazolo[4,5-c]pyridine-6-carboxylate (0.11 g, 0.38 mmol) was dissolved in 10 mL of DMF. Glycine (0.569 g, 7.59 mmol) and sodium ethoxide (0.387 g, 5.69 mmol) were added and the mixture was refluxed for 3 h. The mixture was cooled to room temperature and diluted with 70 mL of water. Concentrated hydrochloric acid was added dropwise until pH was 3. The resulting suspension was filtered and the solid was dried under vacuum to give 92 mg of the title compound. MS: (+) m/z 320.37 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17](I)[C:16]=3[O:22][CH2:23][CH3:24])[CH2:8]2)=[CH:4][CH:3]=1.[OH2:27].[CH3:28][N:29](C=[O:32])C>[C-]#N.[Zn+2].[C-]#N>[C:16]([OH:22])(=[O:32])[C:15]([OH:14])=[O:27].[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([C:28]#[N:29])=[CH:17][C:16]=3[O:22][CH2:23][CH3:24])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O
Reactant: CCOc1c(I)cccc1OCC1CN(Cc2ccc(Cl)cc2)CCO1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOc1cc(C#N)ccc1OCC1CN(Cc2ccc(Cl)cc2)CCO1
Product: O=C(O)C(=O)O
Temperature: 80 °C

Procedure:
A mixture of (±)-4-(4-chlorobenzyl)-2-[(2-ethoxy-iodophenoxy)methyl]-morpholine (1.0 g, 2.1 mmol), zinc cyanide (0.17 g, 1.4 mmol) and tetrakis(triphenylphosphino)palladium(O) (349 mg, 0.3 mmol) in DMF (15 ml) was heated to 80° C. for 3 h. Water was added and the solids were filtered off. The filtrate was extracted twice with ethyl acetate. Drying over magnesium sulfate was followed by evaporation. The crude product was dissolved in ether and an ethereal solution of oxalic acid was added to precipitate the product.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[S:24]([NH2:27])(=[O:26])=[O:25]>O1CCCC1>[NH2:27][S:24]([C:17]1[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=1[NH:15][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][Cl:8])(=[O:25])=[O:26]
Reactant: COc1ccc(N)c(S(N)(=O)=O)c1
Reactant: O=C(Cl)CCCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)CCCCl)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
144 mmol of triethylamine and then, dropwise, a solution containing 135 mmol of 4-chlorobutanoic acid chloride in 30 ml of tetrahydrofuran (THF), are added to a solution containing 96.4 mmol of 2-amino-5-methoxybenzenesulphonamide in 200 ml of THF. After stirring overnight at ambient temperature, the THF is evaporated off and the residue is taken up in water. Following extraction with ethyl acetate, the organic phase is washed and dried. After evaporation, the expected product is obtained in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[C:9]([N:17]=[C:18]=[S:19])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(C)=O>[C:9]([NH:17][C:18]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)=[S:19])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccnc(N)c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: Cc1ccnc(NC(=S)NC(=O)c2ccccc2)c1

Procedure:
A solution of 2-amino-4-methylpyridine (1.08 g, 10 mmol) and benzoyl isothiocyanate (1.63 g, 10 mmol) in acetone (15 mL) was stirred at RT for 1.5 h. The precipitate formed was filtered and washed with acetone to afford 1-benzoyl-3-[4-methylpyridin-2-yl]-thiourea as a solid. This material was stirred with 2 N NaOH solution (15 mL) at 110° C. for 1 h, then cooled to RT, and the precipitate formed was washed with water and dried to provide (4-methylpyridin-2-yl)-thiourea (0.90 g, 53%). MS m/z 168 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:12][C:11]([C:13](O)=[O:14])=[C:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:21]=[N+:22]=[N-:23].[Na+]>CC(C)=O.O.C(N(CC)CC)C.ClC(OCC)=O>[C:1]([O:5][C:6]([C:8]1[S:12][C:11]([C:13]([N:21]=[N+:22]=[N-:23])=[O:14])=[C:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1cc(OC(C)(C)C)c(C(=O)O)s1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1cc(OC(C)(C)C)c(C(=O)N=[N+]=[N-])s1
Reaction time: 0.25 h
Yield: 99882.2 %

Procedure:
A solution of tert-butyl-2-carboxy-3-tert-butoxy-5-thiophenecarboxylate (3 g, 0.01 mmol) in dry acetone (100 ml) was treated, at 0° C., with triethylamine (1.7 ml, 0.012 mmol) added dropwise. The mixture was stirred for 15 minutes and ethyl chloroformate (1.25 ml, 0.013 mmol) added dropwise, at 0° C. After 30 minutes, sodium azide (1.1 g, 0.017 mmol) in water (5 ml) was slowly added, at 0° C. After 4 hours, stirring at ambient temperature, the reaction mixture was filtered and the solvent evaporated. The oily residue was dissolved in CH2Cl2, and the solution washed (2×) with water, dried over MgSO4 and the solvent evaporated to give title compound (3.25 g, 100%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:9][CH2:8][NH:7][C:5](=[O:6])[CH2:4]1.[C:10]([S:13][CH2:14][C@@H:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[C:16](O)=[O:17])(=[O:12])[CH3:11].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:10]([S:13][CH2:14][C@@H:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[C:16]([NH:2][C@H:3]1[CH2:9][CH2:8][NH:7][C:5](=[O:6])[CH2:4]1)=[O:17])(=[O:12])[CH3:11]
Reactant: N[C@H]1CCNC(=O)C1
Reactant: CC(=O)SC[C@@H](Cc1ccccc1C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)SC[C@@H](Cc1ccccc1C)C(=O)N[C@H]1CCNC(=O)C1
Reaction time: 18 h

Procedure:
Prepare 3(S)-amino-δ-valerolactam hydrochloride according to the procedure of J. Chem. Soc. Dalton Trans., 1987, p. 1127. Combine this lactam (0.29 g,2.0 mmol), 2(S)-acetylthiomethyl-3-(2-methylphenyl)propionic acid (0.50 g,2.0 mmol), triethylamine (0.03 g,3.0 mmol), and HOBT (0.30 g,2.0 mmol) in DMF (20 ml). Add DEC (0.38 g,2.0 mmol). Stir 18 hr, partition between EtOAc and H2O, dry and concentrate. Chromatograph on silica, eluting with 3% MeOH/CH2Cl2 to obtain the title compound as a foam, [α]D26 =-28.6° (EtOH)