Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[C:5]([CH:15]=[O:16])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.O>[CH2:23]([O:1][C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[C:5]([CH:15]=[O:16])=[CH:4][CH:3]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(O)c2oc3ccccc3c12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2ccccc2)c2oc3ccccc3c12
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 90.8 %

Procedure:
Intermediate 19 (1 gm, 5.10 mmol) was dissolved in dry DMF (10 ml). Anhydrous potassium carbonate (1.05 gm, 7.65 mmol) was added to the above solution and was stirred for 10 min. at 80° C. To this was added benzyl bromide (0.87 gm, 5.10 mmol) and the reaction mixture was stirred for 2 h. The reaction mixture was cooled to room temperature and diluted with water (100 ml) and extracted with ethyl acetate (3×50 ml). The organic extract was washed with water (50 ml) and brine solution (25 ml) and dried over anhydrous sodium sulfate. Removal of solvent gave the product as a brown solid (1.4 gm).
Reaction SMILES: [I:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[O-2:6].[O-2].[O-2].[Cr+6:9].[C:10]([O:14][C@@H:15]([C:18]1[C:42]([CH3:43])=[CH:41][C:21]2[N:22]=[C:23]([C:25]3[CH:26]=[CH:27][C:28](C4C=C5C(C=NN5C)=CC=4)=[N:29][CH:30]=3)[S:24][C:20]=2[C:19]=1[C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[CH2:16][OH:17])([CH3:13])([CH3:12])[CH3:11].[C:51](#[N:53])[CH3:52]>O>[I:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[O-2:14].[O-2:6].[O-2:2].[Cr+6:9].[C:10]([O:14][C@@H:15]([C:18]1[C:42]([CH3:43])=[CH:41][C:21]2[N:22]=[C:23]([C:25]3[CH:30]=[N:29][CH:28]=[C:27]([C:18]4[CH:15]=[C:52]5[C:21](=[CH:20][CH:19]=4)[N:22]([CH3:23])[N:53]=[CH:51]5)[CH:26]=3)[S:24][C:20]=2[C:19]=1[C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[C:16]([OH:17])=[O:6])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC#N
Reactant: Cc1cc2nc(-c3ccc(-c4ccc5cnn(C)c5c4)nc3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Agent: [Cr+6]
Agent: [O-2]
Agent: [O-][I+3]([O-])([O-])O
Solvent: O
Product: Cc1cc2nc(-c3cncc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A stock solution of periodic acid/chromium trioxide was prepared according to WO 99/52850 by dissolving periodic acid (11.4 g, 50.0 mmol) and chromium trioxide (23 mg, 1.2 mol %) in wet acetonitrile (0.75% H2O) to a volume of 114 mL. This stock solution (0.3 mL) was added to a solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(1-methyl-1H-indazol-6-yl)pyridin-5-yl)benzo[d]thiazol-6-yl)ethanol (15 mg, 0.027 mmol) in 0.75% H2O in ACN (3 mL). The reaction mixture was stirred at rt for 45 minutes, quenched with saturated Na2SO3 solution and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, concentrated and purified by reverse phase HPLC (H2O/ACN+0.1% TFA) to give the desired product after lyophilization. LCMS-ESI+: calc'd for C33H30ClN4O3S: 597.2 (M+H+); found: 597.2, 599.2. 1H NMR (400 MHz, CD3OD) δ 9.13 (s, 1H), 8.98 (s, 1H), 8.67 (s, 1H), 8.16 (s, 1H), 8.12 (s, 1H), 7.92 (s, 1H), 7.83 (dd, J=8.8, 1.6 Hz, 1H), 7.73 (dd, J=13.4, 5.2 Hz, 2H), 7.60 (d, J=8.0 Hz, 3H), 5.27 (s, 1H), 4.11 (s, 3H), 2.63 (s, 3H), 0.98 (s, 9H) (115).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:9]=1[CH:16]([C:22](OCC)=[O:23])[C:17](OCC)=[O:18].C(N(CCCC)CCCC)CCC>[OH-].[Na+]>[OH:18][C:17]1[C:16]([C:9]2[C:10]([F:15])=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[F:7])=[C:22]([OH:23])[N:3]2[N:4]=[CH:5][CH:6]=[C:2]2[N:1]=1
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Product: Oc1nc2ccnn2c(O)c1-c1c(F)cc(F)cc1F
Temperature: 175 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A mixture of 3-amino-pyrazole (0.06 mol), diethyl (2,4,6-trifluorophenyl)-malonate (0.06 mol, obtained from Example 1) and tributylamine (30 ml) was heated with reflux at 175° C. for four hours. The reaction mixture was cooled to 100° C. Aqueous sodium hydroxide (10.3 g/120 ml H2O) was added and the reaction mixture was stirred for 30 min. and cooled to ambient temperature. The organic Phase was separated off and the aqueous Phase was extracted with diethylether. The aqueous Phase was acidified with concentrated hydrochloric acid. The precipitate was collected by filtration and dried to yield 15.7 g (93 %) of the pale yellow product having a melting point of 280° C.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(O)C>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCOC(=O)C(=O)OCC
Reactant: C=C(C)C(=O)OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: CCO
Product: C=C(C)C(=O)OCCOC(=O)C(=O)OCC
Yield: 76.5 %

Procedure:
A 500 ml flask equipped with a decanter, a thermometer, a stirrer and an inlet for nitrogen gas was charged with 65.1 g (0.5 mol) of 2-hydroxyethyl methacrylate and 365.4 g (2.5 mol) of diethyl oxalate, to which 2 g (10 mmol) of p-toluenesulfonic acid (catalyst) and 4 g of hydroquinone (polymerization inhibitor) were added. The mixture was heated to keep 120° C. for4 hours in nitrogen atmosphere with distilling 14 ml (0.25 mol) of ethanol away. The reaction mixture was evaporated to remove excess diethyl oxalate and then distilled under vacuum to obtain 88.1 g (yield 76.5%) of 2-ethoxalyloxyethyl methacrylate (colorless transparent liguid) (bp 98° C./0.3 mmHg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[C:3]=1[F:12].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:13]([O:20][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[C:3]=1[F:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
1,2,3-Trifluoro-4-nitrobenzene (30 g, 0.17 mol), benzyl alcohol (18.4 g, 0.17 mol) and K2CO3 (35 g, 0.25 mol) were combined in DMF (300 mL) and were stirred at RT for 8 h. Water (300 mL) was added, and the mixture was extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine, dried (MgSO4), concentrated in vacuo and purified by column chromatography on silica gel to give 1-benzyloxy-2,3-difluoro-4-nitrobenzene (16 g, 36% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.06 (m, 1H), 7.49-7.30 (m, 6H), 5.37 (s, 2H).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH2:5]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[CH2:5]([N:12]([CH2:13][CH2:14][CH2:15][CH3:16])[C:1]([Cl:4])=[O:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCCCNCc1ccccc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCN(Cc1ccccc1)C(=O)Cl

Procedure:
A solution of 20.0 g of phosgene in 100 ml. of toluene is stirred at 0° C. while a solution of 32.6 g. of N-benzyl-n-butylamine in 50 ml. of toluene is added during 15 minutes. The mixture is filtered and the filtrate is evpaorated. The residue is evaporatively distilled at 105° C. under reduced pressure (250-350 microns) to yield N-benzyl-N-(n-butyl)carbamyl chloride as a colorless liquid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)C.[O-]CC.[Na+].Br[CH2:20]/[CH:21]=[CH:22]/[CH2:23]Br.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:10]([O:9][C:1]([C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:23][CH:22]1[CH:21]=[CH2:20])=[O:8])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrC/C=C/CBr
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C=CC1CC1(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 110.6 %

Procedure:
35.4 g (221 mmol) of diethyl malonate and 402 mL of toluene were added into a three-necked flask (1 L), and thereafter, 82.7 mL (211 mmol) of a 20% sodium ethoxide ethanol solution was added thereto as a base. The obtained mixture was stirred at room temperature for 0.5 hours, and 21.5 g of trans-1,4-dibromo-2-butene (101 mmol; a reagent manufactured by Sigma-Aldrich) was then added to the reaction solution. The obtained mixture was stirred at room temperature for 22 hours, and 241 mL of a 1 M sodium hydroxide aqueous solution was then added to the reaction solution. The mixture was stirred for 1 hour, and an organic layer was then separated. A water layer was re-extracted with 240 mL of toluene, and organic layers were then gathered. The gathered organic layer was washed with 240 mL of water three times. The resultant was filtrated, while washing the residue with toluene. The obtained filtrate was concentrated at 45° C. under reduced pressure, so as to obtain 23.6 g of 1,1-di-ethoxycarbonyl-2-vinylcyclopropane in the form of a crude product of a light yellow oily substance. This crude product contained 21.2 g of 1,1-di-ethoxycarbonyl-2-vinylcyclopropane (yield: 99%).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[N+:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=O)=[CH:28][CH:27]=1)([O-:25])=[O:24].O>O1CCOCC1>[N+:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](=[S:10])[NH2:32])=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: C1COCCO1
Product: NC(=S)c1ccc([N+](=O)[O-])cc1
Yield: 119.3 %

Procedure:
6.06 g (15 mmol) of Lawesson reagent is added to a solution of 4.15 g (25 mmol) of 4-nitrobenzamide in 100 ml of 1,4-dioxan. The reaction mixture is heated under reflux for two hours. After the solution has returned to ambient temperature, it is poured into 150 ml of water and extracted with 5 times 100 ml of ethyl acetate. The organic solution is dried over magnesium sulphate, filtered and concentrated under vacuum in order to produce a yellow oil which is purified on a silica gel column (eluant: heptane/ethyl acetate 1/1). The pure fractions are collected and concentrated under vacuum. 3.26 g of a yellow powder is obtained with a yield of 72%. Melting point: 165-167° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([NH2:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25](=O)[CH2:26][C:27](OCC)=[O:28])=[CH:22][CH:23]=2)[CH:18]=[N:17]1)[CH3:15].CC1C=CC(S(O)(=O)=O)=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[NH:13][C:11]4[N:10]([N:9]=[C:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[N:12]=4)[C:27](=[O:28])[CH:26]=3)=[CH:22][CH:23]=2)[CH:18]=[N:17]1)[CH3:15]
Reactant: CCOC(=O)CC(=O)c1ccc2c(cnn2CC)c1
Reactant: Nc1nc(-c2ccc(F)cc2)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCn1ncc2cc(-c3cc(=O)n4nc(-c5ccc(F)cc5)nc4[nH]3)ccc21
Reaction time: 2.5 h
Yield: 32.9 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1H-1,2,4-triazol-5-amine (100 mg, 0.56 mmol) in diphenyl ether (1 ml) was added ethyl 3-(1-ethyl-1H-indazol-5-yl)-3-oxopropanoate (400 mg, 1.540 mmol) and TsOH (6 mg, 0.03 mmol), and the resulting mixture was strirred for 2.5 h at 170° C. The reaction mixture was then quenched by the addition of ethyl ether (8 ml). The solids were collected by filtration and washed with dichloromethane (5 ml) to afford 5-(1-ethyl-1H-indazol-5-yl)-2-(4-fluorophenyl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a light yellow solid (69 mg, 24%).
Reaction SMILES: [OH:1][C@H:2]([C@H:4]1[CH2:8][N:7]([C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:6](=[O:17])[CH2:5]1)[CH3:3].C1([C@H](N)C)C=CC=CC=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:1][C@H:2]([C@@H:4]1[CH2:5][C:6](=[O:17])[N:7]([C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH2:8]1)[CH3:3])(=[O:37])=[O:36]
Reactant: C[C@H](O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Agent: C[C@@H](N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](OS(C)(=O)=O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-4-((S)-1-hydroxyethyl)-1-((R)-1-phenylethyl)pyrrolidin-2-one 1.16 (prepared in an analogous fashion to Example 1.05, but starting the sequence with (R)-1-phenylethanamine in place of (R)-1-(4-methoxyphenyl)ethanamine) (300 mg, 1.28 mmol) in DCM (6 mL) was added triethylamine (0.25 mL, 1.8 mmol) and the reaction mixture was cooled to 0° C. Then methanesulfonyl chloride (0.11 mL, 1.4 mmol) was added and stirred at the same temperature for 30 min. The reaction mixture was then diluted with DCM and washed successively with 1N HCl, brine and dried over anhydrous magnesium sulfate. The residue was purified by flash column chromatography (SiO2, 80% EtOAc/hexanes to 100% EtOAc) to give (S)-1-((R)-5-oxo-1-((R)-1-phenylethyl)pyrrolidin-3-yl)ethyl methanesulfonate 1.17.
Reaction SMILES: CN(C=O)C.[CH2:6]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21](OS(C(F)(F)F)(=O)=O)[C:20]([S:34][CH3:35])=[CH:19]2)[CH2:7][CH2:8][CH2:9][CH2:10]CCCCC>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:25]([C:24]1[CH:23]=[C:22]2[C:6](=[CH:7][CH:8]=1)[CH:16]=[C:19](/[CH:18]=[CH:17]/[C:21]1[C:20]([S:34][CH3:35])=[CH:19][C:18]3[C:23](=[CH:24][CH:25]=[C:16]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:17]=3)[CH:22]=1)[C:20]([S:34][CH3:35])=[CH:21]2)[CH2:16][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:24][CH2:23][CH3:22]
Reactant: CCCCCCCCCCc1ccc2cc(OS(=O)(=O)C(F)(F)F)c(SC)cc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCc1ccc2cc(/C=C/c3cc4ccc(CCCCCCCCCC)cc4cc3SC)c(SC)cc2c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 257.7 %

Procedure:
Pd(PPh3)4 (322 mg, 0.29 mmol, 7 mol %) was added to a DMF (40 ml) solution of 6-decyl-3-methylthio-2-(trifluoromethanesulfonyloxy)naphthalene (compound (4)-81) (1.9 g, 4.1 mmol) and 1,2-bis(tributylstanyl)ethylene (compound (5)-05). The mixture was heated and stirred at 90° C. for 17 hours in a dark place, diluted with water, and extracted with chloroform. The extracted solution was dried with MgSO4, and condensed. The residue was refined by column chromatography (silica gel, developed with dichloromethane) to obtain trans-1,2-bis(6-decyl-3-methylthionaphthalen-2-yl)ethylene (compound (6)-64) (2.3 g, quantitative) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24](=[O:37])[C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH2:32][CH2:33][NH:34][CH2:35][CH:36]=3)=[CH:27][CH:26]=2)(=[O:22])=[O:21])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:3])=[O:2].[BH3-]C#N.[Na+].[OH-].[Na+].[N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH:50]=O)[CH:45]=1>C(O)(=O)C.CO>[N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24](=[O:37])[C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH2:36][CH2:35][N:34]([CH2:50][C:46]4[CH:45]=[N:44][CH:49]=[CH:48][CH:47]=4)[CH2:33][CH:32]=3)=[CH:27][CH:26]=2)(=[O:21])=[O:22])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:3])=[O:2]
Reactant: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(C2=CCNCC2)cc1
Reactant: O=Cc1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(C2=CCN(Cc3cccnc3)CC2)cc1

Procedure:
A mixture of Example 340A (65 mg, 0.1 mmol), NaBH3CN (48 mg, 0.75 mmol), 2N NaOH (0.15 mL), and 3-pyridinecarboxaldehyde (214 mg, 2 mmol) in acetic acid (0.5 mL) and methanol (1 mL) was stirred for 16 hours. The reaction mixture was concentrated, dissolved in 1:1 DMSO/methanol (1.0 mL) and purified by reverse phase preparative HPLC using 20-90% acetonitrile/water containing 0.1% TFA to provide the desired product. MS (ESI(−)) m/e 628 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ8.78 (br t, 1H), 8.70 (d, 1H), 8.70 (dd, 1H), 8.60 (d, 1H), 8.05 (m, 1H), 7.95 (d, 2H), 7.62 (d, 2H), 7.60 (dd, 1H), 7.40-7.15 (m, 6H), 6.35 (m, 1H), 4.52 (d, 2H), 3.92 (m, 4H), 3.45 (t, 4H), 2.82 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][CH3:13])[CH2:8][CH2:7]1.Cl[C:19]1[N:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=1.C(N(C(C)C)CC)(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([N:12]([CH3:13])[C:19]2[N:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:10][CH2:11]1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: CNC1CCN(Cc2ccc(F)c(F)c2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN(c1ccc(C(F)(F)F)nn1)C1CCN(Cc2ccc(F)c(F)c2)CC1

Procedure:
A solution of D5 (480 mg, 2 mmol), 3-chloro-6-trifluoromethylpyridazine (182 mg, 1 mmol) and diisopropylethylamine (260 mg, 2 mmol) in n-butanol (4 ml) was heated at 190° C. in a microwave reactor (Emrys Optimizer; 0-9 Barr) for 2 h. After this period, the reaction mixture was evaporated in vacuo and the residue extracted with dichloromethane. The organic layer was washed with a saturated solution of sodium hydrogen carbonate, dried (MgSO4) and the solvents evaporated in vacuo. Purification by reverse phase HPLC (conditions as previously described) gave E12 (210 mg, 54%). C18H19F5N4 requires 386; Found 387 (MH+). 1H NMR (CDCl3) δ 1.74 (br.d, J=12.0 Hz, 2H), 1.88 (qd, J=12.0, 3.9 Hz, 2H), 2.17 (td, J=11.8, 2.5 Hz, 2H), 2.96 (br.d, J=11.6 Hz, 2H), 3.00 (s, 3H), 3.47 (s, 2H), 4.85 (t, J=12.1 Hz, 1H), 6.78 (d, J=9.6 Hz, 1H), 6.99-7.05 (m, 1H), 7.10 (dt, J=10.2, 8.1 Hz, 1H), 7.20 (ddd, J=11.4, 7.8, 2.1 Hz, 1H), 7.46 (d, J=9.6 Hz, 1H)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[NH:9][C:10]([S:20][CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[O:22]([CH3:24])[Na]>CO.O>[CH2:21]([S:20][C:10]1[NH:9][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([O:22][CH3:24])[CH:7]=2)=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:11]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CSc1nc(-c2ccc(F)cc2)c(-c2ccnc(Cl)c2)[nH]1
Reactant: CO[Na]
Solvent: CO
Solvent: O
Product: COc1cc(-c2[nH]c(SCc3ccccc3)nc2-c2ccc(F)cc2)ccn1

Procedure:
A suspension of 25a (0.1 g; 0.25 mmol) in methanolic NaOCH3 solution (30%, 2 ml) was diluted with methanol (5 ml) and stirred under reflux for 13 h. The reaction mixture was diluted with H2O and the aqueous solution was extracted with CH2Cl2 (3×). The combined organic extract was washed with saturated NaCl solution, dried over Na2SO4 and concentrated. The oily residue was purified by column chromatography (SiO2 60, CH2Cl2/ethyl acetate 1+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:52]([CH:55]2[CH2:57][CH2:56]2)(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[C:31]([N:35]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N:30][CH:29]=[C:28]3[F:50])[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:58](Cl)(Cl)=[O:59]>C(#N)C.ClCCl>[C:38]([O:37][C:36]([N:35]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=4[S:52]([CH:55]4[CH2:56][CH2:57]4)(=[O:54])=[O:53])[NH:1][C:58](=[O:59])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:23])=[CH:34][CH:33]=2)[C:28]([F:50])=[CH:29][N:30]=1)[C:43](=[O:44])[O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:42])([CH3:40])([CH3:39])[CH3:41]
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c3c2)C(=O)N(C)Cc2cc(N)ccc2S(=O)(=O)C2CC2)ccc1[C@@H](C)CO
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1ccc(S(=O)(=O)C3CC3)c(c1)CN(C)C(=O)[C@@H]2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c2c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 34.5 %

Procedure:
To a solution of 19A (135 mg, 0.168 mmol) in acetonitrile (6 mL) and dichloromethane (3 mL) at 0° C., was added phosgene solution (20% in toluene, 0.106 mL, 0.201 mmol) dropwise. The mixture was stirred at 0° C. for 40 min, then at rt for 10 min. Extra phosgene was removed by bubbling Ar for 20 min. The crude was redissolved in acetonitrile (1.0 mL) and dichloromethane (1.0 mL), and was added dropwise via syringe pump into a solution of TEA (0.187 mL, 1.340 mmol) in dichloromethane (60 mL) at rt over 3.0 h. The solution was stirred at rt over night. The solvent was removed and the crude residue was purified using a prep HPLC equipped with a C18 PHENOMENEX® Luna Axia column (30 mm×75 cm, 5μ). The desired fractions were collected and concentrated to give a mixture of diastereoisomers (114 mg). The diastereoisomers were separated by a prep chiral HPLC [(R,R)-Whelk-01 250×21.1 mm column] to give 19B (48 mg, 0.058 mmol, 34.4% yield). MS (ESI) m/z: 832.6 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[N:10][C:9]=2[C:18]2[C:19]([F:36])=[C:20]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:38]>O.C(OCC)(=O)C>[NH2:38][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[N:10][C:9]=2[C:18]2[C:19]([F:36])=[C:20]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(CO)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(CO)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)s1
Yield: 81 %

Procedure:
N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(2-hydroxy-1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (450 mg, 0.811 mmol) and saturated aqueous ammonium hydroxide (6.0 mL) were heated in a microwave reactor to 90° C. for 90 minutes. The reaction mixture was diluted with water, solution layered with ethyl acetate and pH of the mixture adjusted to 7 giving a gummy residue. The liquors were decanted and set aside; the gum was dissolved in mixture of warm ethyl acetate, dichloromethane and methanol and the solution added to the earlier liquors. The pH of this mixture was re-adjusted to 7.0. Organic phase was separated, dried (MgSO4), filtered and evaporated to give an orange colored foam which was dissolved in ethyl acetate (5 mL). Drop-wise addition of this solution to rapidly stirring hexanes (100 mL) gave a creamy white suspension which was filtered, filter pad washed with fresh hexanes, then air-dried to afford the title compound as a light yellow solid (370 mg, 81% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 10.88 (s, 1H) 7.97 (d, J=5.05 Hz, 1H) 7.64-7.77 (m, 1H) 7.40-7.48 (m, 1H) 7.33-7.39 (m, 1H) 7.18-7.32 (m, 4H) 6.75 (s, 2H) 5.84 (d, J=5.05 Hz, 1H) 5.09 (t, J=5.43 Hz, 1H) 3.51 (d, J=5.31 Hz, 2H) 1.33 (s, 6H). MS (ESI): 536.0 [M+H]+.