Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][CH2:23][C@@H:24]([C:26]3[CH:35]=[CH:34][C:33]([O:36]CC4C=CC=CC=4)=[C:32]4[C:27]=3[CH:28]=[CH:29][C:30](=[O:44])[NH:31]4)[OH:25])=[CH:16][CH:15]=1)[CH2:8]2>[Pd]>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][CH2:23][C@@H:24]([C:26]3[CH:35]=[CH:34][C:33]([OH:36])=[C:32]4[C:27]=3[CH:28]=[CH:29][C:30](=[O:44])[NH:31]4)[OH:25])=[CH:18][CH:19]=1)[CH2:10]2
Reactant: O=c1ccc2c([C@@H](O)CNCCc3ccc(OCCC4C5CC6CC(C5)CC4C6)cc3)ccc(OCc3ccccc3)c2[nH]1
Agent: [Pd]
Product: O=c1ccc2c([C@@H](O)CNCCc3ccc(OCCC4C5CC6CC(C5)CC4C6)cc3)ccc(O)c2[nH]1
Yield: 52.4 %

Procedure:
Obtained from Intermediate 78 (0.33 g, 0.57 mmol) and palladium on charcoal (34 mg, 0.32 mmol) by the same procedure described in Example 1. The crude was purified by column chromatograpy with silica gel, eluting with methylen chloride/methanol (from 20:1 to 10:1) obtaining the title compound as a white solid (0.15 g, 52%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:31]1[C:36]([CH:37]([OH:47])[CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:35][CH:34]=[CH:33][N:32]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:31]4[C:36]([CH:37]([OH:47])[CH2:38][CH2:39][CH2:40][C:41]5[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=5)=[CH:35][CH:34]=[CH:33][N:32]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Reactant: OC(CCCc1ccccc1)c1cccnc1Br
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4ncccc4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 1-(2-bromo-pyridin-3-yl)-4-phenyl-butan-1-ol.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1.[CH3:32][NH2:33]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:33][CH3:32])[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1
Reactant: COc1cc2c(c(-c3cccc(F)c3F)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: CN
Product: CNCC1Cc2cc(OC)cc(-c3cccc(F)c3F)c2O1

Procedure:
The title compound was prepared (0.017 g, 18%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,3-difluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.12 g, 0.27 mmol) and methylamine (0.082 g, 2.7 mmol). mp 148-150° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[N:4]1.[F:13][C:14]([F:41])([F:40])[C:15]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:16]=1[CH2:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[C:24]([CH2:29]Br)[CH2:25][O:26]2)=[C:21]([F:31])[CH:20]=1>CN(C=O)C>[F:41][C:14]([F:13])([F:40])[C:15]1[CH:35]=[C:34]([C:36]([F:37])([F:39])[F:38])[CH:33]=[CH:32][C:16]=1[CH2:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[C:24]([CH2:29][N:3]3[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[N:4]3)[CH2:25][O:26]2)=[C:21]([F:31])[CH:20]=1
Reactant: Fc1cc(OCc2ccc(C(F)(F)F)cc2C(F)(F)F)cc2c1C=C(CBr)CO2
Reactant: CCOC(=O)c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(CC2=Cc3c(F)cc(OCc4ccc(C(F)(F)F)cc4C(F)(F)F)cc3OC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a solution of (7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methanol (200 mg) in MeCN (5 mL) was added triphenylphosphine dibromide (240 mg). The reaction liquid was stirred at room temperature for 2 hours and concentrated under reduced pressure. To the residue were added EtOAc and IPE, the resulting solid was removed by filtration, and the filtrate was concentrated to obtain 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-3-(bromomethyl)-5-fluoro-2H-chromene (230 mg) as a brown liquid. 60% sodium hydride (24 mg) was added to a DMF solution (5 mL) at 0° C., and subsequently, ethyl 1H-pyrazole-4-carboxylate (76 mg) was added thereto. The mixture was stirred at room temperature for 0.5 hours, and a solution of 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-3-(bromomethyl)-5-fluoro-2H-chromene (220 mg) in DMF (5 mL) was added thereto at 0° C. The reaction liquid was stirred at room temperature for 13 hours, quenched with a saturated NH4Cl solution, and then extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=100:0 to 70:30) to obtain ethyl 1-[(7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]-1H-pyrazole-4-carboxylate (111 mg) as a pale yellow solid.
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].O1CCCC1.Cl.[Cl:13][C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([C:25]2[C:26]3[CH:33]=[CH:32][N:31]([CH3:34])[C:27]=3[N:28]=[CH:29][N:30]=2)[CH:17]=1)=[O:15]>CO.ClCCl>[ClH:13].[NH:5]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([C:25]2[C:26]3[CH:33]=[CH:32][N:31]([CH3:34])[C:27]=3[N:28]=[CH:29][N:30]=2)[CH:17]=1)=[O:15])[C:4]([NH2:6])=[NH:3]
Reactant: Cn1ccc2c(-n3cc(C(=O)Cl)c4ccccc43)ncnc21
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: Cn1ccc2c(-n3cc(C(=O)NC(=N)N)c4ccccc43)ncnc21
Temperature: 20 °C
Yield: 40.6 %

Procedure:
0.345 g (15 mmol) of sodium (prewashed in toluene) is added gradually to 100 cm3 of methanol at a temperature in the region of 20° C. under an argon atmosphere. After dissolution with stirring, 1.43 g (15 mmol) of guanidine hydrochloride are added, and the reaction mixture is stirred at a temperature in the region of 20° C. for 2 hours. The reaction mixture is then concentrated to dryness under reduced pressure (2.7 kPa), and the residue is taken up twice successively with 70 cm3 of dichloromethane (stabilized with amylene) and concentrated to dryness under reduced pressure (2.7 kPa). 50 cm3 of tetrahydrofuran and 50 cm3 of dichloromethane are then added, under an argon atmosphere, at a temperature in the region of 20° C., and 3 mmol of 3-chlorocarbonyl-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indole hydrochloride, are then added with stirring. After stirring for 15 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by flash chromatography on silica gel [eluent: ethyl acetate/methanol (80/20 by volume)]. After the various fractions containing the expected product have been concentrated to dryness under reduced pressure (2.7 kPa), the solid obtained is taken up in methanol, and the mixture is refluxed for 10 minutes. After cooling to a temperature in the region of 20° C. and filtered, the solid is dried at a temperature in the region of 40° C. under reduced pressure (2.7 kPa), giving 0.45 g of 3-guanidinocarbonyl-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indole hydrochloride in the form of an off-white solid melting at 244° C. Mass spectrum (DCI): m/e 334 (MH+) (base peak).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])O)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:30](=[O:33])([O-])[O-].[K+].[K+].[CH3:36]I.O>CN(C=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]([CH3:36])[C:10]([C:20]([O:33][CH3:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])=[CH:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: OC(c1cc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1)(C(F)(F)F)C(F)(F)F
Reactant: CI
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(c1cc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1C)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
A mixture of 2.1 g (0.005 mole) of 4,5bis(4-fluorophenyl)-α,α-bis(trifluoromethyl)-1H-pyrrole-2-methanol, 1.4 g anhydrous potassium carbonate and 0.9 g (0.006 mole) of methyl iodide in 25 ml DMF was stirred at room temperature overnight. Another 1.4 g of potassium carbonate and 0.3 g of methyl iodide was added and stirring was continued another two hours. The mixture was poured into water and extracted with ether. The ether layers were backwashed with water three times, then dried and concentrated. The residue was purified by chromatography on silica gel, eluting with hexane/toluene (90/10) to give 1.7 g of the O,N-dimethylated product, m.p. 133°-134° (from ethanol/water). The infrared and nmr spectrum were consistent with the structure.
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]([F:25])([F:24])[F:23])=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[OH:26][C:27]1([C:34]2[O:35][CH:36]=[CH:37][N:38]=2)[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]([F:25])([F:23])[F:24])=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:30]2[CH2:31][CH2:32][C:27]([C:34]3[O:35][CH:36]=[CH:37][N:38]=3)([OH:26])[CH2:28][CH2:29]2)[CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C1CCC(O)(c2ncco2)CC1
Reactant: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](NC2CCC(O)(c3ncco3)CC2)C1
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentanamine (113.0 mg, 0.3188 mmol) of Step C-2 of Example 1 in THF (1 mL) was added 4-hydroxy-4-(1,3-oxazol-2-yl)cyclohexanone (80.3 mg, 0.443 mmol) followed by triethylamine (0.5 mL, 3.6 mmol) and finally sodium triacetoxyborohydride (135 mg, 0.638 mmol). After being stirred overnight, the reaction was quenched by addition of NaOH solution. The resulting solution was extracted with methylene chloride. The extract was dried over MgSO4 and evaporated in vacuo. The residue was purified by flash chromatography eluting with EtOAc/1% NH4OH to give two isomers. Isomer 1: 73 mg. MS calculated for C28H36F3N3O3: (M+H)+520; found 520.1. Isomer 2: 56 mg. MS found 520.1.\
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]([OH:14])=O)[C:6]=2[N:7]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[Cl:32][C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36]>CN(C=O)C.O>[NH2:1][C:2]1[N:3]=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]([NH:36][C:35]3[CH:37]=[CH:38][CH:39]=[C:33]([Cl:32])[CH:34]=3)=[O:14])[C:6]=2[N:7]=1
Reactant: Nc1nc(-c2ccco2)c2nnn(CC(=O)O)c2n1
Reactant: Nc1cccc(Cl)c1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(-c2ccco2)c2nnn(CC(=O)Nc3cccc(Cl)c3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
A suspension of (5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)acetic acid (140 mg, 0.5 mmol) in DMF (1 mL) was treated with carbonyl diimidazole (81 mg, 0.5 mmol), stirred at room temperature for 1 h, treated with 3-chloroaniline (53 μL, 0.5 mmol) and the mixture heated to 50° C. for 16 h. The reaction mixture was cooled, diluted with water (3 mL) and filtered to give the title compound (94 mg, 48%) as a cream solid.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1.N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]2=[O:8])=[CH:12][CH:11]=1
Reactant: Fc1ccc(I)cc1
Reactant: O=C1CCCCCN1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1CCCCCN1c1ccc(F)cc1
Temperature: 100 °C
Yield: 6.4 %

Procedure:
A suspension of ε-caprolactam (10 g, 90 mmol), 1-fluoro-4-iodobenzene (10 ml, 90 mmol), L-proline (4.1 g, 36 mmol), K2CO3 (37 g, 270 mmol), and Cu(I)I (3.4 g, 18 mmol) was stirred in DMSO (50 mL) and heated to 100° C. for 12 hours. Water (50 mL) was added and the reaction mixture was extracted with EtOAc. The organic layer washed with water) and brine, dried with Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (50% EtOAc in hexane) to afford the product (1.2 g, 6.4% yield) as brown oil. LRMS (APCI pos) m/e 208.0 (M+1).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.C(N)C1OCCC1.[Cl:21][C:22]1[CH:59]=[CH:58][C:25]([C:26]2[C:31]([C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[C:37]([C:42]5[N:46](CC)[C:45]6[CH:49]=[CH:50][C:51]([C:53]([OH:55])=O)=CC=6N=5)[CH:38]=4)[N:33]=3)=[CH:30][C:29]([O:56][CH3:57])=[CH:28][CH:27]=2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:59]=[CH:58][C:25]([C:26]2[C:31]([C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[C:37]([C:42]5[N:46]([CH2:45][CH:49]6[CH2:50][CH2:51][CH2:53][O:55]6)[C:2]6[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=6[N:11]=5)[CH:38]=4)[N:33]=3)=[CH:30][C:29]([O:56][CH3:57])=[CH:28][CH:27]=2)=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)nc2cc(C(=O)O)ccc21
Agent: NCC1CCCO1
Product: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4CC4CCCO4)ccc3n2)c1

Procedure:
The title compound was prepared from Resin 534a and tetrahydrofurfurylamine according to the procedure described in the preparation of Compound 534.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]#[N:15])[CH2:9]1)C1C=CC=CC=1.N1C=CC=CC=1.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36]>C(Cl)Cl>[C:14]([C:13]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:10]1[CH2:11][CH2:12][N:8]([C:35]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:36])[CH2:9]1)#[N:15]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N#CC(c1ccccc1)(c1ccccc1)C1CCN(Cc2ccccc2)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#CC(c1ccccc1)(c1ccccc1)C1CCN(C(=O)Oc2ccccc2)C1
Yield: 46.3 %

Procedure:
To a solution of 47 g (0.13 mole) of α-(1-benzyl-3-pyrrolidinyl)-α,α-diphenylacetonitrile and 10.58 g (0.13 mole) of pyridine in 400 ml of methylene chloride was added, dropwise at 0° C., 62.7 g (0.39 mole) of phenyl chloroformate. The reaction mixture was refluxed for 16 hr. The mixture was cooled and washed 3 times with water and twice with dilute sodium hydroxide solution. The methylene chloride layer was then dried, filtered and concentrated in vacuo. The resulting solid was recrystallized twice from ethyl acetate to give 23 g (50%) of title compound, m.p. 154°-155° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:10]([C:13]1[N:18]=[CH:17][C:16]([O:19][C:20]2[N:27]=[CH:26][CH:25]=[CH:24][C:21]=2C=O)=[CH:15][CH:14]=1)([F:12])[F:11].Cl.[CH3:36][O:37][NH2:38].N#N.[CH3:41]CO>>[CH3:36][O:37]/[N:38]=[CH:41]/[C:25]1[CH:24]=[CH:21][C:20]([O:19][C:16]2[CH:17]=[N:18][C:13]([C:10]([F:12])([F:11])[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])([OH:34])[CH2:28][N:29]3[CH:33]=[N:32][N:31]=[N:30]3)=[CH:14][CH:15]=2)=[N:27][CH:26]=1
Reactant: CCO
Reactant: CON
Reactant: O=Cc1cccnc1Oc1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Agent: Cl
Agent: N#N
Product: CO/N=C/c1ccc(Oc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a magnetically stirred mixture of 6-(((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)oxy)nicotinaldehyde (101) (60 mg, 0.126 mmol) in dry EtOH (1.265 mL) was added O-Methylhydroxylamine hydrochloride (21.13 mg, 0.253 mmol) in a 5 mL vial under N2 atmosphere. The reaction mixture was stirred at RT overnight. The reaction mixture was evaporated and the crude residue was purified on silica (ISCO, 12 gram column, gradient to 75% EtOAc/Hexanes over 25 minutes) to afford the title compound. Yield=18 mg (26.9%) of a white foam. 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 8.47 (d, J=2.5 Hz, 1H), 8.19 (d, J=2.3 Hz, 1H), 8.11 (dd, J=8.7, 2.4 Hz, 1H), 8.04 (s, 1H), 7.67 (dd, J=8.7, 2.6 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.45 (s, 1H), 7.36 (td, J=8.8, 6.4 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.83-6.73 (m, 1H), 6.73-6.64 (m, 1H), 5.63 (d, J=14.3 Hz, 1H), 5.10 (d, J=14.3 Hz, 1H), 3.99 (s, 3H). 1H-decoupled 19F NMR (376 MHz, CDCl3) δ −103.20 (d, J=17.7 Hz), −103.89 (ddd, J=31.3, 21.1, 13.6 Hz), −108.11 (d, J=9.5 Hz), −110.21 (d, J=45.0 Hz), −110.90 (d, J=45.0 Hz). MS(ESI): m/z 504.2 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1COCC1.Cl[S:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])(=[O:12])=[O:11]>ClCCl.[Cl-].[Na+].O>[CH3:1][N:2]([CH3:3])[S:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])(=[O:12])=[O:11]
Reactant: COC(=O)CS(=O)(=O)Cl
Reactant: CNC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)N(C)C
Temperature: 0 °C

Procedure:
Dimethylamine in THF (57.9 ml, 116 mmol) was dissolved in dichloromethane (29.0 ml) and cooled to 0° C. Then, methyl (chlorosulfonyl)acetate (prepared according to: Szymonifka, M. J.; Heck, J. V. Tet. Lett. 1989, 30, 2869-72.) (10.0 g, 57.9 mmol) was added dropwise as a solution in dichloromethane (29.0 ml), while maintaining the temperature below 5° C. The resulting solution was allowed to warm to room temperature over the course of 2 h. Then, brine (200 mL) was added and the aqueous phase was extracted with dichloromethane (3×100 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/Hexanes gradient) to afford the title compound as a yellow liquid. 1H NMR (600 MHz, DMSO-D6) δ 4.25 (s, 2H); 3.68 (s, 3H); 2.78 (s, 6H). LRMS (APCI) calculated for C5H12NO4S [M+H]+, 182.0; found 182.0.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:35][CH3:36])=[C:7]([CH:24]=[C:25]([N:27]2[CH:32]=[CH:31][C:30](=[O:33])[NH:29][C:28]2=[O:34])[CH:26]=1)/[CH:8]=[CH:9]/[C:10]1[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][C:11]=1[C:12](Cl)=[O:13])([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH:41]=[CH:40]N=N1.C(=O)([O-])[O-].[K+].[K+]>C1S(=O)(=O)CCC1>[C:1]([C:5]1[C:6]([O:35][CH3:36])=[C:7]([CH:24]=[C:25]([N:27]2[CH:32]=[CH:31][C:30](=[O:33])[NH:29][C:28]2=[O:34])[CH:26]=1)/[CH:8]=[CH:9]/[C:10]1[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][C:11]=1[C:12]1[O:13][CH:40]=[CH:41][N:37]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1c[nH]nn1
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2C(=O)Cl)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2-c2ncco2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 130 °C
Yield: 46 %

Procedure:
To a solution of the product from Example 126, Part A (80 mg, 0.15 mmol) in tetramethylene sulfone (1.5 ml) was added 1H-1,2,3-triazole (10 μL, 0.17 mmol) and potassium carbonate (73 mg, 0.53 mmol). The mixture was heated for 35 min at 130° C. in a microwave reactor. After cooling to room temperature, the mixture was partitioned between 1 N aqueous HCl (10 ml) and EtOAc (2×10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 3% MeOH in CH2Cl2 as the eluent to give the title compound (37 mg, 46%). 1H NMR (300 MHz, DMSO-d6) δ 11.41 (d, J=1.84 Hz, 1H) 10.10 (s, 1H) 8.29 (d, J=1.10 Hz, 1H) 8.05 (d, J=16.18 Hz, 1H) 7.95 (d, J=8.82 Hz, 1H) 7.82 (d, J=2.21 Hz, 1H) 7.74 (d, J=8.09 Hz, 1H) 7.51 (d, J=2.57 Hz, 1H) 7.46 (d, J=0.74 Hz, 1H) 7.39 (dd, J=8.64, 2.39 Hz, 1H) 7.20-7.30 (m, 2H) 5.65 (dd, J=7.91, 2.02 Hz, 1H) 3.80 (s, 3H) 3.07 (s, 3H) 1.38 (s, 9H).
Reaction SMILES: FC(F)(F)C(N[C@@H]1C2C(=CC=C(OC(C)C)C=2)[C@H](O)C1)=O.[CH2:22]([O:29][C:30]([NH:32]/[C:33](=[CH:38]\[C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[C:41]([Cl:46])[CH:40]=1)/[C:34]([O:36][CH3:37])=[O:35])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][C:30]([NH:32][C@@H:33]([CH2:38][C:39]1[CH:40]=[C:41]([Cl:46])[CH:42]=[C:43]([Cl:45])[CH:44]=1)[C:34]([O:36][CH3:37])=[O:35])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)/C(=C/c1cc(Cl)cc(Cl)c1)NC(=O)OCc1ccccc1
Agent: CC(C)Oc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)C[C@H]2O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cc(Cl)cc(Cl)c1)NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 88.3 %

Procedure:
Step BF (2): To a solution of (Z)-methyl 2-(benzyloxycarbonylamino)-3-(3,5-dichlorophenyl)acrylate (46.08 g, 121.3 mmol) in methylene chloride (435 mL) was added (+)-1,2-bis((2S,5S)-2,5-Diethylphospholano)benzene(cyclooctadiene)Rhodium(I) trifluoromethanesulfonate (4.02 g, 6.08 mmol). The solution was split between two Parr bottles and shaken under 50 psi hydrogen for 8 h. The combined reactions were concentrated in vacuo and subjected to silica gel chromatography (25% EtOAc/hexane) to yield (S)-methyl 2-(benzyloxycarbonylamino)-3-(3,5-dichlorophenyl)propanoate (40.94 g, 88% yield). 1H NMR (500 MHz, CDCl3) δ 7.28-7.39 (m, 5H) 7.24 (d, J=7.02 Hz, 1H) 7.00 (s, J=1.53 Hz, 2H) 5.34 (d, J=7.63 Hz, 1H) 5.10 (q, J=12.21 Hz, 2H) 4.58-4.68 (m, 1H) 3.73 (s, 3H) 3.05-3.15 (m, 1H) 2.95-3.05 (m, 1H).
Reaction SMILES: Cl.[S:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[O:11][C:12]1[CH:22]=[CH:21][C:15]2[C:16]([CH2:19][NH2:20])=[CH:17][O:18][C:14]=2[CH:13]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=[O:32])=[CH:26][CH:25]=1.CCN(CC)CC>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([NH:20][CH2:19][C:16]2[C:15]3[CH:21]=[CH:22][C:12]([O:11][C:3]4[S:2][C:10]5[C:5]([N:4]=4)=[N:6][CH:7]=[CH:8][CH:9]=5)=[CH:13][C:14]=3[O:18][CH:17]=2)=[O:32])=[CH:26][CH:25]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: NCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)cc1)NCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.8 %

Procedure:
To C-[6-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-3-yl]-methylamine hydrochloride (100 mg, 0.30 mmol) in DCM (3 mL) was added 4-chlorophenylacetyl chloride (57 mg, 0.30 mmol) and Et3N (0.13 mL, 0.90 mmol). The reaction mixture was stirred (rt, 16 h). Another equivalent of 4-chlorophenylacetyl chloride (57 mg, 0.30 mmol) was added, but the reaction remained at 50% conversion. Two equivalents of 4-chlorophenylacetyl chloride (114 mg, 0.60 mmol) and three equivalents of Et3N (0.13 mL, 0.90 mmol) were added. Upon reaction completion, the mixture was washed with sat'd. aq. NaHCO3 and extracted with DCM. After drying and concentration, the residue was purified by reverse phase HPLC to provide the title compound (47 mg, 35%). MS (ESI): mass calcd. for C23H16ClN3O3S, 449.06; m/z found, 449.9 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.56 (dd, J=4.8, 1.6, 1H), 8.04 (dd, J=7.9, 1.6, 1H), 7.60 (d, J=2.0, 1H), 7.58-7.53 (m, 2H), 7.33-7.29 (m, 2H), 7.28-7.24 (m, 1H), 7.24-7.18 (m, 3H), 5.70 (s, 1H), 4.55 (d, J=5.8, 2H), 3.58 (s, 2H).