Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH:15](N)([CH3:17])[CH3:16]>CN(C=O)C>[CH:15]([NH:1][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([CH3:17])[CH3:16]
Reactant: CC(C)N
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CC(C)Nc1cccc([N+](=O)[O-])c1C#N
Temperature: 50 °C
Yield: 35.7 %

Procedure:
To a solution of 2,6-dinitrobenzonitrile (0.58 g, 3.00 mmol) in DMF (6 mL) was added isopropylamine (0.71 g, 12.00 mmol) and the reaction mixture was stirred at 50° C. under nitrogen for ten minutes. After cooling to room temperature, dilution with H2O and extraction with EtOAc, solvents of the combined organic phases were evaporated and the residue was purified by flash chromatography (Biotage system, 80 g silicagel column) using a Hexane/EtOAc (3:2) solution as eluant, to give 2-(isopropylamino)-6-nitrobenzonitrile (0.22 g, 35%). 1H NMR (400 MHz, DMSO-d6) δ 1.20 (d, J=6.4 Hz, 6H), 3.85-3.80 (m, 1H), 5.94 (d, J=8.0 Hz, NH), 7.26 (d, J=9.0 Hz, 1H), 7.42 (d, J=9.0 Hz, 1H), 7.60 (t, J=8.8 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)=[O:26])=[CH:20][CH:19]=1>CC(O)C.C(N(CC)CC)C>[CH3:13][N:12]([CH3:14])[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([NH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:29][CH:28]=3)=[O:26])=[CH:22][CH:23]=2)[N:11]=1
Reactant: NCc1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CN(C)c1nc(NCc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc2)nc2ccccc12
Yield: 15.1 %

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (42 mg, 0.2 mmol) and biphenyl-4-carboxylic acid (4-aminomethyl-phenyl)-amide hydrochloride (49 mg, 0.14 mmol) in 2-propanol (1 mL) and triethylamine (200 μL) was stirred at reflux for 2 days. The resulting mixture was concentrated and purified by column chromatography (silica gel, CH2Cl2 to 10% 2 M NH3/MeOH in CH2Cl2) to give biphenyl-4-carboxylic acid {4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-phenyl}-amide (10 mg, 15%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([OH:23])=[C:9]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:10](=[O:15])[N:11]2[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:24](I)[CH2:25][CH2:26][CH2:27]CC>>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:9]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:10](=[O:15])[N:11]2[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCCCOc1c(O)c2ccc([N+](=O)[O-])cc2n(C)c1=O
Reactant: CCCCCCI
Product: CCCCCCOc1c(OCCCC)c2ccc([N+](=O)[O-])cc2n(C)c1=O

Procedure:
In accordance with EXAMPLE 2, using 7-nitro-3-hexyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone, hexyl iodide was used instead of methyl iodide, 7-nitro-4-butoxy-3-hexyloxy-1-methyl-2(1H)-quinolinone was provided. Then in accordance with EXAMPLE 3, the title compound (5 1) was obtained by reduction reaction of nitro group. (yield=57%)
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13](C)[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:11]([I:21])[CH:10]=1)(C)(C)C.C(Cl)[Cl:24]>C(O)(C(F)(F)F)=O>[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([I:21])[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([Cl:24])[CH:14]=1
Reactant: ClCCl
Reactant: Cc1cc(CNC(=O)OC(C)(C)C)cc(I)c1NS(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nc1c(Cl)cc(CN)cc1I
Reaction time: 12 h
Yield: 100 %

Procedure:
(3-Iodo-4-methanesulfonylamino-5-methylbenzyl)carbamic acid t-butyl ester (122.0 mg, 0.27 mmol) and CF3COOH (5˜6 drops) were added into methylene chloride. The mixture was stirred for 12 hrs. The mixture was concentrated in vacuo to yield brownish syrup (142.2 mg, 100%).
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[CH2:14]([NH2:17])[CH2:15][CH3:16]>O1CCCC1>[CH2:14]([NH:17][C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([S:1](=[O:3])(=[O:4])[NH2:2])=[CH:13][CH:12]=1)[CH2:15][CH3:16]
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CCCN
Solvent: C1CCOC1
Product: CCCNC(=O)c1ccc(S(N)(=O)=O)cc1
Reaction time: 0.5 h

Procedure:
At room temperature, 10 g (0.05 mol) of 4-sulfamoylbenzoic acid are dissolved in 100 ml of tetrahydrofuran and admixed with 8.1 g (0.05 mol) of N,N′-carbonyldiimidazole. After 30 minutes at room temperature and a further 30 minutes at reflux temperature, 2.9 g (0.05 mol) of propylamine are added at room temperature. After 2 hours, the reaction mixture is concentrated and stirred with water, the precipitate is filtered off with suction and dried.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:19]([F:22])([F:21])[F:20])[O:18][CH:13]2C(OC)=O)=[CH:8][CH:7]=1)[CH3:4]>C(O)C.O>[CH2:3]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]([C:19]([F:20])([F:21])[F:22])[CH:13]=[O:18])=[CH:10][CH:11]=1)[CH3:4]
Reactant: CCOc1ccc(C2(C(F)(F)F)OC2C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1ccc(C(C=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 62 %

Procedure:
Into a solution of 11.41 g of potassium hydroxide in 80 ml of ethanol and 20 ml of water, 29.55 g of methyl 3-(4-ethoxyphenyl)-2,3-epoxy-4,4,4-trifluorobutyrate was added with ice-cooling. The reaction solution was stirred at room temperature for 17 hours. Thereafter, the reaction solution was poured into ice water. The resulting solution was washed with diethyl ether and adjusted to pH 3 with 10% HCl and extracted twice with diethyl ether. The ether layers were combined and washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure and the residue was subjected to distillation under a reduced pressure by heating in an oil bath (130°-140° C.) to obtain 14.66 g of the desired aldehyde (b.p. 100°-105° C./0.3 mmHg).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([NH:10][C:11](=O)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:8][CH3:9]>O1CCCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][CH2:11][NH:10][CH2:7][CH2:8][CH3:9])=[CH:15][CH:16]=1
Reactant: CCCNC(=O)CCc1ccc(OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCNCCCc1ccc(OC)cc1
Temperature: 50 °C

Procedure:
To a stirred mixture of LiAlH4 (8.0 g, 200 mmol) in tetrahydrofuran (100 mL) was added dropwise a solution of 3-(4-methoxyphenyl)-propionic acid n-propyl amid (10.7 g, 49 mmol) (from a) above) in tetrahydrofuran (100 mL). After refluxing for 12 h the mixture was cooled to 50° C. and excess hydride was destroyed by careful addition of water (10 mL), 5% aqueous NaOH (40 mL) and water (20 mL) allowing reflux conditions. The hot slurry was filtered and the white precipitate was washed thoroughly with ethanol. Volatiles were evaporated and the resulting oil dissolved in ethyl acetate (50 mL) what was extracted with 0.5 N aqueous HCl (4×50 mL). The acidic phase was made alkaline (pH=9) by addition of 30% aqueous NaOH and extracted with ethyl acetate (4×50 mL). The organic layers were combined, washed with brine, dried (MgSO4) and evaporated to dryness to give an oil that partially crystallized in diethyl ether as the hydrochloride salt. Recrystallization from acetone/diethyl ether gave white flacky crystalline material. Total yield (as free base): 9.9 g, 48 mmol, 98%, mp 176-177° C. IR (neat) cm−1 2960, 2772, 1611, 1514; 1H-NMR (CDCl3) δ9.46 (br s, 1H), 7.16 (d, 2H), 6.90 (d, 2H),3.72 (s, 3H), 2.82 (br s, 4H), 2.59 (t, 2H), 2.15 (p, 2H), 1.83 (h, 2H), 0.89 (t, 3H) ppm; 13C-NMR (CDCl3) δ156.6, 130.3, 127.7, 112.4, 53.7, 47.9, 45.66, 30.3, 25.9, 17.8, 9.7 ppm; MS (EI) m/z 207 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([O:12][CH3:13])[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>>[C:15]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:9](=[O:11])[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[O:12][CH3:13])=[CH:18][CH:17]=1)#[N:14]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1cccc(O)c1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1cccc(O)c1

Procedure:
(RS)-(3-Hydroxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-(3-hydroxy-phenyl)-2-methoxy-acetamide. Colorless oil.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:17])[C@@H:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C@H:7]([OH:16])[CH2:6]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=1>CS(C)=O>[CH3:3][N:4]([CH3:17])[C@@H:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C@H:7]([O:16][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH2:6]1
Reactant: CN(C)[C@@H]1CCc2ccccc2[C@H](O)C1
Reactant: Fc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)[C@@H]1CCc2ccccc2[C@H](Oc2ccc(Cl)cc2)C1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
0.6 ml of dimethylsulfoxide were added at room temperature to 60 mg of sodium hydride in a 50% oil dispersion and the mixture was heated to 50° C. for 20 minutes and was then cooled to 20° C. 205 mg of cis 7-dimethylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol were added thereto and after stirring the mixture for 15 minutes, 0.13 ml of p-chloro-fluorobenzene was added thereto. The mixture stood for one hour at 20° C. and was heated at 50° C. for 90 minutes and for 3 hours at 100° C. The mixture was cooled to 20° C. and was extracted with 30 ml of methylene chloride. The organic phase was washed with water, dried and evaporated to dryness to obtain 300 mg of raw product which was chromatographed over silica gel. Elution with a 7-3 chloroform-methanol mixture and evaporation of the solvent yielded 250 mg of cis N,N-dimethyl-5-[4-chlorophenoxy]-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-amine in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:20])[C:11]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[N:7]=1.C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>ClC(Cl)C>[F:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([F:19])[C:12]=1[C:11]1[C:10](=[O:20])[CH:9]=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:29]=1[F:28])=[N:7]2
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: Nc1ccc2c(-c3c(F)cccc3F)c(=O)ccn2n1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: O=C(Nc1ccc2c(-c3c(F)cccc3F)c(=O)ccn2n1)c1ccc(F)cc1F
Temperature: 80 °C

Procedure:
To a solution of 2-amino-5-(2,6-difluorophenyl)-6H-pyrido[1,2-b]pyridazin-6-one (50 mg, 0.18 mmol) dissolved in dichloroethane (2 mL) was added triethyl amine (0.079 mL, 0.55 mmol) and 2,4-difluorobenzoyl chloride (49 mg, 0.28 mmol). The mixture was heated to 80° C. for 2 hrs until no further progress was observed. Concentrated reaction to an oil and the crude residue was purified via silica gel chromatography (CH2Cl2/MeOH) to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:14]=1>>[CH3:29][C:27]1[NH:26][N:25]=[C:24]([NH:23][C:15]2[N:14]=[C:13]([O:1][C:2]3[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=3)[C:22]3[C:17]([CH:16]=2)=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:28]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: CC(=O)Nc1ccc(O)cc1
Product: CC(=O)Nc1ccc(Oc2nc(Nc3cc(C)[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from N-(4-hydroxy-phenyl)-acetamide and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give N-{4-[-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-phenyl}-acetamide. LC-MS m/e 374(MH+).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[H-]>CCOCC.C1(C)C=CC=CC=1>[Cl:19][C:15]1[CH:14]=[C:13]([C@@H:4]([O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:7])[CH3:8])[CH:3]=[O:2])[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)O[C@@H](C=O)c1cccc(Cl)c1
Yield: 85.7 %

Procedure:
To a stirred solution of (R)-(3-chloro-phenyl)-(tert-butyl-dimethyl-silanoxy)-acetic acid methyl ester (4.0 g) in anhydrous ether (10 ml) and maintained at <-65° was added dropwise a 1.5M solution of di-isobututylaluminium hydride in toluene (10 ml). When addition was complete the solution was stirred at -65° for a further hour, then quenched with methanol (10 ml). The mixture was allowed to attain room temperature when silica (20 g) was added. Solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with cyclohexane:ethyl acetate (9:1) to give the title compound as a colourless liquid (3.1 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH2:19]([O:21][C:22](=[O:29])[C:23]([NH2:28])([CH2:26][CH3:27])[CH2:24][CH3:25])C>>[CH3:19][O:21][C:22](=[O:29])[C:23]([NH:28][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH2:26][CH3:27])[CH2:24][CH3:25]
Reactant: CCOC(=O)C(N)(CC)CC
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)OC

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 2-amino-2-ethyl-butanoic acid ethyl ester hydrochloride (1:1) (CAN 70974-26-4) as starting materials, LC-MS (UV peak area/ESI) 100%, 361.2120 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:18](O)=O)=[N:9][O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:21]/[N:22]=[C:23](/[C:25]1[CH:42]=[CH:41][C:28]([CH2:29][N:30]2[CH2:33][CH:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31]2)=[CH:27][CH:26]=1)\[NH2:24].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:1]1([C:7]2[C:8]([C:18]3[O:21][N:22]=[C:23]([C:25]4[CH:26]=[CH:27][C:28]([CH2:29][N:30]5[CH2:31][CH:32]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:33]5)=[CH:41][CH:42]=4)[N:24]=3)=[N:9][O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1noc(-c2ccccc2)c1-c1ccccc1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4noc(-c5ccccc5)c4-c4ccccc4)n3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
A mixture of 4,5-diphenylisoxazole-3-carboxylic acid (26.5 mg, 0.1 mmol), (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int.1, (30.5 mg, 0.100 mmol), HOBT (16.85 mg, 0.110 mmol) and EDC (21.09 mg, 0.110 mmol) in DMF (1 mL) was stirred at rt for 18 hr. The reaction mixture was warmed to 60° C. for 2 hr and 70° C. for 2 hr. After cooling to rt overnight, the reaction mixture was partitioned between EtOAc (30 ml) and saturated sodium bicarbonate solution (30 ml). The organic layer was washed with water (2×30 ml) and brine (20 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to a yellow solid that was chromatographed on a 4 gm Isco silica gel cartridge, eluting with a 0-60% EtOAc/Hex gradient. The pure fractions were concentrated to afford tert-butyl 1-(4-(5-(4,5-diphenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (37 mg, 0.069 mmol, 69.2% yield) as a white solid. HPLC retention time=1.90 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH2:13]([OH:16])[C:14]#[CH:15].N1CCOCC1>C1(C)C=CC=CC=1.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>[F:10][C:9]([F:12])([F:11])[O:8][C:4]1[CH:3]=[C:2]([C:15]#[C:14][CH2:13][OH:16])[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)Oc1cccc(I)c1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: OCC#Cc1cccc(OC(F)(F)F)c1
Temperature: 80 °C
Yield: 80.2 %

Procedure:
To a solution of 1-iodo-3-(trifluoromethoxy)benzene (0.5 g, 1.73 mmol) in toluene (10 mL) was added prop-2-yn-1-ol (0.15 g, 2.62 mmol) and morpholine (0.5 mL). Then cuprous iodide (4 mg, 0.02 mmol) and bis(triphenylphosphine)palladium(II) chloride (14 mg, 0.02 mmol) were added to the mixture under nitrogen. The reaction was heated at 80° C. overnight. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:6 to 1:3) to give 3-(3-(trifluoromethoxy)phenyl)prop-2-yn-1-ol (0.3 g, 80.2%) as a yellow oil. LCMS retention time 1.552 min.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:34]=[CH:33][N:32]([Si](C(C)C)(C(C)C)C(C)C)[CH:31]=3)[C@H:14]2[CH3:45])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:47][C:2]([F:1])([F:46])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:34]=[CH:33][NH:32][CH:31]=3)[C@H:14]2[CH3:45])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc[nH]c1
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-{5-(trifluoromethyl)-2-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]benzyl}-1,3-oxazolidin-2-one (Example 149) (22.6 mg, 0.0326 mmol) in THF (2 mL) was added TBAF (65 μL of a 1M solution in THF, 0.065 mmol). After 30 minutes, the reaction was quenched with saturated NH4Cl (5 mL). The mixture was extracted with EtOAc (35 mL) and the organic layer was washed with water and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (25 to 60% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(1H-pyrrol-3-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one. Rf=0.11 (25% EtOAc/hexanes). LCMS=537.1 (M+1)+. 1H NMR (CDCl3, 600 MHz) δ 8.49 (s, 1H), 7.85 (s, 1H), 7.71 (s, 2H), 7.64 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 6.88-6.91 (m, 2H), 6.33 (d, J=1.6 Hz, 1H), 5.53 (d, J=8.0 Hz, 1H), 5.02 (d, J=15.7 Hz, 1H), 4.46 (d, J=15.6 Hz, 1H), 3.80 (m, 1H), 0.49 (d, J=6.6 Hz, 3H).
Reaction SMILES: [SH:1][CH:2]([CH3:13])[C:3]([N:5]1[CH:9]([C:10](O)=[O:11])[CH2:8][S:7][CH2:6]1)=[O:4]>O>[CH3:13][CH:2]1[S:1][C:10](=[O:11])[CH:9]2[CH2:8][S:7][CH2:6][N:5]2[C:3]1=[O:4]
Reactant: CC(S)C(=O)N1CSCC1C(=O)O
Solvent: O
Product: CC1SC(=O)C2CSCN2C1=O
Reaction time: 4 h
Yield: 50.8 %

Procedure:
Polyphosphoric acid (36 g) was added to N-(2-mercaptopropanoyl) thiazolidine-4-carboxylic acid (1.5 g, 6.78 mmol) and the mixture stirred at 50° for a period of 4 hours. The reaction mixture was then dissolved in water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated to give 0.7 g of 6-methyl-1H,3H-thiazolo[4,3-c][1,4]thiazine-5,8-dione as a pale yellow oil.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]2.[C:28]1([SH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[O:11]=[C:9]1[C:10]2=[C:2]([S:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:3]=[CH:4][N:5]2[N:6]=[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])[N:8]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(I)c2c(=O)n1-c1ccccc1
Reactant: Sc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(Sc3ccccc3)c2c(=O)n1-c1ccccc1
Temperature: 70 °C
Yield: 28 %

Procedure:
(S)-tert-Butyl (1-(5-iodo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)carbamate (700 mg, 1.46 mmol) was dissolved in 50 mL dimethylformamide in a pressure reactor. Phenyl hydrosulfide (241 mg, 2.19 mmol), potassium carbonate (302 mg, 2.19 mmol) and copper(I) iodide (416 mg, 2.18 mmol) were added under argon atmosphere and the reaction mixture heated at 70° C. overnight. The reaction mixture was cooled at room temperature and partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase using Isolera® Purification System to give 190 mg (28% yield) to the title compound. Purity 100%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1)([O-])=O.C(O)(=O)C>[Zn].C(O)C>[O:14]1[CH2:13][CH2:12][N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (i) (205 mg, 0.92 mmol) in 50:50 acetic acid:ethanol (10 mL) was treated with zinc dust (370 mg, 5.53 mmol) then stirred at RT under N2 for 4 hr. The mixture was concentrated under vacuum and the residue suspended in EtOAc (20 mL). The solution was filtered to remove undissolved zinc, and then washed with water (50 mL). The aqueous layer was neutralised then extracted with EtOAc (3×20 mL). The organic extracts were combined and concentrated to give (ii). Sample was used in subsequent reactions without further purification. 1H NMR (400 MHz, CDCl3) δ 8.20-8.15 (m, 2H), 7.55-7.50 (m, 2H), 3.76-3.70 (m, 4H), 3.59 (s, 2H), 2.49-2.42 (m, 4H).