Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[N:25]([CH3:26])[N:24]=[CH:23][N:22]=3)[C:19](=O)[C:18]3[C:17]([C:28]([O:30]CC)=O)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].O.[NH2:34][NH2:35]>CO>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:34][NH:35][C:28](=[O:30])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[N:25]([CH3:26])[N:24]=[CH:23][N:22]=2)=[CH:9][CH:10]=1)[CH3:3]
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ncnn1C)C(c1ccc(CN(C)C)cc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: CN(C)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ncnn2C)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 48 %

Procedure:
To a solution of ethyl 2-(4-((dimethylamino)methyl)phenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (506 mg, 1.17 mmol) in methanol (3 mL) was added hydrazine monohydrate (1 mL), and the mixture was stirred at 25° C. for 10 hrs. The mixture was filtered to obtain a white solid (225 mg, yield 48%). LC-MS (ESI) m/z: 402 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.10 (s, 6H), 3.33 (s, 2H), 3.58 (s, 3H), 4.88-4.92 (m, 2H), 7.20-7.22 (m, 3H), 7.34-7.40 (m, 4H), 7.54-7.62 (t, J=8.4 Hz, 1H), 7.79 (s, 1H), 12.20 (s, 1H).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[CH:1](=[N:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NCc1ccccc1
Reactant: CCCC=O
Solvent: Cc1ccccc1
Product: CCCC=NCc1ccccc1

Procedure:
This material is a known compound prepared in the standard fashion. To about 100 mL of toluene was added 28 mL of butyraldehyde, 34 mL of benzylamine, and several grams of 3A molecular sieves. The mixture became warm and turbid after standing for a few minutes. After standing for several hours the mixture was colorless and transparent. The imine product was isolated by distillation under vacuum and characterized by NMR spectroscopy.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([CH2:21][C:22]#[N:23])[CH:14]=1)=O.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][CH2:1][C:3]1[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([CH2:21][C:22]#[N:23])[CH:14]=1)[CH3:25]
Reactant: CCN
Reactant: COc1ccc(CC#N)cc1-c1ccc(C(F)(F)F)cc1C=O
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC#N)ccc1OC

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetonitrile and ethylamine (2M in MeOH).
Reaction SMILES: B#B.[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=O)[NH:9][CH2:8][CH2:7]2.O>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][NH:9][CH2:8][CH2:7]2
Reactant: O=C1NCCc2cc(F)ccc21
Agent: B#B
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc2c(c1)CCNC2
Temperature: 25 °C

Procedure:
Diborane (1 M, THF, 24 mL) was added at 0° C. to a solution of 6-fluoro-3,4-dihydro isoquinolin-1(2H)-one (1.14 g, 6.9 mmol) in THF (8 mL). The mixture was stirred at reflux for 18 h. It was cooled to room temperature and water was added. The mixture was extracted with dichloromethane, and the organic layer was dried over sodium sulfate and concentrated. Purification by column chromatography (hexanes:ethyl acetate 1:1) afforded the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=2)[NH:4][CH:3]=1.Cl[C:21]1[N:26]=[N:25][C:24]([O:27][C@@H:28]2[CH:33]3[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]3)[CH2:29]2)=[CH:23][CH:22]=1.N>>[N:30]12[CH2:31][CH2:32][CH:33]([CH2:34][CH2:35]1)[C@@H:28]([O:27][C:24]1[N:25]=[N:26][C:21]([C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[NH:4][CH:3]=[C:2]4[CH3:1])=[CH:22][CH:23]=1)[CH2:29]2
Reactant: Clc1ccc(O[C@H]2CN3CCC2CC3)nn1
Reactant: Cc1c[nH]c2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: N
Product: Cc1c[nH]c2ccc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)cc12

Procedure:
The product of Example 10A (240 mg, 1 mmol) coupled with the product of Example 9A (250 mg, 1 mmol) according to the procedure in Example 8A, The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 pm, 40×100 mm. Eluting Solvent, MeCN/H2O (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min. flow rate, 75 mL/min., uv, 250 nm) as solid (40 mg, yield, 12%). 1H NMR (300 MHz, CD3OD) δ 1.50-1.64 (m, 1H), 1.69-1.92 (m, 2H), 2.01-2.14 (m, 1H), 2.29-2.35 (m, 1H), 2.37 (s, 3H), 2.81-3.04 (m, 5H), 3.43-3.55 (m, 1H), 5.27-5.34 (m, 1H), 7.06 (d, J=1.4 Hz, 1H), 7.24 (d, J=9.2 Hz, 1H), 7.44 (dd, J=8.5, 0.7 Hz, 1H), 7.71 (dd, J=8.8, 2.0, Hz, 1H), 8.07-8.12 (m, 2H) ppm. MS (DCI/NH3): m/z 335 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH:12]([C:18]([C:20]([F:23])([F:22])[F:21])=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(Cl)Cl>[C:1]1([NH:7][C:8]2[O:9][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:18]([C:20]([F:21])([F:23])[F:22])[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)Nc1ccccc1
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1oc(Nc2ccccc2)nc1C(F)(F)F
Yield: 41.3 %

Procedure:
By the procedure of Example 4, 8.2 g (60 mmol) of phenyl urea was reacted with 10.9 g (50 mmol) of ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 140°-150° C. for 24 hours. The product mixture was treated with methylene chloride, washed with water, dried and concentrated. The residue was recrystallized from methylcyclohexane to yield 6.2 g of crystal product (m.p.=114°-116° C.) identified in Table I.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](O)=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:21].C(N1C=CN=C1)([N:24]1C=CN=C1)=O.C(=O)=O.N>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:24])=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:21]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2ccc(F)c(Cl)c2C1=O
Agent: N
Agent: O=C=O
Solvent: CN(C)C=O
Product: CN1Cc2c(C(N)=O)ncn2-c2ccc(F)c(Cl)c2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
19.8 g (0.0639 mol) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid were suspended in 100 ml of N,N-dimethylformamide while gassing with argon and treated portionwise at room temperature with 10.9 g (0.0671 mol) of 1,1'-carbonyldiimidazole. After the CO2 evolution had finished the beige suspension was stirred at 50° for 30 min., cooled and treated dropwise at a temperature below 25° within about 10 min. with 20 ml of 25% ammonia. After stirring for 15 minutes the brownish solution obtained was poured into 600 ml of ice-water. The mixture was stirred at room temperature for 30 min. and filtered, whereupon the crystals were rinsed with a total of 200 ml of water. After drying there were obtained 14.4 g (73%) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide as beige crystals; m.p. 292°-294°.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>>[F:23][C:24]([F:33])([F:34])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:4]([C:6]2[N:7]=[C:8]([C:15]3[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=2[OH:12])=[O:5])=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: Cn1c(-c2c(F)cccc2F)nc(C(=O)NCc2ccc(C(F)(F)F)cc2)c(O)c1=O

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 4-trifluoromethylbenzylamine (88 mg, 0.5 mmol). The title product was obtained as an off-white solid (38.6 mg, 88% yield). 1HNMR (500 MHz, CDCl3) δ: 12.18 (1H, s), 7.88 (1H, t, J=4.58), 7.60 (2H, d, J=8.24 Hz), 7.53–7.47 (1H, m), 7.43 (2H, d J=8.24 Hz), 7.05 (2H, dd, J=8.24, 7.32 Hz), 4.65 (2H, d, J=6.41 Hz), 3.42 (3H, s). HRMS (ESI) calcd for C20H13F5N3O3 (M−H): 438.0877; found: 438.0878.
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[F:11][C:12]1[C:17]([OH:18])=[CH:16][N:15]=[C:14]2[N:19]([Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:20]=[CH:21][C:13]=12>CN(C=O)C>[F:11][C:12]1[C:17]([O:18][CH:2]([CH3:4])[CH3:3])=[CH:16][N:15]=[C:14]2[N:19]([Si:22]([CH:26]([CH3:28])[CH3:27])([CH:29]([CH3:31])[CH3:30])[CH:23]([CH3:24])[CH3:25])[CH:20]=[CH:21][C:13]=12
Reactant: CC(C)Br
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(O)cnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1F
Temperature: 80 °C
Yield: 28.6 %

Procedure:
2-Bromopropane (120 mg, 0.973 mmol) and potassium carbonate (448 mg, 3.24 mmol) were added to 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol (200 mg, 0.648 mmol) in DMF (3 mL). The reaction was heated to 80° C. in a sealed tube for 18 hours and then cooled down. The reaction mixture was concentrated to dryness. The mixture was then suspended in DCM and filtered. The filtrate was concentrated and purified by chromatography (SP4, 12+M, water/ACN 80/20→10/90, 20CV) to yield 4-fluoro-5-isopropoxy-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (65 mg, 42%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]([NH2:19])=[O:18])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][CH3:15])[C:6]=2[N:16]=1.ClS([N:24]=[C:25]=[O:26])(=O)=O>C(Cl)Cl>[NH2:24][C:25]([NH:1][C:2]1[C:3]([C:17]([NH2:19])=[O:18])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][CH3:15])[C:6]=2[N:16]=1)=[O:26]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Solvent: ClCCl
Product: CCn1c2ccccc2c2cc(C(N)=O)c(NC(N)=O)nc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
A solution of 2-amino-9-ethyl-9H-pyrido[2,3-b]indole-3-carboxamide (1, 71 mg, 0.28 mmol) in DCM (1 mL) was cooled to 0° C. and chlorosulfonyl isocyanate (27 μL, 0.31 mmol) was added. The mixture was stirred at 0° C. under an atmosphere of argon. After 2 h, the reaction was quenched with a few drops of water and concentrated under reduced pressure. The crude product was purified by HPLC (Phenomenex Luna 15 μm C18, aqueous NH4OAc/CH3CN) to yield 2-[(aminocarbonyl)amino]-9-ethyl-9H-pyrido[2,3-b]indole-3-carboxamide (21, 15 mg, 18%). NH4OAc standard conditions. DAD Retention time=6.40 min. M+H=298. 1H NMR (300 MHz, DMSO-d6): δ 11.44 (s, 1H), 9.04 (s, 1H), 8.70 (br s, 1H), 8.30 (br s, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.69 (d, J=8.1 Hz, 2H), 7.49 (t, J=8.1 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.24 (br s, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16](=[O:19])[NH:17][N:18]=3)[CH:15]=2)=[CH:6][CH:5]=1.Br[CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[OH:25][CH2:24][CH2:23][N:17]1[C:16](=[O:19])[N:14]2[CH:15]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=3)[CH:11]=[CH:12][C:13]2=[N:18]1
Reactant: OCCBr
Reactant: O=c1[nH]nc2ccc(-c3ccc(OC(F)(F)F)cc3)cn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=c1n(CCO)nc2ccc(-c3ccc(OC(F)(F)F)cc3)cn12
Temperature: 110 °C

Procedure:
6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (825 mg) from Example 1 above was dissolved in DMA (10 mL), 2-bromoethanol (1.0 g) and potassium carbonate (235 mg) were added. Heated overnight at 110° C. Filtered, concentrated, and purified by chromatography (ethyl acetate/hexanes). 2-(2-hydroxyethyl)-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one was obtained as white solid (830 mg). m/z (ESI)=340.0 (base peak, M+H+); 701.1 (2M+Na+). 2-(2-hydroxyethyl)-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg) was dissolved in dry DMF and the NaH suspension (12 mg, 60% in oil) was added, followed shortly by 2-chloro-5-trifluoromethylpyridine (54 mg). Concentrated and purified on silica using ethyl acetate/hexanes gradient to obtain compound 180 as a white solid (71 mg). m/z (ESI)=486.1 (base peak, M+H+); 508.1 (M+Na+); 993.2 (2M+Na+). 1H NMR (δ, CDCl3, 400 MHz) 8.75 (s, 2H); 7.98 (d, 1H); 7.53 (d, 2H); 7.40-7.30 (m, 3H); 7.18 (d, 1H); 4.90 (t, 2H); 4.49 (t, 2H). 19F NMR (δ, CDCl3, 376 MHz) −58.36 (s, 1F); −61.99 (s, 1F).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[S:11][CH2:12][CH2:13][CH2:14][Cl:15]>CO>[Cl:1][C:2]1[C:3]([S:11][CH2:12][CH2:13][CH2:14][Cl:15])=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cccc(Cl)c1SCCCCl
Solvent: CO
Product: Nc1cccc(Cl)c1SCCCCl
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
The crude 1-chloro-2-[(3-chloropropyl)sulfanyl]-3-nitrobenzene was dissolved in MeOH (150 mL) and degassed with N2. Palladium hydroxide (1.8 g) was added in four portions to this solution in a Parr apparatus. The resulting heterogeneous solution was shaken under hydrogenation conditions (55 psi) at room temp for 18 h. The catalyst was removed via filtration in the same manner as above and the filtrate was concentrated in vacuo. to afford 3-chloro-2-[(3-chloropropyl)sulfanyl]aniline (9.94 g, 93%) as a dark oil: 1H NMR (CHCl3, 300 MHz) δ7.03 (t, 1H, J=8.1 Hz), 6.82 (t, 1H, J=8.1 Hz), 6.63 (t, 1H, J=8.0 Hz), 4.62 (br s, 1H), 3.68 (t, 2H, J=6.4 Hz), 2.92 (t, 2H, J=6.9 Hz), 1.98 (quintet, 2H, J=6.6 Hz) ppm.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=O)=[CH:10][N:9]=1.[CH3:19][C:20]1[C:21]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1>>[CH3:19][C:20]1[C:21]([N:27]2[CH2:28][CH2:29][N:30]([C:12]([C:11]3[CH:10]=[N:9][C:8]([CH2:7][N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:18])=[CH:17][CH:16]=3)=[O:14])[CH2:31][CH2:32]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: COC(=O)c1ccc(CN2CCCS2(=O)=O)nc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(CN4CCCS4(=O)=O)nc3)CC2)c(C)c1
Yield: 82.2 %

Procedure:
Using methyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)nicotinate (108 mg) described in Preparation Example 45 and 1-(3,5-dimethylpyridin-2-yl)piperazine (77 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (141 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH:11]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1.F[B-](F)(F)F.[CH3:24][O+](C)C>C(Cl)Cl>[CH3:24][O:18][C:16]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:17]=1
Reactant: COc1cccc(CCC2CCCCC(=O)N2)c1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NC(CCc2cccc(OC)c2)CCCC1

Procedure:
The product of Example 166 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:9][C:8]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)=[O:4].O.C(=O)(O)[O-].[Na+]>ClCCCl>[O:14]=[C:12]1[C:7]2[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[NH:9][C:8]=2[CH2:10][CH2:11]1
Reactant: COC(=O)c1ccc(CCC(=O)O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1cc2c([nH]1)CCC2=O
Temperature: 100 °C
Yield: 86.2 %

Procedure:
A suspension of polyphosphoric acid (115%, 109 g) and powdered 3-(5-(methoxycarbonyl)-1H-pyrrol-2-yl)propanoic acid (12.1 g, 51.8 mmol) in 1,2-dichloroethane (40 mL) was heated for 1 h at 100° C. with occasional mixing with a large spatula. Water (100 mL) was added and the mixture was carefully poured into a large Erlenmeyer flask containing solid sodium bicarbonate and ice. The reaction was neutralized (pH 7) and then extracted with EtOAc (5×150 mL). The combined organic extracts were washed with water, NaHCO3, brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (0-80% EtOAc/Heptane) to afford 8.0 g of methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (86%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.93-2.98 (m, 2H), 2.99-3.04 (m, 2H), 3.90 (s, 3H), 6.98 (d, J=1.71 Hz, 1H), 9.42 (br s, 1H); LCMS-MS (ESI+) 180.0 (M+H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21].O.Cl>N1C=CC=CC=1>[C:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=CCc1cc(C(=O)O)ccc1O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(=O)O)cc1CC=C(C)C
Reaction time: 48 h
Yield: 51 %

Procedure:
Acetic anhydride (1 mL) was added dropwise to a solution of acid 8 (178 mg, 2.00 mmol) in pyridine (3 mL) at room temperature. After stirring for 48 hours, the mixture was poured into water (6 mL) and acidified to pH=2 by the dropwise addition of 6 M HCl. The suspension was extracted with EtOAc (2×10 mL), and the combined organic fractions were dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (5:1, hexanes:EtOAc) to afford acetate 9 (223 mg, 51%) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 8.01-7.96 (m, 2H), 7.15 (dd, J=3.5, 8.2 Hz, 1H), 5.24 (tt, J=1.3, 7.2 Hz, 1H), 3.30 (d, J=7.2 Hz, 2H), 2.34 (s, 3H), 1.97 (s, 3H), 1.76 (s, 3H).
Reaction SMILES: [N:1]([O-])=O.[Na+].[S:5]([C:9]1[S:25][C:12]2[S:13](=[O:24])(=[O:23])[CH:14]([CH2:18][C:19]([NH:21][NH2:22])=[O:20])[C:15](=[O:17])[NH:16][C:11]=2[CH:10]=1)(=[O:8])(=[O:7])[NH2:6]>O.Cl>[O:17]=[C:15]1[CH:14]([CH2:18][C:19]([N:21]=[N+:22]=[N-:1])=[O:20])[S:13](=[O:23])(=[O:24])[C:12]2[S:25][C:9]([S:5](=[O:7])(=[O:8])[NH2:6])=[CH:10][C:11]=2[NH:16]1
Reactant: O=N[O-]
Reactant: NNC(=O)CC1C(=O)Nc2cc(S(N)(=O)=O)sc2S1(=O)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NC(=O)CC1C(=O)Nc2cc(S(N)(=O)=O)sc2S1(=O)=O
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
A solution of sodium nitrite (0.34 g, 5 mmol) in water (10 ml) was added slowly to a cold (0°-5° C. suspension of (2,3-dihydro-6-sulfamoyl-2,4,4-trioxo-1H-thieno[2,3-b][1,4]thiazin-3-yl)acetic acid hydrazide (1.75 g, 5 mmol) in 1N HCl (150 ml). The reaction mixture was stirred for 0.5 hours in the cold and the resulting solid was collected, rinsed with water and air-dried to yield 1.05 g (2,3-dihydro-2,4,4-trioxo-6-sulfamoyl-1H-thieno-[2,3-b][1,4]thiazin-3-yl)acetyl azide.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Cl:30])[C:19]=1[Cl:31]>CN(C=O)C>[CH3:11][C:10]1([CH3:12])[O:9][B:8]([OH:13])[C:7]2[CH:14]=[CH:15][C:4]([C:3]3[CH2:25][C:24]([C:22]4[CH:21]=[C:20]([Cl:30])[C:19]([Cl:31])=[C:18]([Cl:17])[CH:23]=4)([C:26]([F:29])([F:28])[F:27])[O:1][N:2]=3)=[CH:5][C:6]1=2
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
To a solution of N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (850 mg, 3.55 mmol) and 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (1.47 g, 5.32 mmol) in DMF (10 mL) at rt was added TEA (0.5 mL, 3.55 mmol). The reaction mixture was stirred at rt for 18 h, poured into ice-water and extracted with EA (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give the desired title compound 3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol (510 mg; 30% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.25 (s, 1H), 7.86 (s, 2H), 7.78 (s, 2H), 7.72 (d, J=7.2 Hz, 1H), 4.46 (d, J=19.2 Hz, 1H), 4.35 (d, J=18.4 Hz, 1H), 1.49 (s,6H) ppm; HPLC purity: 95.3% at 220 nm and 96.8% at 254 nm; MS: m/z=478.4 (M+, ESI+).
Reaction SMILES: [CH:1]1([C:5]2[CH:14]=[C:13]([CH3:15])[C:12](I)=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:3][CH2:2]1.[CH3:17][N:18](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:17]([C:12]1[C:13]([CH3:15])=[CH:14][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:18]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(I)c(C)cc1C1CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(C#N)c(C)cc1C1CCC1
Temperature: 100 °C
Yield: 96 %

Procedure:
A mixture of methyl 2-cyclobutyl-5-iodo-4-methylbenzoate (compound 89.3, 3.0 g, 9.1 mmol), Zn(CN)2 (2.3 g, 19.6 mmol) and Pd(PPh3)4 (0.55 g, 0.47 mmol) in DMF (50 mL) was degassed and the system was charged with argon. The mixture was heated at 100° C. overnight, then cooled to room temperature. The mixture was quenched with saturated aqueous FeSO4 (20 mL), then diluted with EtOAc (200 mL). The solids were removed by filtration through Celite® and the filtrate was partitioned between water and EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes:EtOAc 30:1 to 20:1) to yield 2.0 g (96%) of the title compound. 1H NMR (400 MHz, Chloroform-d) δ 8.03 (s, 1H), 7.34 (s, 1H), 4.26-4.13 (m, 1H), 3.89 (s, 3H), 2.59 (s, 3H), 2.46-2.32 (m, 2H), 2.16-1.98 (m, 3H), 1.90-1.78 (m, 1H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][C@@:7]([NH2:16])([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=2)[C@H:6]([CH2:17]O)[CH2:5]1)[CH:2]=[CH2:3].[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH2:1]([N:4]1[CH2:5][C@@H:6]2[C@@:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=3)([N:16]=[C:28]([NH:27][C:19](=[O:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[S:29][CH2:17]2)[CH2:8]1)[CH:2]=[CH2:3]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: C=CCN1C[C@@H](CO)[C@](N)(c2cccc(Br)c2)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C=CCN1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cccc(Br)c2)C1
Temperature: 22 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A solution of [(3R,4S)-1-allyl-4-amino-4-(3-bromophenyl)pyrrolidin-3-yl]methanol (27 g; 86.7 mmol) in tetrahydrofuran (270 mL) is cooled to −5° C. under a nitrogen atmosphere. Benzoyl isothiocyanate (12.3 mL, 91 mmol) is added drop wise keeping the temperature below 0° C. The reaction is allowed to warm to 22° C. over 1 hour. 1,1′-Carbonyldiimidazole (28.1 g, 173.5 mmol) is added in a single portion and the reaction is stirred for 1 hour at 22° C. and then heated to reflux for 16 hours. The solvent is removed in vacuo and the residue dried under vacuum. The crude material is partitioned in methyl tert-butyl ether (500 mL) and water (250 mL). The organic layer is separated, dried over magnesium sulfate, filtered and evaporated to dryness. The crude material is purified over a silica gel gradient of 90/10 to 60/40 methylene chloride/ethyl acetate to give the title compound (27 g, 68%). ES/MS (m/e): 456 (M+1).