Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.CC#N.[CH3:13][N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](Cl)=[S:16]>C(Cl)Cl>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([C:15](=[S:16])[N:14]([CH3:13])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4](=[O:9])[N:3]=1
Reactant: CN(C(=S)Cl)c1ccccc1
Reactant: Nc1nc(O)ncc1F
Solvent: ClCCl
Solvent: CC#N
Product: CN(C(=S)n1cc(F)c(N)nc1=O)c1ccccc1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 37.1 %

Procedure:
A 25 mL screw-top vial was charged with 4-amino-5-fluoropyrimidin-2-ol (100.1 mg, 0.775 mmol), CH3CN (3 mL) and BSA (0.284 mL, 1.162 mmol). The resulting mixture was then agitated on a rotary shaker at 65° C. for 90 min. After cooling to room temperature, methyl(phenyl)carbamothioic chloride (157.6 mg, 0.849 mmol) was added, and the reaction mixture was agitated on a rotary shaker at 65° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with CH2Cl2 (100 mL) and washed with satd aq NaCl solution (50 mL×2). The organic layer was then dried over Na2SO4, filtered, and concentrated in vacuo to afford a green oil. This crude material was then purified by normal phase chromatography (gradient, 0 to 35% MeOH/CH2Cl2) to provide 4-amino-5-fluoro-N-methyl-2-oxo-N-phenylpyrimidine-1(2H)-carbothioamide (80.1 mg, 37%) as a 90% pure beige/green solid: mp 192-196° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J=6.7 Hz, 1H), 7.83 (s, 1H), 7.66 (s, 1H), 7.38 (m, 2H), 7.34-7.26 (m, 3H), 3.71 (s, 3H); ESIMS m/z 279 ([M+H]+).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[H-].[Na+].Br[CH2:11][C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])=[O:13]>C1COCC1>[CH2:1]([O:7][CH2:11][C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])=[O:13])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCCOC(=O)CBr
Reactant: C=CCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCCCOCC(=O)OCCCCC=C

Procedure:
3,5 g (34 mmol) of 5-hexen-1-ol, dissolved in 25 ml of THF, are added dropwise to a suspension of 0.95 g (28 mmol) of NaH in 20 ml of THF. When the addition is complete, 4.8 g (23 mmol) of hex-5-enyl 2-bromoacetate, dissolved in 15 ml of THF, are added dropwise. The mixture is then refluxed overnight. When the reaction is complete, the mixture is left to cool and quenched with 2N HCl. After the phases have separated, the aqueous phase is extracted again with Et2O and twice with EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated on a rotary evaporator. The crude product is purified on silica gel (cyclohexane/EtOAc=40:1; Rf=0.26), giving, as product, a colorless oil in a yield of 4.8 g (67% over 2 stages).
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([CH2:19][CH3:20])=[C:13]1[C:12]1[C:7](=[C:8]([CH3:24])[C:9]([O:22]C)=[C:10]([F:21])[CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br>ClCCl>[CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([CH2:19][CH3:20])=[C:13]1[C:12]1[C:7](=[C:8]([CH3:24])[C:9]([OH:22])=[C:10]([F:21])[CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCC(=O)C(CC)=C1c1cc(F)c(OC)c(C)c1C2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCC12CCC(=O)C(CC)=C1c1cc(F)c(O)c(C)c1C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 9a-butyl-4-ethyl-6-fluoro-7-methoxy-8-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (93 mg, 0.28 mmol) in anhydrous dichloromethane (1.4 mL) was cooled in a dry ice-acetone bath (−78° C.) and the solution treated with 1M boron tribromide in dichloromethane (1.4 mL, 1.4 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 90 minutes. The mixture was partitioned between EtOAc (20 mL) and water (20 mL) containing 2N HCl (2 mL). The organic phase was washed with brine (10 mL), dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by preparative layer chromatography on two 0.05×20×20 cm silica gel GF plates, developing with 5% EtOAc in CH2Cl2. The product bands were eluted with EtOAc, the eluent evaporated under vacuum, and the residue lyophilized from benzene to afford 9a-butyl-4-ethyl-6-fluoro-7-hydroxy-8-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an amorphous solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[CH3:19])[CH:6]=2.Cl.[CH3:21][CH:22]([NH2:27])[C:23]([F:26])([F:25])[F:24].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.CC(C)([O-])C.[Na+]>>[F:18][C:16]1[CH:15]=[CH:14][C:13]([CH3:19])=[C:12]([C:7]2[CH:6]=[C:5]3[C:10]([CH:11]=[C:2]([NH:27][CH:22]([CH3:21])[C:23]([F:26])([F:25])[F:24])[N:3]=[CH:4]3)=[CH:9][CH:8]=2)[CH:17]=1
Reactant: CC(N)C(F)(F)F
Reactant: Cc1ccc(F)cc1-c1ccc2cc(Cl)ncc2c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccc(F)cc1-c1ccc2cc(NC(C)C(F)(F)F)ncc2c1
Temperature: 90 °C
Yield: 37.7 %

Procedure:
A mixture of 3-chloro-7-(5-fluoro-2-methylphenyl)isoquinoline (41 mg, 0.15 mmol), 1-methyl-2,2,2-trifluoroethylamine, hydrochloride (36.5 mg, 0.244 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl (8.4 mg, 0.016 mmol), chloro[2-(dicyclohexylphosphino)-3-,6-dimethoxy-2-4′-6′-tri-i-pr-1,1′-biphenyl)][2-(2-aminoethyl)Ph]Pd(II) (13.7 mg, 0.0172 mmol), and cesium carbonate (148 mg, 0.454 mmol) in 1,4-dioxane (1.5 mL, 19 mmol) was purged with nitrogen and then heated at 90° C., for 2 hours. Sodium-tert-butoxide (49.2 mg, 0.512 mmol) was then added and the reaction mixture heated at 90° C. overnight. The mixture was then partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 19.7 mg (37%) of 7-(5-fluoro-2-methylphenyl)-N-(1,1,1-trifluoropropan-2-yl)isoquinolin-3-amine. LCMS (ESI): RT (Min)=5.716, M+H=349.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 7.84 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.36 (dd, J=9.3, 5.9 Hz, 1H), 7.13 (dd, J=7.8, 5.1 Hz, 2H), 7.01 (d, J=9.1 Hz, 1H), 6.88 (s, 1H), 5.11-4.91 (m, 1H), 2.25 (s, 3H), 1.37 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[C:22]1([CH3:30])[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=1.CO.[OH-].[Na+]>C(OCC)(=O)C>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:30][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(C=CC(=O)c2cc(OCC(F)(F)F)ccc2OCC(F)(F)F)cc1
Temperature: 25 °C

Procedure:
The title compound was prepared by heating a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol), p-tolualdehyde (75 ul, 0.633 mmol), methanol (5 ml) and NaOH (200 ul, 10M) for 24 h. The mixture was cooled to room temperature, diluted with ethyl acetate (100 ml), wash with water and saturated aqueous NaCl, dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by column chromatography using hexane:ethyl acetate (4:1) to give a yellow solid (32 mg, 12.2%). 1H NMR (CDCl3): 7.67 (d, J=15.6 Hz, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.40 (d, J=15.6 Hz, 1H), 7.28 (d, J=3.3 Hz, 1H), 7.22 (d, J=8.1 Hz, 2H), 7.12 (dd, J=3.3, 9.3 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 4.44-4.33 (m, 4H), 2.39 (s, 3H).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]1[C:11]([C:12](=[O:21])[C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)=[C:10]([CH:22]([CH3:24])[CH3:23])[C:9](=[O:25])[NH:8][C:7]1=[O:26].[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C=O)C.CCOCC>[N:27]([CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]1[C:11]([C:12](=[O:21])[C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)=[C:10]([CH:22]([CH3:24])[CH3:23])[C:9](=[O:25])[NH:8][C:7]1=[O:26])=[N+:28]=[N-:29]
Reactant: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2C/C=C/CCl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2C/C=C/CN=[N+]=[N-])c1
Reaction time: 24 h
Yield: 94.4 %

Procedure:
To a stirred solution of 187 mg (0.5 mmol) of the compound obtained from Example 9 in 5 ml of DMF was added 98 mg (1.5 mmol) of sodium azide at room temperature. After 24 hours, the reaction mixture was diluted with ether, washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give a yellow oil, which was purified by flash chromatography using a mixture of ethyl acetate and hexane (1:2) as an eluent to afford 180 mg (yield 94%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[C:10](=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:5]([C:6]([OH:8])=O)[CH:4]=1.[NH2:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[C:15]2[C:10](=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:5]([C:6]([NH:19][C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[O:8])[CH:4]=1
Reactant: COc1cc(C(=O)O)nc2c([N+](=O)[O-])cccc12
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2nnn[nH]2)nc2c([N+](=O)[O-])cccc12

Procedure:
4-Methoxy-8-nitroquinaldic acid (3.6 g) (see Example 16) and N,N'-carbonyldiimidazole (2.5 g) in dimethylformamide (70 ml) were heated on a steam bath for 1 hour. 5-Aminotetrazole (2.5 g) was added and the mixture was heated on a steam bath for 1 hour and cooled. 4-Methoxy-8-nitro-N(1H-tetrazol- 5-yl)quinaldamide, compound with imidazole, m.p. 238°, was filtered off and was triturated with 2 N hydrochloric acid (50 ml). 4-Methoxy-8-nitro-N(1H-tetrazol- 5-yl)quinaldamide was collected and dried, m.p. 268° (d).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.N[NH:18][C:19]([NH2:21])=[S:20].[OH-].[NH4+]>O>[NH2:21][C:19]1[S:20][C:13]([C:12]2[CH:15]=[CH:16][C:9]([Cl:8])=[CH:10][CH:11]=2)=[N:14][N:18]=1
Reactant: NNC(N)=S
Reactant: N#Cc1ccc(Cl)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(-c2ccc(Cl)cc2)s1
Temperature: 0 °C
Reaction time: 16 h
Yield: 35.6 %

Procedure:
To 125 ml of stirred trifluoroacetic acid at room temperature was added 4-chlorobenzonitrile (50.0 g, 0.365 mole), followed by the slow addition of thiosemicarbazide (35.0 g, 0.386 mole). Upon complete addition, the reaction mixture was heated under reflux for 60 hours. The cooled reaction mixture was poured into a mixture of 150 ml of ice and 150 ml of water, then made basic by addition of 150 ml of concentrated ammonium hydroxide. After standing for 16 hours, a crystalline solid was isolated from the mixture by filtration. The solid was recrystallized from 900 ml of ethanol to give 2-amino-5-(4-chlorophenyl)-1,3,4-thiadiazole (27.5 g, mp 227°-229° C.).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][C:13]([O:23][Si](C)(C)C)=[CH:12][CH:11]1[CH3:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(#N)C.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Si:1]([O:8][CH2:9][C@@H:10]1[C:11]([CH3:28])=[CH:12][C:13](=[O:23])[CH2:14][N:15]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC1C=C(O[Si](C)(C)C)CN(C(=O)OC(C)(C)C)[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1=CC(=O)CN(C(=O)OC(C)(C)C)[C@@H]1CO[Si](C)(C)C(C)(C)C
Yield: 58.3 %

Procedure:
The crude (6S)-tert-butyl 6-((tert-butyldimethylsilyloxy)methyl)-5-methyl-3-(trimethylsilyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 77, 12.58 g, 29.27 mmol) in 8 mL ACN was stirred at rt with Pd(OAc)2 (6.57 g, 29.27 mmol) for 2 days. The mixture was diluted with 160 mL EtOAc, filtered through celite, concentrated in vacuo and subjected to flash chromatography (220 g, 0-30% EA/Hex) to obtain the desired product (6.07 g, 58.3%) (over two steps) as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1.CCCCC.[H-].[Na+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:11]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]=3[C:4]3[C:12]2=[CH:13][CH:14]=[C:2]([CH3:1])[CH:3]=3)=[CH:26][CH:25]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)C(=O)CCC3
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2Cc2ccc(F)cc2)CCCC1=O
Reaction time: 0.33 h
Yield: 66.3 %

Procedure:
6-Methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.5457 g, 0.027 mol) is added to a slurry of pentane-washed NaH (0.1369 g, 0.0034 mol) in DMF (3 mL) and after stirring for 20 min, p-fluorobenzyl bromide (0.42 mL, 0.0034 mol) is added, followed by additional DMF (2 mL). After the slurry had stirred for 2.5 h, it is partitioned between water and ethyl acetate. The combined organic layers are washed with water, dried over sodium sulfate and concentrated to dryness. The resulting solids are chromatographed on silica gel (200 mL) using dichloromethane (100%) to give 0.6929 g (82%) of the title compound. An aliquot is recrystallized from ethyl acetate/heptane; mp 209.5-210° C.; MS (ESI+) for C20H18FNO m/z 308.2 (M+H)+; IR (drift) 2939, 1629, 1510, 1467, 1449, 1413, 1362, 1225, 1219, 1190, 1158, 1107, 1094, 832, 797 cm−1; 1H NMR (CDCl3) δ2.23, 2.47, 2.59, 2.85, 5.27, 6.99, 7.05, 7.12, 8.11. Anal. Calcd for C20H18FNO: C, 78.15; H, 5.90; N, 4.56. Found: C, 77.64; H, 5.87; N, 4.44.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:47]([O:51][C:52]([N:54]1[CH2:63][CH2:62][C:57]2([CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:56][CH2:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48].Cl.Br[C:66]1[CH:71]=[CH:70][N:69]=[CH:68][CH:67]=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:47]([O:51][C:52]([N:54]1[CH2:55][CH2:56][C:57]2([CH2:61][N:60]([C:66]3[CH:71]=[CH:70][N:69]=[CH:68][CH:67]=3)[CH2:59][CH2:58]2)[CH2:62][CH2:63]1)=[O:53])([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)CC1
Reactant: Brc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccncc1)C2
Reaction time: 0.25 h
Yield: 53 %

Procedure:
BINAP (293 mg, 0.47 mmol) and Pd(OAc)2 (317 mg, 1.4 mmol) was added to a mixture of 2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (5.66 g, 23.6 mmol), 4-bromopyridine HCl (4.58 g; 23.6 mmol) and sodium tert-butylate (6.8 g, 70.8 mmol) in toluene and the reaction mixture was degassed under argon for 20 minutes and heated under reflux for 4 h. The mixture was then diluted with ethyl acetate, stirred for 15 minutes and filtered over Celite. The organic phase was washed with water and sat. NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography. Yield: 53%
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:13])=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[C:3]([Cl:13])=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
A mixture of ethyl 5,6-dichloronicotinate (1.0 g, 4.5 mmol) and aqueous NaOH (2 N, 6.75 mL, 13.5 mmol) in a mixed solvents of THF/MeOH/water (50 mL, 4/1/1) was stirred at room temperature for 0.5 h. After concentration, the mixture was acidified with 2 N HCl to pH around 2. The resulting mixture was extracted with ether (30 mL×3). The organic layer was washed with water (50 mL×3), dried over Na2SO4, and concentrated to afford 5,6-dichloronicotinic acid (800 mg, 91% yield) as a white solid. LCMS (ESI) m/z: 192.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:21])([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:10]([F:14])([F:13])[C:11]#[N:12].P([O-])(OCC)(SCC)=[S:23].O.[ClH:32].O1CCOCC1>C(OCC)C>[ClH:32].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:21])([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:10]([F:13])([F:14])[C:11](=[S:23])[NH2:12]
Reactant: N#CC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCOP([O-])(=S)SCC
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: NC(=S)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
To 100 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanenitrile were added 0.2 ml of diethyl dithiophosphate and 0.04 ml of water. The resulting mixture was subjected to reaction at 80°-90° C. for 5hours. The reaction mixture was purified by a column chromatography (eluant: chloroform/methanol=50/1) to obtain an oily matter. To the oily matter was added 0.5 ml of a 2N hydrochloric acid-dioxane solution, and then diethyl ether was added. The resulting crystals were collected by filtration to obtain 110 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1yl)butanethioamide hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:9]([F:12])([F:11])[F:10])[C:6]=1[C:7]#[N:8].S(=O)(=O)(O)[OH:20].C(=O)(O)[O-].[Na+]>>[NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:9]([F:10])([F:12])[F:11])[C:6]=1[C:7]([NH2:8])=[O:20]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(N)sc(-c2ccccc2)c1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Product: NC(=O)c1c(N)sc(-c2ccccc2)c1C(F)(F)F
Temperature: 50 °C

Procedure:
A mixture of 2-amino-4-trifluoromethyl-5-phenyl-3-thiophenenitrile (0.12 g) and concentrated sulphuric acid (1.5 ml) was stirred and heated at 50° C. for 8 h. The reaction mixture was added to saturated aqueous sodium bicarbonate until a pH of 7 was obtained. The product was extracted into ethyl acetate (100 ml) and the organic layer was dried with anhydrous sodium sulfate (3 g), filtered and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate/isohexane mixtures. The solvent was removed and the product collected (0.07 g).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[CH:8][S:9][C:5]=2[CH:4]=1)#[N:2].CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.[CH:32]([C:34]1[C:42]([O:43][CH3:44])=[CH:41][C:40]([CH3:45])=[C:39]2[C:35]=1[CH:36]=[CH:37][N:38]2[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[O:33]>C1COCC1.[Li+].CC([N-]C(C)C)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[C:8]([CH:32]([OH:33])[C:34]3[C:42]([O:43][CH3:44])=[CH:41][C:40]([CH3:45])=[C:39]4[C:35]=3[CH:36]=[CH:37][N:38]4[C:46]([O:48][C:49]([CH3:51])([CH3:50])[CH3:52])=[O:47])[S:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C=O
Reactant: N#Cc1ccc2ncsc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)c1nc2ccc(C#N)cc2s1
Reaction time: 0.33 h

Procedure:
To a solution of 6-cyanobenzothiazol (CAS #:58249-61-9) (54.60 mg, 0.341 mmol) in THF (1.06 mL), LDA in Heptane/THF/Ethylbenzene (205 uL, 0.409 mmol) was added at −78° C. After 20 mins, a solution of tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 19-D) (79 mg, 0.273 mmol) in THF (1.68 mL) was added to the reaction mixture at −78° C. After stirring for 1.5 h, the reaction was quenched with MeOH, sat. aq. NH4Cl solution and brine. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, concentrated, and purified using FCC eluting with Heptane/EtOAc to provide the title compound. MS (ESI−) m/z 448 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([S:19]([O-:21])=[O:20])[CH:13]=[CH:12]2.[Na+].Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@@H:30]([OH:32])[CH3:31].N>CS(C)=O.[Cu]I>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([S:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@@H:30]([OH:32])[CH3:31])(=[O:21])=[O:20])[CH:13]=[CH:12]2
Reactant: C[C@H](O)c1ccccc1Br
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3F)ccc2c1
Agent: [Cu]I
Agent: N
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@H](O)c1ccccc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3F)ccc2c1
Temperature: 110 °C
Yield: 26.5 %

Procedure:
Sodium 6-(2,4-difluorophenyl)naphthalene-2-sulfinate (Step 3, 486 mg, 1.49 mmol), (1S)-1-(2-bromophenyl)ethanol (260 mg, 1.29 mmol) and copper(I) iodide (1.23 g, 6.46 mmol) were combined in dimethylsulfoxide (10 mL) and degassed. The reaction was heated to 110° C. for 2 hours. The cooled reaction mixture was poured into conc. ammonia solution and extracted with diethyl ether (x4). The combined organic layers were washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 5% then 10% diethyl ether/dichloromethane, followed by trituration with isohexane. A second column, eluting with 60% diethyl ether/isohexane, followed by trituration with isohexane, gave the title compound (145 mg). 1H NMR (500 MHz, CDCl3) δ 8.56 (1H, s), 8.17 (1H, d, J=7.9 Hz), 8.06-7.98 (3H, m), 7.79-7.76 (3H, m), 7.66 (1H, t, J=7.5 Hz), 7.54-7.48 (2H, m), 7.03-6.95 (2H, m), 5.65 (1H, q, J=6.2 Hz), 2.51 (1H, s), 1.35 (3H, d, J=6.3 Hz); m/z (ES+) 407 [(M-OH)+].
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].[H-].[Na+].[CH2:9](Br)[CH:10]=[CH2:11]>CN(C=O)C.CCOCC>[CH2:11]([O:6][C:2]([CH3:3])([CH3:1])[C:4]#[CH:5])[CH:10]=[CH2:9]
Reactant: C=CCBr
Reactant: C#CC(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CC(C)(C)OCC=C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
To stirred solution of 2-methylbut-3-yn-2-ol (7.33 ml, 75 mmol) in DMF (100 mL) was added 60% NaH (3.00 g, 75 mmol) at 0° C. After 30 min, the cold bath was removed stirred for 1 h at rt. To this was added allyl bromide (9.74 ml, 113 mmol) over 5 min and continued stirring for 16 h. Then, diluted with Et2O (250 mL), washed with water (5×50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated to give yellow liquid (5.64 g). HNMR of this indicated it is 2:1 mixture of product and unreacted alcohol. This was used without purification. 1H NMR (500 MHz, CDCl3) δ 5.93-6.02 (m, 1H), 5.32 (qd, J=1.7, 17.2 Hz, 1H), 5.18 (qd, J=1.5, 10.4 Hz, 1H), 4.13 (td, J=1.4, 5.6 Hz, 2H), 2.45 (s, 1H), 1.52 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1>[Fe](Cl)(Cl)Cl.C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Agent: Cl[Fe](Cl)Cl
Solvent: c1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccc(Br)cc1F

Procedure:
4-Bromo-2-fluoro-benzenesulfonyl chloride (2 g), benzene (1.3 ml) and iron (III) chloride (35 mg) were heated in a sealed tube using a microwave at 200 Watts for 15 seconds. After cooling purification by flash column chromatography (eluent 20% EtOAc/Hexane) gave the subtitle compound as a solid, yield 1.8 g.