Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[CH2:31][C:30]6[C:25](=[CH:26][C:27](OC)=[CH:28][CH:29]=6)[C:24]5=[O:34])[C:18]=4[CH3:35])=[CH:15][N:14]=[C:13]([C:36]([NH2:38])=[O:37])[C:9]=3[NH:10]2)=[CH:6][CH:5]=1)#[N:2].[Cl:39]C1C=CC(C=O)=C(C=1)C(O)=O.[BH4-].[Na+]>CO>[Cl:39][C:27]1[CH:26]=[C:25]2[C:30]([CH2:31][N:23]([C:19]3[C:18]([CH3:35])=[C:17]([C:16]4[C:8]5[C:7]6[C:11](=[CH:12][C:4]([CH2:3][C:1]#[N:2])=[CH:5][CH:6]=6)[NH:10][C:9]=5[C:13]([C:36]([NH2:38])=[O:37])=[N:14][CH:15]=4)[CH:22]=[CH:21][CH:20]=3)[C:24]2=[O:34])=[CH:29][CH:28]=1
Reactant: O=Cc1ccc(Cl)cc1C(=O)O
Reactant: COc1ccc2c(c1)C(=O)N(c1cccc(-c3cnc(C(N)=O)c4[nH]c5cc(CC#N)ccc5c34)c1C)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(CC#N)ccc4c23)cccc1N1Cc2ccc(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 17 %

Procedure:
A mixture of 3-(1-aminoxycarbonyl)-7-cyanomethyl)-9H-pyrido[3,4-b]indole-4-yl-2-methylaniline 7 (40 mg, 0.112 mmol), 5-chloro-2-formylbenzoic acid (51.6 mg, 0.28 mmol) and 4 angstrom molecular sieves (0.5 g) in methanol (15 mL) was stirred at RT for 24 h. After that the mixture was cooled to −20° C. and sodium borohydride (29.6 mg, 0.78 mmol) was added and the reaction mixture was allowed to warm up to 10° C. The solvent was removed under reduced pressure, quenched with saturated NH4Cl solution (5 ml) and extracted with EtOAc (2×10 ml). Combined organic extracts were washed with water, brine, dried over Na2SO4 and concentrated. The crude product obtained was purified by silica gel column chromatography eluting with 5% MeOH in CHCl3 to give the desired product (10 mg, 0.019 mmol, 17% yield) as a yellow sticky solid.
Reaction SMILES: [CH2:1]([CH:9]1[C:14]2=[C:15]3[CH2:21][CH2:20][CH2:19][CH2:18][C:16]3=[N:17][C:13]2=[C:12]([C:22]([C:24]2[O:28]C(C=O)=[CH:26][CH:25]=2)=[O:23])[CH:11]=[CH:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C-:31]#N.[Na+].[C:34]([OH:37])(=[O:36])[CH3:35]>CO.[O-2].[O-2].[Mn+4]>[CH3:31][O:36][C:34]([C:35]1[O:28][C:24]([C:22]([C:12]2[CH:11]=[CH:10][CH:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:14]3[C:13]=2[N:17]=[C:16]2[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=32)=[O:23])=[CH:25][CH:26]=1)=[O:37]
Reactant: [C-]#N
Reactant: CC(=O)O
Reactant: CCCCCCCCC1C=CC(C(=O)c2ccc(C=O)o2)=C2N=C3CCCCC3=C21
Agent: [Mn+4]
Agent: [Na+]
Agent: [O-2]
Solvent: CO
Product: CCCCCCCCC1C=CC(C(=O)c2ccc(C(=O)OC)o2)=C2N=C3CCCCC3=C21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3.7 g of the aldehyde derivative from Example 155, 2.0 g of sodium cyanide and 10 g of activated manganese dioxide in 200 mL of methanol was added 1.0 g of acetic acid at room temperature. The reaction mixture was stirred for 2 hours at room temperature, filtered on celite and extracted with ethyl acetate. The crude material (3.5 g) was purified on a short pad of silica gel giving 2.9 g (73%) of 5-[(1,2,3,4-tetrahydro-9-octyl-9H-dibenzo[b,d]pyrrol-6-yl)carbonyl]-2-furancarboxylic acid methyl ester as a yellow oil.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]4[N:17]=[C:18]([NH2:20])[N:19]=[C:15]4[CH:14]=[CH:13][CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:28][CH2:29][C:30](Cl)=[O:31].O>ClCCl>[Cl:28][CH2:29][C:30]([NH:20][C:18]1[N:19]=[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)[N:16]2[N:17]=1)=[O:31]
Reactant: O=C(Cl)CCl
Reactant: Nc1nc2cccc(-c3ccc4c(c3)OCCO4)n2n1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1nc2cccc(-c3ccc4c(c3)OCCO4)n2n1
Reaction time: 8 h

Procedure:
To a solution of 5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.4 g, 1.5 mmol) in dichloromethane (20 mL), triethylamine (0.62 mL, 4.47 mmol) and chloroacetyl chloride (0.142 mL, 1.8 mmol) were added successively. The mixture was then stirred overnight. Water was added and the mixture was extracted with dichloromethane, dried over magnesium sulphate and concentrated under reduced pressure. The crude was used without further purification. Yield: 0.52 g, 100%; LCMS Method: 2: 3.57 min, 345-347 [M+1].
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:11])=[C:8]([CH:10]=1)[NH2:9].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH2:12]([N:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]1[CH:10]=[C:4]([Br:3])[CH:5]=[CH:6][C:7]=1[Cl:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Nc1cc(Br)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(Br)cc1N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
Under argon, 9.69 g (242.16 mmol, 60% in mineral oil) of sodium hydride were suspended in 100 ml of THF, and the mixture was cooled to 0° C. 20.0 g (96.86 mmol) of 5-bromo-2-chloroaniline, dissolved in 50 ml of THF, were then slowly added dropwise, and the mixture was stirred at 0° C. for 30 min 39.76 g (232.47 mmol) of benzyl bromide, dissolved in 150 ml of THF, were then slowly added to the reaction mixture, and the mixture was then warmed to room temperature. The mixture was stirred at RT overnight and then carefully poured onto 150 ml of ice-water. The organic phase was separated off, and the aqueous phase was then extracted three more times with ethyl acetate. The combined organic phases were dried over sodium sulphate. After filtration, the solvent was removed under reduced pressure. Isopropanol was added to the crude product obtained, and the crystals formed were filtered off with suction and dried at 40° C. under high vacuum. This gave 14 g of the title compound. The filtrate was evaporated and the residue obtained was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave a further 7.57 g of the title compound (total yield: 21.57 g, 58% of theory).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[NH:4][N:3]=1.[F:13][C:14]([F:21])([F:20])[C:15](=O)[CH2:16][C:17]#[N:18].[NH2:22][C:23]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[N:28]=1)=[CH:24][C:25]#[N:26].C(O)(=O)C>C(O)CCCC.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:16]([C:17]#[N:18])=[C:15]([C:14]([F:21])([F:20])[F:13])[NH:22][C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[N:28]=4)=[C:24]3[C:25]#[N:26])[CH:9]=2)[NH:4][N:3]=1
Reactant: N#CC=C(N)c1cccc(C(F)(F)F)n1
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Reactant: N#CCC(=O)C(F)(F)F
Solvent: CCCCCO
Solvent: CC(=O)O
Solvent: O
Product: Cc1n[nH]c2ccc(C3C(C#N)=C(c4cccc(C(F)(F)F)n4)NC(C(F)(F)F)=C3C#N)cc12
Temperature: 130 °C
Reaction time: 1 h

Procedure:
A solution of 150 mg (0.936 mmol) 3-methyl-1H-indazole-5-carbaldehyde (Example 1A) in n-pentanol (4 ml) containing powdered 4 Å molecular sieve was treated with 128 mg (0.936 mmol) 4,4,4-trifluoro-3-oxobutanenitrile (Example 8A) and stirred at 130° C. for 1 h. Then, 94 mg (0.44 mmol) 3-amino-3-[6-(trifluoromethyl)pyridin-2-yl]prop-2-enenitrile (Example 7A) and acetic acid (1.2 ml) were added, and the mixture was stirred at 130° C. for further 15 min. Upon cooling, water (6 ml) was added, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 ml), and the solution was washed several times with brine, then with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (1 ml) containing 4 Å molecular sieve. A solution of tetra-n-butylammonium fluoride (TBAF, 1 N in THF, 1.5 ml) was added, and the mixture was stirred at 70° C. for 5 h. Upon cooling, the mixture was concentrated under reduced pressure, and the crude product was finally purified by preparative RP-HPLC (methanol/water+0.1% TFA gradient) to yield 15 mg (7% of th.) of the racemic title compound.
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].[Br:6][Si](C)(C)C.[CH2:11]([OH:14])[CH2:12]O>>[Br:6][CH:3]([CH3:4])[CH2:2][CH:1]1[O:14][CH2:11][CH2:12][O:5]1
Reactant: OCCO
Reactant: C/C=C/C=O
Reactant: C[Si](C)(C)Br
Product: CC(Br)CC1OCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
Crotonaldehyde (9.18 g, 108 mmol) was added dropwise to a stirring solution of bromotrimethylsilane (24 g, 156 mmol) at 0° C., stirred for 1 hour at 0° C. then warmed to room temperature and stirred for a further 1 hour. Ethylene glycol (9.5 g, 156 mmol) and p-tolunesulphonic acid (100 mg) was added and the solution was heated to reflux, water was removed by use of Dean and Stark apparatus. On completion the mixture was cooled to room temperature and washed with aqueous sodiumhydrogen carbonate solution (saturated, 2×50 ml).The residue was purified by vacuum distillation to give 2-(2-bromopropyl)-1,3-dioxolane (18.8 g, 40–42° C. @1 mm Hg, 89%)
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:8]=[CH:9][CH:10]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>COCCOC>[CH3:1][N:2]([CH3:17])[CH2:3][C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CN(C)C(=O)c1ccccc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: CN(C)Cc1ccccc1-c1ccccc1
Temperature: 25 °C
Yield: 106.9 %

Procedure:
Under a dry nitrogen atmosphere, 6.1 g (0.027 mole) of N,N-dimethyl-[1,1'-biphenyl]-2-carboxamide was dissolved with stirring in 250 ml of dry 1,2-dimethoxyethane. To this solution was added portionwise 1.3 g (0.034 mole) of lithium aluminum hydride. Upon complete addition, the reaction mixture was heated at reflux temperature for 18 hours. The reaction mixture was then cooled to room temperature, and 1.22 ml (0.068 mole) of water was added dropwise. The reaction mixture was filtered, and the filtrate concentrated under reduced pressure to give 6.1 g (100% yield) of N,N-dimethyl-[1,1'-biphenyl]-2-methanamine as a yellow liquid.
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[CH2:4][CH2:5][N:6]([CH3:8])[CH3:7].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1>C(O)C>[BrH:1].[BrH:1].[CH3:7][N:6]([CH3:8])[CH2:5][CH2:4][C:3]1[N:10]=[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]2[CH:2]=1
Reactant: Nc1ccccn1
Reactant: CN(C)CCC(=O)CBr
Solvent: CCO
Product: Br
Product: CN(C)CCc1cn2ccccc2n1

Procedure:
A solution of 1-bromo-4-dimethylaminobutan-2-one (13.8 g.) and 2-aminopyridine (4.7 g.) in ethanol (50 ml.) was heated under reflux for 2 hours. Cooling filtration from 1-methylpyrrolidin-3-one methobromide (5.6 g.) followed by concentration and recrystallisation of the residue from methanol gave 2-(2-dimethylaminoethyl)-imidazo [1,2-a] pyridine dihydrobromide, m.p. 262° - 264°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:17]([O-])=O.[Na+].[Sn](Cl)[Cl:22].[OH-].[Na+]>Cl.O>[ClH:22].[CH2:1]([O:8][C:9]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:10]=1[NH:11][NH2:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Br)cc1OCc1ccccc1
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NNc1ccc(Br)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
To a stirred slurry of 2-(benzyloxy)-4-bromoaniline (12.60 g, 45.3 mmol) in concentrated HCl (150 mL) was added a solution of sodium nitrite (3.44 g, 49.9 mmol) in water (20 mL). The reaction mixture was stirred at 0° C. for 30 min before adding a slurry of tin dichloride (25.8 g, 136.0 mmol) in concentrated HCl (35 mL). The reaction mixture was stirred at 0° C. overnight, warmed to ambient temperature, made basic to pH 10 by addition of sodium hydroxide and extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and treated with 1.25M HCl in methanol (10 mL). The solution was concentrated in vacuo to give (2-(benzyloxy)-4-bromophenyl)hydrazine hydrochloride (5.64 g, 38%) as a brown solid: 1H NMR (CD3OD, 300 MHz) δ 7.31-7.47 (m, 5H), 7.06 (dd, J=8.4, 2.1 Hz, 1H), 6.96 (d, J=2.1 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 5.01 (s, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH2:16](Br)[C:17]#[CH:18].C(Cl)(Cl)Cl>CN(C)C=O>[C:1]([N:4]([C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[C:16]#[C:17][CH3:18])(=[O:3])[CH3:2]
Reactant: C#CCBr
Reactant: CC(=O)Nc1nc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC#CN(C(C)=O)c1nc2ccccc2s1
Temperature: 50 °C
Yield: 62 %

Procedure:
2-Acetylaminobenzothiazole (e) (6.0 g) was dissolved in dimethylformamide (50 ml) and 50% sodium hydride (1.648 g) was added thereto in small portions with stirring under ice-cooling. The mixture was heated at 50° C. for 1 hour, then cooled to room temperature and 2-propynyl bromide (3.0 ml) was added thereto. The mixture was heated at 60° C. for 4 hours and evaporated to remove the solvent. After addition of water, the residue was extracted with benzene. The extract was washed with water, and evaporated to remove the solvent. The residue was applied to column chromatography on silica gel (120 g) to give 2-(N-acetyl-N-propynylamino)benzothiazole (f) (4.43 g, yield 62%) from chloroform eluate:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:17]=[CH:16][C:15]2[N:14]([CH3:18])[C:13](=[O:19])[C@@H:12]([CH2:20][CH3:21])[N:11]([CH:22]([CH3:24])[CH3:23])[C:10]=2[N:9]=1.[C:25](Cl)(=[O:27])[CH3:26].C(O)(C(F)(F)F)=O>>[CH2:20]([C@H:12]1[N:11]([CH:22]([CH3:23])[CH3:24])[C:10]2[N:9]=[C:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[NH:1][C:25](=[O:27])[CH3:26])[N:17]=[CH:16][C:15]=2[N:14]([CH3:18])[C:13]1=[O:19])[CH3:21]
Reactant: CC(=O)Cl
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3N)nc2N1C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3NC(C)=O)nc2N1C(C)C

Procedure:
The title compound was prepared similarly to the methods described in Example 114, with (R)-2-(3-aminopyridin-4-yl)-7-ethyl-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 93) instead of (R)-2-(3-aminopyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 91) and with acetyl chloride instead of chloromethylcarbonate. LCMS (0.05% TFA): 369.1 m/z (M+H)+; 1H-NMR (DMSO-d6, 500 MHz): δ: 9.71 (s, 1H), 8.43 (d, 1H, J=5.0 Hz), 8.27 (d, 1H, J=5.0 Hz), 8.25 (s, 1H), 4.59 (m, 1H), 4.49 (m, 1H), 3.38 (s, 3H), 2.26 (s, 3H), 1.92 (m, 1H), 1.80 (m, 1H), 1.47 (t, 6H, J=6 Hz), 0.81 (t, 3H, J=7.5 Hz).
Reaction SMILES: [N:1]([CH2:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)([F:7])[F:6])=[N+:2]=[N-:3].C(C1C=C(SC2C=C(C)C(O)=C(C(C)(C)C)C=2)C=C(C)C=1[OH:24])(C)(C)C.C1C=C(Cl)C=C(C(OO)=O)C=1>ClCCCl>[N:1]([CH2:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=1[O-:24])([F:7])[F:6])=[N+:2]=[N-:3]
Reactant: Cc1cc(Sc2cc(C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Reactant: [N-]=[N+]=NCC(F)(F)c1ccccn1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Product: [N-]=[N+]=NCC(F)(F)c1cccc[n+]1[O-]
Temperature: 55 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
To the solution of 2-(2-azido-1,1-difluoro-ethyl)-pyridine (example 59c), 2.6 g, 14 mmol) and 3-tert-butyl-4-hydroxy-5-methylphenyl sulfide (0.5 g, 1.4 mmol) in 1,2-dichloroethane (40 mL) was added MCPBA (77%, 4.2 g, 18.2 mmol). The reaction mixture was stirred at 55° C. for 12 h. After cooling to room temperature, the reaction mixture was poured into a saturated aqueous NaHCO3/NaS2O3 solution (100 mL) and extracted with methylene chloride (3×100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 50%-100% ethyl acetate in hexane in 30 min) afforded 2-(2-azido-1,1-difluoro-ethyl)-pyridine N-oxide (2.7 g, 96%) as a clear oil. LC-MS m/e 201 (MH+).
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:9]=[CH:8][C:7]2[C:10]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[O:11][CH2:12][C:6]=2[CH:5]=1.C1C(=O)N(Cl)C(=O)C1.[Cl:31][C:32]1[CH:37]=[C:36]([C:38]([C:40]([F:43])([F:42])[F:41])=[CH2:39])[CH:35]=[C:34]([Cl:44])[C:33]=1[F:45]>CN(C=O)C>[Cl:31][C:32]1[CH:37]=[C:36]([C:38]2([C:40]([F:43])([F:42])[F:41])[O:1][N:2]=[C:3]([C:4]3[N:9]=[CH:8][C:7]4[C:10]5([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]5)[O:11][CH2:12][C:6]=4[CH:5]=3)[CH2:39]2)[CH:35]=[C:34]([Cl:44])[C:33]=1[F:45]
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C=NO)ncc12
Reactant: C=C(c1cc(Cl)c(F)c(Cl)c1)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)ncc12
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 6′-((hydroxyimino)methyl)-1′H-spiro[azetidine-3,3′-furo[3,4-c]pyridine]-1-carboxylate (0.15 g, 0.49 mmol, 1 eq) in DMF (5.0 mL) was added NCS (84 mg, 0.63 mmol, 1.2 eq) at room temperature in dark under nitrogen atmosphere. Resulting reaction mixture was stirred at 45° C. for 1 hour. After chloro intermediate formation, 1,3-dichloro-2-fluoro-5-(1-trifluoromethyl-vinyl)-benzene (0.163 g, 0.63 mmol, 1.2 eq.) was added followed by addition of KHCO3 (79 mg, 0.79 mmol, 1.5 eq). Resulting reaction mixture was stirred at room temperature for 16 hours in dark under nitrogen atmosphere. After complete consumption of chloro intermediate, reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3×20 mL). Combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get brown thick oil (0.2 g, crude). Crude compound was purified by column chromatography in 100-200 mesh size silica gel. Desired compound was eluted in 25% ethyl acetate in hexane to afford title compound as off white solid (0.14 g, 51%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 3.88 (d, J=18.4 Hz, 1H), 4.12-4.16 (m, 2H), 4.25 (d, J=18.16 Hz, 1H), 4.35 (dd, J1=3.3 Hz, J2=9.34 Hz, 2H), 5.12 (s, 2H), 7.57 (d, J=6 Hz, 2H), 7.90 (s, 1H), 8.70 (s, 1H). LC-MS (m/z): 562.1 (M+H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([C:7]([OH:10])([CH3:9])[CH3:8])=[CH:3][CH:2]=1.[Br:12]N1C(=O)CCC1=O.CCOC(C)=O.O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:11][C:1]1[CH:2]=[CH:3][C:4]([C:7]([OH:10])([CH3:8])[CH3:9])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(C)(C)O)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(O)c1ccc(CBr)cc1
Yield: 82 %

Procedure:
To a stirring solution of 2-p-tolylpropan-2-ol (500 mg, 3.3 mmol) in carbon tetrachloride at room temperature under argon was added N-bromosuccinimide (590 mg, 3.3 mmol), followed by benzoyl peroxide (16 mg, 0.06 mmol). The reaction mixture was stirred at reflux for 4 h. The reaction mixture was concentrated under reduced pressure to obtain a colorless gum. EtOAc (20 mL) and water (20 mL) were added and the layers were separated. The organic layer was dried (MgSO4), filtered and concentrated under vacuum to obtain crude product, which was purified by flash chromatography (silica gel column eluted with 30% EtOAc/hexanes) to isolate 620 mg of the title compound as a colorless gum. HPLC/MS: retention time=2.908 min, [M+H—H2O]+=211.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5](F)=[C:6]([C:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)=O)[CH:7]=1.O.[NH2:23][NH2:24]>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[F:21])[NH:24][N:23]=[C:8]2[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: O=C(c1ccc2ccccc2c1)c1cc(Br)c(F)cc1F
Reactant: NN
Solvent: O
Product: Fc1cc2[nH]nc(-c3ccc4ccccc4c3)c2cc1Br

Procedure:
A total of 7.0 g of (5-bromo-2,4-difluorophenyl)naphthalene-2-yl-methanone obtained in Production Example II-17-a was allowed to react with hydrazine monohydrate by the procedure of Production Example II-10-c and thereby yielded 1.5 g of the title compound as a colorless powder.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19](=[O:22])[CH2:20]Br)=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([O-:26])(=[S:25])[CH3:24].[K+].ClCCl.C(O)(=S)C>CO>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19](=[O:22])[CH2:20][S:25][C:23](=[O:26])[CH3:24])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC([O-])=S
Reactant: O=C(CBr)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Agent: CC(O)=S
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)SCC(=O)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1

Procedure:
The mono-brominated sulfonamide from step 2 (0.194 g, 0.509 mmol) was was dissolved in methanol (2 ml) before potassium thioacetate (0.0639 g, 0.560 mmol) was added as a solid. LC-MS of the resulting yellow solution shows the reaction is complete in minutes. Evaporation of the volatiles leaves a tan residue which was taken up into dichloromethane (4 ml), during which the disulfide of the thioacetic acid was deposited and filtered. The desired thioester could then be recrystallized from dichloromethane/hexanes (0.080 g, 0.214 mmol, 42%). LC-MS (ES+): 376 [MH]+ m/e. 1H-NMR (DMSO): 7.87 (d, 3H), 7.78 (s, 1H), 7.7 (m, 1H), 7.57 (m, 3H), 4.41 (s, 2H), 3.99 (t, 2H), 3.06 (t, 2H), 2.34 (s, 3H)
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](=[O:23])[NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=2)=[CH:6][N:5]=[C:4]([NH:24][C:25](=[O:35])[CH2:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[N:3]=1.CCOCC>FC(F)(F)C(O)=O>[OH:1][C:2]1[C:7]([C:8](=[O:23])[NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=2)=[CH:6][N:5]=[C:4]([NH:24][C:25](=[O:35])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[N:3]=1
Reactant: CC(C)(C)OC(=O)CCC(=O)Nc1ncc(C(=O)NCc2cccc(-c3ccccc3)c2)c(O)n1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC(=O)Nc1ncc(C(=O)NCc2cccc(-c3ccccc3)c2)c(O)n1
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A solution of tert-butyl 4-({4-hydroxy-5-[(3-phenylphenyl)methylcarbamoyl]pyrimidin-2-yl}amino)-4-oxobutanoate (110 mg) in trifluoroacetic acid (1.5 mL) was left standing at room temperature for 1 hour. Ether (30 mL) was added to the reaction solution, and the resulting suspension was filtered. The product collected by filtration was washed with ether and hexane and dried under reduced pressure to obtain the title compound (88 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22]C=1Cl)[CH2:5][N:6]([CH3:20])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][NH:18][CH3:19])[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].CCN(CC)CC.[CH3:32][N:33]=[C:34]=[O:35].[CH2:36]([Cl:38])Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:36]=1[Cl:38])[CH2:5][N:6]([CH3:20])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]([CH3:19])[C:34]([NH:33][CH3:32])=[O:35])[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: ClCCl
Reactant: CNCCN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: CN=C=O
Solvent: CCN(CC)CC
Product: CNC(=O)N(C)CCN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reaction time: 1 h
Yield: 52 %

Procedure:
To a stirred solution of 4-hydroxy-1-(2-methylamino-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide (Compound 15) (155 mg, 0.379 mmol) in CH2Cl2 (5 mL) was added Et3N (0.14 mL, 1.0 mmol) followed by methyl isocyanate (29 μL, 0.5 mmol) at room temperature. After 1 h, the reaction mixture was concentrated and the resulting residue was dissolved in methanol and purified by preparative HPLC on a C18 column using water/methanol (0.1% TFA) as eluent. The fractions containing the product were combined, concentrated and lyophilized to give the title compound as a white powder (107.6 mg, 52% yield). 1HNMR (500 MHz, CDCl3) δ: 11.56 (1H, br s), 7.41 (1H, d, J=8.2 Hz), 7.34 (1H, s), 7.10 (1H, d, J=8.2 Hz), 4.66 (1H, br s), 4.57 (2H, s), 4.28 (2H, s), 3.62 (2H, t, J=5.8 Hz), 3.56 (2H, t, J=5.8 Hz), 3.02 (3H, s), 2.89 (3H, s), 2.70 (3H, s). HRMS calcd for C18H23Cl2N4O4 (M+H): 429.1096. found: 429.1082.