Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([F:11])=[C:4]([F:10])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.C(OCC)C.C([Li:21])(C)(C)C>CCCCC>[F:1][C:2]1[C:7]([Li:21])=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[C:3]=1[F:11]
Reactant: Fc1cc(F)c(F)c(F)c1F
Reactant: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: [Li]c1c(F)c(F)c(F)c(F)c1F
Temperature: -65 °C

Procedure:
Inside of a 100 ml volume glass three-neck flask equipped with a 50 ml volume glass dropping funnel, temperature resistor and septum rubber was sufficiently replaced with nitrogen. Into the flask, 5 g (29.8 mmol) of pentafluorobenzene and 30 ml of diethyl ether were charged, of which solution was cooled to -65° C. Thereafter, 12.3 (29.8 mmol) of 16.1 wt. % pentane solution of tert-butyllithium charged into the dropping funnel were added dropwise while making the inner temperature not to exceed -55° C. After the completion of dropwise addition, the reaction mixture was kept at a temperature of -65°~-55° C. with stirring to give pentafluorophenyllithium. To the prepared solution of pentafluorophenyllithium was added 1 mol/L hexane solution (7.45 mL, 7.45 mmol) of boron trihalide at a temperature of -65°~-55° C., kept for 30 minutes at the same temperature with stirring and then the temperature was elevated up to the room temperature to afford a solution of lithium tetrakis(pentafluorophenyl)borate, which was subjected to quantitative determination employing pentafluorotoluene as an inner standard by means of 19FNMR. The yield was 92.3%.
Reaction SMILES: [Br-].[Na+].[C:3]([O-:6])(=[O:5])[CH3:4].[Na+].Cl[CH2:9][C@H:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1>CN(C)C=O>[C:3]([O:6][CH2:9][C@H:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1)(=[O:5])[CH3:4]
Reactant: CC(=O)[O-]
Reactant: CC1(C)OC[C@H](CCl)O1
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1COC(C)(C)O1
Temperature: 150 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
Sodium bromide (57.93 g, 0.563 mol) and sodium acetate (46.18 g, 0.563 mol) were added to a mixture of (R)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane (84.76 g, 0.563 mol) prepared by the same manner as Example 3 and N,N-dimethylformamide (800 ml) and the resulting mixture was stirred for 15 hours at 150° C. After cooling the salt was filtered off and N,N-dimethylformamide was removed in vacuo and water was added to the residue and extracted with toluene. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and condensed in vacuo. The crude product was distilled to give 60.81 g of (R)-4-acetoxymethyl-2,2-dimethyl-1,3-dioxolane (yield 62%, b.p. 78° C. at 10 mmHg).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([NH2:12])[NH:9][N:8]=1.[NH:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](=O)[CH2:24][C:25](OCC)=[O:26])=[CH:22][C:17]=2[N:16]=[N:15]1.CC1C=CC(S(O)(=O)=O)=CC=1>CCCCO>[NH:16]1[C:17]2[CH:22]=[C:21]([C:23]3[NH:12][C:10]4[N:9]([N:8]=[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=5[CH3:13])[N:11]=4)[C:25](=[O:26])[CH:24]=3)[CH:20]=[CH:19][C:18]=2[N:14]=[N:15]1
Reactant: Cc1ccccc1-c1n[nH]c(N)n1
Reactant: CCOC(=O)CC(=O)c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: Cc1ccccc1-c1nc2[nH]c(-c3ccc4nn[nH]c4c3)cc(=O)n2n1
Temperature: 120 °C
Reaction time: 5 h
Yield: 39.8 %

Procedure:
To a solution of 3-o-tolyl-1H-1,2,4-triazol-5-amine (150 mg, 1.0 eq) in n-BuOH (2 ml) was added ethyl 3-(1H-benzo[d][1,2,3]triazol-5-yl)-3-oxopropanoate (240 mg, 1.2 eq) and TsOH (20 mg) and the reaction was stirred for 5 h at 120° C. in an oil bath. The product was collected by filtration and washed with MeOH (3×1 ml) to afford 5-(1H-benzo[d][1,2,3]triazol-6-yl)-2-o-tolyl-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one (117.6 mg, 40% yield) as a yellow solid.
Reaction SMILES: [CH:1]([C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:19]=1)(=[O:17])=[O:16])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)(C)C.O>[OH:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([C:5]2[C:6]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:1]([CH3:3])[CH3:2])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(S(=O)(=O)c3c(-c4ccccc4)noc3C(C)C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)c1onc(-c2ccccc2)c1S(=O)(=O)c1ccc(O)cc1
Yield: 81.5 %

Procedure:
A mixture of 2.5 g (0.005 mol) of 5-isopropyl-3-phenyl-4-(4-tosyloxy-benzenesulphonyl)-isoxazole and 0.8 g (0.02 mol) of sodium hydroxide in 20 ml of isopropanol and 10 ml of water was heated under reflux for 2.5 hours. After reacting, the mixture was allowed to cool, diluted with 50 ml of water and acidified with concentrated hydrochloric acid. The product so obtained was suction-filtered and washed with water to obtain 1.4 g of the desired compound which was purified by elution chromatography on silica using chloroform as eluent.
Reaction SMILES: [CH3:1]N(C)C=O.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:30][C:31](=[O:42])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH3:41].CI>O>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[N:30]([CH3:1])[C:31](=[O:42])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH3:41]
Reactant: COc1ccccc1COC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1ccccc1COC(=O)N(C)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (11 mg), and 2-methoxybenzyl N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (66 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of methyl iodide (77 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (50 mg, yield 75%).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[NH:17][C:18](=[O:25])[C:19](=[CH:23][CH:24]=3)[C:20](O)=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)[Cl:27].C[Si](Cl)(C)C.S(Cl)(Cl)=O>C(N(CC)CC)C>[N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[NH:17][C:18](=[O:25])[C:19](=[CH:23][CH:24]=3)[CH2:20][Cl:27])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(-c2ccc(S(=O)(=O)N3CCCCC3)cc2)[nH]c1=O
Reactant: ClCCl
Agent: C[Si](C)(C)Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=c1[nH]c(-c2ccc(S(=O)(=O)N3CCCCC3)cc2)ccc1CCl

Procedure:
From 5.0 g. of 6-[4-(1-piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in 150 ml. of methylene chloride, 2.0 ml. of triethylamine, 1.75 ml. of trimethylsilyl chloride and 2.0 ml. of thionyl chloride, following the procedure of a) above, there is obtained 6-[4-(1-piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[N:17]=[CH:18][C:19]([CH:22]=O)=[N:20][CH:21]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:15][C:16]1[CH:21]=[N:20][C:19]([CH2:22][N:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)=[CH:18][N:17]=1
Reactant: CN1CCNCC1
Reactant: O=Cc1cnc(Cl)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN1CCN(Cc2cnc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium triacetoxyborohydride (870 mg) was added to a solution of 5-chloropyrazine-2-carbaldehyde (390 mg) and 1-methylpiperazine (0.335 mL) in acetonitrile (10 mL) at 0° C. The reaction mixture was stirred at room temperature for 4 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to give the title compound (285 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[N:30][C:5]2[N:6]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:7]3[C:12]([C:4]=2[CH:3]=1)=[CH:11][C:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=1)=[CH:9][CH:8]=3.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[CH:31]=[N:30][C:5]2[N:6]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:7]3[C:12]([C:4]=2[CH:3]=1)=[CH:11][C:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[CH:9][CH:8]=3
Reactant: COc1ccc(-c2ccc3c(c2)c2cc(Cl)cnc2n3S(=O)(=O)c2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(c1ccccc1)n1c2ccc(-c3ccc(O)cc3)cc2c2cc(Cl)cnc21
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of 3-chloro-6-(4-methoxyphenyl)-9-(benzenesulfonyl)-9H-pyrido[2,3-b]indole (222 mg, 1.11 mmol, 1eq.) in CH2Cl2 at 0° C., BBr3 (4.46 ml, 1M in CH2Cl2 4.46 mmol) was added dropwise. After 3 h at room temperature, the reaction mixture is hydrolysed with H2O and extracted with AcOEt (3×50 ml), dried with MgSO4, then filtered. The solvents were removed under reduced pressure and the crude material was purified by flash chromatography (CH2Cl2 then AcOEt) to afford 4-(3-chloro-9-(benzenesulfonyl)-9H-pyrido[2,3-b]indol-6-yl)phenol (409 mg, 0.94 mmol, 85% yield. 1H NMR 1H ((CD3)2CO, 300 MHz), δ 8.67 (d, 1H, J=2.3 Hz), 8.45-8.51 (m, 4H), 8.16-8.20 (m, 2H), 7.93 (dd, 1H, J=2.1 Hz, 8.9 Hz), 7.54-7.68 (m, 5H), 6.98 (d, 2H, J=8.6 Hz).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([F:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH2:37].C1COCC1>>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:37][CH3:36])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([F:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)c(F)cc3F)c(=O)n(C)c2n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)c(F)cc3F)c(=O)n(C)c2n1
Yield: 36 %

Procedure:
Using a procedure analogous to Example A1, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2,4-difluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (80 mg, 0.160 mmol) and 2.00N methylamine in THF (0.9 mL, 1.80 mmol) were combined to afford 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2,4-difluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (31 mg, 36% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.53 (s, 9H), 2.90 (s, 3H), 3.52-3.59 (m, 3H), 7.31-7.38 (m, 2H), 7.78-7.90 (m, 3H), 8.12-8.16 (m, 1H), 8.48 (s, 1H), 8.63-8.70 (m, 1H), 8.65 (s, 1H); MS (ESI) m/z: 483.3 (M+H+).
Reaction SMILES: [OH:1][C@@H:2]([CH3:6])[C:3]([NH2:5])=[O:4].[C:7]([Si:11]([CH3:14])([CH3:13])Cl)([CH3:10])([CH3:9])[CH3:8].N1C=CC=CC=1>CN(C=O)C>[Si:11]([O:1][C@@H:2]([CH3:6])[C:3]([NH2:5])=[O:4])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:14])[CH3:13]
Reactant: C[C@H](O)C(N)=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C[C@H](O[Si](C)(C)C(C)(C)C)C(N)=O

Procedure:
A solution of (S)-2-hydroxypropanamide (13-1) (30 g, 337 mmol) and tert-butyldimethylchlorosilane (66.0 g, 438 mmol) in pyridine (101 ml, 1246 mmol) and DMF (90 ml) was stirred at room temperature for 16 h. The reaction mixture was filtered to remove insolubles and the filtrate was partitioned between saturated aqueous sodium bicarbonate solution (500 mL) and EtOAc (500 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (2×100 mL), brine (3×100 mL) and water (3×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to afford 13-2 as a viscous yellow oil. MS: m/z=204.0 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C:23](=O)[O:22][C:21]2=[O:28]>>[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:22])[N:1]([CH:2]1[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=3)[O:5][C:4]([CH3:14])([CH3:15])[CH:3]1[OH:16])[C:21]2=[O:28]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Product: CC1(C)Oc2ccc(C#N)cc2C(N2C(=O)c3ccc(Cl)cc3C2=O)C1O

Procedure:
Following the procedure in Example 89, using (3S,4R)-4-amino-3-hydroxy-2,2-dimethyl-chroman-6-carbonitrile and 5-chloro-isobenzofuran-1,3-dione as starting materials, the title compound was prepared as a pale yellow solid.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:13][CH:12]3[N:14]([CH3:15])[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH:6]=1.[Cl:16][C:17]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]2[C:18]=1[CH:19]=[C:20]([C:28]1[C:29]([NH2:43])=[N:30][CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=1)[N:21]=[CH:22]2.C(=O)([O-])[O-].[K+].[K+]>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.COCCOC.O>[Cl:16][C:17]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]2[C:18]=1[CH:19]=[C:20]([C:28]1[C:29]([NH2:43])=[N:30][CH:31]=[C:32]([C:2]3[CH:3]=[N:4][N:5]([CH:7]4[CH2:13][CH:12]5[N:14]([CH3:15])[CH:9]([CH2:10][CH2:11]5)[CH2:8]4)[CH:6]=3)[CH:33]=1)[N:21]=[CH:22]2
Reactant: CN1C2CCC1CC(n1cc(I)cn1)C2
Reactant: CC1(C)OB(c2cnc(N)c(-c3cc4c(Cl)ccc(F)c4cn3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CN1C2CCC1CC(n1cc(-c3cnc(N)c(-c4cc5c(Cl)ccc(F)c5cn4)c3)cn1)C2
Temperature: 100 °C

Procedure:
A solution of 3-(4-iodopyrazol-1-yl)-8-methyl-8-azabicyclo[3.2.1]octane (42.7 mg, 0.135 mmol), 3-(5-chloro-8-fluoroisoquinolin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-ylamine (0.070 g, 0.18 mmol), potassium carbonate (55.9 mg, 0.404 mmol), and Pd(PPh3)4 (9 mg, 0.008 mmol) in previously degassed DME/Water (4:1) (3.0 mL) was placed in a microwave tube and evacuated and charged with N2 (2×). The reaction mixture was heated in the microwave reactor to 100° C. for 45 min. The reaction mixture was diluted with EtOAc and washed with H2O (2×), brine (2×), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by chromatography on silica gel [eluting with 10% MeOH in CHCl3], passing through an SCX cartridge, and finally by the MDP. The fractions containing product were combined, concentrated in vacuo, and partitioned between CHCl3 and sat. NaHCO3. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo resulting in the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=1.64-1.72 (m, 2H), 1.77-1.86 (m, 2H), 1.97-2.06 (m, 2H), 2.07-2.17 (m, 2H), 2.26 (s, 3H), 3.20 (br. s., 2H), 4.47 (tt, J=11.7, 5.9 Hz, 1H), 6.89 (br. s., 2H), 7.54 (dd, J=9.9, 8.4 Hz, 1H), 7.87 (s, 1H), 8.03 (dd, J=8.4, 4.8 Hz, 1H), 8.15 (d, J=2.2 Hz, 1H), 8.25 (s, 1H), 8.35 (d, J=2.2 Hz, 1H), 8.37 (s, 1H), 9.64 (s, 1H). MS (ES+): m/z=463.13/465.15 (76/24) [MH+]. HPLC: tR=1.88 min (ZQ2, polar—5 min).
Reaction SMILES: C1(C[O:8][C:9](=[O:28])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[O:20][CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)CCCCC1.[Li+].[OH-]>>[CH:22]1([CH2:21][O:20][C:11]2[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=2[C:9]([OH:28])=[O:8])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(OCC1CCCCC1)c1ccc(C(F)(F)F)cc1OCC1CCCCC1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1ccc(C(F)(F)F)cc1OCC1CCCCC1
Yield: 89.8 %

Procedure:
2-Cyclohexylmethoxy-4-trifluoromethyl-benzoic acid cyclohexylmethyl ester (528 mg, 1.33 mmol) was reacted with 1N LiOH (2.65 mg, 2.65 mmol) as described above to give 2-cyclohexylmethoxy-4-trifluoromethyl-benzoic acid (361 mg, 90%) after drying by vacuum.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH:15]=2)=[CH:2]1.CN(C)C=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:38][O:39][CH:40]1[CH2:44][CH2:43][N:42]([C:45]2[CH:46]=[C:47]([S:51](Cl)(=[O:53])=[O:52])[CH:48]=[CH:49][CH:50]=2)[CH2:41]1>O1CCCC1>[CH3:38][O:39][CH:40]1[CH2:44][CH2:43][N:42]([C:45]2[CH:46]=[C:47]([S:51]([N:1]3[C:9]4[C:4](=[N:5][CH:6]=[CH:7][CH:8]=4)[C:3]([C:10]4[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH:15]=4)=[CH:2]3)(=[O:53])=[O:52])[CH:48]=[CH:49][CH:50]=2)[CH2:41]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3cccnc23)CC1
Reactant: COC1CCN(c2cccc(S(=O)(=O)Cl)c2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC1CCN(c2cccc(S(=O)(=O)n3cc(C4=CCN(C(=O)OC(C)(C)C)CC4)c4ncccc43)c2)C1
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
Into a 1-Neck round-bottom flask tert-butyl 4-(1H-pyrrolo[3,2-b]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.000334 mol) was stirred in tetrahydrofuran (3 mL, 0.04 mol) and N,N-dimethylformamide (3 mL, 0.04 mol) at 5° C. and 1.0 M of sodium bis(trimethylsilyl)amide in tetrahydrofuran (0.50 mL) was added. The reaction was stirred for 20 minutes at 5° C. 3-(3-Methoxypyrrolidin-1-yl)benzenesulfonyl chloride (138 mg, 0.000501 mol) in tetrahydrofuran (3 mL, 0.04 mol) was added by syringe at 5° C. and the reaction was stirred for 30 minutes. The reaction was extracted with ethyl acetate and was washed with water and brine. The solvent was rotovaped.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.ClCCl.O.N1C=CC=CC=1>[Cl:11][C:7]1[C:3]2[C:4](=[O:6])[O:5][C:13](=[O:15])[NH:1][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cccc(Cl)c1C(=O)O
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Temperature: 50 °C
Yield: 98609.3 %

Procedure:
To a stirred solution of 2-amino-6-chloro benzoic acid (10 g, 0.0583 mmol) in acetonitrile (60 mL, 1 M), was added pyridine (9.4 mL, 0.117 mmol, 2 equiv), and triphosgene (17.3 g, 0.058 mmol, 1 equiv) in dichloromethane (85 mL, 0.7 M). The orange reaction solution was heated at 50° C. for two hours then cooled to room temperature. The solution was diluted with water (50 mL), and the organic and aqueous layers were separated. The aqueous layer was washed with dichloromethane (3×50 mL), the combined organic layers were washed once with brine (50 mL), and dried over magnesium sulfate. The solvent was removed in vacuo leaving a light brown solid. The solid was titrated with hexanes to yield 5-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (11.3 g, 97%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:29])[NH:27][OH:28])=[CH:22][CH:21]=3)=[N:14]2)[CH:7]=1)[CH3:2].N1C=CC=CC=1.Cl[C:38](OCC)=[O:39].Cl>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:30])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20]3[CH:21]=[CH:22][C:23]([C:26]4[NH:29][C:38](=[O:39])[O:28][N:27]=4)=[CH:24][CH:25]=3)=[N:14]2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(C(=N)NO)cc3)ccc2=O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(-c4noc(=O)[nH]4)cc3)ccc2=O)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
500 mg (123 mmol) of ethyl(3-{3-[4-(N-hydroxycarbamimidoyl)phenyl]-6-oxo-6H-pyridazin-1-ylmethyl}phenyl)carbamate are dissolved in 20 ml of DMF, and 300 μl of pyridine are added. 128 μl (1.35 mmol) of ethyl chloroformate are subsequently added, and the solution is stirred at 100° C. for 24 h. 10 ml of 1 N HCl and water are added to the reaction mixture. The batch is evaporated to dryness, ethyl acetate is added, and the mixture is extracted with water. The organic phase is dried over sodium sulfate, evaporated to dryness and purified by means of preparative HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]#[N:14])([O-:3])=[O:2].[C:15]([O-])([O-])=O.[K+].[K+].CI>CC(N(C)C)=O>[CH3:15][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([C:13]#[N:14])=[N:8]1
Reactant: N#Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(=O)N(C)C
Product: Cn1nc(C#N)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
5-nitro-1H-indazole-3-carbonitrile (150 mg, 0.797 mmol) was taken up in DMA (4 mL) and K2CO3 (331 mg, 2.392 mmol) was added, followed by dropwise addition of MeI (0.060 mL, 0.957 mmol). The reaction was stirred at rt overnight. The reaction mixture was quenched with a saturated solution of NaHCO3 and Na2S2O3, then diluted with EtOAc. The organic layer was washed with sat'd NaHCO3, then brine, and dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography eluting with 0%-50% EtOAc/Hex. 1-methyl-5-nitro-1H-indazole-3-carbonitrile (134 mg) was obtained as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:14]=3)[OH:12])=[C:9]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[S:8][C:7]=2[CH:34]=1>[O-2].[O-2].[O-2].[Cr+6].N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:17][CH:18]=3)=[O:12])=[C:9]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)[S:8][C:7]=2[CH:34]=1
Reactant: COc1ccc2c(C(O)c3ccc(CCCN4CCCCC4)cc3)c(C3CCCCC3)sc2c1
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Product: COc1ccc2c(C(=O)c3ccc(CCCN4CCCCC4)cc3)c(C3CCCCC3)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
88 mg of chromium trioxide was added to 5 ml of pyridine to give a yellow gruel-like solution, a pyridine solution of 105 mg of (6-methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(1-piperidinyl)propyl]phenyl]methanol was added, and the mixture was stirred at room temperature for 1 hour. After addition of ice to the reaction mixture, the mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resultant crude product was purified by TLC (developing solvent, chloroform:methanol=19:1) to obtain 47 mg of (6-methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(1-piperidinyl)propyl]phenyl]methanone.