Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:21]=3[C:29]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[C:32]([F:38])=[CH:31][C:30]=3[O:39][CH3:40])[C@H:14]2[CH3:41])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>CO>[NH2:26][C:24]1[CH:23]=[CH:22][C:21]([C:29]2[CH:34]=[C:33]([CH:35]([CH3:36])[CH3:37])[C:32]([F:38])=[CH:31][C:30]=2[O:39][CH3:40])=[C:20]([CH2:19][N:15]2[C@@H:14]([CH3:41])[C@@H:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:43])([F:42])[F:1])[CH:4]=3)[O:17][C:16]2=[O:18])[CH:25]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc([N+](=O)[O-])cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: CO
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(N)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
A solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4′-fluoro-5′-isopropyl-2′-methoxy-4-nitrobiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (1.94 g, 3.16 mmol) in methanol (20 mL) was subject to H2 (40 psi., Parr shaker) at 20° C. for 1.5 h. LCMS indicated the presence of trace starting material. The crude mixture was filtered through a bed of Celite (521). The filtrate was evaporated in vacuo to afford a glass as the product. LC-MS: 585.32 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 1:1 mixture of rotamers δ 7.83 (s, 1 H), 7.67 (s, 2 H), 6.93-7.06 (m, 2 H), 6.87 (s, 0.5H), 6.72-6.82 (m, 1.5H), 5.57 (d, J=8.0 Hz, 0.5H), 5.36 (d, J=8.0 Hz, 0.5H), 4.77 (d, J=5.5 Hz, 0.51-1), 4.74 (d, J=6.5 Hz, 0.5 H), 3.95 (d, J=15.5 Hz, 0.5 H), 3.75-3.86 (m, 1.5 H), 3.73 (s, 3 H), 3.12-3.24 (m, 1H), 1.11-1.29 (m, 6 H), 0.47 (d, J=6.5 Hz, 1.5H), 0.29 (d, J=6 Hz, 1.5 H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]([N+:9]([O-])=O)=[CH:7][N:6]([CH3:12])[N:5]=1.CCOC(C)=O>CO.[Pd]>[CH3:1][O:2][CH2:3][C:4]1[C:8]([NH2:9])=[CH:7][N:6]([CH3:12])[N:5]=1
Reactant: COCc1nn(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COCc1nn(C)cc1N
Reaction time: 8 h
Yield: 70.8 %

Procedure:
10% wt Pd/C (50% wet) (2 g) was added to a stirred solution of 3-(methoxymethyl)-1-methyl-4-nitropyrazole (2.02 g) in MeOH (60 ml) and the mixture stirred under an atmosphere of hydrogen overnight. The reaction mixture was filtered through a plug of celite, and the cake washed with EtOAc (200 ml). The volatiles were removed under reduced pressure to give the crude product as a brown oil. Subsequent column chromatography (SiO2; 100% EtOAc) of the crude material gave 3-(methoxymethyl)-1-methylpyrazol-4-amine (1.18 g, 70%) as a brown liquid. NMR Spectrum: (CDCl3) 2.9 (m, 2H), 3.35 (s, 3H), 3.74 (s, 3H), 4.46 (s, 2H), 6.91 (s, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][C:22]([CH3:28])=[N:23]4)[CH2:14][CH2:13]2)=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[C:29]([Cl:32])(=[O:31])[CH3:30]>>[ClH:32].[ClH:32].[CH3:1][O:2][C:3]1[C:9]([CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][C:22]([CH3:28])=[N:23]4)[CH2:16][CH2:17]2)=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:29](=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: COc1c(N)cccc1CCN1CCN(c2cccc3nc(C)ccc23)CC1
Product: COc1c(CCN2CCN(c3cccc4nc(C)ccc34)CC2)cccc1NC(C)=O
Product: Cl
Yield: 42 %

Procedure:
The title compound was prepared in 42% yield according to the general procedure for the preparation of amides (Method B) starting from starting from 2-(methoxy)-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline and acetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([CH:17]([CH3:20])[CH:18]=O)[C:13]=3[CH:21]=2)[CH:5]=[C:4]([F:22])[C:3]=1[C:23]([F:26])([F:25])[F:24].Cl.[NH2:28][NH:29][C:30]([NH2:32])=[O:31].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([CH:17]([CH3:18])[CH:20]=[N:28][NH:29][C:30]([NH2:32])=[O:31])[C:13]=3[CH:21]=2)[CH:5]=[C:4]([F:22])[C:3]=1[C:23]([F:26])([F:25])[F:24]
Reactant: CC(C=O)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C=NNC(N)=O)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21

Procedure:
A mixture of 6-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl)oxy]-α-methyl-1H-benzotriazole-1-acetaldehyde (0.0295 mole), semicarbazide hydrochloride (4.0 g, 0.035 mole), and sodium acetate (5.8 g, 0.071 mole) in aqueous ethanol is heated to reflux temperature, cooled and filtered. The solid filter cake is recrystallized from ethanol to give the title compound as a solid, mp 170°-171° C., identified by elemental and NMR analyses.
Reaction SMILES: [ClH:1].C(N(CC)C1C=CC=CC=1)C.[F:13][C:14]([F:26])([F:25])[C:15]([NH:17][NH:18][C:19](=O)[C:20]([F:23])([F:22])[F:21])=O.P(Cl)(Cl)([Cl:29])=O>>[Cl:1][C:15](=[N:17][N:18]=[C:19]([Cl:29])[C:20]([F:23])([F:22])[F:21])[C:14]([F:26])([F:25])[F:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(NNC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cl
Solvent: CCN(CC)c1ccccc1
Product: FC(F)(F)C(Cl)=NN=C(Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
A mixture of N,N-diethylaniline hydrochloride (18.5 g, 0.1 mol), 1,2-bis(trifluoroacetyl)hydrazine (10.3 g, 0.46 mol) and phosphoryl chloride (160 mL) was stirred for 30 minutes under nitrogen in a flask fitted with a condenser leading to a cold trap (−78° C.). The mixture was heated under reflux for 5 h and then allowed to cool and stored overnight. The flask contents and the small amount of material which had condensed in the cold trap were combined and the two layers which had formed were separated. The layer was added to ice water (85 mL) and the mixture vigorously stirred for 1 h in a flask fitted with a condenser. Separation of the lower organic layer gave the main batch of the crude product (6.4 g). The original dark upper layer was treated similarly with ice water (75 mL) and the organic layer subjected to preliminary purification by trap-to-trap distillation in vacuum to afford a second batch of crude product (1.6 g). Distillation of the combined product through a vacuum-jacketed Vigreux column gave 2,5-dichloro-1,1,1,6,6,6-hexafluoro-3,4-diazahexa-2,4-diene (6.3 g, 53%) as an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][S:10][CH2:9][CH2:8]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[NH:21][CH:22]=[C:23]([CH2:31][CH2:32][CH2:33]OS(C3C=CC(C)=CC=3)(=O)=O)[C:24]=2[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:16][CH:15]=1.O>C(#N)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[NH:21][CH:22]=[C:23]([CH2:31][CH2:32][CH2:33][SH:10]3[CH2:11][CH2:12][NH:7][CH2:8][CH2:9]3)[C:24]=2[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: C1CSCCN1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2c[nH]c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Fc1ccc(-c2[nH]cc(CCC[SH]3CCNCC3)c2-c2ccncc2)cc1
Temperature: 25 °C
Yield: 82.9 %

Procedure:
163 mg (1.18 mmol) of potassium carbonate and 122 μl (1.29 mmol) of thiomorpholine were added to a solution of 450 mg (1.07 mmol) of 2-(4-fluorophenyl)-3-(pyridin-4-yl)-4-[3-(p-toluenesulfonyloxy)propyl]-1H-pyrrole [prepared as described in step 23(iv) above] in 50 ml of acetonitrile. The resulting mixture was heated under reflux overnight. After cooling the reaction mixture to room temperature, water was added and then this was extracted with ethyl acetate. The organic extract was washed with water and then concentrated by evaporation under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column using a 95:5 by volume mixture of ethyl acetate and methanol as the eluant to give 340 mg (yield 83%) of the title compound as a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][N:9]([S:13](Cl)(=[O:15])=[O:14])[CH2:8][C:7]=2[CH:17]=1.[NH2:18][C:19]1[C:24]2[CH:25]=[C:26]([CH2:28][CH:29]([NH:39]S(C3C=CC(OC4CCOCC4)=CC=3)(=O)=O)[C:30]([N:32]3[CH2:37][CH2:36][CH:35]([CH3:38])[CH2:34][CH2:33]3)=[O:31])[S:27][C:23]=2[CH:22]=[CH:21][N:20]=1>>[NH2:18][C:19]1[C:24]2[CH:25]=[C:26]([CH2:28][CH:29]([NH:39][S:13]([N:9]3[CH2:8][C:7]4[CH:17]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[O:12][CH2:11][CH2:10]3)(=[O:15])=[O:14])[C:30]([N:32]3[CH2:33][CH2:34][CH:35]([CH3:38])[CH2:36][CH2:37]3)=[O:31])[S:27][C:23]=2[CH:22]=[CH:21][N:20]=1
Reactant: COc1ccc2c(c1)CN(S(=O)(=O)Cl)CCO2
Reactant: CC1CCN(C(=O)C(Cc2cc3c(N)nccc3s2)NS(=O)(=O)c2ccc(OC3CCOCC3)cc2)CC1
Product: COc1ccc2c(c1)CN(S(=O)(=O)NC(Cc1cc3c(N)nccc3s1)C(=O)N1CCC(C)CC1)CCO2

Procedure:
This compound was prepared from 210 mg of 7-methoxy-2,3-dihydro-5H-benzo[f][1,4]-oxazepine-4-sulfonyl chloride and 210 mg of 30a using the procedure described for 58c. Yield: 70 mg (oil), (+)-FAB-MS: 560 (MH+).
Reaction SMILES: [K].[CH3:2][CH:3]([CH3:5])[O-:4].[K+].Br[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([Br:14])[CH:13]=1>CC(O)C.[Cu]>[Br:14][C:12]1[CH:13]=[C:8]([O:4][CH:3]([CH3:5])[CH3:2])[CH:9]=[N:10][CH:11]=1
Reactant: CC(C)[O-]
Reactant: Brc1cncc(Br)c1
Agent: [Cu]
Agent: [K+]
Agent: [K]
Solvent: CC(C)O
Product: CC(C)Oc1cncc(Br)c1
Temperature: 25 °C
Yield: 71.2 %

Procedure:
Potassium metal (6.59 g, 168.84 mmol) was dissolved in dry 2-propanol (60.0 mL) under nitrogen. The resulting potassium isopropoxide was heated with 3,5-dibromopyridine (20.00 g, 84.42 mmol) and copper powder (1 g, 5% by weight of 3,5-dibromopyridine at 140° C. in a sealed glass tube for 14 h. The reaction mixture was cooled to ambient temperature and extracted with diethyl ether (4×200 mL). The combined ether extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product obtained was purified by column chromatography over aluminum oxide, eluting with ethyl acetate-hexane (1:9, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing a pale-yellow oil (12.99 g, 71.2%).
Reaction SMILES: [H-].[Na+].SCCCCS.Br[CH2:10][CH2:11][P:12]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13]>CCCCCC>[CH:11]([P:12](=[O:13])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[CH2:10]
Reactant: CCOP(=O)(CCBr)OCC
Agent: SCCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: C=CP(=O)(OCC)OCC
Temperature: 0 °C
Yield: 90 %

Procedure:
A sample of 60% NaH in mineral oil (188 mmol) was placed in a 2-neck round bottom flask and charged with dry hexane (20 mL). This solution was allowed to stir ten minutes, after which the hexane-mineral oil layer was removed by syringe. The flask was charged with dry tetrahydrofuran (100 mL), followed by dropwise addition of HS(CH2)4SH (82 mmol) with constant stirring. The resulting solution was cooled at 0° C. and BrCH2CH2P(O)(OC2H5)2 (164 mmol) was added dropwise with constant stirring over a period of 30 minutes. Excess NaH was quenched by addition of 50 mL of deionized water. The solution was extracted from ethyl acetate (3×50 mL) and washed with a saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. Upon filtering, the solvent was removed in vacuo to afford compound 2 in 90% yield along with a trace amount of diethyl vinylphosphonate. The compounds were separated on a silica gel column (20 cm; 60 mesh) using 90:10 ethyl acetate to hexane solvent mixture. Removal of the solvent in vacuo, afforded compound 2 as a viscous, yellow-green oil with an overall yield of 92% (36 g). Low resolution FAB/MS Anal. Calcd. for C16H36O6P2S2 : 450.1428. Found: [M+H+ ], m/z=451.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][Cl:7].[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O-:17])=[O:16].C([O-])([O-])=O.[K+].[K+]>>[ClH:7].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][N:27]1[CH2:28][CH2:29][N:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N+:15]([O-:17])=[O:16])[CH2:25][CH2:26]1
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: O=[N+]([O-])c1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(CN2CCN(c3ccccc3[N+](=O)[O-])CC2)cc(OC)c1OC
Product: Cl
Yield: 64.8 %

Procedure:
8.3 g of 3,4,5-trimethoxybenzyl chloride and 4.15 g of N-(2-nitrophenyl)-piperazine and 3.5 g of K2CO3 are reacted and processed according to example 2. 5.5 g of N-(3,4,5-trimethoxy-benzyl)-N'-(2-nitrophenyl)-piperazine hydrochloride is obtained. Mp.: 248° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:29]=[CH:28][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[N:21]2)=[CH:17][CH:16]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:25]([C:23]3[CH:22]=[N:21][N:20]([CH2:19][C:18]4[CH:28]=[CH:29][C:15]([O:14][CH3:13])=[CH:16][CH:17]=4)[CH:24]=3)=[O:26])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: COc1ccc(Cn2cc(C(=O)O)cn2)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2cc(C(=O)Nc3c[nH]c4ncc(Br)c(F)c34)cn2)cc1
Yield: 39.8 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (300 mg, 1.30 mmol, Example 1, Step H), 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid (636 mg, 2.74 mmol), BOP-Cl (697 mg, 2.74 mmol), and triethylamine (0.909 mL, 6.52 mmol) in DCM (5 mL) was processed as described in Example 62, Step A, to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamide (230 mg, 39% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH:13](OCC)=[O:14].[H-].[Na+]>COCCOC>[CH:13]([CH:7]([CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:14]
Reactant: CCOC=O
Reactant: CCOC(=O)CCc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1ccco1
Yield: 75 %

Procedure:
Ethyl 3-(2-furyl)propionate was reacted with 1.1 equivalents ethyl formate and 1.0 equivalents sodium hydride in 1,2-dimethoxyethane at room temperature to give ethyl 2-formyl-3-(2-furyl)propionate as an oil in 75% yield.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].BrC1C=CC([F:26])=CC=1C(O)=O>>[F:26][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: O=C(O)c1cc(F)ccc1Br
Product: O=C(O)c1cc(F)ccc1-n1nccn1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A11 using 2-bromo-5-fluorobenzoic acid. MS (ESI) 208 (M+H).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[C:21]=1[N:28]1[C:32]2=[N:33][CH:34]=[N:35][C:36]([O:37][C@@H:38]([CH2:49][O:50][C@H:51]([CH3:64])[CH2:52][O:53][Si](C(C)C)(C(C)C)C(C)C)[C:39]([NH:41][C:42]3[CH:47]=[N:46][C:45]([CH3:48])=[CH:44][N:43]=3)=[O:40])=[C:31]2[CH:30]=[N:29]1.C(O)(=O)C>C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[C:21]=1[N:28]1[C:32]2[N:33]=[CH:34][N:35]=[C:36]([O:37][C@@H:38]([CH2:49][O:50][C@H:51]([CH3:64])[CH2:52][OH:53])[C:39]([NH:41][C:42]3[CH:47]=[N:46][C:45]([CH3:48])=[CH:44][N:43]=3)=[O:40])[C:31]=2[CH:30]=[N:29]1
Reactant: Cc1cnc(NC(=O)[C@H](CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)Oc2ncnc3c2cnn3-c2c(Cl)cccc2C#N)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)[C@H](CO[C@H](C)CO)Oc2ncnc3c2cnn3-c2c(Cl)cccc2C#N)cn1
Temperature: 22 °C
Reaction time: 20 h
Yield: 85.8 %

Procedure:
1M TBAF in THF (5.11 mL, 5.11 mmol) was added to (2S)-2-(1-(2-chloro-6-cyanophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyrazin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate AZ1) (3.4 g, 5.11 mmol) and acetic acid (0.307 g, 5.11 mmol) in THF (35 mL). The resulting solution was stirred at 22° C. for 20 hours. It was quenched with NH4Cl solution (sat., 25 mL) and diluted with EtOAc (50 mL). The organic phase was washed with saturated sodium bicarbonate (25 mL), water (20 mL), brine (20 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with EtOAc to afford the product (2.23 g, 85%). This was crystallised from EtOAc (10 mL) and iso-hexane (6 mL) to give the desired product as a white crystalline powder (1.9 g, 73%) confirmed to be of the same crystalline form as that described previously.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH:11]([NH:13][C:14](=[O:29])[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=2)([CH3:17])[CH3:16])[CH3:12])[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].[C:38](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O.CCOCC>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH:11]([NH:13][C:14](=[O:29])[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=2)([CH3:17])[CH3:16])[CH3:12])[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2]
Reactant: O=C([O-])[O-]
Reactant: CC(NC(=O)C(C)(C)Oc1ccc(C(F)(F)F)cn1)C(Cc1ccc(O)cc1)c1cc(F)cc(C#N)c1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(CC(c2cc(F)cc(C#N)c2)C(C)NC(=O)C(C)(C)Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 25 °C

Procedure:
To a solution of N-[2-(3-cyano-5-fluorophenyl)-3-(4-hydroxyphenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide from Example 7, Step B (14 mg, 0.028 mmol) in 1.5 mL of dimethylformamide at 0° C. was added cesium carbonate (14 mg, 0.042 mmol) and methyl iodide (5 uL, 0.084 mmol), and the reaction was allowed to warm up to room temperature over 2 h. The resulting mixture was diluted with ether (20 mL), washed with water and brine and concentrated to dryness. The residue was purified by flash column chromatography eluting with 10 to 40% ethyl acetate in hexane to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.27 (d, 1H), 7.96 (s, 1H), 7.94 (d, 1H), 7.93 (d, 1H), 7.29 (m, 1H), 7.18 (br s, 1H), 7.13 (m, 1H), 7.03 (d, 1H), 6.45 (ABq, 4H), 4.24 (m, 1H), 3.67 (s, 3H), 3.03 (dd, 1H), 2.88 (m, 1H), 2.57 (dd, 1H), 1.75 (s, 3H), 1.73 (s, 3H), 0.82 (d, 3H). LC-MS: m/e 530 (M+H)+ (3.9 min).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[BrH:12]>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][N:3]=1
Reactant: Br
Reactant: Brc1nccc2ccccc12
Product: Brc1cnc(Br)c2ccccc12

Procedure:
5.The starting material was prepared by reaction of 1-bromoisoquinoline with HBr to give 1,4-dibromoisoquinoline, m.p. 95°-96°, followed by reaction of this compound with trimethyloxonium tetrafluoroborate in CH2Cl2 to give 1,4-dibromo-2-methylisoquinolinium tetrafluoroborate; n.m.r. in solvent A:-3.5(s, 3H); 7.2-8.4(m, 5H).
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH:9]([NH2:15])[CH2:8][C:7]=2[CH:6]=1)=[O:4].[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[S:24](Cl)(=[O:26])=[O:25].[OH:28][NH2:29].[OH-].[K+]>ClCCl>[OH:28][NH:29][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH:9]([NH:15][S:24]([C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[F:16])(=[O:26])=[O:25])[CH2:8][C:7]=2[CH:6]=1)=[O:4]
Reactant: NO
Reactant: COC(=O)c1ccc2c(c1)CC(N)CC2
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NO)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(F)cc1F)CC2

Procedure:
The title compound was prepared in two steps according to Scheme 6 by (1) treating amine VII with 2,4-difluorobenzenesulfonyl chloride and TEA in dichloromethane, and (2) treating the ester intermediate with aqueous HONH2 and KOH. MS: calc'd (MH+) 383, exp (MH+) 383.4. 1H NMR (CD3OD, 400 MHz), 7.97 (m, 1H), 7.47 (d, 1H, J=8.0 Hz), 7.37 (s, 1H), 7.24 (m, 1H), 7.18 (m, 2H), 3.55 (m, 1H), 2.95 (m, 2H), 2.82 (m, 1H), 2.69 (m, 1H), 1.95 (m, 1H) 1.73 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:9])([CH3:8])[S:6](=[O:11])(=[O:10])[CH2:5][C@:4]([C:14]2[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=2[F:21])([CH2:12][F:13])[N:3]=1.C(=O)(O)[O-].[Na+]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:1][C:2]1[C:7]([CH3:9])([CH3:8])[S:6](=[O:11])(=[O:10])[CH2:5][C@@:4]([CH2:12][F:13])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])[N:3]=1
Reactant: CC1(C)C(N)=N[C@](CF)(c2cc(Br)ccc2F)CS1(=O)=O
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)C(N)=N[C@](CF)(c2ccccc2F)CS1(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a solution of (S)-5-amino-3-(5-bromo-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide (3.22 g, 8.44 mmol) in ethanol (15 mL) and ethyl acetate (5 mL) was added sodium bicarbonate (138 mg, 1.69 mmol) and 10 wt % palladium on carbon (0.90 g, 8.44 mmol). The flask was evacuated and backfilled with hydrogen three times, and stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through a Celite pad, and the filter cake was rinsed with ethyl acetate and ethanol. The combined filtrates were concentrated in vacuo and the residue was redissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and evaporated to provide the title compound (2.49 g, 8.23 mmol) as an off-white solid. LC/MS (ESI+) m/z=303 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[O-]CC.[Na+].[N:17](OCCC(C)C)=O.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[OH:35]>C(O)C>[Cl:1][C:2]1[C:3]([N:12]=[N:17][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][C:26]=2[OH:35])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CC(C)CCON=O
Reactant: Oc1ccc2ccccc2c1
Reactant: Nc1ncc(C(F)(F)F)cc1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Oc1ccc2ccccc2c1N=Nc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction flask was loaded with 3-chloro-5-(trifluoromethyl)-2-aminopyridine (4.0 g), ethanol (13 ml), and sodium ethoxide (1.4 g), followed by dropwise addition of isopentyl nitrite (2.9 g) to the flask in 30 minutes with stirring. After the dropwise addition was ended, heating was started and the mixture was stirred at 75 to 80° C. for four hours. The heating was stopped, and the reaction mixture was cooled to room temperature, followed by dropwise addition of 2-naphthol (1.7 g) dissolved in ethanol (5 ml) to the mixture in one hour. The resultant mixture was stirred at room temperature for one hour, heated, and stirred at 75 to 80° C. for additional one hour, followed by stopping the heating and then leaving the mixture to stand overnight. The reaction mixture was filtrated to remove insoluble components, and the filtrate was condensed by an evaporator. The residue was dissolved in ethyl acetate (100 ml) and, after being successively washed with an aqueous solution of sodium hydroxide and water, the ethyl acetate layer was condensed by an evaporator, followed by addition of methanol to the residue for crystallization. The resultant was filtrated and the crystals were dried to give intended red orange crystals (1.9 g).
Reaction SMILES: [S:1]1[C:5]([SH:6])=[N:4][N:3]=[C:2]1[SH:7].[H-].[Na+].Br[CH2:11][CH:12]([CH3:14])[CH3:13].Cl[C:16]1[C:17]([C:22]#[N:23])=[N:18][CH:19]=[CH:20][N:21]=1>CN(C=O)C.C1C=CC=CC=1>[CH2:11]([S:6][C:5]1[S:1][C:2]([S:7][C:16]2[C:17]([C:22]#[N:23])=[N:18][CH:19]=[CH:20][N:21]=2)=[N:3][N:4]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: N#Cc1nccnc1Cl
Reactant: CC(C)CBr
Reactant: Sc1nnc(S)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(C)CSc1nnc(Sc2nccnc2C#N)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared according to the procedure described in Example 4 by using 1,3,4-thiadiazole-2,5-dithiol (300 mg, 2.00 mmol), NaH (60% dispersion in mineral oil, 88 mg, 2.20 mmol), 1-bromo-2-methylpropane (0.25 ml, 2.30 mmol), NaH (60% dispersion in mineral oil, 88 mg, 2.20 mmol), and 3-chloropyrazine-2-carbonitrile (280 mg, 2.00 mmol) in DMF and benzene (8 ml, 1/1) by stirring at room temperature under nitrogen atmosphere overnight.