Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH3:40])[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20](B(O)O)[C:21]4[S:25][C:24]([N:26]5[CH2:31][N:30]([CH3:32])[CH2:29][N:28]([CH2:33][CH3:34])[C:27]5=[O:35])=[N:23][C:22]=4[CH:36]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH:41]OS([O-])=O.[K+].Cl>CC(C)=O.C(=O)([O-])O.[Na+].O.CCOC(C)=O>[CH2:33]([N:28]1[CH2:29][N:30]([CH3:32])[CH2:31][N:26]([C:24]2[S:25][C:21]3[C:20]([OH:41])=[CH:19][C:18]([C:15]4[CH:14]=[N:13][C:12]([N:9]5[CH2:10][CH2:11][C:6]([CH3:40])([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]5)=[N:17][CH:16]=4)=[CH:36][C:22]=3[N:23]=2)[C:27]1=[O:35])[CH3:34]
Reactant: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(B(O)O)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Reactant: O=S([O-])OO
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(O)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Temperature: 0 °C
Yield: 117.2 %

Procedure:
[5-[2-(4-Ethoxycarbonyl-4-methyl-1-piperidyl)pyrimidin-5-yl]-2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-1,3-benzothiazol-7-yl]boronic acid (Intermediate 12) (1.88 g, 3.32 mmol) was dissolved in acetone (60 mL) and cooled to 0° C. Oxone (2.45 g, 3.98 mmol), dissolved in sodium hydrogen carbonate (sat aq) (40 mL), was added dropwise to the reaction mixture, resulting in a dark red solution. After addition, the mixture was stirred for 5 min at 0° C. before 1M HCl was added, bring the reaction mixture to ˜pH 2. The reaction mixture was diluted with water (100 mL) and EtOAc (100 mL). The organic layer was removed, and the aqueous layer was extracted twice more with EtOAc (2×100 mL). The organic fractions were dried and concentrated in vacuo to give a dark brown solid. Flash chromatography (40 g silica column), eluting with 0-100% EtOAc gradient in n-heptane, gave desired product (2.1 g, dark red solid). 1H NMR (MeOD) δ 8.61 (s, 2H), 7.41 (d, J=1.4 Hz, 1H), 6.84 (d, J=1.5 Hz, 1H), 5.21 (s, 2H), 4.47-4.36 (m, 4H), 4.28-4.20 (m, 2H), 3.53-3.44 (m, 2H), 3.35-3.25 (m, 2H, obscured under solvent), 2.67 (s, 3H), 2.19 (d, J=13.5 Hz, 2H), 1.56-1.46 (m, 2H), 1.36-1.21 (m, 9H). MS: [M−H]− 538.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([O:22]C)=[O:21])=[CH:12][N:11]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[C:13]([C:20]([OH:22])=[O:21])=[CH:12][N:11]=1
Reactant: COC(=O)c1cnc(Nc2ccc(Cl)cc2Cl)nc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc(Nc2ccc(Cl)cc2Cl)nc1C(F)(F)F
Yield: 84.5 %

Procedure:
To a solution of methyl 2-(2,4-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylate (107 g) in methanol (700 ml) was added a solution of potassium hydroxide (50 g) in methanol (700 ml) and the solution stirred at reflux for 24 h. Methanol was removed under reduced pressure and water (800 ml) added. The solution was washed with ether (3×400 ml, which removed the remaining 2,4-dichloroaniline) and concentrated hydrochloric acid added to adjust the acidity to pH 1. The precipitated solid was filtered, washed with 2N HCl and water until the pH of the filtrate was neutral. The solid was dried in vacuo at 50° C. to afford 2-(2,4-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (86.9 g)
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH2:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+]>C1COCC1>[CH2:8]1[C:9]2[NH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[CH2:18][CH:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: CCOC(=O)C1CCc2[nH]c3ccccc3c2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCc2[nH]c3ccccc3c2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 0.1 %

Procedure:
2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid ethyl ester (34.5 g, 142 mol) was dissolved in 375 mL of THF. Lithium hydroxide hydrate (23.8 g, 566 mmol) was added. The mixture was stirred at room temperature 48 h, at which time TLC showed complete consumption of starting ester. The mixture was acidified with 1 N HCl and was extracted with ethyl acetate. The organic layer was washed with brine, then was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 30.4 g (99%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22](Br)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:40])([F:39])[C:29]1[CH:30]=[C:31](OB(O)O)[CH:32]=[CH:33][CH:34]=1.O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:26])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([C:28]([F:40])([F:39])[F:27])[CH:34]=3)=[CH:21][N:20]=2)[N:15]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ncc(Br)cn2)cs1
Reactant: OB(O)Oc1cccc(C(F)(F)F)c1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ncc(-c3cccc(C(F)(F)F)c3)cn2)cs1
Yield: 91.9 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(5-bromopyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (920 mg) synthesized in Example 162-1 and 3-(trifluoromethyl)phenylboric acid (380 mg) were dissolved in dioxane (10 mL) and 2 mol/L sodium carbonate (5 mL), tetrakis(triphenylphosphine)palladium (115 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1 to 2:1) to give the title compound (890 mg) as a white solid.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[Na].CCO.[Cl:20][C:21]1[CH:26]=[C:25]([CH2:27]Cl)[CH:24]=[C:23]([C:29]([F:32])([F:31])[F:30])[C:22]=1[NH2:33]>O1CCOCC1.O>[C:1]([NH:4][C:5]([CH2:27][C:25]1[CH:24]=[C:23]([C:29]([F:31])([F:32])[F:30])[C:22]([NH2:33])=[C:21]([Cl:20])[CH:26]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: Nc1c(Cl)cc(CCl)cc1C(F)(F)F
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)C(Cc1cc(Cl)c(N)c(C(F)(F)F)c1)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
24.11 g (0.11 mol) diethyl 2-acetylamino-malonate was added to a freshly prepared solution of 2.55 g (0.11 mol) sodium in 200 mL abs. EtOH under a nitrogen atmosphere and the mixture was stirred for 15 minutes at RT. A solution of 27.00 g (0.11 mol) 2-chloro-4-chlormethyl-6-trifluoromethyl-phenylamine (Intermediate product 55) in 100 mL 1,4-dioxane was rapidly added dropwise and the mixture was stirred for 4 hours at RT. 500 mL water were added and the mixture was stirred for a further 16 hours. The precipitate formed was filtered off, washed with water and dried i. vac.
Reaction SMILES: C([C:3]1([C:18]([F:21])([F:20])[F:19])[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:17])[C:9]=2[F:16])[O:4]1)C.O.[OH-].[Li+].C(O)C>C1COCC1.O>[Cl:17][C:8]1[C:9]([F:16])=[C:10]2[C:5](=[CH:6][CH:7]=1)[O:4][CH:3]([C:18]([F:21])([F:19])[F:20])[C:12]([C:13]([OH:15])=[O:14])=[CH:11]2
Reactant: CCC1(C(F)(F)F)Oc2ccc(Cl)c(F)c2C=C1C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)C1=Cc2c(ccc(Cl)c2F)OC1C(F)(F)F
Temperature: 25 °C
Yield: 29.7 %

Procedure:
To the solution of ethyl 6-chloro-5-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid (1.1 g, 3.4 mmol) in 5 mL of THF was added a solution of lithium hydroxide hydrate (0.72 g, 17 mmol) in 5 mL of water. To the resulting mixture was added 5 mL of ethanol. The resulting solution was heated to reflux over three hrs. The reaction turned red. After cooling to room temperature, the volatiles were removed, the residue was diluted with water. The resulting solution was acidified at 0° C. with ice cold dilute hydrochloric acid. The product was then extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate. After removing the solvent, the residue was purified on reverse phase HPLC. It gave a yellow solid (0.3 g). LC-MS(ES+) 297.2(M+1, 100). 1H NMR (CDCl3/CD3OD/400 MHz) 7.85(s, 1H), 7.24(m, 1H), 6.69(d, J=8.8 Hz, 1H), 5.63(q, J=6.4 Hz, 1H). 19F (CDCl3/CCD3OD/400 MHz) −78.94(d, J=6.8 Hz), −111.92(d, J=7.5 Hz). 13C NMR(CDCl3/CD3OD/400 MHz) 165.4, 155.0(d, J=64.4 Hz), 152.3, 133.2, 129.4, 123.3 (q, J=287.3 Hz) 118.5 114.2(d, J=4.3 Hz), 112.6, 110.1 (d, J=4.7 Hz), 70.9(q, J=33.2 Hz). HRSM((EI+) m/z calc. for (C11H5ClF4O3): 295.9863(M+), found 295.9875(M+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-])=O>CO.[Pd]>[NH2:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(O)c(N)c1
Reaction time: 70 h
Yield: 69.4 %

Procedure:
A stirred mixture of methyl 4-hydroxy-3-nitrobenzoate (3.22 g, 0.0163 mol) and 5% Pd-C (12.9 g) in MeOH (30 mL) was hydrogenated under an atmospheric pressure for 70 hr at room temp. Insoluble catalyst was removed, and the filtrate was evaporated in vacuo. The residue was chromatographed on silica-gel with EtOH—CHCl3 (1:20, v/v) as eluent to afford 1.89 g (69%) methyl 3-amino-4-hydroxybenzoate as a pale brown syrup.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[CH:6]=1.CO[CH2:11][Cl:12]>C(O)(=O)C>[CH3:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[C:6]=1[CH2:11][Cl:12]
Reactant: COCCl
Reactant: Cc1cc(C)c(C)s1
Solvent: CC(=O)O
Product: Cc1sc(C)c(CCl)c1C
Temperature: 25 °C
Reaction time: 91 h

Procedure:
24.6 G. of 2,4,5-trimethyl-thiophene, 14.8 g. of freshly distilled chloromethyl methyl ether and 52 g. of glacial acetic acid were combined in a glass pressure bottle and stirred at room temperature for 4-178 hours. The resulting reaction mixture was poured into ice water, stirred for 10 min. and extracted with benzene. The combined benzene extracts were washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The resulting 2,4,5-trimethyl-3-chloromethyl-thiophene was used for the next step without any further purification.
Reaction SMILES: C(OC)(=O)CCCCC=C.[C:11]([S:15]([N:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26]C)=[O:24])=[O:16])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([S:15]([N:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:16])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCCCC=NS(=O)C(C)(C)C
Agent: C=CCCCCC(=O)OC
Product: COC(=O)CCCCC=NS(=O)C(C)(C)C

Procedure:
Methyl 6-((tert-butylsulfinyl)imino)hexanoate was prepared from methyl hept-6-enoate according to the procedure described for ethyl 6-((tert-butylsulfinyl)imino)hexanoate. Purification by FC (DCM/MeOH=25/1) afforded methyl 6-((tert-butylsulfinyl)imino)hexanoate as a yellow oil. LC-MS (conditions D): tR=0.87 min.; [M+H]+: 248.17 g/mol.
Reaction SMILES: [F:1][CH:2]([F:17])[C@:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[NH:8][C:7](=O)[CH2:6][O:5][CH2:4]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[NH3:32].O.[OH:34][S:35]([OH:38])(=[O:37])=[O:36]>C(Cl)Cl.C1COCC1.CO>[S:35]([OH:38])([OH:37])(=[O:36])=[O:34].[F:1][CH:2]([F:17])[C@@:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH2:4][O:5][CH2:6][C:7]([NH2:32])=[N:8]1
Reactant: O=C1COC[C@](c2ccccc2F)(C(F)F)N1
Reactant: N
Agent: O=S(=O)(O)O
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: NC1=N[C@@](c2ccccc2F)(C(F)F)COC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-5-difluoromethyl-5-(2-fluoro-phenyl)-morpholin-3-one (120 g, 489.4 mmol) in CH2Cl2 (1.2 L) was added P2S5 (108 g, 489.4 mmol) at room temperature. The resulted yellow suspension was heated to reflux for 3.5 h. The reaction mixture was filtered through a pad of silica gel (200˜300 mesh), washed with CH2Cl2 for 3 times to get a brown solution. The solvent was removed to provide the crude product as an orange solid, which was dispersed in THF (100 mL), then 25% NH3 water solution (750 mL) was added at room temperature. 27 hours later, the reaction mixture was extracted with IPAC. The combined organic phase was washed with water, concentrated to provide a yellow oil. The crude product was dissolved in IPAC (1.2 L) and MeOH (60 mL) and some solid undissolved was removed through filtration. Then conc. H2SO4 (57.6 g, 587.3 mmol) was added to get a white suspension. The suspension was stirred at room temperature overnight and filtered to provide the title compound as a white solid: ESIMS: 245; [(M−H2SO4+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 9.60 (bs, 1H), 8.82 (br s, 1H), 7.52 (m, 2H), 7.35 (m, 2H), 6.75 (t, 1H), 4.65 (dd, 2H), 4.36 (d, 1H), 4.14 (d, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][N:16]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37])[C:17]([CH:19]1[C:24](=O)[C@:23]2([CH3:29])[C:26]([CH3:28])([CH3:27])[C@H:20]1[CH2:21][CH2:22]2)=[O:18])=O)(C)(C)C>ClCCl>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[N:16]1[C:17](=[O:18])[C:19]2[C@H:20]3[C:26]([CH3:28])([CH3:27])[C@:23]([CH3:29])([CH2:22][CH2:21]3)[C:24]=2[NH:15]1
Reactant: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@@]2(C)CC[C@@H]1C2(C)C)c1ccc(F)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.5 %

Procedure:
Trifluoroacetic acid (80 mL) was added to a solution of crude N′-(2,4-difluoro-phenyl)-N′-((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (˜100 mmol) in dichloromethane (80 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min, and then at room temperature for 4 h. The solvent was evaporated. The residue was taken up in dichloromethane (500 mL) and washed with water (4×600 mL) adding brine to help separate the layers when necessary. The solution was further washed with brine (250 mL), dried (magnesium sulfate), filtered, and evaporated. The solids were triturated with 10% dichlormethane/hexanes, filtered, washed with 5% dichloromethane/hexanes and then hexanes, stored over a weekend in the freezer, and then dried under high vacuum to give (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (25.71 g, 84%) as a light brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([CH3:11])[C:3]=1[C:12]([OH:14])=[O:13].[C:15]1([S:21]([NH2:24])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:15]1([S:21]([NH:24][C:8]([C:6]2[CH:5]=[C:4]([CH3:11])[C:3]([C:12]([OH:14])=[O:13])=[C:2]([CH3:1])[CH:7]=2)=[O:10])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc(C(=O)O)cc(C)c1C(=O)O
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NS(=O)(=O)c2ccccc2)cc(C)c1C(=O)O
Temperature: 0 °C

Procedure:
2,6-Dimethyl-1,4-benzenedicarboxylic acid (from Preparation 7) (500 mg, 2.6 mmol) and benzene sulfonamide (486 mg, 3.1 mmol) were combined in dry DMF (25 mL), and EDCI (494 mg, 2.6 mmol) was then added with stirring at 0° C. The mixture was stirred for 2 hours at 0° C. and 2 days at room temperature, then 1 N HCl (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with 1 N HCl (1×), water (5×), and brine (3×); dried (Na2SO4); and rotary evaporated to give the crude product (used as such in the next step) as a white solid; NMR (acetone-d6) showed 8.0-7.4 ppm (multiplet with a singlet at 7.7 ppm, 7H) and 2.4 ppm (singlet, 6H).
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1C(OC(C)(C)C)=O)=O.[N:20]1([CH2:26][CH2:27][OH:28])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH2:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:12][C@@H:3]([CH2:1][N:23]2[CH2:24][CH2:25][N:20]([CH2:26][CH2:27][OH:28])[CH2:21][CH2:22]2)[NH:4]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C=O
Reactant: OCCN1CCNCC1
Product: OCCN1CCN(C[C@@H]2Cc3ccccc3CN2)CC1

Procedure:
Following a procedure analogous to that for the synthesis of Example 107, (S)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (58 mg, 0.22 mmol) and 2-(piperazin-1-yl)ethanol (33 μL, 0.267 mmol) provided a crude oil which was used without purification in the preparation of Example 115. MS(ESI+) m/z 276.2 (M+H)+.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[C:17]([C:19]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:20]=2)[CH:16]=[CH:15][N:14]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2ccnc(Cl)c2)sc2ccccc12
Yield: 7.9 %

Procedure:
Methyl thiosalicylate (3.6 g, 21.6 mmol) and 2-chloro-4-cyanopyridine (3.0 g, 21.7 mmol) were dissolved in toluene (5.0 ml), and triethylamine (4.5 ml, 32.3 mmol) was added thereto. The reaction mixture was refluxed for 22 hrs. The reaction mixture was subjected to a silica gel (120 g) column chromatography, eluted with hexane-ethyl acetate (1:2, v/v) and recrystallized from acetone-ethyl acetate to give 2-(2-chloro-4-pyridyl)-4H-1,3-benzothiazine-4-one (0.47 g, 8.0%) as white crystals.
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([C:13]([OH:15])=O)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][NH2:31])=[C:25]([CH3:32])[N:24]=1)([CH3:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][NH:31][C:13]([C:11]2[O:10][N:9]=[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:12]=2)=[O:15])=[C:25]([CH3:32])[N:24]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Reactant: O=C(O)c1nc(Cc2ccccc2)no1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1nc(Cc2ccccc2)no1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3-Benzyl-[1,2,4]oxadiazole-5-carboxylic acid (330 mg, 1.5 mmol), (5-Aminomethyl-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (389 mg, 1.5 mmol), HATU (1.1 g, 3.1 mmol) and DIPEA (0.8 mL, 4.7 mmol) in 10 mL DMF was stirred at room temperature for 16 h. The mixture was evaporated and the residue was partitioned between ethyl acetate and 1 N aq. HCl. The organic layer was dried over MgSO4 and evaporated in vacuo. The crude product was purified by preparative HPLC (Waters Sunfire Prep C18 PBD 5 um, 30×100 mm, 5 to 100% ACN and 0.1% TFA, flow 40 ml/min). LCMS (method A) RtA=1.834 min; [M+H]+=438.1.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]1([F:19])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[F:11][C:12]1([F:19])[CH2:18][CH2:17][CH2:16][N:15]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14][CH2:13]1
Reactant: FC1(F)CCCNCC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: Cn1ncc([N+](=O)[O-])c1N1CCCC(F)(F)CC1
Yield: 100 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 4,4-difluoroazepane gave 4,4-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepane as a white solid (0.41 g, 100%). 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 3.79 (s, 3H), 3.39-3.23 (m, 4H), 2.35-2.20 (m, 4H), 2.00-1.92 (m, 2H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[CH:15]2[N:11]3[C:12](=[C:16]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#N)=[CH:21][CH:20]=4)[N:17]=[CH:18][C:10]3=[CH:9][CH2:8][C:7]1=[O:27])[CH2:13][CH2:14]2.C(O)=[O:35]>O=[Pt]=O.C1COCC1>[CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[CH:15]2[N:11]3[C:12](=[C:16]([C:19]4[CH:20]=[CH:21][C:22]([CH:23]=[O:35])=[CH:25][CH:26]=4)[N:17]=[CH:18][C:10]3=[CH:9][CH2:8][C:7]1=[O:27])[CH2:13][CH2:14]2
Reactant: COc1ccc(CN2C(=O)CC=C3C=NC(c4ccc(C#N)cc4)=C4CCC2N34)c(OC)c1
Reactant: O=CO
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CC=C3C=NC(c4ccc(C=O)cc4)=C4CCC2N34)c(OC)c1
Temperature: 60 °C

Procedure:
A suspension of (A5) and PtO2 (0.1 eq.) in a solvent mixture of HCO2H (80% sol. in water)/THF=2.5:1 (0.2 M) was heated to 60° C. for 4 h. After cooling, the catalyst was filtered through a pad of celite, then, the solvent was reduced in vacuo and the residue partioned between sat. aq. NaHCO3 and DCM. The aqueous phase was separated and extracted several times with DCM. The combined organic extracts were washed with brine and dried (Na2SO4). Evaporation of the solvent gave the title compound which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3, 300K) δ 9.96 (1H, s), 7.78 (2H, d, J=7.8 Hz), 7.85-7.78 (3H, m), 7.72 (1H, d, J=8.6 Hz), 7.29 (1H, d, J=7.8 Hz), 7.27-7.18 (1H, m), 6.50-6.40 (2H, m), 4.78 (2H, s), 3.79 (3H, s), 3.75 (3H, s), 3.70-3.60 (2H, m), 3.30-3.20 (2H, m). MS (ES+) C26H23N3O4 requires: 441, found: 442 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[C:23]1[CH:24]=[N:25][N:26](C(OC(C)(C)C)=O)[CH:27]=1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=2)[CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O.CN(C=O)C>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([C:23]4[CH:27]=[N:26][NH:25][CH:24]=4)=[C:2]([C:45]4[CH:44]=[CH:43][CH:42]=[C:41]([N:38]5[CH2:37][CH2:36][O:35][CH2:40][CH2:39]5)[CH:46]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc(N2CCOCC2)c1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(-c3cnn(C(=O)OC(C)(C)C)c3)sc2n1
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: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(N4CCOCC4)c3)c(-c3cn[nH]c3)sc2n1
Temperature: 110 °C

Procedure:
A mixture of 1,1-dimethylethyl 4-(3-bromo-4-{[(3-chlorophenyl)sulfonyl]amino}-6-methylthieno[2,3-b]pyridin-2-yl)-1H-pyrazole-1-carboxylate (Description 75) (100 mg, 0.171 mmol), 3-(morpholino)phenylboronic acid, pinacol ester (74.3 mg, 0.257 mmol), potassium carbonate (95 mg, 0.685 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.96 mg, 3.43 μmol) were weighed into a microwave vial. 1,4-Dioxane (1.5 mL), DMF (0.75 mL) and water (0.38 mL) were added and the mixture heated in a microwave at 110° C. for 30 min. At this point, both reaction mixtures were combined and concentrated. Purification by chromatography on silica, eluting with a gradient of 0-100% ethyl acetate in DCM, followed by MDAP (acidic conditions), afforded the title compound (44 mg). LCMS (A) m/z: 566 [M+1]+, Rt 1.24 min (acidic).