Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C@H:9]([O:11][C:12]([C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20](=[O:52])[C@@H:21]([NH:37][C:38](=[O:51])[C@@H:39]([NH:43][C:44](OC(C)(C)C)=[O:45])[CH:40]([CH3:42])[CH3:41])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:24]=3)[NH:15]2)=[O:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1)=[CH2:2].[CH:53](N(CC)C(C)C)(C)C.C(N=C=NCCCN(C)C)C.[OH:73][C:74]1[C:82]2N=NN[C:78]=2[CH:77]=[CH:76][CH:75]=1>ClCCl>[CH:8]([C:3]1[CH:4]=[C:5]([C@H:9]([O:11][C:12]([C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20](=[O:52])[C@@H:21]([NH:37][C:38](=[O:51])[C@@H:39]([NH:43][C:44](=[O:45])[CH2:75][C@H:74]([O:73][CH3:53])[CH2:82][CH2:78][CH:77]=[CH2:76])[CH:40]([CH3:42])[CH3:41])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][Si:30]([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:31])[CH3:32])[CH:24]=3)[NH:15]2)=[O:13])[CH3:10])[CH:6]=[CH:2][CH:1]=1)=[CH2:7]
Reactant: Oc1cccc2[nH]nnc12
Reactant: CCN(C(C)C)C(C)C
Reactant: C=Cc1cccc([C@@H](C)OC(=O)[C@@H]2CCCN(C(=O)[C@H](Cc3cccc(O[Si](C)(C)C(C)(C)C)c3)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)N2)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: C=CCC[C@H](CC(=O)N[C@H](C(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)O[C@H](C)c2cccc(C=C)c2)N1)C(C)C)OC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 31.7 %

Procedure:
A stirred solution of (S)-1-{(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid (R)-1-(3-vinyl-phenyl)-ethyl ester (367 mg, 0.50 mmol) in anhydrous dichloromethane (10 mL) was cooled to 0° C. then treated with trimethylsilyl trimethanesulfonate (135 μL, 2.0 mmol). The reaction mixture was stirred at 0° C. for 1.5 hours, then N,N-diisopropylethylamine (350 μL, 2.0 mmol) was added and the mixture was evaporated. The residue was dissolved in acetonitrile (5 mL) and (R)-3-methoxy-hept-6-enoic acid was added followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (134 mg, 0.70 mmol) and hydroxybenzotriazole (81 mg, 0.50 mmol). The reaction was stirred at room temperature under a nitrogen atmosphere for 16 hours. It was then evaporated to dryness before partitioning between ethyl acetate (20 mL) and water (20 mL). The aqueous was extracted with further ethyl acetate (20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using ethyl acetate/iso-hexanes 13:7 to give the title compound (123 mg, 32%) as a colourless solid. 1H NMR (300 MHz, CDCl3) δ 0.16 (s, 6H), 0.80-1.00 (m, 17H), 1.34-1.94 (m, 12H), 2.00-2.20 (m, 5H), 2.34-2.53 (m, 3H), 2.63-3.03 (m, 3H), 3.38 (s, 3H), 3.52-3.70 (m, 2H), 4.27-4.38 (m, 2H), 4.92-5.10 (m, 2H), 5.29 (d, J=10.9 Hz, 1H), 5.64-5.98 (m, 2H), 6.52-6.99 (m, 4H), 7.22-7.42 (m, 2H). LCMS (m/z) 777.0 [M+H] Tr=5.96 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1Cl.O.[NH2:10][NH2:11]>O1CCOCC1.C(O)(C)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:10][NH2:11]
Reactant: NN
Reactant: Clc1ccncc1Br
Solvent: CC(C)O
Solvent: C1COCCO1
Solvent: O
Product: NNc1ccncc1Br
Temperature: 100 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture of 3-bromo-4-chloropyridine (5 g, 0.026 mol) and hydrazine hydrate (80% in water, 80 mL) in dioxane (100 mL) was stirred at 100° C. overnight. After cooling down to RT, the mixture was concentrated. The residue was partitioned between 300 mL of EA and 300 mL of aq. sat. NH4Cl. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to get crude product which was suspended in 30 mL of cold isopropyl alcohol and filtered. The collected solid was dried in air to get 4.2 g (87%) of 3-bromo-4-hydrazinylpyridine as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 8.07 (d, J=5.6 Hz, 1H), 7.37 (s, 1H), 7.01 (d, J=5.6 Hz, 1H), 4.36 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13](=O)[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>O.C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH3:9])[C:13]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[N:12][CH2:11][CH2:10]2
Reactant: COc1ccc(CCNC(=O)CCc2ccc(Cl)cc2)cc1C
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1C
Product: COc1cc2c(cc1C)CCN=C2CCc1ccc(Cl)cc1
Yield: 52.3 %

Procedure:
Heat a mixture of the amide from step A (10.0 g), phosphorous pentoxide (25 g), phosphorous oxychloride (15 mL) and xylene (250 mL) at reflux for 2 h. Cool the reaction mixture, slowly add water (500 mL), basify using NaOH and extract with benzene. Concentrate the benzene extract to a residue and triturate with diethyl ether to give 6-methyl-7-methoxy-1-[2-(4-chlorophenyl)ethyl]-3,4-dihydroisoquinoline (4.95 g), mp=122°-124° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:16]I.O>C1COCC1>[C:3]([O:7][C:8]([NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][O:13][CH3:16])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 25.9 %

Procedure:
A suspension of 60% NaH (635.7 mg, 15.89 mmol) in THF (10 ml) was cooled to 0° C. To the mixture was added a solution of 2-t-butoxycarbonylamino-2-methyl-1-propanol (1.5398 g, 8.14 mmol) in THF (5 ml) dropwise, and stirred for 1.5 hours. To the mixture was added a solution of methyl iodide (0.50 ml, 8.03 mmol) in THF (5 ml) dropwise at 0° C., and stirred for 2.5 hours. The reaction mixture was added to water and extracted three times with ethyl acetate. The extract was dried over MgSO4, concentrated and purified by silica gel chromatography (hexane/ethyl acetate=5/1-0/1) to give the title compound (422 mg; 26%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH:9]([N:15]1C(=O)C2C(=CC=CC=2)C1=O)[C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].O.NN>C1COCC1.CO>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH:9]([NH2:15])[C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(c1ccsc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCC(N)c1ccsc1
Temperature: 60 °C

Procedure:
To a stirred solution of [2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-thiophen-3-yl-ethyl]-carbamic acid tert-butyl ester (23 g, crude) in THF (100 mL) and methanol (100 mL) was added hydrazine hydrate (63 g, 1.26 mol). The mixture was heated to 60° C. for 2 hours and then cooled to 20° C. The reaction mixture was filtered and the filtration was concentrated to dryness. The residue was purified by column chromatography (methanol:dichloromethane, 1:50) to afford (2-amino-2-thiophen-3-yl-ethyl)-carbamic acid tert-butyl ester. (Yield 8.6 g, 57% for the two steps). LC-MS: [M+H]+ 243.
Reaction SMILES: CN(C)C=O.[CH3:6][N:7]([C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1)[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[N:12]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(N(CC)CC)C>O>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[N:12]=[C:8]([N:7]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][CH:32]=3)[CH3:6])[S:9][CH:10]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1ccc(N(C)c2nc(-c3ccc([N+](=O)[O-])cc3)cs2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N(C)c2nc(-c3ccc(N)cc3)cs2)cc1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
Under a nitrogen stream, N,N-dimethylformamide (1.20 L, 10.0 v/w) was added to ethyl 4-(N-methyl-N-(4-(4-nitrophenyl)-2-thiazolyl)amino)benzoate (123 g, 0.321 mol) obtained in Example 3(2). With stirring at room temperature, sodium hydrosulfite (80% purity, 210 g, 0.963 mol) was added. After stirring at room temperature for 10 min., distilled water (123 ml, 1.0 v/w) was added carefully. After stirring at 100° C. for 1.5 hr., triethylamine (223 ml, 1.61 mol) was added at 80° C., and the mixture was cooled to room temperature with water. After stirring at room temperature for 1 hr., distilled water (1.1 L, 9.0 v/w) was added. After stirring at room temperature for 30 min., the mixture was extracted twice with ethyl acetate (1.20 L) and the organic layer was washed successively with distilled water (400 ml) and saturated brine (400 ml), and dried over magnesium sulfate (60 g). The magnesium sulfate was filtered off, the solvent was evaporated, the residue was boiled with toluene and dried in vacuo to give the title compound (67.0 g, yield 63.0%) as a yellow to orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH2:10]([C:12](=O)[C:13]([O-:15])=[O:14])[CH3:11].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)C=C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(#N)C.C(O)C>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:4]2[C:3]=1[CH:11]([C:24]1[CH:23]=[CH:20][CH:19]=[C:18]([F:17])[CH:25]=1)[CH2:10][CH:12]([C:13]([OH:15])=[O:14])[NH:5]2
Reactant: C=Cc1cccc(F)c1
Reactant: CCC(=O)C(=O)[O-]
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: O=C(O)C1CC(c2cccc(F)c2)c2c(Cl)cc(Cl)cc2N1

Procedure:
Compound 29 was prepared by the basic process from 5.0 mmol 3,5-dichloroaniline, 5.5 mmol ethylglyoxalate solution (50% toluene), 15.0 mmol 3-fluorostyrene and 5.0 mmol trifluoroacetic acid in 30.0 ml acetonitrile. Subsequent saponification was carried out using 1.0 ml of sodium hydroxide solution (6N water) in 20.0 ml of ethanol.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]([O:17]CC)=[O:16])=[N:11]2)=[CH:6][CH:5]=1.CO.O>C1COCC1>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[N:11]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccn(-c2ccc(OC(F)F)cc2)n1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccn(-c2ccc(OC(F)F)cc2)n1
Temperature: 80 °C

Procedure:
To a solution of ethyl 1-(4-(difluoromethoxy)phenyl)-1H-pyrazole-3-carboxylate (350 mg, 1.24 mmol) in a mixture of THF (3.1 ml), methanol (1.6 ml), Water (1.6 ml) lithium hydroxide hydrate (89 mg, 3.72 mmol) was added. The solution was heated to 80° C. for 2 h. Most of the organic solvent was removed under reduced pressure. Sodium bicarbonate solution and ethyl acetate were added and the organic layer was separated. The aqueous layer was made acid by addition of 25% aqueous hydrochloric acid and the mixture was extracted 2 times with ethyl acetate. The organic layers were combined, dried (MgSO4) and evaporated. The product was dried in vacuo and was directly used for the next step.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[C:26]([O:30][C:31](=[O:48])[N:32]([C:40]1[S:41][C:42]([CH:46]=[O:47])=[C:43]([Cl:45])[N:44]=1)[CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)([CH3:29])([CH3:28])[CH3:27]>O1CCCC1>[C:26]([O:30][C:31](=[O:48])[N:32]([C:40]1[S:41][C:42]([CH:46]([OH:47])[C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=2)=[C:43]([Cl:45])[N:44]=1)[CH2:33][C:34]1[CH:35]=[CH:36][N:37]=[CH:38][CH:39]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N(Cc1ccncc1)c1nc(Cl)c(C=O)s1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2sc(N(Cc3ccncc3)C(=O)OC(C)(C)C)nc2Cl)c2cccnc21
Temperature: 0 °C
Yield: 86.6 %

Procedure:
To a solution of 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (96, 0.44 g, 1.1 mmol) in tetrahydrofuran (20 mL) at −20° C., isopropylmagnesium chloride (2M in tetrahydrofuran, 0.6 mL, 1.2 mmol) was added dropwise. The reaction mixture was allowed to warm to 0° C. in 10 minutes. The reaction mixture was then cooled to −40° C. A solution of (4-chloro-5-formyl-thiazol-2-yl)-pyridin-4-ylmethyl-carbamic acid tert-butyl ester (518, 0.26 g, 0.73 mmol) in tetrahydrofuran (4 mL) was added to the reaction mixture. The reaction mixture was allowed to warm to −10° C. over 30 minutes. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexanes to provide the desired compound as a yellow solid (519, 397 mg, 86%). MS (ESI) [M+H+]+=628.3.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[C:12]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)#[CH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N+:34]([C:36]([CH3:39])([CH3:38])[CH3:37])#[C-:35]>CO.O>[C:36]([NH:34][C:35]1[N:7]2[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=[CH:5][C:6]2=[N:9][C:17]=1[C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([C:12]#[CH:13])[CH:15]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: C#Cc1cccc(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: C#Cc1cccc(-c2nc3ccc(C(F)(F)F)cn3c2NC(C)(C)C)c1
Reaction time: 0.08 h
Yield: 54.4 %

Procedure:
5-(trifluoromethyl)pyridin-2-amine (100 mg, 617 μmol, Eq: 1.00), 3-ethynylbenzaldehyde (84.3 mg, 648 μmol, Eq: 1.05) and p-toluenesulfonic acid monohydrate (35.2 mg, 185 μmol, Eq: 0.3) were dissolved in MeOH (1.00 mL) and the intensive yellow solution was stirred for 5 min. To this yellow solution was added dropwise 2-isocyano-2-methylpropane (51.3 mg, 70.2 μL, 617 μmol, Eq: 1.00) and the corresponding yellow solution was stirred for 2 h. Water was added, the oil was separated from water/MeOH phase and purified by flash column chromatography (40 g SiO2, Hex/EtOAc 100:0 to 0:100) to yield a yellow solid (120 mg, 54.4%). MS: 357.0 [M]+; 1H-NMR (D6-DMSO): δ 8.89 (s, 1H), 8.38 (s, 1H), 8.27 (d, 1H), 7.72 (d, 1H), 7.52-7.40 (m, 3H), 4.94 (s, 1H), 4.22 (s, 1H), 1.04 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:39][O:40][C:41]1[CH:83]=[CH:82][C:44]([CH2:45][N:46]2[C:50]3=[N:51][CH:52]=[CH:53][C:54]([O:55][C:56]4[CH:61]=[CH:60][C:59]([NH2:62])=[CH:58][C:57]=4[F:63])=[C:49]3[C:48]([C:64]3[CH:65]=[N:66][N:67]([CH:69]4[CH2:74][CH2:73][N:72]([C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[CH2:71][CH2:70]4)[CH:68]=3)=[N:47]2)=[CH:43][CH:42]=1.CCN(C(C)C)C(C)C>O.CN(C=O)C>[F:63][C:57]1[CH:58]=[C:59]([NH:62][C:15]([C:12]2[C:13](=[O:14])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[CH:10][CH:11]=2)=[O:17])[CH:60]=[CH:61][C:56]=1[O:55][C:54]1[CH:53]=[CH:52][N:51]=[C:50]2[N:46]([CH2:45][C:44]3[CH:43]=[CH:42][C:41]([O:40][CH3:39])=[CH:83][CH:82]=3)[N:47]=[C:48]([C:64]3[CH:65]=[N:66][N:67]([CH:69]4[CH2:74][CH2:73][N:72]([C:75]([O:77][C:78]([CH3:80])([CH3:81])[CH3:79])=[O:76])[CH2:71][CH2:70]4)[CH:68]=3)[C:49]=12
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 3.4 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (0.0840 g, 0.358 mmol obtained from Example 19, step C), EDCI (0.0687 g, 0.358 mmol), HOBT (0.0549 g, 0.358 mmol), and DMF (5 mL). The reaction mixture was stirred for 30 minute and tert-butyl 4-(4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.110 g, 0.179 mmol) and Hunig's base (0.0463 g, 0.358 mmol) were added. The reaction mixture was stirred for 18 hours, then diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude material was purified by preparative TLC (0.5 mm thickness) eluting with CHCl3/MeOH(NH3 7N) 4:1. To the isolated product was added TFA (2 mL) and the solution was heated to 70° C. for 1 hour. The solution was concentrated and triturated with DCM/MeOH 1:1. The solids were collected by filtration to provide 5.1 mg (5%) of the desired product. LRMS M+1 (610.0) observed.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][O:10][NH:11][C:12](=[O:29])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[CH3:28])(C)(C)C.OS(O)(=O)=O.O>CO>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][O:10][CH2:9][CH2:8][CH2:7][OH:6])=[O:29])=[C:14]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[CH3:28])[CH:15]=1
Reactant: Cc1cc(I)ccc1Nc1cc(F)ccc1C(=O)NOCCCO[Si](C)(C)C(C)(C)C
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: Cc1cc(I)ccc1Nc1cc(F)ccc1C(=O)NOCCCO
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of N-[3-(tert-Butyl-dimethyl-silanyloxy)-propoxy]-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide (4.0 g, 7.27 mmol) in methanol (5 mL) at ambient temperature was added 5 M H2SO4 in methanol (0.073 mL, 0.364 mmol). After 1 h of stirring, to the reaction was added additional 5 M H2SO4 in methanol (0.035 mL, 0.182 mmol). After 2 h of stirring, the reaction was adjusted to pH 7 using saturated NaHCCO3 (aq) (c. a. 1.5 mL), followed by addition of water (35 mL). The aqueous layer was extracted with ethyl acetate (1×20 mL, 2×10 mL). The extracts were combined, washed with brine, and dried over magnesium sulfate. The resultant mixture was filtered, and the filtrate solvent was removed in vacuo to obtain an oil that was dried on a vacuum pump over the weekend. The oil was purified by flash chromatography, eluted with a gradient of 100% hexanes to 100% ethyl acetate in 50 min. The solvent was removed in vacuo of combined fractions to obtain a solid which was dried on a vacuum pump for c. a. 6 h. Recrystalized solid in a mixture of hexanes and ethyl acetate to afford 4-fluoro-N-(3-hydroxy-propoxy)-2-(4-iodo-2-methyl-phenylamino)-benzamide as a solid (2.4 g, 74% yield): m.p. 120.8-122.4 C.; 1H-NMR (400 MHz, (CD3)2CO) δ 10.91 (br s, 1H), 9.59 (br. S, 1H), 9.68 (m, 2H), 7.57 (d, 1H, J=8.54 Hz), 7.18 (d, 1H, J=8.34 Hz), 6.72 (m, 1H); 6.53 (m, 1H); 4.12 (t, 2H, J=6.11 Hz), 3.71 (t, 2H, J=5.86 Hz), 2.26 (s, 3H), 1.86 (m, 2H); 19F-NMR (376 MHz, (CD3)2CO) δ −108.14; MS 445.1 m/z (AP+), 443.1 m/z (AP−). Anal. Calcd. for C17H18FIN2O3: C, 45.96; H,L 4.08; N, 6.31; F, 4.28; I, 28.57. Found: C, 45.78; H, 3.88; N, 6.14; F, 4.30; I, 28.27.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][CH2:41][NH2:42].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([CH:7]=1)[C:4]([NH:42][CH2:41][CH2:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[Cl:33])=[O:6]
Reactant: NCCc1ccccc1Cl
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(NCCc1ccccc1Cl)c1cc(Br)ccc1Cl
Yield: 90.2 %

Procedure:
To a stirred solution of 2-chloro-5-bromobenzoic acid (1.5 g, 6.3 mmol), EDCI (1.63 g, 8.5 mmol), and HOBT (1.15 g, 8.5 mmol) in DMF (20 ml) was added 2-(2-chlorophenyl)ethylamine (1.06 ml, 7.5 mmol). After 15 minutes triethylamine (1.18 ml, 8.5 mmol) and DMF (5 ml) was added. After 2 hours at ambient temperature the mixture was diluted with ethyl acetate (50 ml) and washed with 1 N HCl followed by a saturated solution of sodium bicarbonate, followed by water, and then brine. The organic layer was separated and dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 2.12 g of an amorphous solid. Mass Spectrum (ES+) 374.6, (ES−) 372.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:12]([CH3:14])=[O:13])[C:9]([OH:11])=[O:10].C(O[C:19](=O)[CH3:20])(=O)C.S(=O)(=O)(O)O.[C:27](=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:11])[O:10][C:19]([CH3:20])([CH3:27])[O:13][C:12]=1[CH3:14]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)C(C(=O)O)c1ccccc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1=C(c2ccccc2F)C(=O)OC(C)(C)O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-(2-fluorophenyl)acetoacetic acid (5.1 g), acetone (4.2 ml), and acetic anhydride (5.4 ml) was kept at -20° C. and concentrated sulfuric acid (0.3 ml) was added thereto. This was kept at -15° C. and the reaction was carried out for 48 hours. The reaction mixture was added to an aqueous 10 % sodium carbonate solution (150 ml) which was ice-cooled, and the mixture was stirred for a short time at room temperature. White crystals which formed were collected by filtration, and washed well with water and then with hexane. The crystals obtained were dried well under reduced pressure to obtain the captioned compound (5.2 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[SH:13])=[O:4].[OH-].[Na+]>>[F:12][C:11]1[C:6]2[NH:5][C:3](=[O:4])[CH2:2][S:13][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(CCl)Nc1c(F)cccc1S
Agent: [Na+]
Agent: [OH-]
Product: O=C1CSc2cccc(F)c2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
2-Chloroacetylamino-3-fluorothiophenol (2.0 g) was added to 2 N aqueous sodium hydroxide solution (25 ml), followed by stirring at room temperature (25° C.) for 3 hours. The precipitated crystals were filtered, washed with water and dried to obtain 1.5 g of the objective 5-fluoro-2,3-dihydro-1,4-benzothiazine-3-one (m.p. 190°-191° C.).
Reaction SMILES: C[Si](C)(C)CCOC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([CH:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([CH:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3nc(OC4CCN(C(=O)OCC[Si](C)(C)C)CC4)sc3c2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3nc(OC4CCNCC4)sc3c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 117.8 %

Procedure:
To a solution of tert-butyl 4-(2-((1-((2-(trimethylsilyl)ethoxy)carbonyl)-piperidin-4-yl)oxy)benzo[d]thiazol-6-yl)piperidine-1-carboxylate (385 mg, 0.685 mmol) in THF (5 mL) was added a solution of TBAF (1 M in THF, 3.4 mL, 3.4 mmol). The mixture was stirred at rt for 4 h. The mixture was diluted with EtOAc (8 mL), washed with aq. NaOH (1 N, 5 mL), then brine. The organic layer was dried (Na2SO4), filtered, and concentrated to afford tert-butyl 4-(2-(piperidin-4-yloxy)benzo[d]thiazol-6-yl)piperidine-1-carboxylate (337 mg, 0.807 mmol, 84% purity, 100% yield). The product was used without further purification. LCMS (m/z)=418 (M+H)+.