Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][C:13]=3[CH:26]=2)O1.Br[C:29]1[S:33][CH:32]=[N:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[S:33]1[C:29]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:14][C:13]=3[CH:26]=2)=[CH:30][N:31]=[CH:32]1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: Brc1cncs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cncs3)cc2C1
Yield: 50.9 %

Procedure:
A solution of tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (73 mg, 0.19 mol), 5-bromothiazole (40 mg, 0.26 mmol), 1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (22 mg, 0.03 mmol) and potassium carbonate (0.14 g, 1.0 mmol) in N,N-dimethylacetamide/water 5:1 (5.5 mL) was heated to 90° C. for 1 hour. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (30 mL) and brine (20 mL), and then dried over anhydrous sodium sulfate and concentrated. Purified by silica gel column chromatography (ethyl acetate/hexanes, 1:2) to give tert-butyl 7-(thiazol-5-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (44 mg, 70% yield). MS (EI) for C17H20N2O3S: 333 (MH+).
Reaction SMILES: [OH-].[K+].CO.[OH:5][C:6]1([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]3[CH:25]=[C:24]([NH:26][C:27]4[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=4)[CH:23]=[C:22]([CH3:37])[CH:21]=3)[CH:19]=2)[CH2:10][CH2:9][CH:8]([C:11]([O-:13])=[O:12])[CH2:7]1>Cl>[OH:5][C:6]1([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]3[CH:25]=[C:24]([NH:26][C:27]4[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=4)[CH:23]=[C:22]([CH3:37])[CH:21]=3)[CH:19]=2)[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[CH2:7]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(C3(O)CCC(C(=O)[O-])C3)c2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(C3(O)CCC(C(=O)O)C3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of KOH in MeOH (1 M, 2 mL, 2.00 mmol) was added to the 3-hydroxy-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-3-yl]cyclopentanecarboxylate (60 mg, 0.123 mmol). The reaction mixture was stirred at room temperature, overnight, diluted with 2N HCl and extracted with DCM (3×). The combined organic layers were dried under reduced pressure to give 3-hydroxy-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-3-yl]cyclopentanecarboxylic acid. MS ESI calc'd for C23H22F3N4O3 [M+H]+ 459. found 459. 1H NMR (500 MHz, MeOD) δ 9.01 (s, 1H), 8.92 (d, J=6.0 Hz, 1H), 8.74 (d, J=5.0 Hz, 1H), 8.19 (s, 1H), 7.63 (s, 2H), 7.35 (s, 1H), 7.17 (d, J=5.0 Hz, 1H), 2.51-2.00 (m, 7H), 1.19 (s, 3H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[C:5]([O:9][C:10]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].OS([O-])(=O)=O.[Na+]>CCOCC>[C:5]([O:9][C:10]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:1][CH3:2])([OH:22])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2ccccc21
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCC1(O)CCN(C(=O)OC(C)(C)C)c2ccccc21
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
To a flame-dried 25-mL rb flask containing ethylmagnesium bromide (4.0 mL of a 3.0M solution in Et2O, 12.0 mmol, 3.0 equiv), at -10° C. was added dropwise a solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-quinolone (1.0 g, 4.0 mmol) in Et2O (4 mL). The reaction mixture was stirred at -10° C. for 15 min, then allowed to warm to rt over 10 min. A 1.0M solution of NaHSO4 (10 mL) was then rapidly added. The resulting biphasic mixture was extracted with EtOAc (3×10 mL), and the combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc, 4:1), affording 800 mg (71%) of the desired product as a clear yellow oil (Rf 0.14, hexanes/EtOAc, 4:1). Data for 1-tert-butoxycarbonyl-4-ethyl-1,2,3,4-tetrahydro-4-hydroxyquinoline: 1H NMR (400 MHz, CDCl3) 7.68 (d, 1H, J=8.4, 8-H), 7.47 (dd, 1H, J=7.9, 1.7, 5-H), 7.21 (ddd, 1H, J=7.4, 7.4, 1.6, 6-H), 7.09 (ddd, 1H, J=7.8, 7.8, 1.1, 7-H), 4.03 (ddd, 1H, J=12.9, 7.1, 4.7, 2-H), 3.47 (ddd, 1H, J=13.1, 8.6, 4.3, 2-H), 2.11 (ddd, 1H, J=13.5, 8.6, 4.8, 3-H), 1.86 (m, 3H, 3-H, CH2CH3), 1.52 [s, 9H, C(CH3)3 ], 0.89 (t, 3H, J=7.5, CH3).
Reaction SMILES: [CH3:1][CH:2]([CH2:13][Cl:14])[CH2:3][Si:4]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)(Cl)Cl.[CH2:15]([OH:18])[CH2:16][CH3:17].Cl>>[CH3:1][CH:2]([CH2:13][Cl:14])[CH2:3][Si:4]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([O:18][CH2:15][CH2:16][CH3:17])[O:18][CH2:15][CH2:16][CH3:17]
Reactant: CCCO
Reactant: CC(CCl)C[Si](Cl)(Cl)C1CCCCC1
Agent: Cl
Product: CCCO[Si](CC(C)CCl)(OCCC)C1CCCCC1

Procedure:
The same apparatus as that described in Example 1 was used. 1367 g (5 mols) of (2-methyl-3-chloropropyl)-cyclohexyl-dichlorosilane were introduced into the flask. At a starting temperature of 60° C., 300 g (5 mols) of n-propanol were added at a uniform rate over a period of 140 minutes. Thereafter the mixture was heated in 120 minutes to 145° C., accompanied by the escape of dissolved hydrogen chloride. The system was from this time forward evacuated to such an extent that it began to boil at a sump temperature of 145° C. An additional 300 g (5 mols) of n-propanol were introduced into the boiling reaction mixture over a period of 140 minutes. The reaction mixture was allowed to react for 35 minutes more, and then the crude product was worked up by vacuum distillation.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]1[N:12]=[C:13]([N:16]2[CH2:19][CH:18]([OH:20])[CH2:17]2)[S:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl>[C:1]([NH:9][CH2:10][C:11]1[N:12]=[C:13]([N:16]2[CH2:17][CH:18]([O:20][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:19]2)[S:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCc1csc(N2CC(O)C2)n1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(CNC(=O)c3ccccc3)cs2)C1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a solution of 1-[4-(benzoylaminomethyl)-1,3-thiazol-2-yl]-3-hydroxyazetidine (582 mg, 2.01 mmol) (obtained as described in Reference Example 64(2)) in methylene chloride (30 ml) were added methanesulfonyl chloride (0.19 ml, 2.41 mmol), triethylamine (0.34 ml, 2.41 mmol) and pyridine (5.8 ml) in an ice bath and the mixture was stirred for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 1-[4-(benzoylaminomethyl)-1,3-thiazol-2-yl]-3-methanesulfonyloxyazetidine (739 mg, yield 100%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1F)#[N:2].[NH:14]1[CH:18]=[CH:17][CH:16]=[N:15]1.[H-].[Na+]>CN(C)C=O.O>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N:14]1[CH:18]=[CH:17][CH:16]=[N:15]1)#[N:2]
Reactant: COC(=O)c1ccc(C#N)c(F)c1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(C#N)c(-n2cccn2)c1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
Methyl 4-cyano-3-fluorobenzoate (0.30 g) and 1H-pyrazole (0.14 g) were dissolved in N,N-dimethylformamide (10 ml). To the reaction solution, sodium hydride (0.10 g) was added under ice cooling while stirring the mixture, and the mixture was stirred for 30 min. After increasing the temperature to room temperature, the solution was further stirred for 2 hours. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with water, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude product, which was then purified by column chromatography to give methyl 4-cyano-3-(1H-pyrazol-1-yl)benzoate (0.28 g, yield 73%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([O:11]CC)=[O:10])=[N:4]1)[CH3:2].[OH-].[K+].O>C(O)C>[CH2:1]([N:3]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([OH:11])=[O:10])=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1cc(C)n(CC)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCn1nc(C(=O)O)cc1C
Yield: 61.1 %

Procedure:
Ethyl 1-ethyl-5-methylpyrazole-3-carboxylate (10.93 g) in ethanol (70 ml) was treated with KOH (3.69 g), followed by water (30 ml), and the mixture was stirred and heated under reflux for 6 h. The ethanol was removed using a rotary evaporator and ethyl acetate/water were added. The pH of the mixture was adjusted to 3.0 and the layers were separated. The aqueous layer was re-extracted with ethyl acetate. The combined ethyl acetate layers were extracted with excess aqueous NaHCO3. The NaHCO3 extract was poured into excess acid, and the pH was then adjusted to 3, and NaCl was added to the solution. The mixture was then repeatedly extracted with ethyl acetate, and the combined extracts were dried (MgSO4) and evaporated. The residue was triturated with diethyl ether to give the acid as a solid (5.65 g) υmax (CH2Cl2) 2754, 2598, 1698, 1498, 1464, 1387, and 1233 cm−1; δ(CDCl3) 1.40 (3H, t, J 7.3 Hz), 2.32 (3H,s), 4.19 (2H, q, J 7.3 Hz), 6.61 (1H,s) ppm; (Found m/z 154.0740. C7H10N2O2 requires m/z 154.0742).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:15][CH2:14][CH2:13][O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOCCCl)C(C)=O
Yield: 100 %

Procedure:
Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 60 g.), 1-bromo-2-chloroethane (54.1 g.), potassium carbonate (78 g.) and N,N-dimethylformamide (200 ml.) were treated in a similar manner to that of Example F-(1) to give ethyl 2-(2-chloroethoxyimino)-3-oxobutyrate (syn isomer, 83.6 g.), oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][N:8]=1)=O.S(O)(O)(=O)=O.[CH3:23][S:24][C:25](=[NH:27])[NH2:26].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH3:23][S:24][C:25]1[N:27]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][N:8]=2)[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[N:26]=1
Reactant: CSc1ccc(C(=O)CC(=O)C(F)(F)F)nc1
Reactant: CSC(=N)N
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CSc1ccc(-c2cc(C(F)(F)F)nc(SC)n2)nc1
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4,4,4-trifluoro-1-(5-methylsulfanyl-pyridin-2-yl)-butane-1,3-dione (0.600 g, 2.28 mmol) in glacial acetic acid (6 mL) was added 2-methyl 2-thiopseudourea sulphate (0.761 g, 2.74 mmol) and sodium acetate (0.224 g, 2.74 mmol). The reaction was heated to 120° C. under nitrogen for 21 hours. The reaction was allowed to cool before the addition of water (10 mL), leading to precipitation of a solid. The reaction mixture was poured onto water (10 mL) and stirred for 15 minutes at 22° C. The precipitate was filtered from the aqueous solution, washed with water, and dried in vacuo to yield the title compound as a grey solid: MS m/z 317 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.[CH3:9][C:10]1[C:11]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=3)=[O:24])[CH2:19][CH2:18]2)=[N:12][CH:13]=[C:14]([CH3:16])[CH:15]=1>>[CH3:9][C:10]1[C:11]([N:17]2[CH2:18][CH2:19][N:20]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([N:4]4[CH2:3][CH:2]([CH3:1])[CH2:6][S:5]4(=[O:8])=[O:7])=[CH:27][CH:26]=3)=[O:24])[CH2:21][CH2:22]2)=[N:12][CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: CC1CNS(=O)(=O)C1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)CS4(=O)=O)cc3)CC2)c(C)c1
Yield: 31.3 %

Procedure:
Using 4-methylisothiazolidine 1,1-dioxide (270 mg) described in Preparation Example 9 and [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (421 mg) described in Preparation Example 113 and by the reaction and treatment in the same manner as in Example 4, the title compound (134 mg) was obtained.
Reaction SMILES: [I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C.[CH3:24][C:25]([CH3:28])([O-])[CH3:26].[K+].[C:30]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)C=O)#[N:31].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:24][C:25]([CH3:28])=[CH:26][C:38]1[CH:39]=[C:32]([CH:33]=[CH:34][CH:37]=1)[C:30]#[N:31]
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1cccc(C=O)c1
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)=Cc1cccc(C#N)c1
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a suspension of isopropyltriphenylphosphonium iodide (24.7 g) in tetrahydrofuran (100 ml) was added a solution of potassium tert-butoxide (7.71 g) in tetrahydrofuran (50 ml) at 25° C. over 20 minutes, and the mixture was stirred for 30 minutes at the same temperature. A solution of 3-cyanobenzaldehyde (5.0 g) in tetrahydrofuran (50 ml) was added at 0° C. over 20 minutes, and the mixture was stirred at 25° C. for 1 hour. The mixture was poured into a mixture of ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. The residue was chromatographed on silica gel (200 g) eluting with 10% ethyl acetate in hexane to give 3-(2-methyl-1-propenyl)benzonitrile (4.21 g) as a pale yellow oil.
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:20])C(=O)C1.[CH3:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([C:31]2[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=2[C:33]#[N:34])[N:23]=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([C:31]2[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=2[C:33]#[N:34])[N:23]=1
Reactant: Cc1nn(-c2ccccc2C#N)c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccccc1-n1nc(CBr)c2ccccc21
Yield: 93.3 %

Procedure:
AIBN (141 mg, 0.857 mmol) and NBS (839 mg, 4.72 mmol) were added to a suspension of 2-(3-methyl-1H-indazol-1-yl)benzonitrile (1 g, 4.29 mmol) in CCl4 (20 mL) and the mixture heated to reflux for 2 h. The mixture was concentrated and the residue was purified by silica gel chromatography to give the title compound (1.25 g, 93%) as an off white solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].I[CH:10]([CH3:12])[CH3:11].[OH-].[Na+]>C(O)C.O.[OH-].[K+]>[CH:10]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)([CH3:12])[CH3:11]
Reactant: CC(C)I
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)Oc1ccc(O)cc1
Yield: 46969.8 %

Procedure:
To a mixture of hydroquinone (20.0 g, 0.182 mmol) and 2-iodopropane (30.9 g, 0.182 mmol) in ethanol (25 mL) at refluxing was added KOH (88%, 12.2 mg, 0.191 mmol) in water (30 mL) over a period of 60 minutes. The resulting mixture was refluxed for 3 hours. The mixture was poured into 1N NaOH and extracted with ether (1×). The aqueous layer was acidified with 10% HCl to pH ˜5 and extracted with ether (2×). The combined extracts were washed with brine, dried over MgSO4 and concentrated. The residue was purified on silica gel eluting with ethyl acetate:hexane (1:8) to provide the title compound (13.01 g, 47.0%).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Cl.Cl[CH2:7][C:8]1[N:9]=[CH:10][S:11][CH:12]=1.CCCCC.C(OCC)(=O)C>C(O)C.C(=O)([O-])O.[Na+]>[S:11]1[CH:12]=[C:8]([CH2:7][NH:4][CH:1]2[CH2:3][CH2:2]2)[N:9]=[CH:10]1
Reactant: ClCc1cscn1
Reactant: NC1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCC
Product: c1nc(CNC2CC2)cs1
Temperature: 25 °C
Reaction time: 20 h
Yield: 33.5 %

Procedure:
20 ml (0.29 mol) of cyclopropylamine was added to a solution of 4.9 g (29.0 mmol) of 4-(chloromethyl)-thiazole hydrochloride in 45 ml ethanol and 45 ml of saturated aqueous sodium hydrogen carbonate. The reaction mixture was stirred for 20 hrs at ambient temperature and extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over magnesium sulphate and concentrated in vacuum. Column chromatography (gradient n-pentane/ethyl acetate) yielded 1.5 g (32% yield) of N-(1,3-thiazol-4-ylmethyl)cyclopropylamine. At ambient temperature a solution of 0.28 g (1.4 mmol) of 3-(difluoromethyl)-1-methyl-pyrazole-4-carbonyl chloride in 2 ml of tetrahydrofurane was added drop wise to a solution of 0.20 g (1.3 mmol) of N-(1,3-thiazol-4-ylmethyl)-cyclopropylamine and 0.6 ml triethylamine in 4 ml tetrahydrofurane. The reaction mixture was stirred for 16 hrs at ambient temperature and quenched with water. The watery layer was extracted three times with ethyl acetate (3×20 ml), the combined organic layers were dried over magnesium sulphate and concentrated in vacuum. Column chromatography (gradient n-pentane/ethyl acetate) yielded 0.13 mg (51% yield) of N-cyclopropyl-N-(1,3-thiazol-4-yl-methyl)-1-methyl-3-difluoromethyl-pyrazole-4-carboxamide (M+1=313).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19]>CC#N>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: NC1CCCC1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(S(=O)(=O)NC2CCCC2)ccc1Cl
Temperature: 0 °C

Procedure:
Cyclopentylamine (1.5 mL, 15.6 mmol) in MeCN (10 mL) was added over 10 min to an ice-cooled solution of 4-chloro-3-nitrobenzenesulfonyl chloride (2.0 g, 7.8 mmol) in MeCN (20 mL). After 1 h at rt the mixture was poured into ice-water and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and concentrated to give the sub-title compound. Yield 2.2 g (92%).
Reaction SMILES: [CH3:1][N:2]([N:4]=[N:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([O:13]C)=[O:12])[CH3:3].[OH-].[Na+].Cl>CO.O>[CH3:3][N:2]([N:4]=[N:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([OH:13])=[O:12])[CH3:1]
Reactant: COC(=O)c1sccc1N=NN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)N=Nc1ccsc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
To a solution of methyl 3-[(dimethylamino)diazenyl]thiophene-2-carboxylate (200 mg, 0.93 mmol) in methanol (10 mL) was added a solution of sodium hydroxide (93 mg, 2.3 mmol) in water (2 mL) and stirred at rt for 2 h. The mixture was diluted with ice cold water and acidified with dil. HCl and extracted with chloroform. The combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-ethyl acetate (80:20) as eluents to give the product as an off-white solid (70 mg, 38%), mp 108-110° C. IR (neat) νmax 3402, 3082, 2923, 1708, 1218, 1116, 1066, 1016, 880, 773 cm−1; 1H NMR (400 MHz, CDCl3): δ 12.21 (1H, s), 7.47 (1H, d, J=5.2 Hz), 7.30 (1H, d, J=5.2 Hz), 3.65 (3H, s), 3.28 (3H, s); LC-MS (positive ion mode): m/z 200 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH3:45])([CH3:44])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[N:14][C:13]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]4[N:30]5[CH2:31][CH2:32][N:33](C(OC(C)(C)C)=O)[CH2:34][C:29]5=[N:28][N:27]=4)=[CH:22][C:21]=2[O:42][CH3:43])=[CH:12]3)[CH:6]=[N:5]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:43][O:42][C:21]1[CH:22]=[C:23]([C:26]2[N:30]3[CH2:31][CH2:32][NH:33][CH2:34][C:29]3=[N:28][N:27]=2)[CH:24]=[CH:25][C:20]=1[NH:19][C:13]1[N:14]=[CH:15][C:16]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:7]1[CH:6]=[N:5][N:4]([CH2:3][C:2]([CH3:45])([OH:1])[CH3:44])[CH:8]=1)=[CH:18][CH:17]=2
Reactant: COc1cc(-c2nnc3n2CCN(C(=O)OC(C)(C)C)C3)ccc1Nc1cc2cc(-c3cnn(CC(C)(C)O)c3)ccc2cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2nnc3n2CCNC3)ccc1Nc1cc2cc(-c3cnn(CC(C)(C)O)c3)ccc2cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.9 %

Procedure:
To a solution of tert-Butyl 3-(4-(6-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)isoquinolin-3-ylamino)-3-methoxyphenyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (Example 55, 29 mg, 0.047 mmol) in DCM (10 mL) at 0° C. was added TFA (0.35 mL). The reaction was stirred at room temperature for 16 hours before concentrating in vacuo. The residue was purified by elution through an SCX-2 column using 2M NH3/MeOH to afford the title compound as a yellow solid (17.5 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15](Cl)[CH:14]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=[C:15]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(Nc2nc(Cl)cc(-c3ccccc3)n2)cc1Cl
Reactant: C1CNCCN1
Product: COc1ccc(Nc2nc(-c3ccccc3)cc(N3CCNCC3)n2)cc1Cl

Procedure:
(3-Chloro-4-methoxy-phenyl)-(4-chloro-6-phenyl-pyrimidin-2-yl)-amine compound (1 g, 2.8 mmol) on treatment with piperazine (0.24 g, 2.8 mmol), as described above yielded the desired compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)O1.Br[C:24]1[N:25]=[C:26]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[S:27][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>CS(C)=O.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>[F:38][C:35]1[CH:34]=[CH:33][C:32]([S:29]([C:26]2[S:27][CH:28]=[C:24]([C:9]3[CH:21]=[CH:20][C:12]4[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=4[CH:10]=3)[N:25]=2)(=[O:31])=[O:30])=[CH:37][CH:36]=1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: O=S(=O)(c1ccc(F)cc1)c1nc(Br)cs1
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: CS(C)=O
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2ccc(-c3csc(S(=O)(=O)c4ccc(F)cc4)n3)cc2s1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A RBF was charged with N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.5 g, 1 mmol), 4-bromo-2-(4-fluorophenylsulfonyl)thiazole (0.4 g, 1 mmol), 2 M Na2CO3 (1 mL, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (0.2 g, 0.2 mmol), and dioxane (6 mL). The flask was placed into a pre-heated (95° C.) bath and allowed to stir under an inert atmosphere overnight. The mixture was diluted with DMSO and filtered. The crude was purified by reverse-phase HPLC to give N-(6-(2-(4-fluorophenylsulfonyl)thiazol-4-yl)benzo[d]thiazol-2-yl)acetamide as an off-white solid. MS (ESI pos. ion) m/z: 434 (MH+). Calculated exact mass for C18H12FN3O3S3: 433. 1H NMR (400 MHz, DMSO-d6): 8.53 (s, 1H), 8.30 (s, 1H), 8.21 (s, 2H), 7.81 (s, 1H), 7.56 (s, 3H), 2.07 (s, 3H).