Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=3[C:6]3[C:13]([OH:23])=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:15]([CH3:17])=[N:16][C:5]2=3)[CH2:3][CH2:2]1.CCN(CC)CC.[O:31](S(C(F)(F)F)(=O)=O)[S:32]([C:35]([F:38])([F:37])[F:36])(=O)=[O:33]>ClCCl>[CH:1]1([N:4]2[C:12]3[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=3[C:6]3[C:13]([O:23][S:32]([C:35]([F:38])([F:37])[F:36])(=[O:33])=[O:31])=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:15]([CH3:17])=[N:16][C:5]2=3)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)nc2c(c1O)c1c(n2C2CC2)CCCC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc2c(c3c(n2C2CC2)CCCC3)c1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 94.9 %

Procedure:
An ice cold mixture of ethyl 9-cyclopropyl-4-hydroxy-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-3-carboxylate (1.362 g, 4.33 mmol) in dichloromethane (DCM) (20 ml) was treated with Et3N (0.906 ml, 6.50 mmol) and Tf2O (0.805 ml, 4.77 mmol), and then stirred at 0° C. for 90 min. The mixture was concentrated and purified with column chromatography (0-50% EtOAc/Hexane, 120 g silica gel) to give ethyl 9-cyclopropyl-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-3-carboxylate (1.8341 g, 4.11 mmol, 95% yield) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.39 (q, J=7.2 Hz, 2 H), 3.17-2.98 (m, 1 H), 2.90-2.78 (m, 4 H), 2.75 (s, 3 H), 1.99-1.88 (m, 2 H), 1.88-1.76 (m, 2 H), 1.40 (t, J=7.2 Hz, 3 H), 1.22-1.07 (m, 4 H); LCMS (m/z) ES+=447 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH3:17].CC([O-])=O.[K+]>CC(N(C)C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:11][N:12]1[C:16]([C:2]2[CH:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=2)=[CH:15][N:14]=[C:13]1[CH3:17]
Reactant: Cc1nccn1C
Reactant: COc1cc(Br)cnc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc(-c2cnc(C)n2C)cnc1N
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A suspension of 5-bromo-3-methoxypyridin-2-amine (55.5 mg, 0.273 mmol), 1,2-dimethyl-1H-imidazole (52.6 mg, 0.547 mmol), Pd(OAc)2 (2.5 mg, 0.011 mmol), KOAc (53.7 mg, 0.55 mmol) in DMA (3 mL) was stirred at 150° C. under microwave irradiation for 8 hours. The reaction mixture was filtered, diluted with NaCl solution and extracted with EtOAc. The organic layer was purified by eluting through an SCX-2 column using 2M NH3/MeOH followed by Biotage silica gel column chromatography eluting with 0-12% MeOH/EtOAc to give the title compound as yellow waxy solid (9 mg, 15%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]([CH2:12][C:13]([OH:15])=O)[N:4]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl.[CH3:37][N:38]([C@H:52]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:55][CH2:54][CH2:53]1)[C:39]([C:41]1[N:42]=[C:43]([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[S:44][CH:45]=1)=[O:40].C(N(CC)CC)C>C(OCC)(=O)C>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[N:5]([CH2:12][C:13]([N:49]2[CH2:50][CH2:51][CH:46]([C:43]3[S:44][CH:45]=[C:41]([C:39]([N:38]([CH3:37])[C@H:52]4[C:61]5[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=5)[CH2:55][CH2:54][CH2:53]4)=[O:40])[N:42]=3)[CH2:47][CH2:48]2)=[O:15])[N:4]=1
Reactant: CN(C(=O)c1csc(C2CCNCC2)n1)[C@@H]1CCCc2ccccc21
Reactant: O=C(O)Cn1nc(C(F)(F)F)cc1C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C(F)(F)F)CC2)n1)[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3,5-bis-(trifluoromethyl)-1H-pyrazole-1-acetic acid (190 mg, 0.73 mmol) (i.e. the product of Example 14, Step A) in ethyl acetate (5.0 mL) was treated with 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 1.0 mL, 1.6 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to a stirred suspension of N-methyl-2-(4-piperidinyl)-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-thiazolecarboxamide monohydrochloride (i.e. the product of Example 6, Step C) (210 mg, 0.53 mmol), triethylamine (0.5 mL, 3.75 mmol) in ethyl acetate (5 mL). The reaction mixture was then stirred at room temperature for 12 h. The resulting suspension was concentrated in vacuo and purified by MPLC on silica gel using ethyl acetate/hexanes as eluant to give 110 mg of the title product, a compound of the present invention as an oil.
Reaction SMILES: [C:1]([C:4]1([C:7]([NH:9][C:10]2[CH:40]=[CH:39][C:13]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]#[C:25][CH:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)[S:23][C:16]=34)=[C:12]([F:41])[CH:11]=2)=[O:8])[CH2:6][CH2:5]1)(=[O:3])[NH2:2].F[C:43]([F:48])(F)[C:44](O)=O>>[F:41][C:12]1[CH:11]=[C:10]([N:9]([C:4]2[CH:5]=[CH:6][C:43]([F:48])=[CH:44][CH:1]=2)[C:7]([C:4]2([C:1]([NH2:2])=[O:3])[CH2:6][CH2:5]2)=[O:8])[CH:40]=[CH:39][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[CH:21]=[C:22]([C:24]#[C:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:23][C:16]=12
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2cc3nccc(Oc4ccc(NC(=O)C5(C(N)=O)CC5)cc4F)c3s2)CC1
Product: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(C#CC5CCNCC5)sc34)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 117.6 %

Procedure:
A mixture of tert-butyl 4-(2-(7-(4-(1-(carbamoyl)cyclopropanecarboxamido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)ethynyl)piperidine-1-carboxylate (Example 124, Step B, 20 mg, 0.0297 mmol) and 2,2,2-trifluoroacetic acid (339 mg, 2.97 mmol) were stirred at room temperature for 30 minutes. The reaction was concentrated in vacuo, using toluene to azeotrope (3×5 mL). The residue was partioned between EtOAc (5 mL) and 1:1 water/saturated aqueous NaHCO3 (5 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (2×5 mL). The combined organic phases were washed with brine (5 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The product was purified by preparative TLC (0.5 mm thickness, Rf=0.22), eluting with 10% MeOH (containing 7N NH3) in CHCl3. The product was obtained as a beige powder (10 mg, 55%). HPLC: 93% purity (220 nm); LRMS (APCI+): 94% purity, 220 nm, m/z 573 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 8.47 (d, J=6 Hz, 1H), 8.30 (s, 1H), 7.76 (m, 1H), 7.52 (s, 1H), 7.44 (m, 2H), 7.24 (m, 2H), 7.06 (t, J=9 Hz, 2H), 6.51 (d, J=6 Hz, 1H), 3.12 (m, 3H), 2.79 (m, 3H), 2.00 (m, 2H), 1.80 (m, 4H), 1.62 (m, 2H).
Reaction SMILES: [N+:1](=[C:3]([C:17]([CH3:19])=[O:18])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-:2].[I-].[Na+].C(N(CC)CC)C.[CH3:29][Si:30](Cl)([CH3:32])[CH3:31]>C(#N)C>[N+:1](=[C:3]([C:17]([O:18][Si:30]([CH3:32])([CH3:31])[CH3:29])=[CH2:19])[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)=[O:5])=[N-:2]
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(O[Si](C)(C)C)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
Into 5 ml of dry acetonitrile were suspended 263 mg (1 millimole) of p-nitrobenzyl 2-diazoacetoacetate and 210 mg (1.4 millimoles) of sodium iodide. To the mixture were added 220 μl (1.6 millimoles) of triethylamine and then 190 μl (1.5 millimoles) of trimethylsilyl chloride while agitating in an argon atmosphere at a room temperature. After the resulting orange suspension was agitated at a room temperature for an hour, it was concentrated under a reduced pressure. To the residue was added 20 ml of dry hexane, and the resultant was agitated for 30 min. at a room temperature. Insoluble materials were removed by filtration and the hexane solution was concentrated to dryness under a reduced pressure to give 330 mg (yield 98 %) of the desired compound in a yellow solid. The physical properties of the product were in agreement with those of the product obtained in Example 1.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[C:14]12([C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=3[O:32][CH3:33])[CH2:27]Br)[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.Cl>CN(C=O)C.O>[C:14]12([C:24]3[CH:25]=[C:26]([CH2:27][S:3][C:4]4[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=4)[CH:29]=[CH:30][C:31]=3[O:32][CH3:33])[CH2:15][CH:16]3[CH2:17][CH:18]([CH2:19][CH:20]([CH2:22]3)[CH2:21]1)[CH2:23]2
Reactant: COC(=O)c1ccc(S)cc1
Reactant: COc1ccc(CBr)cc1C12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(SCc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1

Procedure:
1.44 g (48 mmol) of sodium hydride (80% in oil) and 25 ml of DMF were introduced into a three-necked flask under a stream of nitrogen. A solution of 6.73 g (40 mmol) of methyl 4-mercaptobenzoate in 60 ml of DMF was added dropwise and the mixture was stirred until the evolution of gas had ceased. A solution of 16.1 g (48 mmol) of 3-(1-adamantyl)-4-methoxybenzyl bromide in 90 ml of DMF was then added and the mixture was stirred at room temperature for eight hours. The reaction medium was poured into water, acidified to pH 1 with hydrochloric acid and extracted with ethyl ether. The organic phase was separated out after settling had taken place, washed with water, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a column of silica eluted with a mixture of dichloromethane and hexane (40/60). After evaporation of the solvents, 16.75 g (99%) of the expected methyl ester, having a melting point of 143°-5° C., were recovered.
Reaction SMILES: C(N=[N+]=[N-])C1C=CC=CC=1.[N:11]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[N+:12]=[N-:13].[C:23]([C:25]1[S:26][C:27]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:28]([CH3:30])[N:29]=1)#[CH:24]>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][N:11]2[CH:24]=[C:23]([C:25]3[S:26][C:27]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:28]([CH3:30])[N:29]=3)[N:13]=[N:12]2)=[CH:17][CH:18]=1
Reactant: C#Cc1nc(C)c(C(=O)OCC)s1
Reactant: [N-]=[N+]=NCCc1ccc(F)cc1
Agent: [N-]=[N+]=NCc1ccccc1
Product: CCOC(=O)c1sc(-c2cn(CCc3ccc(F)cc3)nn2)nc1C
Yield: 82 %

Procedure:
Following the procedure as described in Example 2, making variations as necessary to replace benzylazide with 1-(2-azidoethyl)-4-fluorobenzene to react with ethyl 2-ethynyl-4-methylthiazole-5-carboxylate, the title compound was obtained as a white solid in 82% yield: 1H NMR (300 MHz, CDCl3) δ 7.87 (s, 1H), 7.09-6.98 (m, 2H), 6.98-6.89 (m, 2H), 4.59 (t, J=7.2 Hz, 2H), 4.30 (q, J=7.1 Hz, 2H), 3.20 (t, J=7.2 Hz, 2H), 2.68 (s, 3H), 1.34 (t, J=7.1 Hz, 3H); MS (ES+) m/z 361.3 (M+1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.S(Cl)([Cl:16])(=O)=O>>[Cl:16][C:6]1[CH:5]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: O=S(=O)(Cl)Cl
Reactant: Oc1ccc(OC(F)(F)F)cc1
Product: Oc1ccc(OC(F)(F)F)cc1Cl
Yield: 94.1 %

Procedure:
A solution of 4-trifluoromethoxyphenol (20 g, 0.11 mole) and sulfuryl chloride (18.20 mL, 0.22 mole) was stirred at room temperature for five hours. The excess of sulfuryl chloride was evaporated by rotary evaporator. The residue was dissolved in 50 mL of dichloromethane and washed with 50 mL of H2O. The organic layer was separated, dried over MgSO4, filtered and concentrated to yield 22 g of the product. The crude product was purified over a silica gel column using 10% ethyl acetate in hexane to yield 16.4 g of the product. 1H-NMR (DMSO, 500-MHz), δ 10.59 (s, 1H), 7.43 (d, J=2.75 Hz, 1H), 7.18 (dd, J1=2.75 Hz, J2=7.16 Hz, 1H), 7.03 (d, J=7.16 Hz, 1H). MS (electro-spray) [M−H] 211.4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[NH:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Br:27])[CH:21]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:33].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[N:18]([C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Br:27])[CH:21]=1)[CH3:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: Cc1cccc(OCCCC(=O)OC(C)(C)C)c1NC(=O)c1ccc(Cl)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(OCCCC(=O)OC(C)(C)C)c1N(C)C(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a solution of 4-[2-(3-bromo-4-chloro-benzoylamino)-3-methyl-phenoxy]-butyric acid tert-butyl ester (10.2 g, 21.3 mmol) in dry DMF (100 mL) at 0° C. under N2, NaH (60% in mineral oil, 1.7 g, 42.6 mmol) was added in several portions with stirring. 10 minutes later, iodomethane (2.0 mL, 32.1 mmol) was added. The mixture was warmed to room temperature by removal of ice bath and stirring was continued for 1 hr. Water (10 mL) was then added and organics were extracted by ethyl acetate, which was then washed by water and brine, and was dried over MgSO4. After concentration, the crude product was purified by silica gel chromatography eluting with ethyl acetate/hexane (1/4) to yield 4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-3-methyl-phenoxy}-butyric acid tert-butyl ester (9.5 g).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:26][C:27](=[O:37])[NH:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[N:19]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C(OO)=[O:46])C=CC=1>ClCCl>[CH:1]1([CH2:6][C@H:7]([CH2:26][C:27](=[O:37])[NH:28][O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[N+:19]=3[O-:46])=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cccc(NC(=O)[C@@H]2CC=NN2C(=O)[C@@H](CC(=O)NOCc2ccccc2)CC2CCCC2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCc1cccc(NC(=O)[C@@H]2CC=NN2C(=O)[C@@H](CC(=O)NOCc2ccccc2)CC2CCCC2)[n+]1[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
To a solution of (5S)-1-((2R)-2-(cyclopentylmethyl)-4-oxo-4-{[(phenylmethyl)oxy]amino}butanoyl)-N-(6-ethyl-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxamide (119 mg, 0.24 mmol) in dichloromethane (DCM) (5 mL) stirred under nitrogen at 0° C. was added 3-chlorobenzenecarboperoxoic acid (122 mg, 0.71 mmol) in one portion. The reaction mixture was stirred at 0° C. for 10 min, then warmed to room temperature and stirred overnight. The reaction mixture was then quenched with sat. aq. NaHCO3 and extracted with DCM. The organic phase was dried over Na2SO4, filtered, and concentrated to provide the crude product, which was purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-65% MeCN:H2O) to afford (5S)-1-((2R)-2-(cyclopentylmethyl)-4-oxo-4-{[(phenylmethyl)oxy]amino}butanoyl)-N-(6-ethyl-1-oxido-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxamide (61 mg, 0.12 mmol, 50% yield) as a white solid. MS: 522 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[CH3:11][S-:12].[Na+].C(OCC)(=O)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:12][CH3:11])[CH:5]=[O:6]
Reactant: C[S-]
Reactant: O=Cc1ccc(F)c(F)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CSc1ccc(C=O)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
The 3,4-diflourobenzaldehyde (52.1 g, 0.36 mol) was dissolved in acetonitrile (500 mL). Sodium thiomethoxide (25.6 g, 0.36 mol) was added in four equal portions at 15 minute intervals. The slightly exothermic reaction was stirred at room temperature for 4 hours. The reaction mixture was poured into ethyl acetate (500 mL) and extracted with saturated sodium bicarbonate (2×200 mL) followed by saturated ammounium chloride (2×100 mL). The solution was dried over sodium sulfate and solvent removed at reduced pressure. The 3-flouro-4-(methylthio)-benzaldehyde (38.5 g, 0.22 mol) was isolated by vacuum distillation (135-145° C. at 25 mm Hg) as clear liquid. (61% yield) ESHRMS m/z 171.0302 (calcd for M+H, 171.0280).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH2:16][NH2:17])[C:10]=2[N:9]=[CH:8]1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:30]=[C:29]([CH:31]3[CH2:33][CH2:32]3)[NH:28][N:27]=2)[C:22]([F:34])=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:31]1([C:29]2[CH:30]=[C:26]([NH:25][C:23]3[C:22]([F:34])=[CH:21][N:20]=[C:19]([NH:17][CH2:16][C:15]4[C:10]5[N:9]=[CH:8][N:7]([CH:2]6[CH2:3][CH2:4][CH2:5][CH2:6][O:1]6)[C:11]=5[CH:12]=[CH:13][CH:14]=4)[N:24]=3)[NH:27][N:28]=2)[CH2:33][CH2:32]1
Reactant: Fc1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Reactant: NCc1cccc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Fc1cnc(NCc2cccc3c2ncn3C2CCCCO2)nc1Nc1cc(C2CC2)n[nH]1
Temperature: 120 °C
Yield: 56.7 %

Procedure:
A tube was charged with 58 (273 mg, 1.18 mmol), 55 (150 mg, 0.59 mmol), DIPEA (0.5 ml) and IPA (4 mL), degassed, sealed and heated at 120° C. for 72 h. The solvent was evaporated in vacuo to afford 150 mg (57%) of N4-(3-cyclopropyl-1H-pyrazol-5-yl)-5-fluoro-N2-((1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-4-yl)methyl)pyrimidine-2,4-diamine (280)—as yellow solid: MS (ESI) m/z=449.7 [M+1]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[O:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[CH3:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:12]([N:11]([CH2:2][CH:3]([C:5]1[O:6][CH:7]=[CH:8][CH:9]=1)[OH:4])[CH3:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNCc1ccccc1
Reactant: O=C(CBr)c1ccco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN(Cc1ccccc1)CC(O)c1ccco1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.8 %

Procedure:
2-(Bromoacetyl)furan (95 g) is added slowly to a stirred mixture of 75 g of N-methylbenzylamine and 70 g of potassium carbonate in 300 ml of methanol at 20°-30° C. The mixture is stirred at room temperature for 2.5 hours, and the insoluble matter is filtered off. To the filtrate is added 20 g of sodium borohydride at 10°-20° C. with stirring, and the mixture is stirred at room temperature for 3 hours. The solvent is then distilled off under reduced pressure, water is added to the residue, and the separated oil is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Distillation of the residue gives 80 g of 2-(N-benzyl-N-methylamino)-1-(2-furyl)ethanol as pale yellow viscous oil, boiling at 130°-138° C. (0.2 mmHg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].N1C=CC=CC=1.[C:21](Cl)([Cl:23])=[O:22]>C1C=CC=CC=1>[Cl:23][C:21]([O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[O:22]
Reactant: O=C(Cl)Cl
Reactant: COCCOCCOCCOCCO
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COCCOCCOCCOCCOC(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 12.9 g. (62 mmoles) of tetraethylene glycol monomethyl ether and 4.9 g. (62 mmoles) of pyridine is added dropwise to 77 ml. (124 mmoles) of a 17.2% solution of phosgene in benzene stirred in an ice bath with protection from moisture. The pyridine hydrochloride precipitates during the 35 to 40 minute addition and stirring is continued in the ice bath for an additional 2 hours. The reaction mixture is allowed to warm to room temperature and stirred overnight. The benzene solution is decanted from the pyridine hydrochloride which is washed with additional benzene. A stream of nitrogen is passed through the solution to remove excess phosgene as well as most of the benzene. The residual oil is dissolved in benzene-hexane and filtered to remove additional pyridine hydrochloride. The filtrate is evaporated to dryness in vacuo affording 17.1 g. of a residual oil, the infrared analysis of which reveals a strong carbonyl absorption and minimal hydroxyl absorption. The oil is used as is in the next step.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1)[NH2:3].[F:11][C:12]([F:19])([F:18])[C:13](=O)[CH2:14][C:15]#[N:16].Cl>C(O)C>[CH3:10][C:7]1[N:8]=[CH:9][C:4]([N:2]2[C:15]([NH2:16])=[CH:14][C:13]([C:12]([F:19])([F:18])[F:11])=[N:3]2)=[CH:5][CH:6]=1
Reactant: N#CCC(=O)C(F)(F)F
Reactant: Cc1ccc(NN)cn1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(-n2nc(C(F)(F)F)cc2N)cn1
Yield: 17.3 %

Procedure:
A mixture of 5-hydrazinyl-2-methylpyridine hydrochloride (5.0 g, 31 mmol) and 4,4,4-trifluoro-3-oxo-butyronitrile (9.0 g, 65 mmol) in ethanol (50 mL) was treated with cone HCl (5.0 mL, 60 mmol) and the resultant mixture was heated to reflux overnight. The solvent was removed in vacuo and the residue was dissolved in EtOAc and neutralized with saturated Na2CO3 solution. The organic layer was dried (Na2SO4), concentrated in vacuo and purified by pre-HPLC to give 2-(6-methyl-pyridin-3-yl)-5-trifluoromethyl-2H-pyrazol-3-ylamine (1.3 g, 10% yield over 2 steps). 1HNMR (400 MHz, CDCl3) δ 9.17 (d, J=1.6 Hz, 1 H), 8.40 (dd, J=8.4, 2.4 Hz, 1 H), 7.62 (d, J=8.4 Hz, 1 H), 5.97 (s, 1 H), 2.80 (s, 3 H); MS (ESI) m/z: 243.2 (M+H+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20](O)=[O:21])[C:13]=3[N:12]=2)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:47]1([C:53]2[N:54]=[C:55]([NH2:58])[NH:56][CH:57]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[C:47]1([C:53]2[N:54]=[C:55]([NH:58][C:20]([C:19]3[C:13]4[N:12]=[C:11]([C:3]5[N:2]=[CH:1][C:10]6[C:5]([CH:4]=5)=[CH:6][CH:7]=[CH:8][CH:9]=6)[NH:15][C:14]=4[CH:16]=[CH:17][CH:18]=3)=[O:21])[NH:56][CH:57]=2)[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: O=C(O)c1cccc2[nH]c(-c3cc4ccccc4cn3)nc12
Reactant: Nc1nc(-c2ccccc2)c[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(Nc1nc(-c2ccccc2)c[nH]1)c1cccc2[nH]c(-c3cc4ccccc4cn3)nc12
Yield: 17.4 %

Procedure:
120 mg (0.4 mmol) of 2-isoquinolin-3-yl-1H-benzoimidazole-4-carboxylic acid was reacted with 400 mg (1.1 mmol) of HBTU and 160 mg (1.0 mmol) of 4-phenyl-1H-imidazol-2-ylamine (160 mg, 1 mmol) according to the general procedure A. The residue was purified by flash column chromatography (EtOAc) to provide 2-isoquinolin-3-yl-1H-benzoimidazole-4-carboxylic acid (4-phenyl-1H-imidazol-2-yl)-amide (30 mg, 17.5%). LCMS: 431 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:22](I)[CH3:23].O>CS(C)=O>[CH2:22]([N:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=1)[CH3:23]
Reactant: COc1ccc(NC(=O)c2ccc(OC)cc2)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCN(C(=O)c1ccc(OC)cc1)c1ccc(OC)cc1
Reaction time: 0.5 h

Procedure:
A mixture composed of 600 mg of 4-methoxy-N-(4-methoxy-phenyl)benzamide and 150 mg of 60% sodium hydride was stirred in 7.5 ml of dimethyl sulfoxide at 50° C. for 10 minutes. Then, 1.05 ml of ethyl iodide was added, and the reaction mixture was stirred for 30 minutes. After water was added to the reaction mixture, the product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off, the resulting crude product was purified by TLC (using a 80:1 mixture of chloroform and acetone as the developing solvent) to obtain 591 mg of N-ethyl-4-methoxy-N-(4-methoxyphenyl)benzamide.