Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C1C=CC=CC=1.[F:10][C:11]1[C:12](=O)[NH:13][C:14](=O)[NH:15][CH:16]=1.P(Cl)(Cl)([Cl:21])=O.[ClH:24]>>[F:10][C:11]1[C:12]([Cl:21])=[N:13][C:14]([Cl:24])=[N:15][CH:16]=1
Reactant: Cl
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CN(C)c1ccccc1
Product: Fc1cnc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Example 30A was also prepared as follows. Dimethylaniline (195 mL, 1.54 mol) was added to a slurry of 5-fluorouracil (99.73 g, 0.77 mol) in phosphorus oxychloride (215 mL, 2.31 mol) at 95° C. under a nitrogen atmosphere. The reaction mixture was stirred at this temperature for 3.5 h, cooled to room temperature and then slowly added to a stirred mixture of ice (200 g) and 6 M HCl (200 mL). The resulting slurry was extracted with dichloromethane (2×400 mL) and the combined organic extracts were washed with DI water (4×275 mL), dried over MgSO4 and concentrated under reduced pressure to afford 111.77 g (87%, 98.1% AUC by HPLC) of 5-fluoro-2,4-dichloro-pyrimidine as an amber oil. A molar solution of sodium hydroxide (1.34 L) was slowly added to a solution of the 5-fluoro-2,4-dichloro-pyrimidine (111.77 g, 0.67 mol) in THF (377 mL) at 0° C. After the reaction mixture was stirred for about 30 min at room temperature, the pH was adjusted to 6 by a slow addition of 1.0 M HCl. The aqueous solution was extracted with ethyl acetate (440 mL) to remove impurities following which the pH was adjusted to 1 with 1.0 M HCl. The acidic aqueous solution was extracted with ethyl acetate (4×555 mL) and the combined organic extracts were washed with brine (111 mL), dried over MgSO4 and concentrated under reduced pressure to produce 88.35 g (89%, 99.2% AUC by HPLC) of 2-chloro-5-fluoro-3H-pyrimidin-4-one as an off-white powder.
Reaction SMILES: C1(COC2N=C(C(O)=O)C=CC=2C2CCOC2)CC1.[CH:20]1([CH2:23][O:24][C:25]2[N:30]=[C:29]([C:31]([OH:33])=O)[CH:28]=[CH:27][C:26]=2[CH:34]2[CH2:38][CH2:37][CH2:36][O:35]2)[CH2:22][CH2:21]1.[NH2:39][C@@H:40]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:41]([NH2:43])=[O:42]>>[C:41]([C@@H:40]([NH:39][C:31]([C:29]1[CH:28]=[CH:27][C:26]([CH:34]2[CH2:38][CH2:37][CH2:36][O:35]2)=[C:25]([O:24][CH2:23][CH:20]2[CH2:21][CH2:22]2)[N:30]=1)=[O:33])[CH2:44][CH:45]([CH3:47])[CH3:46])(=[O:42])[NH2:43]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(O)c1ccc(C2CCCO2)c(OCC2CC2)n1
Agent: O=C(O)c1ccc(C2CCOC2)c(OCC2CC2)n1
Product: CC(C)C[C@H](NC(=O)c1ccc(C2CCCO2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using the mixture of 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid and 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid (mixture from Example 114 d), and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=376.2 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH:9]=[N+]=[N-].[Cl:12][CH2:13][C:14](=[O:38])[C@:15]1([OH:37])[C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C@H:29]([C@@H:30]([OH:34])[CH2:31]2)[C@:27]2([CH3:28])[C:22](=[CH:23][C:24](=[O:35])[CH:25]=[CH:26]2)[CH2:21][CH2:20]3)[CH2:17][C@H:16]1[OH:36]>CCOCC.CO>[Cl:12][CH2:13][C:14](=[O:38])[C@:15]1([OH:37])[C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C@H:29]([C@@H:30]([OH:34])[CH2:31]2)[C@:27]2([CH3:28])[C:22](=[CH:23][C:24](=[O:35])[CH:25]=[CH:26]2)[CH2:21][CH2:20]3)[CH2:17][C@H:16]1[O:36][CH2:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](O)[C@]2(O)C(=O)CCl
Reactant: [N-]=[N+]=CCOC1CCCCO1
Solvent: CCOCC
Solvent: CO
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](OCCOC1CCCCO1)[C@]2(O)C(=O)CCl

Procedure:
A solution of 2-(tetrahydropyran-2-yloxy)-1-diazoethane (prepared from 0.21 mole of N-[2-(tetrahydropyran-2-yloxy)ethyl]urea as described in Example 1) in 400 ml of 3:1 ether-pentane is diluted with 100 ml each of ether and methanol at 0°C and stirred vigorously while 21-chloro-11β,16α,17-trihydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate (12 mmoles) is added. After nitrogen evolution ceases the solvents are removed in vacuo to yield the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[N:7]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[N:24]=[CH:25][NH:26]C=2)[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C.N1CCOCC1>C1COCC1.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>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[N:7]([CH2:19][CH2:20][CH2:21][C:22]2[N:26]=[CH:25][N:24]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:23]=2)[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCCc1c[nH]cn1)c(=O)n2CCCC
Reactant: BrCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CCCCn1c(=O)n(CCCc2cn(Cc3ccccc3)cn2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 2.7 %

Procedure:
A solution of 3-butyl-8-chloro-1-[4-(1H-imidazol-4-yl)butyl]-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (300 mg, 0.77 mmol) in anhydrous THF (5 ml) was treated with benzyl bromide (144 mg, 0.84 mmol) and DIPEA (147 μl, 0.84 mmol). The mixture was left to stir at rt under nitrogen for 4 days. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The crude was purified by a silica SPE column using a 0.5-5% MeOH/DCM gradient. The product fractions were combined and concentrated under high vacuum. The product was dissolved in THF (5 ml) then Pd(PPh3)4 (88 mg, 0.077 mmol) and morpholine (670 μl, 7.67 mmol) were added and the mixture left to stir at rt under nitrogen for 3 h. 88 mg of Pd(PPh3)4 (0.077 mmol) was added and the mixture was left to stir at rt under nitrogen for 16 h. The mixture was partitioned between EtOAc and H2O. The organic layer was separated and the aqueous layer was extracted with EtOAc (×2). The organic layers were combined, washed with brine, dried (MgSO4) and concentrated. The crude product was purified by MDAP to give the title compound as a white solid (9 mg, 2%).
Reaction SMILES: C(Cl)(=[O:6])C(C)(C)C.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)[CH:9]=1.C(N(CC)CC)C.Cl.[NH2:27][CH2:28][CH:29](O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=1>ClCCl>[OH:36][C:32]1[CH:31]=[C:30]([C:29](=[C:14]([CH2:15][CH2:16][OH:18])[C:10]2[CH:9]=[N:8][CH:13]=[CH:12][CH:11]=2)[C:28]([NH2:27])=[O:6])[CH:35]=[CH:34][CH:33]=1
Reactant: NCC(O)c1cccc(O)c1
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(O)/C=C/c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)C(=C(CCO)c1cccnc1)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
Pivaloyl chloride (5.17 ml, 1.05 eq.) was added to a solution of trans-3-(3-pyridyl)acrylic acid (5.96 g, 40 mmol) and triethylamine (5.6 ml, 40 mmol) in dichloromethane (80 ml) and stirred at room temperature for 10 minutes. A solution of dl-α-aminomethyl-3-hydroxybenzylalcohol hydrochloride (7.58 g, 40 mmol) and triethylamine (11.1 ml, 80 mmol) in dichloromethane (80 ml) was added and stirred at room temperature for 1 hour. The precipitated crystal was collected to yield the titled compound (7.51 g, 66%).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]Br.O>CN(C)C=O>[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][S:9][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([CH3:1])[C:11]([CH3:12])=[CH:10][C:5]=2[N:6]=1
Reactant: Cc1cc2nc(S)[nH]c2cc1C
Reactant: COC(=O)c1ccccc1CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccccc1CSc1nc2cc(C)c(C)cc2[nH]1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 89.5 %

Procedure:
To the resulting 5,6-dimethylbenzimidazole-2-thiol (89 mg, 0.50 mmol) in dimethylformamide (2 ml), triethylamine (84 μl, 0.6 mmol) and 2-bromomethyl benzoic acid methyl ester (137 mg, 0.6 mmol) were added. After the resulting solution was stirred at 80° C. for 1.5 hours, water was added, followed by extraction with ethyl acetate. After drying the ethyl acetate phase with anhydrous magnesium sulfate, it was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (146 mg, yield 90%). The compound was confirmed by identification of molecular weight using LC-MS. Calculated M=326.11, measured (M+H)+=327.2
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[N:9]=[CH:8]2)=O.[CH3:24][O:25][CH2:26][CH2:27][NH:28][CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[CH3:24][O:25][CH2:26][CH2:27][N:28]([CH2:1][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[N:9]=[CH:8]2)[CH3:29]
Reactant: CNCCOC
Reactant: NS(=O)(=O)c1ccc(Nc2ncc3cccc(C=O)c3n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: COCCN(C)Cc1cccc2cnc(Nc3ccc(S(N)(=O)=O)cc3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 4-(8-formylquinazolin-2-ylamino)benzenesulfonamide (11 mg, 30 umole) and 2-methoxy-N-methylethanamine (37 ul, 30 umole) in 500 ul of NMP was added a few drops of acetic acid. The reaction solution was stirred at room temperature for overnight. Sodium triacetoxy borohydride (7 mg, 33 umole) was added. The reaction mixture was stirred for 2 hr at ambient temperature. The reductive amination went to completion to give 4-(8-(((2-methoxyethyl)(methyl)amino)methyl)quinazolin-2-ylamino)benzenesulfonamide that was then purified on prep HPLC to give product as powder. ES/MS m/z 402.2 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:10]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[C:26](O)=O)([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:13]([O:12][C:10]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[C:26]1[NH:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=2[N:9]=1)=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ccc(I)cc1N
Reactant: O=C(O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCCC[C@H]1c1nc2cc(I)ccc2[nH]1
Temperature: 0 °C
Yield: 47 %

Procedure:
To a mixture of 4-iodo-benzene-1,2-diamine (1.5 g, 6.4 mmol) and (S)-N-Cbz-2-piperidine-carboxylic acid (available commercially at Aldrich) (1.7 g, 6.4 mmol) in DMF (20 mL) at 0° C. is added DIPEA (3.3 mL, 19.2 mmol) followed by HATU (3.0 g, 7.69 mmol). The reaction mixture is stirred at 0° C., brought to room temperature and stirred overnight. The reaction mixture is than concentrated in vacuum and the residue is dissolved in AcOH (15 mL) and stirred at 60° C. for 4 hours. The mixture is concentrated in vacuum and the residue is dissolved in EtOAc and washed with water, 1N HCl and brine, dried over sodium sulfate and concentrated in vacuum. The residue is purified by flash column chromatography on silica gel (MeOH/DCM 0% to 20%) to give the title compound (1.4 g, 47%).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.Br[CH:22]1[C@@H:26]([F:27])[C@H:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[C@@H:24]([CH2:37][O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)[S:23]1>C(Cl)Cl>[NH2:6][C:5]1[CH:7]=[CH:8][N:1]([CH:22]2[C@@H:26]([F:27])[C@H:25]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=3)[C@@H:24]([CH2:37][O:38][CH2:39][C:40]3[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=3)[S:23]2)[C:2](=[O:3])[N:4]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: Cc1ccc(COC[C@H]2SC(Br)[C@@H](F)[C@@H]2OCc2ccc(C)cc2)cc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: ClCCl
Product: Cc1ccc(COC[C@H]2SC(n3ccc(N)nc3=O)[C@@H](F)[C@@H]2OCc2ccc(C)cc2)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To another reaction vessel, 0.10 g of cytosine and 0.58 mL of N,O-bis(trimethylsilyl)acetamide were added in a nitrogen atmosphere, and the obtained mixture was then stirred at 80° C. for 1.5 hours. After cooling in air, the methylene chloride solution containing (3S,4S,5R)-2-bromo-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)meth yl)thiolane was added to the reaction mixture, and the obtained mixture was then stirred at 60° C. for 2.5 hours. Thereafter, methylene chloride was added to the reaction mixture, and the thus obtained mixture was washed with a saturated sodium hydrogen carbonate aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 90/10), so as to obtain 72 mg of (3S,4S,5R)-2-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)thiolane in the form of a light yellow solid.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl-].[NH4+:5].[Cl:6][C:7]1[CH:14]=[C:13]([C:15]2[CH2:19][C:18]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=2)[CH:12]=[CH:11][C:8]=1[CH:9]=O>O.N.CO.C(OCC)(=O)C>[NH2:5][CH:9]([C:8]1[CH:11]=[CH:12][C:13]([C:15]2[CH2:19][C:18]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=2)=[CH:14][C:7]=1[Cl:6])[C:1]#[N:2]
Reactant: [C-]#N
Reactant: O=Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: N#CC(N)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 103.6 %

Procedure:
In a solution of 0.18 g of sodium cyanide and 0.29 g of ammonium chloride in 5 mL of 28% ammonia water, a solution of 1.0 g of 2-chloro-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]benzaldehyde synthesized in Step 6 of Synthetic Example 6 in 30 mL of methanol was added, and stirred at 60° C. for 2 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, diluted with 60 mL of ethyl acetate, washed with water (30 mL×2), and the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous magnesium sulfate in that order, and the solvent was distilled off under reduced pressure to obtain 1.10 g of the aimed product as pale brown resinous substance.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[CH3:27][O:28][CH2:29][C@H:30]([O:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:42]=1[N:41]=[C:40]([CH:43]=O)[CH:39]=[CH:38]2)[CH3:31].C(O)C.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:26][C:2]([F:25])([F:1])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:43]([C:40]3[CH:39]=[CH:38][C:37]4[C:42](=[C:33]([O:32][C@H:30]([CH3:31])[CH2:29][O:28][CH3:27])[CH:34]=[CH:35][CH:36]=4)[N:41]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: COC[C@@H](C)Oc1cccc2ccc(C=O)nc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Agent: O=C([O-])O
Agent: O=Ic1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: COC[C@@H](C)Oc1cccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.7 %

Procedure:
A solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (0.33 g, 0.87 mmol) and (R)-8-(1-methoxypropan-2-yloxy)quinoline-2-carbaldehyde (0.21 g, 0.87 mmol) in ethanol (4.3 mL, 0.87 mmol) was allowed to stir at ambient temperature for 12 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (4.3 mL) and iodosobenzene diacetate (0.31 g, 0.95 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 (25-100% acetonitrile/water) to give the title compound (0.38 g, 73%).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([C:31]#[N:32])[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]2[CH:22]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:24]([CH3:26])=[CH:25][C:9]1=2.Cl.C(N(CC)CC)C.[N-:50]=[N+:51]=[N-:52].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:37][C:36]([F:39])([F:38])[C:34]1[CH:33]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:40])[F:41])[CH:35]=1)[CH2:6][N:7]([C:31]1[N:50]=[N:51][NH:52][N:32]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[C:10]2[CH:22]=[C:23]([C:27]([F:28])([F:29])[F:30])[C:24]([CH3:26])=[CH:25][C:9]1=2
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nn[nH]n1
Yield: 98.8 %

Procedure:
Heat a mixture of (S)-tert-butyl 5-[(3,5-bistrifluoromethylbenzyl)cyanoamino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (2.0 g, 3.36 mmol), triethylamine hydrochloride (694 mg, 5.04 mmol) and sodium azide (328 mg, 5.04 mmol) in anhydrous toluene (20 mL) at reflux under nitrogen for 12 h. Dilute the cooled mixture with ethyl acetate (100 mL) and wash with 2 N HCl (2×50 mL), water (50 mL) and brine (50 mL) and dry over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure to provide the title compound as an off-white foam (2.12 g, >99%), which is used in the next step without purification. ESI MS m/z 637 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:22]=[CH:21][C:15]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[CH:14][CH:13]=2)=[N:6][C:7]=1[C:8]([NH:10][NH2:11])=[O:9].[N:23]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[C:24]=S.C(Cl)CCl>C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:18]([CH3:19])[CH3:20])=[O:17])=[CH:21][CH:22]=2)=[N:6][C:7]=1[C:8]1[O:9][C:24]([NH:23][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:11][N:10]=1
Reactant: S=C=NCc1ccccc1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)NN)n2)cc1
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(NCc4ccccc4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
A mixture of 4-(5-amino-6-(hydrazinecarbonyl)pyrazin-2-yl)-N,N-dimethylbenzamide (75 mg, 0.2497 mmol), isothiocyanatomethylbenzene (37.26 mg, 33.12 μL, 0.2497 mmol) and dry THF (1.500 mL) was stirred at RT for 4 hours. The reaction mixture was evaporated to dryness and treated with DCM followed by EDC (71.81 mg, 0.3746 mmol) and the resultant mixture allowed to stir at RT overnight. The reaction mixture was filtered and the resultant green precipitate dried under vacuum (78 mg, 73% Yield). 1H NMR (400.0 MHz, DMSO) d 2.96 (s, 3H), 3.00 (s, 3H), 4.50 (d, J=6.1 Hz, 2H), 7.29 (d, J=7.2 Hz, 1H), 7.35-7.42 (m, 4H), 7.51-7.53 (m, 2H), 7.65 (br s, 2H), 8.06 (dd, J=1.5, 6.9 Hz, 2H) and 8.81 (d, J=12.4 Hz, 2H) ppm; MS (ES+) 416.2
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:12](I)([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].[CH3:22][C:23]([CH3:25])=O>>[CH:12]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH:23]([CH3:25])[CH3:22])[CH:3]=1)([CH3:14])[CH3:13]
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: CC(C)=O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)OC(=O)Cc1cccc(OC(C)C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Combine 3-hydroxy-phenyl acetic acid (9.26 g, 60.9 mmol), isopropyl iodide (42.6 g, 250 mmol), and acetone (80 mL). Add portionwise, potassium carbonate (16.9 g, 122 mmol). Heat to reflux with vigorous mechanical stirring. After 20 hours, cool to ambient temperature and evaporate in vacuo to give a residue. Partition the residue between diethyl ether and 5% sodium hydroxide solution. Extract the organic layer with water and a saturated sodium chloride solution. Dry the organic layer over MgSO4, filter and evaporate in vacuo to obtain a liquid. Bulb-to-bulb distillation gives 3-isopropoxy-phenyl-acetic acid isopropyl ester: bp; 125° C. at 0.2 mm of Hg.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:5]=[C:4]([S:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])=[CH:18][CH:17]=2)[N:3]=1.Cl.[CH:29]1([C:32]2([F:36])[CH2:35][NH:34][CH2:33]2)[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.ClCCl>O1CCOCC1>[CH:29]1([C:32]2([F:36])[CH2:35][N:34]([C:2]3[CH:7]=[C:6]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[N:5]=[C:4]([S:15][C:16]4[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]5[CH2:27][CH2:26]5)=[O:24])=[CH:18][CH:17]=4)[N:3]=3)[CH2:33]2)[CH2:31][CH2:30]1
Reactant: FC1(C2CC2)CNC1
Reactant: O=C(Nc1ccc(Sc2nc(Cl)cc(Nc3ccccn3)n2)cc1)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Sc2nc(Nc3ccccn3)cc(N3CC(F)(C4CC4)C3)n2)cc1)C1CC1

Procedure:
Prepared according the procedure used for the synthesis of compound I-1, starting with N-(4-(4-Chloro-6-(pyridin-2-ylamino)pyrimidin-2-ylthio)phenyl)cyclopropane carboxamide (110 mg, 28 mmol), 3-cyclopropyl-3-fluoroazetidine hydrochloride (60 mg, 0.39 mmol), and DiPEA (0.15 mL, 0.9 mmol) in 1,4-dioxane. After column chromatography, the product containing fraction (TLC: SiO2, dichloromethane/7.5% 2-propanol, Rf=0.65; HPLC: 70/90% purity, Rf=8.813 minutes) was purified further by preparative HPLC to yield 4 mg after evaporation and lyophilization with a purity of 96+% (HPLC method B, Rf=5.841 minutes).