Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH2:41][S:42][CH2:43][C@H:44]([O:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[CH2:45][O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[C:20](=[O:40])[NH:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C1COCC1.CN(C=O)C>[NH2:18][C@@H:19]([CH2:41][S:42][CH2:43][C@H:44]([O:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[CH2:45][O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[C:20](=[O:40])[NH:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34]
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCOCCOCCOCCC(=O)OC(C)(C)C)OCCCCCCCCCCCC
Solvent: C1CCNCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCC(=O)OC(C)(C)C)OCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (15R,19R)-tert-butyl 15-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-19-(dodecyloxy)-14-oxo-4,7,10,21-tetraoxa-17-thia-13-azatritriacontan-1-oate (1 eq) was added 20% piperidine (50 eq) in 4:1 THF/DMF. The resulting solution was stirred for 15 minutes at 25° C. and then concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% MeOH/DCM to give the title product as a white solid.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)=[CH:5][CH:4]=[C:3]([OH:15])[CH:2]=1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>>[OH:15][C:3]1[CH:2]=[CH:1][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:18](=[O:19])[N:17]([CH3:16])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccc(Cc2ccc(O)cc2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(Cc2ccc(O)cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4,4′-dihydroxydiphenylmethane and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (21%, white crystals which turn red after standing). HPLC-MS: m/z=324.2 (M+1); Rt: 4.21 min.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[NH:8]1[CH2:9][CH:10]=[C:11]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:12][CH2:13]1
Reactant: CCOC(=O)c1ccc2c(C3=CCN(Cc4ccccc4)CC3)c[nH]c2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)c1ccc2c(C3=CCNCC3)c[nH]c2c1

Procedure:
5 g ethyl 3-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-6-carboxylate and 2.3 g palladium hydroxide are suspended in 180 ml of methanol and hydrogenated at 50 psi for 2 hours at ambient temperature. The catalyst is suction filtered and the mother liquor is evaporated to dryness. 3.6 g (V-2) are obtained as a solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5](/[C:13](=[N:15]/[C:16]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:17]=2[C:18]#[N:19])/[CH3:14])[CH2:4][CH2:3]1.CN(C)C(=O)C.[OH-].[Na+]>[Cl-].[Zn+2].[Cl-].O>[O:25]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:14]=[C:18]([NH2:19])[C:17]3[C:16](=[CH:23][CH:22]=[C:21]([CH3:24])[CH:20]=3)[N:15]=2)[CH2:4][CH2:3]1
Reactant: C/C(=N\c1ccc(C)cc1C#N)N1CCS(=O)(=O)c2ccccc2C1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N)c2c1
Temperature: 160 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
A mixture of 2-{[(1E)-1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethylidene]amino}-5-methylbenzonitrile (1.5 g, 4.24 mmol), zinc chloride (578 mg, 4.24 mmol) and N,N-dimethylacetamide (4 mL) was heated with stirring at 160° C. for 3 hours under argon. After the reaction mixture was cooled to about 40° C., an aqueous solution of sodium hydroxide (2 N, 20 mL) was introduced. After being stirred for 10 minutes at room temperature, the reaction mixture was poured into water. The formed solid was collected by filtration, and dried in vacuo to give 1.5 g of the product as a brown powder. MS obsd. (ESI+) [(M+H)+] 354, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.90-7.84 (m, 2 H), 7.66-7.62 (m, 2 H), 7.48 (t, J=7.2 Hz, 1 H), 7.32 (d, J=8.4 Hz, 1 H), 7.23 (dd, J=1.6, 8.8 Hz, 1 H), 6.29 (s, 2 H), 6.23 (s, 1 H), 4.97 (s, 2 H), 4.36 (brs, 2 H), 3.60 (t, J=4.8 Hz, 2 H), 2.34 (s, 3 H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C)C=O.O>[N:15]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)CCCCCCCCCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCCCCCCCCCC(=O)O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To 11-bromoundecanoic acid (1.73 g) dissolved in N,N-dimethylformamide (DMF) was added sodium azide (1.5 g), and the mixture was heated to a temperature of 80° C. and stirred for 5 hours. The reaction mixture was then diluted with cooling water and extracted with ethyl acetate to give 11-azidoundecanoic acid. To the mixed solution of 11-azidoundecanoic acid (1 g) and para-nitrophenol (612 mg) in DMF was added N,N'-dicyclohexylcarbodiimide (920 mg), and the mixture was stirred for 12 hours. The reaction mixture was filtered and concentrated to give the active ester of 11-azidoundecanoic acid. To the active ester (284 mg) dissolved in DMF were further added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (300 mg) and triethylamine (1.1 ml), and the mixture was stirred for 12 hours. The solvent was removed by distillation, and the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK410 in the yield of 171 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16]2[C@@H:15]3[CH2:17][C@@H:14]3[CH2:13][C:12]=2[C:11]([C:18](O)=[O:19])=[N:10]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH2:63][C:64]([CH3:68])([CH3:67])[CH2:65][OH:66]>CN(C=O)C.O>[OH:66][CH2:65][C:64]([NH:63][C:18]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:17][C@H:15]3[C:16]=2[N:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:10]=1)=[O:19])([CH3:68])[CH3:67]
Reactant: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Reactant: CC(C)(N)CO
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CO)NC(=O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a stirred solution of Intermediate 1 (see Example 1.1, 2 g, 7.24 mmol), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 4.52 g, 8.69 mmol) and DIEA (2.52 mL, 14.48 mmol) in DMF (20 mL) was added 2-amino-2-methylpropan-1-ol (0.833 mL, 8.69 mmol). The reaction was stirred at room temperature overnight, then poured into water, and extracted with ethyl acetate. The combined organics were dried and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a white solid (2.08 g). LCMS m/z=348.4 [M+H]+; 1H NMR (400 MHz, CDCl3) ppm 0.48 (td, J=4.7, 3.3 Hz, 1H), 1.16 (td, J=7.8, 4.9 Hz, 1H), 1.371 (s, 3H), 1.376 (s, 3H), 2.08-2.13 (m, 1H), 2.25-2.31 (m, 1H), 2.94 (d, J=16.8 Hz, 1H), 3.04 (dd, J=16.4, 6.2 Hz, 1H), 3.68 (d, J=3.5 Hz, 2H), 4.81-4.84 (m, 1H), 6.88 (bs, 1H), 6.99-7.05 (m, 2H), 7.59-7.65 (m, 1H).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=1)#[CH:9]>>[F:17][C:12]1[CH:11]=[C:10]([C:8]#[C:9][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:15]=[CH:14][C:13]=1[F:16]
Reactant: Ic1cccnc1
Reactant: C#Cc1ccc(F)c(F)c1
Product: Fc1ccc(C#Cc2cccnc2)cc1F
Yield: 21 %

Procedure:
Prepare essentially as described in EXAMPLE 46 using 3-iodopyridine (445 mg, 2.17 mmol) and 4-ethynyl-1,2-difluorobenzene, (prepared essentially as described in PREPARATION 14), (300 mg, 2.17 mmol) to give the title compound (87.6 mg, 21%).
Reaction SMILES: CS(C)=O.[F:5][C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][C:19]=1/[CH:20]=[CH:21]/[N+:22]([O-:24])=[O:23])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C(O)(=O)C.[BH4-].[Na+]>O>[F:5][C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][C:19]=1[CH2:20][CH2:21][N+:22]([O-:24])=[O:23])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccccn2)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1ccc(OCc2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
To a dimethyl sulfoxide (20.0 mL) solution of 2-(3-fluoro-4-((E)-2-nitro-vinyl)-phenoxymethyl)pyridine (1.20 g) described in Manufacturing Example 95-1-2 and acetic acid (1.00 mL) was added sodium borohydride (249 mg, 6.57 mmol) at room temperature while cooling appropriately under nitrogen atmosphere, which was stirred for 30 minutes at room temperature. Water was then added dropwise at room temperature while cooling appropriately. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, followed by crystallization with an ethyl acetate-heptane system and filtration to obtain the title compound (614 mg, 50.7%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccccc1S
Product: Oc1ccccc1SCc1ccccc1
Yield: 78 %

Procedure:
This compound was prepared in 78% yield from 2-mercaptophenol and benzyl bromide according to the procedure for 16p in Example VII. Pale Oil; 1H NMR (CDCl3): δ 3.87 (s, 2H), 6.56 (s, 1H), 6.83 (t, J=7.30 Hz, 1H), 6.95 (d, J=8.00 Hz, 1H), 7.10 (m, 2H), 7.26-7.29 (m, 5H); 13C NMR (CDCl3): δ 41.49, 114.84, 118.29, 120.75, 127.24, 127.55, 128.66, 128.90, 129.05, 131.53, 136.54, 137.69, 157.24.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[C:14](=O)[C:13](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:12][S:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:24]([NH:27][NH2:28])[CH2:25][CH3:26]>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:28][N:27]([CH2:24][CH2:25][CH3:26])[C:14]3[C:13](=[CH:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[CH2:12][S:11][CH2:10][C:9]2=3)=[CH:4][CH:3]=1
Reactant: O=C1C(=Cc2ccc(Cl)cc2)CSCC1=Cc1ccc(Cl)cc1
Reactant: CCCNN
Solvent: CC(Cl)Cl
Product: CCCN1NC(c2ccc(Cl)cc2)C2=C1C(=Cc1ccc(Cl)cc1)CSC2
Temperature: 25 °C
Yield: 8.7 %

Procedure:
A mixture of tetrahydro-3,5-bis-(4-chlorophenylmethylene)-4H-thiopyran-4-one (6 g, 16.6 mmole) and N-propylhydrazine (1.3 g, 16.6 mmole) in dichloroethane (100 ml) is heated at reflux temperature for 2.5 hours and cooled to room temperature overnight. The reaction mixture is washed with dilute HCl and water, then dried over CaCl2. After the solvent is removed in vacuo, the residue (yellow solid) is chromatographed on a dry-packed Al2O3 column (neutral, activity I). The fractions eluted with 0-5% EtOAc/hexane give the major product. Further elution of the column with EtOAc, then with CHCl3, and after crystallization from acetoneacetonitrile, gives 0.6 g (9%) of the title compound in crystalline form (99% pure) m.p. 192°-194.5°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]/[C:13]1[CH:21]=[C:20]2[C:16]([C:17](/[CH:30]=[CH:31]/[C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[N:18][N:19]2COCC[Si](C)(C)C)=[CH:15][CH:14]=1>CO.CCO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]/[C:13]1[CH:21]=[C:20]2[C:16]([C:17](/[CH:30]=[CH:31]/[C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)=[N:18][NH:19]2)=[CH:15][CH:14]=1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(/C=C3/C(=O)Nc4ccc(Br)cc43)cc21
Solvent: CO
Solvent: CCO
Product: O=C1Nc2ccc(Br)cc2/C1=C\c1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Temperature: 80 °C

Procedure:
A solution of (E)-5-bromo-3-((3-((E)-2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-indazol-6-yl)methylene)indolin-2-one (75 mg, 0.131 mmol) in 12 mL of a 2:1:1 mixture of MeOH/EtOH/4M HCl was heated to 80° C. for 24 hours. LC-MS indicated a mixture of the title compound plus a partially deprotected methoxymethyl indazole compound (see Example A63). The solvents were removed and the mixture was purified by prep-HPLC to give 7.3 mg (13%) of the title compound as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 13.87 (s, 1H), 10.82 (s, 1H), 8.76 (d, J=5.78 Hz, 2H), 8.45 (d, J=8.00 Hz, 1H), 8.23-8.13 (m, 3H), 8.04 (s, 1H), 7.96 (s, 1H), 7.73 (d, J=16.6 Hz, 1H), 7.64 (s, 1H), 7.60 (d, J=7.81 Hz, 1H), 7.43 (d, J=7.31 Hz, 1H), 6.87 (d, J=8.11 Hz, 1H); MS ESI 443.3 [M+H]+, calcd for [C23H15BrN4O+H]+ 443.05.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[N:7]=1)=[O:4].C([Li])CCC.[Br:21]CCBr.O>C1COCC1.C(OCC)(=O)C>[Br:21][C:11]1[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:15])([CH3:14])[CH3:1])=[N:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=1
Reactant: COc1cccc(NC(=O)C(C)(C)C)n1
Reactant: BrCCBr
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(Br)c(NC(=O)C(C)(C)C)n1
Temperature: 0 °C
Reaction time: 7 h
Yield: 60.1 %

Procedure:
A solution of 2,2-dimethyl-N-[6-(methyloxy)-2-pyridinyl]propanamide (55.011 g, 264.467 mmol) in THF (450 ml) in a three necked 1 L flask with an internal thermometer under argon was cooled to −78° C. and treated with n-butyl lithium (232 ml, 581.847 mmol) over 15 minutes and then allowed to warm to 0° C. and stirred at 0° C. for 7 h. The mixture was then recooled to −78° C. and treated with 1,2-dibromoethane (27.3 ml, 317 mmol) over 10 minutes and then the solution was allowed warm to room temperature and stirred at room temperature for 30 minutes by which time all the solid which had formed dissolved again. Gas was evolved at this stage so a gas bubbler was placed on one of the flasks necks. Water (100 ml) was then carefully added over 10 minutes. Further water (500 ml) was then added and the mixture was extracted with diethyl ether (3×500 ml). The combined organic solvents were then dried (MgSO4), filtered, evaporated to give the crude product. This was then dissolved in warm ethyl acetate (100 ml) and allowed to stand in the freezer overnight. The resultant solid which crystallised out was filtered off, washed with ice-cooled diethyl ether (20 ml) and dried in vacuo to give product as a white solid (45.660 g, 159.011 mmol, 60% yield). The filtrate was evaporated and the residue was chromatographed (0-25% ethyl acetate/40-60 petroleum ether) to give recovered starting material (7.264 g, 34.9 mmol), and product as a white solid (8.038 g, 27.992 mmol, 10% yield). The product from recrystallisation and silica chromatography were identical by NMR and LC-MS and so were combined.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]2[NH:12][CH:13]=[C:14]([NH2:15])[C:3]=12.[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[C:22](O)=[O:23].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl.O>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][N:5]=[C:4]2[NH:12][CH:13]=[C:14]([NH:15][C:22]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][N:16]=3)=[O:23])[C:3]=12
Reactant: Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12
Reactant: O=C(O)c1cnccn1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12)c1cnccn1
Reaction time: 1 h
Yield: 79.3 %

Procedure:
4-Chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-amine (0.200 g, 0.849 mmol, Example 11, Step G) and pyrazine-2-carboxylic acid (0.221 g, 1.78 mmol) were placed in DCM (5 mL) at room temperature. BOP-Cl (0.454 g, 1.78 mmol) was then added, followed by the addition of triethylamine (0.592 mL, 4.24 mmol). The reaction was stirred for 1 hour. 3M aqueous LiOH (3 mL) was then added, and the reaction was stirred for 10 minutes. Water (10 mL) and DCM (10 mL) were then added, and the reaction was filtered. The resulting solid was slurried with 10:1 DCM:MeOH and filtered to give solid N-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazine-2-carboxamide (0.23 g, 79% yield).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:3][CH:4]2[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:14])[CH2:6][CH2:5]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: NC1CCN(CCCC(=O)c2ccccc2)CC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CCCN1CCC(NS(=O)(=O)c2ccc(Cl)cc2)CC1)c1ccccc1

Procedure:
Using an analogous procedure to Example 2 4-amino-1-(4-phenyl-4-oxobutyl)piperidine dihydrochloride may be reacted with p-chlorobenzenesulphonyl chloride to give the title compound.
Reaction SMILES: C(N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)C.[OH:50][CH2:51][CH2:52][CH2:53][CH2:54][N:55]1[CH:59]=[C:58]([C:60]2[CH:61]=[CH:62][C:63]([NH:71][C:72]3[C:77]([C:78]([F:81])([F:80])[F:79])=[CH:76][N:75]=[C:74]([NH:82][C:83]4[CH:97]=[CH:96][C:86]([CH2:87][P:88](=[O:95])([O:92]CC)[O:89][CH2:90][CH3:91])=[CH:85][C:84]=4[O:98][CH3:99])[N:73]=3)=[C:64]3[C:68]=2[CH2:67][N:66]([CH3:69])[C:65]3=[O:70])[CH:57]=[N:56]1>>[OH:50][CH2:51][CH2:52][CH2:53][CH2:54][N:55]1[CH:59]=[C:58]([C:60]2[CH:61]=[CH:62][C:63]([NH:71][C:72]3[C:77]([C:78]([F:81])([F:80])[F:79])=[CH:76][N:75]=[C:74]([NH:82][C:83]4[CH:97]=[CH:96][C:86]([CH2:87][P:88](=[O:92])([OH:95])[O:89][CH2:90][CH3:91])=[CH:85][C:84]=4[O:98][CH3:99])[N:73]=3)=[C:64]3[C:68]=2[CH2:67][N:66]([CH3:69])[C:65]3=[O:70])[CH:57]=[N:56]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1
Yield: 101.9 %

Procedure:
Prepared analogously to Compound 3A using diethyl (4-{[4-({7-[1-(4-hydroxybutyl)-1H-pyrazol-4-yl]-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 17B, 73 mg, 101 μmol) to afford 71 mg of the title compound (100%). 1H NMR (400 MHz, CD3OD) δ 8.49 (d, J=6.57 Hz, 1H), 8.23 (s, 1H), 8.04 (br. s., 1H), 7.77 (s, 2H), 7.57 (d, J=8.84 Hz, 1H), 7.11 (s, 1H), 6.95 (d, J=8.08 Hz, 1H), 4.42 (s, 2H), 4.22 (t, J=7.07 Hz, 2H), 3.82-3.92 (m, 5H), 3.59 (t, J=6.44 Hz, 2H), 3.07-3.11 (m, 3H), 3.03 (d, J=21, 2H), 1.97 (quin, J=7.33 Hz, 2H), 1.51-1.60 (m, 2H), 1.17 (t, J=7.07 Hz, 3H). MS (ESI): m/z 690.80 [M+H]+. UPLC: tR=1.07 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2F)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:15][NH2:16]>>[CH:1]1([C:6]2[C:8]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:16][N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccccc1F)C1CCCC1
Reactant: NN
Product: c1ccc2c(C3CCCC3)n[nH]c2c1
Temperature: 130 °C
Yield: 89 %

Procedure:
Dissolve Cyclopentyl-(2-fluoro-phenyl)-methanone (2.5 g 13.005 mmoles) in hydrazine (20 ml) heat to 130° C. for 72 hrs. Cool mixture to 0° C. Filter the precipitate and wash with cold water to give the title compound: 2.171 g (yield=89%) MS ES+ 187.12:MSES− 185.22.
Reaction SMILES: [N:1]1[C:10]2[N:9]3[CH2:11][CH2:12][O:13][CH2:14][CH:8]3[CH2:7][NH:6][C:5]=2[CH:4]=[N:3][C:2]=1[C:15]1[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=1.CC(C)([O-])C.[Na+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1>CS(C)=O>[CH3:39][S:36]([C:33]1[CH:34]=[CH:35][C:30]([CH2:29][N:6]2[CH2:7][CH:8]3[CH2:14][O:13][CH2:12][CH2:11][N:9]3[C:10]3[N:1]=[C:2]([C:15]4[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=4)[N:3]=[CH:4][C:5]2=3)=[CH:31][CH:32]=1)(=[O:37])=[O:38]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: Nc1ncc(-c2ncc3c(n2)N2CCOCC2CN3)cn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(CN2CC3COCCN3c3nc(-c4cnc(N)nc4)ncc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.1 %

Procedure:
To a solution of 5-(5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)pyrimidin-2-amine (EXAMPLE 1, 70.2 mg, 0.246 mmol) in DMSO (1.2 mL) was added sodium tert-butoxide (28.4 mg, 0.295 mmol). The resulting mixture was stirred at room temperature for 5 minutes after which 1-(bromomethyl)-4-(methylsulfonyl)benzene (0.5 mL, 0.271 mmol) was added dropwise. The resulting brown solution was stirred at room temperature for 2 hours. The reaction mixture was quenched with aqueous saturated NH4Cl, diluted with ethyl acetate, and washed with aqueous saturated NH4Cl (3×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by LC/MS and the pure fractions were combined and lyophilized to give a yellow solid (4.6 mg, 4%). The product's regiochemistry was confirmed by 2D NOESY. 1H NMR (400 MHz, DMSO-d6) δ 3.16-3.25 (m, 7 H), 3.44-3.46 (m, 1 H), 3.53-3.57 (m, 1 H), 3.80-3.97 (m, 1 H), 3.98-4.03 (m, 1 H), 4.65 (s, 2 H), 4.76-4.80 (d, 1 H), 7.37 (s, 1 H), 7.42 (br s, 2 H), 7.61-7.63 (d, J=8.0 Hz, 2 H) 7.91-7.93 (d, J=8.0 Hz, 2 H), 9.00 (s, 2 H). ESI-MS m/z [M+H]+ calc'd for C21H23N7O3S, 454.16; found 454.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[CH3:21][Zn+]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH3:21])[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Reactant: C[Zn+]
Agent: [Cl-]
Product: Cc1cc2c(cn1)C(C)(C)CN2C(=O)OC(C)(C)C
Yield: 55 %

Procedure:
Prepared from 6-chloro-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester by a method analogous to that of Preparation 117 using methyl zinc chloride (2.0 M in THF, 9.75 mmol), to give the title compound (510 mg, 55%) as a colourless oil. MS: [M+H]+=263.
Reaction SMILES: [N:1]1[N:2]=[N:3][C:4](=[O:6])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[O:13]1[CH:15]([CH3:16])[CH2:14]1>CN(C=O)C>[OH:13][CH2:14][CH2:15][CH2:16][C:5]1[C:4](=[O:6])[N:3]=[N:2][N:1]=1
Reactant: CC1CO1
Reactant: O=C1C=NN=N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1N=NN=C1CCCO
Temperature: 60 °C
Yield: 283.4 %

Procedure:
To a mixture of triazolone 35 (248 mg, 0.5 mmol) and potassium carbonate (138 mg, 1 mmol) in DMF (6 ml), 1,2-epoxypropane (870 mg, 15 mmol) was added. The reaction mixture was heated at 60° C. for 18 h and concentrated in vacuo. The residue was treated with crushed ice, extracted with ethyl acetate (3×30 ml). The combined extract was washed with brine, dried (Na2SO4) and the solvent was removed under reduced pressure. The resulting crude product was purified on a column of silica gel (EtOAc/MeOH, 9:1) to give the hydoxypropyltriazolone 42 as a colorless solid (200 mg, 72%).