Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[CH2:3][NH:4][CH2:5][CH:6]([OH:19])[CH2:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.F[C:23](F)(F)CN>>[CH3:2][CH:3]([NH:4][CH2:5][CH:6]([OH:19])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=12)[CH3:23]
Reactant: OC(CNCC(F)(F)F)COc1cccc2ccccc12
Reactant: NCC(F)(F)F
Product: CC(C)NCC(O)COc1cccc2ccccc12
Temperature: 100 °C
Yield: 68 %

Procedure:
(RS)-1-(2,2,2-TRIFLUOROETHYLAMINO)-3-(1-NAPHTHYLOXY)-2-PROPANOL ##STR2## A mixture of (2RS)-1'-(2,3-epoxypropoxy)naphthalene (1.4 g, 6.49 mmole) and 2,2,2,-trifluroethylamine (25 g, 252.4 mmole) were heated in a sealed glass tube for about 115 hours at 100° C., Excess amine was distilled under vacuum and collected. The remaining solid was dissolved in ether and washed twice with 250 ml of water. The ethereal solution was treated with dry hydrogen chloride gas to convert the amine to its hydrochloride salt which is collected as a off white solid ; m.p. 178°-180° C.; (yield 68%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:7][C:6]=1[CH3:17])=O.[NH2:18][C:19]([NH2:21])=[S:20]>CCO>[CH2:13]([O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]2[N:18]=[C:19]([NH2:21])[S:20][CH:2]=2)=[C:6]([CH3:17])[CH:7]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: NC(N)=S
Reactant: Cc1cc(OCC(C)C)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(OCC(C)C)cc(C)c1-c1csc(N)n1
Yield: 81.6 %

Procedure:
A mixture of 2-bromo-1-(4-isobutoxy-2,6-dimethylphenyl)ethanone (5.84 g, 19.5 mmol) and thiourea (1.49 g, 19.6 mmol) in 95% EtOH (28 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(4-isobutoxy-2,6-dimethylphenyl)thiazol-2-amine (4.4 g) as white solids in 82% yield: 1H NMR (500 MHz, CDCl3) δ 6.61 (s, 2 H), 6.24 (s, 1H), 3.70 (d, J=6.5 Hz, 2 H), 2.15 (s, 6 H), 2.07 (m, 1H), 1.01 (d, J=6.7 Hz, 6 H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[CH3:31][O:32][C:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH:40]2[CH2:45][N:44]3[CH:46]=[C:47]([C:49]([OH:51])=O)[N:48]=[C:43]3[CH2:42][CH2:41]2)=[CH:35][C:34]=1[CH3:52].[CH2:53]([CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>CN(C=O)C>[CH2:53]([CH:60]1[CH2:65][CH2:64][N:63]([C:49]([C:47]2[N:48]=[C:43]3[CH2:42][CH2:41][CH:40]([C:36]4[CH:37]=[C:38]([CH3:39])[C:33]([O:32][CH3:31])=[C:34]([CH3:52])[CH:35]=4)[CH2:45][N:44]3[CH:46]=2)=[O:51])[CH2:62][CH2:61]1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: COc1c(C)cc(C2CCc3nc(C(=O)O)cn3C2)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1c(C)cc(C2CCc3nc(C(=O)N4CCC(Cc5ccccc5)CC4)cn3C2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TBTU (212 mg; 0.66 mmol) and N-methylmorpholine (181 μl; 167 mg; 1.65 mmol) were added to a solution of 6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (165 mg; 0.49 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then 4-benzylpiperidine (116 μl; 116 mg; 0.7 mmol) was added. The reaction mixture was stirred for 4 h at room temperature and then poured onto water. The precipitated solid was filtered out. Yield: 182 mg (81%)
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]2[N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:13][C:3]=12.[H][H]>C1COCC1.CCO.[Pd]>[CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]2[N:11]([S:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[CH:12]=[CH:13][C:3]=12
Reactant: Cc1c([N+](=O)[O-])cnc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(N)cnc2c1ccn2S(=O)(=O)c1ccccc1
Yield: 99.8 %

Procedure:
To a mixture of 4-methyl-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine, (410 mg, 1.29 mmol) in THF (15 mL) and EtOH (10 mL) was added 10% palladium on carbon (10 wt % of Pd/C; 45 mg) under argon. The mixture was hydrogenated using a hydrogen balloon at room temperature for 16 hours. The reaction mixture was flushed with nitrogen and filtered through a plug of Celite® and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel using hexane:EtOAc (4:6) to get 4-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-amine, (370 mg). 1H NMR (300 MHz, CD3OD) δ: 7.96-8.04 (m, 2H), 7.83 (s, 1H), 7.53-7.64 (m, 2H), 7.42-7.52 (m, 2H), 6.65 (d, J=4.1 Hz, 1H), 2.26 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[F:68][CH:69]1[CH2:74][CH2:73][N:72]([CH2:75][CH2:76][NH2:77])[CH2:71][CH2:70]1>CN(C=O)C>[F:68][CH:69]1[CH2:74][CH2:73][N:72]([CH2:75][CH2:76][NH:77][C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:31])[CH2:71][CH2:70]1
Reactant: NCCN1CCC(F)CC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCC(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
To a mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (151 mg, 0.3 mmol), triethylamine (0.084 mL, 0.6 mmol) and BOP reagent (199 mg, 0.45 mmol) in DMF (0.5 mL) was added 2-(4-fluoro-piperidin-1-yl)-ethylamine (48 mg, 0.32 mmol) in DMF (0.5 mL). The mixture was stirred at rt for overnight. After the usual workup, the residue was purified on a silica gel column to give 90 mg (47%) of the titled compound.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.[C:33]([N:36]1[CH2:40][CH2:39][CH2:38][C@@H:37]1[C:41](O)=[O:42])(=[O:35])[CH3:34].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[C:33]([N:36]1[CH2:40][CH2:39][CH2:38][C@@H:37]1[C:41]([N:25]1[CH2:24][CH2:23][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:8]3[CH:7]=[C:6]([NH:5][CH2:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)=[O:42])(=[O:35])[CH3:34]
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Reactant: CC(=O)N1CCC[C@@H]1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCC[C@@H]1C(=O)N1CCC(c2ccc(Nc3cc(NCc4cccc(F)c4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Yield: 102.5 %

Procedure:
The mixture of compound 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (50 mg, 0.11 mmol), (R)-acetyl-pyrrolidine-2-carboxylic acid (35 mg, 0.22 mmol), DIEA (180 μL, 1.1 mmol) in 4 mL NMP was stirred at RT. To it was added BOP (210 mg, 0.55 mmol). The mixture was stirred for overnight, quenched with TFA, and subjected to reverse phase preparative HPLC to isolate the title compound (65 mg). MS found for C31H34F2N6O3 as (M+H)+ 577.5. UV: λ=259 nm. 1H NMR (a pair of rotomers): (CD3OD) δ 8.13 (with 8.15, 1H, s), 7.36 (with 7.32, 2H, d, J=8.8 Hz), 7.25 (1H, m), 7.16 (1H, m), 7.13-7.07 (3H, m), 5.83 (with 5.79, 1H, s), 4.95 (1H, m), 4.65 (1H, m), 4.56 (with 4.55, 2H, s), 4.20 (1H, m), 3.66 (2H, m), 3.30 (1H, m), 2.92 (1H, m), 2.79 (1H, m), 2.27 (1H, m), 2.12 (with 2.10, 3H, s), 2.07-1.85 (5H, m), 1.68 (2H, m) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([CH2:16]OS(C)(=O)=O)[C@@H:13]([OH:22])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C)C=O>[N:23]([CH2:16][C@@H:14]1[C@@H:13]([OH:22])[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:15]1)=[N+:24]=[N-:25]
Reactant: CS(=O)(=O)OC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Temperature: 100 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
(3R,4R)-1-Benzyloxycarbonyl-3-hydroxy-4-methanesulfonyloxymethylpyrrolidine (125 mg) was then dissolved in N,N-dimethylformamide (3 mL) and sodium azide (50.0 mg) was added. The mixture was stirred at 100° C. for 1 hour and was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (5 mL). The solution was then washed with water (2×1 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant: ethyl acetate) to give (3R,4R)-3-azidomethyl-1-benzyloxycarbonyl-4-hydroxypyrrolidine as a milky white syrup (91.0 mg). This compound was identical to the compound obtained by Process A.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[C:19]([F:32])[C:18]=1[CH:33]([F:35])[CH3:34].[F-].[K+].CC#N>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[C:18]([CH:33]([F:35])[CH3:34])[C:19]=2[F:32])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15]
Reactant: CC(F)c1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(Cl)c(C(C)F)c2F)c(F)c(N)c1OC
Yield: 81 %

Procedure:
Methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate (0.400 g, 1.705 mmol), 2-(4-chloro-2-fluoro-3-(1-fluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (prepared as described in WO2009029735 A1 20090305; 0.671 g, 2.216 mmol), PdCl2(PPh3)2 (0.120 g, 0.170 mmol), and KF (0.258 g, 4.43 mmol) were combined in a 1:1 mixture of CH3CN (2.84 mL) and H2O (2.84 mL). The reaction mixture was irradiated in a Biotage microwave at 115° C. in a sealed vial for 20 min. The cooled reaction mixture was partitioned between EtOAc and H2O. The organic phase was dried and concentrated. The product was purified by flash chromatography (SiO2, 5-40% EtOAc in hexane gradient) to provide the title compound as a sticky brown-orange solid (0.545 g, 81%): 1H NMR (400 MHz, CDCl3) δ 7.53-7.46 (m, 1H), 7.29 (dt, J=8.4, 1.1 Hz, 1H), 6.39-6.03 (m, 1H), 4.61 (s, 2H), 3.97 (d, J=2.1 Hz, 6H), 1.85-1.68 (m, 3H); 19F NMR (376 MHz, CDCl3) δ −113.81, −113.87, −113.90, −113.95, −137.05, −137.14, −175.47, −175.52; ESIMS m/z 375 ([M+H]+), 373 ([M−H]−).
Reaction SMILES: C(O[C:4](=[O:17])[C:5](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Br:16])[C:6]#[N:7])C.[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>CO>[Br:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][N:8]=[C:5]([C:6]#[N:7])[C:4]([NH:22][CH2:18][CH2:19][CH2:20][CH3:21])=[O:17]
Reactant: CCCCN
Reactant: CCOC(=O)C(C#N)=NNc1ccccc1Br
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCNC(=O)C(C#N)=NNc1ccccc1Br
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a microwave vial charged with [(2-bromophenyl)-hydrazono]-cyanoacetic acid ethyl ester (387 mg, 1.31 mmol) was added methanol (3 mL) and n-butylamine (520 uL, 5.24 mmol). The reaction temperature rose approximately 30° C. and everything went into solution. After 25 minutes, additional n-butylamine (260 uL, mg, 2.6 mmol) and triethyl amine (182 uL, 1.3 mmol) were added. The reaction was stirred at room temperature overnight and then concentrated to afford the title compound which was used without further purification (420 mg, 99%). 1H NMR (300.132 MHz, CDCl3) δ 14.33 (s, 1H), 7.67 (dd, J=8.3, 1.5 Hz, 1H), 7.53 (dd, J=8.1, 1.3 Hz, 1H), 7.34 (td, J=7.8, 1.2 Hz, 1H), 7.01 (dt?ddd, J=6.1 Hz, J=8.0 Hz, J=1.5 Hz, 1H), 6.22 (bs, 1H), 3.40 (dt, J=5.9, 7.2 Hz, 2H), 1.65-1.35 (m, 4H), 0.96 (td, J=7.3, 1.9 Hz, 3H). MS APCI, m/z=323/325 (M+H). HPLC 2.94 min
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:29](=[O:30])[CH2:28][C@@H:27]6[NH:31][C@@H:24]([CH2:25][CH2:26]6)[CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:37][C:38]([CH3:40])=O>>[CH3:35][N:34]([CH3:36])[C:32]([C:7]1[N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[C:29](=[O:30])[CH2:28][C@@H:27]5[N:31]([CH:38]([CH3:40])[CH3:37])[C@@H:24]([CH2:25][CH2:26]5)[CH2:23]4)=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=1)=[O:33]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@@H]5CC[C@H](CC4=O)N5)cn3)nc2n1C1CCCC1
Reactant: CC(C)=O
Product: CC(C)N1[C@@H]2CC[C@H]1CN(c1ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc1)C(=O)C2
Yield: 86.4 %

Procedure:
Following general reductive alkylation method 1, 7-Cyclopentyl-N,N-dimethyl-2-(5-((1S,6R)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (65 mg, 0.133 mmol) was combined with acetone (0.05 mL, 0.665 mmol) which gave 7-cyclopentyl-2-[5-((1S,6R)-9-isopropyl-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (61 mg) in 86% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.67 (s, 1H), 8.44 (d, J=8.59 Hz, 1H), 8.12 (s, 1H), 8.08 (d, J=2.53 Hz, 1H), 7.46 (dd, J=8.59, 2.53 Hz, 1H), 6.38 (s, 1H), 4.73 (t, J=9.09 Hz, 1H), 4.24 (d, J=14.65 Hz, 1H), 3.59 (m, 2H), 3.21 (br. s., 1H), 3.08 (m, 7H), 2.97 (br. s., 1H), 2.53 (m, 3H), 1.95 (m, 6H), 1.66 (m, 3H), 1.07 (t, J=5.81 Hz, 6H).
Reaction SMILES: [C:1]([C:3]1[C:8](=O)[NH:7][C:6]([C:10]2[CH:21]=[CH:20][C:13]([C:14]([O:16]C(C)C)=[O:15])=[CH:12][CH:11]=2)=[CH:5][C:4]=1[S:22][CH3:23])#[N:2].P(Cl)(Cl)([Cl:26])=O.CN(C=O)C.Cl>O>[Cl:26][C:8]1[N:7]=[C:6]([C:10]2[CH:21]=[CH:20][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH:5]=[C:4]([S:22][CH3:23])[C:3]=1[C:1]#[N:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1cc(-c2ccc(C(=O)OC(C)C)cc2)[nH]c(=O)c1C#N
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(-c2ccc(C(=O)O)cc2)nc(Cl)c1C#N
Temperature: 110 °C
Yield: 97.7 %

Procedure:
A suspension of isopropyl 4-(5-cyano-4-(methylthio)-6-oxo-1,6-dihydropyridin-2-yl)benzoate (1.6 g, 4.87 mmol) in phosphoryl trichloride (14.94 g, 97 mmol) was heated to 110° C. for 60 h, cooled to room temperature and carefully added to cold water (50 mL). The resultant mixture was carefully quenched with saturated. NaHCO3(200 mL), and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4) and concentrated to give a mixture of acid and ester. The material was treated with DMF (10 ml) and 6 N HCl (10 ml), heated to 100° C. for 1 h, cooled to room temperature and diluted with water (50 ml) and filtered. The solid was washed with water (10 ml), dried under vacuum to give 4-(6-chloro-5-cyano-4-(methylthio)pyridin-2-yl)benzoic acid (1.45 g. 70% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (2H, d, J=8.53 Hz), 8.10 (2H, d, J=8.53 Hz), 7.95 (1H, s), 2.87 (3H, s); MS (ES+) m/z: 305 (M+H); LC retention time: 3.45 min (analytical HPLC Method A).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([C@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[CH:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[OH:28][C:29]([CH3:36])([CH3:35])[C:30]#[C:31][C:32](O)=[O:33]>>[NH2:22][C:20]1[C:21]2[C:13]([C:12]#[C:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)=[CH:14][N:15]([C@H:23]3[CH2:27][CH2:26][N:25]([C:32](=[O:33])[C:31]#[C:30][C:29]([OH:28])([CH3:36])[CH3:35])[CH2:24]3)[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: COc1cc(C#Cc2cn([C@H]3CCNC3)c3ncnc(N)c23)cc(OC)c1
Reactant: CC(C)(O)C#CC(=O)O
Product: COc1cc(C#Cc2cn([C@H]3CCN(C(=O)C#CC(C)(C)O)C3)c3ncnc(N)c23)cc(OC)c1

Procedure:
In accordance with Example 4 (Step 1), except that (S)-5-((3,5-dimethoxyphenyl)ethynyl)-7-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (i.e., the intermediate obtained in Example 38 (Step 4)) and 4-hydroxy-4-methylpent-2-ynoic acid were used, the title compound was obtained as a colorless, amorphous substance. Table 1 shows the physical properties thereof.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[C:10]([N:12]([OH:14])[CH3:13])=[NH:11].[C:20]([C:27]([O:29][CH2:30][CH3:31])=[O:28])#[C:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(O)C>[CH2:30]([O:29][C:27]([C:20]1([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:14][N:12]([CH3:13])[C:10]([C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=2[N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][S:2]2(=[O:1])=[O:19])=[N:11]1)=[O:28])[CH3:31]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: CN(O)C(=N)c1ccccc1N1CCCCS1(=O)=O
Solvent: CCO
Product: CCOC(=O)CC1(C(=O)OCC)N=C(c2ccccc2N2CCCCS2(=O)=O)N(C)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a stirred solution of 2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-N-hydroxy-N-methyl-benzamidine (3.5 g) in ethanol (100 mL, 200 proof) was added diethyl acetylene-dicarboxylate (3.2 mL, 20 mmol) and the resulting mixture stirred at room temperature for 30 min. The mixture was concentrated and purified on a silica gel column (10%–30% ethyl acetate/hexanes) to afford the title compound as a yellow oil (3.62 g, 40% yield). 1HNMR (300 MHz, CDCl3) δ: 7.57 (2H, td, J=7.14, 1.28 Hz,), 7.50 (1H, td, J=7.68, 1.83 Hz), 7.39 (1H, td, J=7.50, 1.46 Hz), 4.34–4.22 (2H, m), 4.18 (2H, q, J=7.08 Hz), 3.42 (1H, d, J=16.47 Hz), 3.22–3.18 (2H, m), 3.07 (3H, s), 3.05 (1H, d, J=16.46 Hz), 2.38–2.24 (2H, m), 2.00–1.42 (2H, m), 1.33 (3H, t, J=7.14 Hz), 1.26 (3H, t, J=7.14 Hz). HRMS calcd for C20H28SN3O7 (M+H): 454.1648; found: 454.1650.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:28](I)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:19]2[N:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][N:24]=2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCI
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(CC)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
2-[(4-{2-[(5-Ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (8.90 g) synthesized in Example 265-1 and heptyl iodide (5.92 g) were dissolved in N,N-dimethylformamide (100 mL), potassium tert-butoxide (2.94 g) was added thereto, and the mixture was stirred at room temperature for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=7:1) to give the title compound (6.20 g) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([C:26]2([CH2:30][C:31]#[N:32])[CH2:29][NH:28][CH2:27]2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33](=O)[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([C:26]2([CH2:30][C:31]#[N:32])[CH2:29][N:28]([CH2:33][CH3:34])[CH2:27]2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CNC5)n4)n3Cc3ccccc3)n12
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CC(CC#N)(n2ccc(-c3cc4c(ccc5nnc(C)n54)n3Cc3ccccc3)n2)C1

Procedure:
Prepared by the method of Example 93, using {3-[3-(6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (8.5 mg, 0.020 mmol, from Example 90) in DCM (0.4 mL), and acetaldehyde (5.6 μL, 0.10 mmol, Aldrich), followed by sodium triacetoxyborohydride (13 mg, 0.060 mmol). Yield: (6.7 mg, 74%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.Br.Br.[C:24]12[CH2:31][NH:30][CH2:29][C:28]=1[CH2:27][NH:26][CH2:25]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([N:26]4[CH2:27][C:28]5[CH2:29][NH:30][CH2:31][C:24]=5[CH2:25]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: C1NCC2=C1CNC2
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4=C(CNC4)C3)c(F)c(F)c2c1=O
Reaction time: 8 h
Yield: 74.4 %

Procedure:
0.6 g of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1.2 g of 3,7-diazabicyclo[3.3.0]oct-1(5)-ene dihydrobromide and 1.3 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were suspended in 20 ml of acetonitrile, and then the reaction mixture was refluxed for 10 hours. This reaction mixture was kept overnight at the room temperature, and the produced precipitate was filtered and then the residue was washed with ethanol to obtain 0.58 g the title compound (yield 74%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13]O.S(Cl)([Cl:17])=O>ClCCl.O>[Cl:17][CH2:13][C:3]1[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][O:6][C:2]=1[CH3:1]
Reactant: O=S(Cl)Cl
Reactant: Cc1onc(-c2ccccc2)c1CO
Solvent: ClCCl
Solvent: O
Product: Cc1onc(-c2ccccc2)c1CCl
Temperature: 0 °C
Reaction time: 2 h
Yield: 9.4 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (4.5 g, 236 mmol) in dichloromethane (50 mL) was added at 0° C. thionyl chloride (3.6 g, 2.7 mL, 306 mmol) dropwise over 3 min and the solution stirred at 0° C. for 2 h. After this time, the mixture was diluted with water (50 mL) and the organic phase separated and washed with brine. The aqueous phase was extracted with dichloromethane and the combined extracts dried over sodium sulfate, filtered and evaporated to afford the title compound (4.6 g, 93%) which was obtained as a light brown liquid. MS: m/e=208.1 [M+H]+.