Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH3:26])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[N:10]3[N:9]=2)[CH:7]=1.[F:27][C:28]([F:40])([F:39])[S:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1>O1CCCC1>[CH2:19]([CH:18]([C:17]1[N:10]2[C:11]([C:12](=[O:14])[NH:13][C:8]([C:6]3[CH:7]=[C:2]([NH:1][C:37]([NH:36][C:33]4[CH:34]=[CH:35][C:30]([S:29][C:28]([F:39])([F:27])[F:40])=[CH:31][CH:32]=4)=[O:38])[CH:3]=[CH:4][C:5]=3[O:24][CH2:25][CH3:26])=[N:9]2)=[C:15]([CH3:23])[N:16]=1)[CH2:21][CH3:22])[CH3:20]
Reactant: O=C=Nc1ccc(SC(F)(F)F)cc1
Reactant: CCOc1ccc(N)cc1-c1nn2c(C(CC)CC)nc(C)c2c(=O)[nH]1
Solvent: C1CCOC1
Product: CCOc1ccc(NC(=O)Nc2ccc(SC(F)(F)F)cc2)cc1-c1nn2c(C(CC)CC)nc(C)c2c(=O)[nH]1

Procedure:
Analogously to the procedure of example 54, 230 mg (0.647 mmol) of the amino compound from example 48A are reacted with 284 mg (1.29 mmol) of 4-(trifluoromethylthio)phenyl isocyanate in 20 ml of tetrahydrofuran for 4 hours. The crude product is purified by silica gel chromatography using toluene and ethyl acetate as mobile phase.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12](=[O:19])[CH2:13][O:14][CH2:15][CH2:16][CH:17]=[CH2:18])[CH3:10].[CH3:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([CH3:44])[C:28]=1[O:29][CH2:30][CH2:31][C:32]1[N:33]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:35][C:36]=1[CH3:37])[CH:24]=[O:25]>C1COCC1>[CH2:9]([O:11][C:12](=[O:19])[CH:13]([O:14][CH2:15][CH2:16][CH:17]=[CH2:18])[CH:24]([C:23]1[CH:22]=[C:21]([CH3:20])[C:28]([O:29][CH2:30][CH2:31][C:32]2[N:33]=[C:34]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[O:35][C:36]=2[CH3:37])=[C:27]([CH3:44])[CH:26]=1)[OH:25])[CH3:10]
Reactant: Cc1cc(C=O)cc(C)c1OCCc1nc(-c2ccccc2)oc1C
Reactant: C=CCCOCC(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCCOC(C(=O)OCC)C(O)c1cc(C)c(OCCc2nc(-c3ccccc3)oc2C)c(C)c1
Reaction time: 0.17 h
Yield: 42.1 %

Procedure:
To a stirred 2 M solution of LDA in THF (0.38 ml, 0.76 mmol) was added a cooled (−78° C.) solution of but-3-enyloxy-acetic acid ethyl ester (120 mg, 0.76 mmol) in THF (3 ml) at −78° C. (for the preparation of but-3-enyloxy-acetic acid ethyl ester see: A. F. Noels, A. Demonceau, N. Petiniot, A. J. Hubert, P. Teyssié, Tetrahedron 1982, 38, 2733-2739). The solution was stirred for 10 min and then a solution of 3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde (254 mg, 0.76 mmol, example 117) in THF (3 ml) was added. The reaction mixture was stirred 30 min at −78° C. and then quenched by the addition of sat. NH4Cl at −78° C. The solution was diluted with water and ethyl acetate, the layers were separated and the aqueous phase was extracted two times with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent gave a yellow oil which was purified by column chromatography (silica gel, hexane/AcOEt=9/1) to give 160 mg (0.32 mmol, 43%) of the title compound as a mixture of diastereomers as colorless oil.
Reaction SMILES: [BH4-].[Na+].[I-].[CH3:4][C:5]([CH3:21])=[CH:6][CH2:7][O:8][C:9]1[C:10]([C:14]2[CH:15]=[N+:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[N:11][S:12][N:13]=1>C(O)C>[CH3:4][C:5]([CH3:21])=[CH:6][CH2:7][O:8][C:9]1[C:10]([C:14]2[CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][CH:19]=2)=[N:11][S:12][N:13]=1
Reactant: CC(C)=CCOc1nsnc1-c1ccc[n+](C)c1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)=CCOc1nsnc1C1=CCCN(C)C1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (220 mg, 6 mmol) was added to a solution of 3-(4-(3-methyl-2-butenyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (0.92 g, 2.3 mmol) in ethanol (99.9%, 15 ml) and the reaction mixture was stirred at -10° C. for 0.5 h. After evaporation the residue was dissolved solved in water and extracted with ethyl acetate. The dried organic phases were evaporated and the residue purified by column chromatography (Si02, eluent: ethyl acetate/methanol (4:1)). The title compound was crystallized as the oxalate salt from acetone to yield 380 mg. (M.p. 150°-151° C.; M+ : 265; Compound 27).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.CC(C)([O-])C.[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]3[CH:17]=[C:16]([N:18]4[CH2:19][C@H:20]([CH3:25])[NH:21][C@H:22]([CH3:24])[CH2:23]4)[CH:15]=[CH:14][C:13]=3[O:26][CH3:27])(=[O:10])=[O:9])=[CH:6][CH:7]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2cccc(Cl)c2)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (E106) (75 mg, 0.17 mmol) and (3-chlorophenyl)boronic acid (56 mg, 0.36 mmol) in DME (3 ml) was added potassium tert-butoxide (180 mg, 1.60 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then evaporated in vacuo and purified using an SCX cartridge eluting with methanol followed by ammonia (2M in methanol). The appropriate fractions were combined and evaporated in vacuo and the residue purified further by mass directed autoprep HPLC to afford the title compound (E111). MS (ES+) m/e 486/488 [M+H]+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:15]4[N:16]=[C:17](S(C)(=O)=O)[N:18]=[CH:19][C:14]=4[C:13](=[O:24])[C:12]([C:25]([NH2:27])=[O:26])=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[C:38]([NH2:42])[CH:39]=[CH:40][CH:41]=2)[CH2:31][CH2:30]1>CC(O)C>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:15]4[N:16]=[C:17]([NH:42][C:38]5[CH:39]=[CH:40][CH:41]=[C:36]([CH2:35][N:32]6[CH2:31][CH2:30][N:29]([CH3:28])[CH2:34][CH2:33]6)[CH:37]=5)[N:18]=[CH:19][C:14]=4[C:13](=[O:24])[C:12]([C:25]([NH2:27])=[O:26])=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ncc2c(=O)c(C(N)=O)cn(-c3ccc4c(c3)CCC4)c2n1
Reactant: CN1CCN(Cc2cccc(N)c2)CC1
Solvent: CC(C)O
Product: CN1CCN(Cc2cccc(Nc3ncc4c(=O)c(C(N)=O)cn(-c5ccc6c(c5)CCC6)c4n3)c2)CC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a suspension of 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (from Example 23 (b), 7 mg) in 1 mL of i-PrOH was added 3-(4-methyl-piperazin-1-ylmethyl)-phenylamine (5 mg). The mixture was stirred at 90° C. for 1 hr. After cooling down, the solvent was evaporated and the product was purified chromatographically (CH2Cl2/CH3OH/NH4OH (10:1:0.1, v/v)). The title compound was obtained as white solid (2.7 mg, 29%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.39 (br, 1H), 9.34 (s, 1H), 8.76 (s, 1H), 7.48 (br, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.29 (br, 1H), 7.17 (s, 1H), 7.12 (d, J=8.0 Hz, 1H), 6.94 (br, 2H), 5.67 (br, 1H), 3.29 (br, 2H), 3.00 (t, J=7.3 Hz, 2H), 2.92 (t, J=7.3 Hz, 2H), 2.49 (br, 7H), 2.33 (br, 4H), 2.15 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H31N7O2: 510.25 (M+H), Found: 510.1.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][O:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([N+:30]([O-:32])=[O:31])[CH:24]=2)=[CH:19][CH:18]=1)=[O:16].COC(=O)C1C=CC(O[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]CCCCCCCC)=CC=1>CCOCC>[CH3:13][O:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C@@H:44]([CH3:43])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[C:25]([N+:30]([O-:32])=[O:31])[CH:24]=2)=[CH:21][CH:22]=1)=[O:16]
Reactant: COC(=O)c1ccc(-c2ccc(O)c([N+](=O)[O-])c2)cc1
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CCOCC
Product: CCCCCCCC[C@H](C)Oc1ccc(-c2ccc(C(=O)OC)cc2)cc1[N+](=O)[O-]
Yield: 66 %

Procedure:
DEAD (323 mg, 1.85 mmol), phenol 40 (440 mg, 1.61 mmol), R-2-decanol (268 mg, 1.69 mmol), and TPP (486 mg, 1.85 mmol) in 16 ml anhydrous ether were reacted according to the procedure for compound 35a. The crude product was concentrated and purified via flash chromatography over silica gel with gradual elutions from 95/5 to 65/35 (Hex/EtOAc). Evaporation of the solvent yielded 439 mg (66%) of a yellow solid.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH:4]([CH3:6])[CH3:5].[NH2:8][C:9]([NH2:11])=[S:10]>CCO>[CH:4]([C:3]1[N:8]=[C:9]([NH2:11])[S:10][CH:2]=1)([CH3:6])[CH3:5]
Reactant: CC(C)C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: CC(C)c1csc(N)n1
Yield: 91.4 %

Procedure:
1-Bromo-3-methyl-butan-2-one (10.5 g, 64 mmol, prepared as described in Org. Syn. Coll. Vol. 6, p. 193 (1988)) was added to a stirring slurry of thiourea (4.601 g, 60 mmol) in 20 mL EtOH. The reaction mixture was heated to reflux for 90 minutes, then cooled and concentrated under reduced pressure. The residue was dissolved in water, and the resulting solution was diluted with concentrated aqueous NaOH until pH was adjusted to about 12. The mixture was extracted with diethel ether, and the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to give 4-isopropyl-thiazol-2-ylamine (7.8 g) as an oil.
Reaction SMILES: ClC1C=CC(OS([N:10]=C=O)(=O)=O)=CC=1.[O:15]=[C:16]1[C:21]2[CH:22]=[C:23]3[C:28](=[C:29]([CH2:30][CH2:31][CH3:32])[C:20]=2[O:19][C:18]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:17]1)[NH:27][C:26]([C:33]([O:35][CH3:36])=[O:34])=[CH:25][C:24]3=O.Cl>C(#N)C>[NH2:10][C:24]1[C:23]2[C:28](=[C:29]([CH2:30][CH2:31][CH3:32])[C:20]3[O:19][C:18]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:17][C:16](=[O:15])[C:21]=3[CH:22]=2)[N:27]=[C:26]([C:33]([O:35][CH3:36])=[O:34])[CH:25]=1
Reactant: CCCc1c2[nH]c(C(=O)OC)cc(=O)c2cc2c(=O)cc(C(=O)OCC)oc12
Reactant: O=C=NS(=O)(=O)Oc1ccc(Cl)cc1
Agent: Cl
Solvent: CC#N
Product: CCCc1c2nc(C(=O)OC)cc(N)c2cc2c(=O)cc(C(=O)OCC)oc12

Procedure:
4-Chlorophenoxysulphonylisocyanate (0.2 ml, 290 mg) was added to a suspension of ethyl 6,9-dihydro-4,6-dioxo-8-methoxycarbonyl-10-propyl-4H-pyrano[3,2-g] quinoline-2-carboxylate (385 mg, 1 mmol) in acetonitrile (5 ml), and then refluxed for 0.5 h. The solution was allowed to cool, ethanolic hydrogen chloride solution (2 ml) was added, and after 5 minutes the pale yellow solution was poured into aqueous ammonial solution (0.88 specific gravity, 5 ml) at 5° C., to give a thick orange precipitate. Filtration and washing with ethanol (10 ml) gave the title compound, 320 mg (83%) as an orange powder, mp 268°-270° C. (decomposes).
Reaction SMILES: [CH2:1]([O:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]1[C:16](=[O:17])[N:15]2[CH:18]=[N:19][C:20]([C:21](Cl)=[O:22])=[C:14]2[N:13]=[N:12]1>C1COCC1.O>[CH2:1]([O:8][NH:9][C:21]([C:20]1[N:19]=[CH:18][N:15]2[C:16](=[O:17])[N:11]([CH3:10])[N:12]=[N:13][C:14]=12)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOCc1ccccc1
Reactant: Cn1nnc2c(C(=O)Cl)ncn2c1=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1nnc2c(C(=O)NOCc3ccccc3)ncn2c1=O
Reaction time: 0.5 h
Yield: 63 %

Procedure:
O-benzylhydroxylamine (195 μL, 1.68 mmol, 2 eq.) was added to a solution of crude 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl chloride (200 mg, 0.84 mmol; see Arrowsmith et al., J. Med. Chem., 2002, Vol. 45, No. 25, p. 5458) in THF (6 mL) and a precipitate formed instantly. The resulting suspension was stirred for 1 hour and 30 minutes and was then poured into ice. The suspension was diluted with water and the precipitate was filtered and washed successively with water, ethyl acetate and diethyl ether to give 158 mg of the pure title compound as an off-white solid (63% yield). δH (DMSO-d6): 11.9 (1H, s), 8.85 (1H, s), 7.42-7.50 (2H, m), 7.36-7.42 (3H, m), 4.96 (2H, s), 3.88 (3H, s).
Reaction SMILES: CN(C)C=O.Cl[C:7]([O:9][CH2:10][CH3:11])=[O:8].[O:12]=[C:13]1[N:18]2[C:19]3[C:24]([NH:25][CH2:26][C:17]2=[N:16][CH:15]=[C:14]1[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=[CH:21][CH:20]=3>O>[O:12]=[C:13]1[N:18]2[C:19]3[C:24]([N:25]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:26][C:17]2=[N:16][CH:15]=[C:14]1[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=[CH:21][CH:20]=3
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1cnc2n(c1=O)-c1ccccc1NC2
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2n(c1=O)-c1ccccc1N(C(=O)OCC)C2
Reaction time: 8 h
Yield: 39.5 %

Procedure:
4 ml of dry dimethylformamide were saturated with nitrogen for 10 minutes before 150 mg of ethyl chloroformate and 280 mg of ethyl 5,6-dihydro-1-oxo-1H-pyrimido [1,2-a] quinoxaline-2-carboxylate were added thereto. The solution obtained was left at room temperature overnight and then was poured into water. The mixture was extracted with ethyl acetate and the organic phase was dried over MgSO4 and evaporated to dryness. The residue was chromatographed over silica gel and eluted with ethyl acetate to obtain 140 mg (41% yield) of diethyl 5,6-dihydro-1-oxo-1H-pyrimido [1,2-a] quinoxaline-2,6-dicarboxylate melting at 140°-2° C.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([O:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: COc1ccc(O)cc1
Product: CCCCOC(=O)c1nc(Oc2ccc(OC)cc2)c2ccccc2c1O

Procedure:
Synthesized from 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and 4-methoxy-phenol in analogy to Example D-20 d); MS-(+)-ion: M+1=368.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1.[NH2:31][C@H:32]1[CH2:37][CH2:36][CH2:35][C@@H:34]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:33]1>C1COCC1>[F:20][C:14]1[C:15]([NH:31][C@H:32]2[CH2:37][CH2:36][CH2:35][C@@H:34]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:43])([CH3:42])[CH3:44])[CH2:33]2)=[N:16][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:9]=2)=[N:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(F)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H](N)C1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](NC(=O)OC(C)(C)C)C4)n3)c3cc(F)cnc32)cc1
Temperature: 50 °C

Procedure:
5-fluoro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 44c, (5.9 g, 10.5 mmol) and tert-butyl N-[(1R,3S)-3-aminocyclohexyl]carbamate (3 g, 12.60 mmol) were dissolved in THF (100 mL). The reaction mixture was heated to 50° C. for 6 hours, then cooled to room temperature. Celite was added and the solvent was removed under reduced pressure. The Celite-supported residue was purified by silica gel chromatography (20-80% EtOAc/hexanes gradient to provide 3.7 g of tert-butyl N-[(1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]carbamate.
Reaction SMILES: CO.C([O:5][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[S:13][C:14]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([F:23])[C:15]=2[N:16]=1)C.[OH-].[Na+]>O>[F:23][C:17]1[C:15]2[N:16]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:24])=[O:5])[S:13][C:14]=2[C:20]([F:21])=[CH:19][C:18]=1[F:22]
Reactant: CCOC(=O)CCCCCc1nc2c(F)c(F)cc(F)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
To methanol (3 ml) was added 6-(4,5,7-trifluorobenzothiazol-2-yl)hexanoic acid ethyl ester (390 mg, 1.18 mmol) and aqueous 2N sodium hydroxide (0.7 ml, 1.4 mmol) and the mixture was stirred at room temperature for 1 hour. The resultant reaction mixture was diluted with water and washed with ether. The aqueous phase was acidified with 7% hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried and then evaporated to yield a residue, which was crystallized from hexane-isopropyl ether to give 6-(4,5,7-trifluorobenzothiazol-2-yl)hexanoic acid (170 mg, 48%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH:10]=[N:9][C:8](SC)=[N:7][C:6]=2[N:5]([CH3:14])[C:4](=[O:15])[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.Cl.[F:28][C:29]1([F:36])[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([NH:35][CH:32]3[CH2:33][CH2:34][C:29]([F:36])([F:28])[CH2:30][CH2:31]3)=[N:7][C:6]=2[N:5]([CH3:14])[C:4](=[O:15])[CH:3]=1
Reactant: CSc1ncc2c(N)cc(=O)n(C)c2n1
Reactant: NC1CCC(F)(F)CC1
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1c(=O)cc(N)c2cnc(NC3CCC(F)(F)CC3)nc21
Reaction time: 1 h
Yield: 24.2 %

Procedure:
To a solution of 5-amino-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (163 mg, 0.733 mmol) in DCM (200 mL) was added 3-chloroperoxybenzoic acid (77% max., 164 mg, 0.733 mmol) at RT and the resulting mixture was stirred for 1 h. The reaction mixture was then evaporated under reduced pressure and the residue was dissolved in anhydrous dimethyl sulfoxide (7.3 mL). To a portion of this solution (1.8 mL) was added TEA (0.13 mL, 0.90 mmol), followed by 4,4-difluorocyclohexylamine hydrochloride (62 mg, 0.36 mmol) at RT. The reaction mixture was stirred at 80° C. for 4.5 h and was then quenched with water. The resulting mixture was extracted twice with EtOAc (20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (from 0 to >10% of MeOH/DCM in 10 min.) to give 27 mg (49% yield) of 5-amino-2-(4,4-difluoro-cyclohexylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid. MS=310 [M+H]+.
Reaction SMILES: C(OC([N:8]1[C@H:12]([C:13](O)=O)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.[NH2:18][C:19]1[CH:20]=[C:21]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[CH:22]=[CH:23][C:24]=1[NH2:25]>>[NH2:8][C@H:12]([C:13]1[NH:25][C:24]2[CH:23]=[CH:22][C:21]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=3)=[CH:20][C:19]=2[N:18]=1)[CH2:11][OH:10]
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)O)COC1(C)C
Reactant: N#Cc1ccc(-c2ccc(N)c(N)c2)cc1
Product: N#Cc1ccc(-c2ccc3[nH]c([C@@H](N)CO)nc3c2)cc1

Procedure:
The title compound was prepared according to Method 1 using (S)-3-(tert-butoxycarbonyl)-2,2-dimethyloxazolidine-4-carboxylic acid and 3′,4′-diaminobiphenyl-4-carbonitrile (Preparation 82). The residue was purified through an SCX cartridge followed by reverse phase column chromatography eluting with 0-60% MeCN in water.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[CH3:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=1)[C:31](O)=[O:32]>>[CH3:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=1)[C:31]([NH:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2)=[O:32]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Reactant: Cc1cc(C(=O)O)ccn1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2ccnc(C)c2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-methyl-isonicotinic acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH:3]=1.C([O-])(=O)C.[Na+].[I:30]Cl>C(O)(=O)C.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[C:3]=1[I:30]
Reactant: ClI
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)cc(N)c2F)c1F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)c(I)c(N)c2F)c1F
Temperature: 80 °C
Yield: 42.3 %

Procedure:
Propan-2-yl 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate (600 mg, 1.682 mmol) was dissolved in acetic acid (5.6 mL). Sodium acetate (1.5 g, 18.50 mmol) was added followed by iodine monochloride (2.2 g, 13.45 mmol). An exotherm of approximately 10° C. was observed during the addition. The reaction mixture was heated at 80° C. for 20 h. The reaction mixture was then diluted with water and extracted with EtOAc. The organic layer was washed with water, satd aq NaHCO3 solution, dried (MgSO4) and then concentrated to dryness. The residue was applied to a silica gel column (80 g) then eluted (0-70% acetone-hexanes gradient) to give an orange solid (343 mg, 42%): mp 134-135° C.; 1H NMR (400 MHz, acetone-d6) δ 7.41 (dd, J=8.5, 1.6 Hz, 1H), 7.33 (dd, J=8.5, 6.8 Hz, 1H), 6.29 (s, 2H), 5.29-5.14 (septet, 1H), 3.98 (d, J=1.1 Hz, 3H), 1.37 (d, J=6.3 Hz, 6H); EIMS m/z 396.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([CH3:21])=[N:11][C:12]([O:16][CH2:17][C:18]([OH:20])=O)=[N:13][C:14]=1[CH3:15])=O)(C)(C)C.[CH3:22][NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[CH2:26][CH2:25]1>>[NH2:8][C:9]1[C:14]([CH3:15])=[N:13][C:12]([O:16][CH2:17][C:18]([N:23]([CH3:22])[CH:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:33][CH:32]=3)[CH2:26][CH2:25]2)=[O:20])=[N:11][C:10]=1[CH3:21]
Reactant: Cc1nc(OCC(=O)O)nc(C)c1NC(=O)OC(C)(C)C
Reactant: CNC1CCN(Cc2ccc(C(F)(F)F)cc2)CC1
Product: Cc1nc(OCC(=O)N(C)C2CCN(Cc3ccc(C(F)(F)F)cc3)CC2)nc(C)c1N

Procedure:
The title compound was synthesized from Compound 9 and N-methyl-1-(4-(trifluoromethyl)benzyl)-piperidine-4-amine in the same manner as in Example 64 and recrystallized from methylene chloride.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[NH2:9][NH2:10].O>C(O)C>[CH:2]([C:3]1[CH:4]=[C:5]([NH2:6])[NH:10][N:9]=1)([CH3:8])[CH3:1]
Reactant: NN
Reactant: CC(C)C(=O)CC#N
Solvent: O
Solvent: CCO
Product: CC(C)c1cc(N)[nH]n1

Procedure:
A solution of 4-methyl-3-oxopentanenitrile (Compound [CCLX]) (8.8 g, 79.2 mmol, 1.00 equiv) and NH2NH2.H2O (80%, 7.5 g, 120 mmol, 1.50 equiv) in ethanol (300 mL) was heated to reflux for 1 h under nitrogen. After removed the solvent under vacuum, the residue was loaded onto a silica gel column with dichloromethane/methanol as an eluent to give Compound [CCLXI] as a yellowish oil: LC-MS m/e 126 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 5.17 (s, 1H), 2.75 (septet, J=6.9 Hz, 1H), 1.14 (d, J=6.9 Hz, 6H).