Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][C:11]([OH:13])=[O:12].S(=O)(=O)(O)O.[CH3:19]O>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][C:11]([O:13][CH3:19])=[O:12]
Reactant: O=C(O)Cc1cc2ccccc2o1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc2ccccc2o1

Procedure:
Benzofurane-2-acetic acid 4 (305 g, 1.73 mol) was dissolved in methanol (1,000 ml) and concentrated sulfuric acid (20 ml). The mixture, which was originally a suspension, was stirred at reflux for 120 minutes. Half of the methanol was distilled off and a mixture consisting of water, KOH, and ethyl acetate (2,000 ml/65 g/1,000 ml) was added. After mixing well, the organic layer was allowed to separate and was isolated. The aqueous phase was extracted once more with ethyl acetate (500 ml) and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The crude product was a reddish oil weighing 316 g, which was purified by flash vacuum distillation at 0.1 mm Hg (bp 80-90° C.). The yield of distilled product, a colorless oil, was 288 g (1.51 mol, 86%). Anal. (C11H10O3) C, H: calculated 69.46, 5.30; found 69.49, 5.36.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[C:9]([CH3:12])[C:10]=1[NH2:11])=[O:4].[N:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1>N1C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[C:9]([CH3:12])[C:10]=1[NH:11][S:32]([C:29]1[CH:28]=[CH:27][C:26]([O:25][C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)=[CH:31][CH:30]=1)(=[O:33])=[O:34])=[O:4]
Reactant: COC(=O)c1cc(-c2ccccc2)cc(C)c1N
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccncc2)cc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2)cc(C)c1NS(=O)(=O)c1ccc(Oc2ccncc2)cc1
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a solution of 1.43 g (5.93 mmol) of the product of Example 40 in 20 mL of pyridine was added 1.98 g (6.52 mmol) 4-(pyridin-4-yloxy)-benzenesulfonyl chloride and the reaction was stirred overnight. Additional 4-(pyridin-4-yloxy)-benzenesulfonyl chloride (0.5 g, 1.6 mmol) was added twice over the next two days. The reaction was then diluted with water and extracted three times with dichloromethane. The organics were combined, washed with brine, dried over Na2SO4, concentrated in vacuo and chromatographed on silica gel using gradient elution (100% hexane to 100% ethyl acetate) to provide 5-methyl-4-[4-(pyridin-4-yloxy)-benzenesulfonylamino]-biphenyl-3-carboxylic acid methyl ester 2.54 g (90%) as a white solid. Electrospray Mass Spec: 475.2 (M+H)+
Reaction SMILES: [Si](O[CH2:9][C@@H:10]([N:17]([CH3:30])[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[F:29])=[O:19])[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])(C(C)(C)C)(C)C.Cl>CO>[F:29][C:23]1[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][NH:20][C:18](=[O:19])[N:17]([C@@H:10]([CH3:9])[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH3:30]
Reactant: COC(=O)CC[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)NCc1cccc(F)c1F
Agent: Cl
Solvent: CO
Product: COC(=O)CC[C@H](C)N(C)C(=O)NCc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a solution of (S)-methyl 5-(tert-butyldimethylsilyloxy)-4-(3-(2,3-difluorobenzyl)-1-methylureido)pentanoate (9.7 g, 21.6 mmol) in MeOH (40 mL) was added HCl (4 N in dioxane, 5.4.0 mL, 21.6 mmol). The resulting solution was stirred at RT for 1 h. The mixture was concentrated and re-dissolved in EtOAc. The organic mixture was washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (S)-methyl 4-(3-(2,3-difluorobenzyl)-1-methylureido)pentanoate (6.84 g, crude) as a white solid, which was used without further purification. LRMS (M+H+)/m/z 331.2.
Reaction SMILES: CN(C=[N:5][S:6]([CH2:9][C:10]([CH2:14][CH3:15])([CH3:13])[CH2:11][OH:12])(=[O:8])=[O:7])C.Cl[C:17]1[C:18]([CH3:26])=[CH:19][C:20]2[N:21]([N:23]=[CH:24][N:25]=2)[N:22]=1>>[CH2:14]([C:10]([CH3:13])([CH2:9][S:6](=[O:7])(=[O:8])[NH2:5])[CH2:11][O:12][C:17]1[C:18]([CH3:26])=[CH:19][C:20]2[N:21]([N:23]=[CH:24][N:25]=2)[N:22]=1)[CH3:15]
Reactant: Cc1cc2ncnn2nc1Cl
Reactant: CCC(C)(CO)CS(=O)(=O)N=CN(C)C
Product: CCC(C)(COc1nn2ncnc2cc1C)CS(N)(=O)=O

Procedure:
Using 3-(N,N-dimethylaminomethylene)aminosulfonyl-2-ethyl-2-methyl-1-propanol and 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction as in Example 6 was conducted to produce the title compound. m.p. 189°-190° C.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]([C@@H:41]([CH3:49])[CH:42]([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45])[C:8](=[O:40])[C@@H:9]([NH:22]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][CH:12]=2)[C:3]2[CH:50]=[CH:51][CH:52]=[CH:53][C:2]1=2.N1CCCCC1>>[NH2:22][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[CH:13][CH:12]=1)[C:8]([N:7]([CH2:6][C:4]1[C:3]2[CH:50]=[CH:51][CH:52]=[CH:53][C:2]=2[S:1][CH:5]=1)[C@@H:41]([CH3:49])[CH:42]([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45])=[O:40]
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Yield: 97.2 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (9H-fluoren-9-yl)methyl(S)-1-((benzo[b]thiophen-3-ylmethyl)((S)-1,1-diethoxypropan-2-yl)amino)-3-(4-tert-butoxyphenyl)-1-oxopropan-2-ylcarbamate (Compound III-10) (500 mg, 0.68 mmol) was treated with piperidine and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound (339 mg, 98%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(N(CC)CC)C.Cl.[F:12][C:13]([F:47])([F:46])[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:17]=[C:16]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([C:36]3[CH:37]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=3)[CH:31]=2)[N:15]=1>C1COCC1>[CH3:1][N:2]([CH3:3])[S:42]([C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([C:32]2[CH:31]=[C:30]([C:16]3[N:15]=[C:14]([C:13]([F:12])([F:46])[F:47])[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=4)[N:17]=3)[CH:35]=[CH:34][N:33]=2)[CH:37]=1)(=[O:43])=[O:44]
Reactant: CNC
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 90.5 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of dimethylamine solution (60% in water) (0.27 ml, 3.21 mmol), triethylamine (0.29 ml, 2.1 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.58 g, 1.0 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.5 g, 97%). MS (ISP) 552.7 [(M+H)+]; mp 225° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9](=[O:19])[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][N:14]=3)[N:12]=[C:3]12.C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCCC1>[CH2:31]([O:30][C:28](=[O:29])[NH:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9](=[O:19])[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][N:14]=3)[N:12]=[C:3]12)[CH3:32]
Reactant: CCOC(=O)Cl
Reactant: NC1CCCCn2c1nc(-c1ccncn1)cc2=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)NC1CCCCn2c1nc(-c1ccncn1)cc2=O
Reaction time: 0.17 h
Yield: 72.7 %

Procedure:
0.3 g (1.17 mmol) of (+/−)10-amino-2-pyrimidin-4-yl-7,8,9,10-tetrahydropyrimido[1,2-a]azepin-4(6H)-one (compound 3.4 of example 3) was diluted in 8 mL of tetrahydrofuran. 0.18 mL (1.28 mmol) of triethylamine was added at 0° C. and the mixture was stirred for 10 min and 0.12 mL (1.28 mmol) of ethyl chloroformate was added. The resulting mixture was stirred at room temperature for 1 h and quenched by adding a saturated solution of ammonium chloride. The product was extracted with dichloromethane, dried over sodium sulfate and the solvent was evaporated. The residue was triturated with diethyl ether and filtered to afford 0.28 g (72%) of (4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepin-10-yl)-carbamic acid ethyl ester as a yellow solid (Mp.: 168-170° C.). The compound was used as such in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:30]3=[N:31][CH:32]=[N:33][C:34](Cl)=[C:29]3[CH:28]=[N:27]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][CH:23]([N:26]2[C:30]3=[N:31][CH:32]=[N:33][C:34]([O:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:12])=[CH:5][C:6]=4[F:11])=[C:29]3[CH:28]=[N:27]2)[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)c1ccc(O)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Temperature: 160 °C
Yield: 36.9 %

Procedure:
A mixture of 3-fluoro-4-hydroxy-benzoic acid methyl ester (Combi-Blocks Inc, San Diego, Calif., USA; 31 mg, 0.178 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 60 mg, 0.178 mmol), and potassium carbonate (54 mg, 0.391 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to afford 4-[4-(2-fluoro-4-methoxycarbonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (31 mg, 37%) as a white solid. Mass spectrum MH+=472.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[N:15][CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:42][C:43]1[CH:44]=[CH:45][C:46]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[C:47]([CH:51]=1)[C:48](O)=[O:49]>CN(C)C=O>[Br:42][C:43]1[CH:44]=[CH:45][C:46]([O:52][CH2:53][C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)=[C:47]([CH:51]=1)[C:48]([NH:17][C:13]1[CH:14]=[N:15][CH:16]=[C:11]([F:10])[CH:12]=1)=[O:49]
Reactant: Nc1cncc(F)c1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
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(Nc1cncc(F)c1)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Diisopropylethylamine (0.28 ml, 1.63 mmol), 5-fluoro-3-pyridinamine (73.0 mg, 0.65 mmol) and HATU (371 mg, 0.98 mmol) were added to a solution of 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5; 200 mg, 0.651 mmol) in N,N-dimethylformamide (50 ml) at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was then purified by chromatography on silica using 0-100% ethyl acetate/hexane. However a number of impurities persisted and the residue was re-purified by MDAP to yield the title compound. 45 mg.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([CH2:24][CH3:25])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([CH2:24][CH3:25])[CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CCc1cc(Cl)ccc1CO
Product: CCc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chloro-2-ethylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.23 (3H, t, J=7.6 Hz), 2.70 (2H, q, J=7.6 Hz), 5.20 (2H, s), 5.78 (1H, d, J=2.0 Hz), 7.20 (1H, dd, J=2.4 Hz, 8.4 Hz), 7.25 (1H, d, J=1.6 Hz), 7.36 (1H, d, J=8.4 Hz), 7.39 (1H, dd, J=1.6 Hz, 5.2 Hz), 7.59 (1H, d, J=2.0 Hz), 7.99 (1H, s), 8.67 (1H, d, J=4.8 Hz). [M+H] Calc'd for C18H15ClN4O, 339; Found, 339
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([OH:34])=O)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH:40]([CH2:43][OH:44])[CH2:41][OH:42]>>[OH:42][CH2:41][CH:40]([NH:39][C:32](=[O:34])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[S:27]([CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:28])=[O:29])[CH2:43][OH:44]
Reactant: NC(CO)CO
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Product: O=C(NC(CO)CO)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 38.1 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl] sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and serinol (46 mg, 0.50 mmol, 1.0M in DMF) were combined (reaction time 3 days at room temperature) to give 23 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 604 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Br[CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: BrCCCOC1CCCCO1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(CCCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
2.8 g of sodium hydride as a 60% dispersion in oil are added in small portions at RT to a solution of 13.35 g of 3,4-dichlorophenylacetonitrile in 100 ml of THF and the reaction mixture is stirred for 3 hours at RT. It is cooled to -20° C., a solution of 16 g of 2-(3-bromopropoxy)tetrahydropyran in 30 ml of THF is added dropwise and the reaction mixture is stirred for 3 hours while the temperature is allowed to rise to RT. It is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water, with a buffer solution of pH 4 and with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a toluene/AcOEt mixture (100/3; v/v) as the eluent to give 11 g of the expected product.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[N:6]([CH3:10])[N:5]=2)[CH2:3][CH2:2]1.[F:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[CH:20]=2)[CH:15]=[CH:14][C:13]=1[NH:31][C:32](=O)[O:33]C(C)=C.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:32]([NH:31][C:13]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]5[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=5)[CH:20]=4)=[CH:17][C:12]=3[F:11])=[O:33])[N:6]([CH3:10])[N:5]=2)[CH2:3][CH2:2]1
Reactant: C=C(C)OC(=O)Nc1ccc(Oc2ccnc(-c3cnn(C)c3)c2)cc1F
Reactant: Cn1nc(C2CC2)cc1N
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C5CC5)nn4C)c(F)c3)ccn2)cn1
Temperature: 70 °C
Reaction time: 8 h
Yield: 13.4 %

Procedure:
To a solution of 3-cyclopropyl-1-methyl-1H-pyrazol-5-amine (60 mg, 0.434 mmol) in dioxane (1 mL) was added prop-1-en-2-yl 2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenylcarbamate from Example 21 (0.16 g, 0.434 mmol), and DBU (6.61 mg, 0.043 mmol) and the mixture was stirred overnight at 70° C. The reaction was checked by LC-MS, solvent was removed and the residue was purified by silica gel column chromatography (EtOAc/hexane→CH2Cl2/MeOH). Pure fractions were combined and concentrated. The residue was dissolved in CH3CN:H2O (1:1, 2 mL) and lyophilized to obtain 1-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (26 mg, 13% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.92 (s, 1H), 8.82 (d, J=2.0 Hz, 1H), 8.39 (d, J=6.0 Hz, 1H), 8.28 (s, 1H), 8.18 (t, J=9.6 Hz, 1H), 7.99 (s, 1H), 7.26 (m, 2H), 7.02 (m, 1H), 6.70 (dd, J=2.4, and 6.0 Hz, 1H), 3.87 (s, 3H), 3.59 (s, 3H), 1.76 (m, 1H), 0.80 (m, 2H), 0.59 (m, 2H); MS (ESI) m/z; 448.1 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].Cl[C:16]1[N:21]=[C:20]([NH:22][CH:23]([CH3:30])[CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:19]([Cl:31])=[CH:18][N:17]=1>>[Cl:31][C:19]1[C:20]([NH:22][CH:23]([CH3:30])[CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[N:21][C:16]([NH:14][C:11]2[CH:12]=[CH:13][C:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:9][CH2:8][C:7]=3[CH:10]=2)=[N:17][CH:18]=1
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: CC(CNS(C)(=O)=O)Nc1nc(Cl)ncc1Cl
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(NC(C)CNS(C)(=O)=O)n3)cc2CC1

Procedure:
N-{2-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-propyl}-methanesulfonamide was prepared from 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-propyl]-methanesulfonamide in an analogous manner to Example 300b. Product isolated as a pale pink foam (84 mg, 41%). LCMS (m/e) 453 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.94 (s, 1H), 7.32 (d, 1H, J=7.7 Hz), 7.25 (s, 1H), 7.06 (d, 1H, J=8.0 Hz), 6.90 (s, 1H), 5.30-5.17 (m, 2H), 4.41-4.31 (m, 1H), 3.46-3.37 (m, 1H), 3.30-3.19 (m, 1H), 3.33-2.86 (m, 4H), 2.91 (s, 3H), 2.72-2.60 (m, 5H), 2.59 (q, 2H, J=6.9 Hz), 1.37 (d, 3H, J=5.9 Hz), 1.12 (t, 3H, J=6.9 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH2:24])=[N:23][C:18]3=[CH:17][CH:16]=2)[CH:11]=[CH:10][C:9]=1[F:25])([CH3:4])([CH3:3])[CH3:2].[C:27](Cl)(=[O:29])[CH3:28].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH:24][C:27](=[O:29])[CH3:28])=[N:23][C:18]3=[CH:17][CH:16]=2)[CH:11]=[CH:10][C:9]=1[F:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)sc3n2)ccc1F
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)OC(C)(C)C)c3)nc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
To a solution of tert-butyl{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-fluorophenyl}carbamate (1.13 g, 3.0 mmol) produced in Example C63(iv) and N,N-dimethylpyridine-4-amine (1.22 g, 10 mmol) in pyridine (10 mL) was added dropwise acetyl chloride (0.79 g, 10 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and triturated with diethyl ether to give the title compound (0.65 g, 52%) as a white amorphous.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:11]=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][C:15]=1[F:16].[C:19](O)(=[O:21])C.O>C1COCC1>[F:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[C:11]=1[CH:19]=[O:21]
Reactant: COc1ccc(F)c(F)c1
Reactant: CC(=O)O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)c(F)c1C=O
Temperature: -75 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of lithium diisopropylamide, 2M in TBF/n-heptane (171 mL, 341 mmol) was further diluted with dry THF (250 mL) and cooled under nitrogen to −75° C. 3,4-Difluoroanisole (46.8 g, 325 mmol) in dry THF (100 mL) was added dropwise and the mixture stirred at −75° C. for 1 h. Dry N,N-dimethylformnamide (27.6 mL, 358 mmol) was added dropwise and the mixture stirred for 10 mins at −70° C. Acetic acid (30 mL) and water (400 mL) were added, warming the temperature to 10° C. Extracted into diethyl ether (2×300 mL). Combined extracts were washed with water (250 mL), aqueous hydrochloric acid (0.2 N, 400 mL) and brine (2×250 mL), dried (MgSO4) and the solvent evaporated in vacuo to give a red/orange oil which crystallised. Purification was by recrystallisation from diethyl ether/petroleum ether 40-60 to give (53.0g, 95%) of solid; δH (300 MHz, CDCl3) 10.40 (1H, s, CHO), 7.37 (1H, q, ArH), 6.71 (1H, m, ArH), and 3.93 (3H, s OCH3).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:26]=[CH:25][C:14]3[N:15]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.CCN(C(C)C)C(C)C.[N:37]([CH:40]([CH3:42])[CH3:41])=[C:38]=[O:39]>CN1C(=O)CCC1>[CH:40]([NH:37][C:38]([N:21]1[CH2:22][CH2:23][CH2:24][C@H:19]([NH:18][C:16]2[S:17][C:13]3[CH:12]=[C:11]([O:10][C:8]4[CH:7]=[CH:6][N:5]=[C:4]([C:3]([NH:2][CH3:1])=[O:27])[CH:9]=4)[CH:26]=[CH:25][C:14]=3[N:15]=2)[CH2:20]1)=[O:39])([CH3:42])[CH3:41]
Reactant: CC(C)N=C=O
Reactant: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCNC4)sc3c2)ccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCN(C(=O)NC(C)C)C4)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the solution of (S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide (13 mg, 30 μmol) and DIPEA (17 μL, 100 μmol) in 300 μL of NMP was added 2-isocyanatopropane (5 μL, 50 μmol). The reaction solution was stirred at room temperature for 18 hours. The crude reaction solution was purified on prep HPLC and evaporated in vaccuo to give (S)-4-(2-(1-(isopropylcarbamoyl)piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (5.9 mg, 12 μmol as white powder. ES/MS m/z 469.2 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH:4]1[CH2:10][CH3:11])[CH3:2].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([O:9][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH2:5][CH:4]1[CH2:10][CH3:11])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCC1CC(O)CCN1CC
Product: CCC1CC(Oc2ccc([N+](=O)[O-])cc2)CCN1CC

Procedure:
In a manner similar to Preparation 2, react 1,2-diethyl-4-piperidinol with 4-fluoronitrobenzene to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1.[CH3:32][NH2:33]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:33][CH3:32])[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1
Reactant: CN
Reactant: COc1cc2c(c(-c3cccc(F)c3F)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Product: CNCC1Cc2cc(OC)cc(-c3cccc(F)c3F)c2O1

Procedure:
The title compound was prepared (0.017 g, 18%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,3-difluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.12 g, 0.27 mmol) and methylamine (0.082 g, 2.7 mmol). mp 148-150° C.