Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[NH2:26])[C:5]([C:7]1[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=1[C:9]([O:11]CC1C=CC=CC=1)=O)=[O:6].[CH3:27][O:28][C:29]([NH:31][C:32](=NC(OC)=O)SC)=[O:30]>C(O)(=O)C>[CH3:27][O:28][C:29](=[O:30])[NH:31][C:32]1[NH:26][C:25]2[CH:24]=[CH:23][C:4]([C:5](=[O:6])[C:7]3[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=3[C:9]([CH2:5][C:4]3[CH:23]=[CH:24][CH:25]=[CH:2][CH:3]=3)=[O:11])=[CH:3][C:2]=2[N:1]=1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: Nc1ccc(C(=O)c2ccccc2C(=O)OCc2ccccc2)cc1N
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cc(C(=O)c3ccccc3C(=O)Cc3ccccc3)ccc2[nH]1
Temperature: 25 °C

Procedure:
A solution of benzyl 2-(3,4-diaminobenzoyl)benzoate (25 g, 72 mmole) and 1,3-bis(methoxy carbonyl)-2-methyl-2-thiopseudourea (19.3 g, 94 mmole) in acetic acid (100 ml) was heated to 75° C. for 45 minutes. The solution was cooled to room temperature and concentrated in-vacuo. The resultant oil was diluted in ethyl acetate (300 mL) and washed with 1N sodium hydroxide (200 mL), water (2×200 mL), dried over sodium sulfate, filtered and concentrated in-vacuo. The resultant solid was re-crystallized using ethyl ether and ethyl acetate (2:1). The solid was isolated by vacuum filtration and washed ethyl ether to afford [5-(2-benzylcarbanoyl-benzoyl)-1H-benzoimidazol-2-yl]-carbamic acid methyl ester, 21.4 g, 49.8 mmol, (69%) as a yellow solid. 1H NMR (400 MHz, d6-DMSO): 8.04 (br s, 1H), 7.77-7.68 (m, 3H), 7.52-7.41 (m, 3H), 7.28-7.10 (m, 5H), 5.05 (s, 2H), 3.76 (s, 3H); MS (EI) for C24H20N4O4: 430 (MH+)
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:3]=12.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2c(c1O)CCCCCC2
Product: CCOC(=O)c1cnc2c(c1Cl)CCCCCC2

Procedure:
A solution of 5 g of ethyl 5,6,7,8,9,10-hexahydro-4-hydroxycycloocta[b]pyridine-3-carboxylate in 20 ml of phosphorus oxychloride is refluxed for one hour and evaporated to dryness under reduced pressure. A solution of the residue in methylene chloride is treated with ice and water, and basified with 10 N sodium hydroxide. The layers are separated, the aqueous phase reextracted with methylene chloride, and the combined organic layers dried with magnesium sulfate, filtered, and solvent removed at reduced pressure to obtain ethyl 5,6,7,8,9,10-hexahydro-4-chlorocycloocta[b]pyridine-3-carboxylate as an oil which solidifies on standing, m.p. 33°-36°.
Reaction SMILES: [Si](O[C@@H](CC)C(O)=O)(C(C)(C)C)(C1C=CC=CC=1)[C:2]1C=CC=CC=1.[NH2:25][CH2:26][CH2:27][CH2:28][C@:29]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:33]([C:34](=[O:39])[C@@H:35]([O:37][CH3:38])[CH3:36])[N:32]=[C:31]([C:40]2[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=2[F:47])[S:30]1>>[NH2:25][CH2:26][CH2:27][CH2:28][C@:29]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:33]([C:34](=[O:39])[C@@H:35]([O:37][CH3:38])[CH2:36][CH3:2])[N:32]=[C:31]([C:40]2[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=2[F:47])[S:30]1
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN)c1ccccc1
Reactant: CC[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Product: CC[C@H](OC)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN)c1ccccc1

Procedure:
Prepared as in Example 71 using (S)-2-(tert-butyldiphenylsilyloxy)butanoic acid in place of (S)-2-(tert-butyldiphenylsilyloxy)propanoic acid. MS APCI (+) m/z 434 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.48 (m, 3H), 7.35 (app t, 2H, J=8 Hz), 7.28 (m, 1H), 7.13 (m, 2H), 4.53 (dd, 1H, J=7 Hz, 4 Hz), 3.40 (s, 3H), 3.26 (m, 1H), 2.86 (m, 2H), 2.42 (m, 1H), 1.94 (m, 2H), 1.74 (m, 2H), 0.96 (t, 3H, J=8 Hz). Stereochemistry was assigned by comparison to (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3 (2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.Cl.Cl.Cl.[CH3:53][N:54]1[CH2:57][CH:56]([N:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:55]1.C(N(CC)CC)C>CN(C)C=O>[F:48][C:27]1[CH:28]=[C:29]([NH:32][C:33]([C:35]2([C:38]([NH:39][C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)=[O:47])[CH2:36][CH2:37]2)=[O:34])[CH:30]=[CH:31][C:26]=1[O:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:8]([N:61]2[CH2:62][CH2:63][N:58]([CH:56]3[CH2:57][N:54]([CH3:53])[CH2:55]3)[CH2:59][CH2:60]2)=[O:7])[CH:24]=1
Reactant: CN1CC(N2CCNCC2)C1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)cc4F)ccn3)CC2)C1
Reaction time: 25 h
Yield: 33.6 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) were added 1-(1-methylazetidin-3-yl)piperazine trihydrochloride (106 mg) and triethylamine (0.167 ml) at room temperature, followed by stirring for 25 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (20.2 mg, 33%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:21]=[C:11]3[N:12]=[C:13](S(C)(=O)=O)[N:14]=[C:15]([NH2:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC#N>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:21]=[C:11]3[N:12]=[C:13]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[N:14]=[C:15]([NH2:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CNCCN1
Reactant: CS(=O)(=O)c1nc(N)n2nc(-c3cccc(F)c3)nc2n1
Solvent: CC#N
Product: Nc1nc(N2CCNCC2)nc2nc(-c3cccc(F)c3)nn12
Temperature: 25 °C

Procedure:
18 mmol of 2-(3-fluoro-phenyl)-5-methanesulfonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (prepared as described Caulkett et al., J. Chem. Soc. Perkin Trans I. 801-808 (1995)) was suspended in 50 mL of CH3CN along with 5 eq. of piperazine. The reaction mixture was stirred under reflux for 2 hours. It was then cooled to room temperature and concentrated under reduced pressure. The residue was taken up in CH2Cl2 and washed with H2O, brine, dried with Na2SO4, and concentrated under reduced pressure. The resulting crude product was purified by chromatography (95% CH2Cl2, 4% MeOH, 1% Et3N) to afford 2-(3-fluoro-phenyl)-5-piperazin-1-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:8]([CH3:17])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25].Cl>C1C=CC=CC=1>[C:24]([NH:1][C:2]1[C:10]([CH3:11])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:8]([CH3:17])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1c(C)cc(C(=O)O)c(N)c1C
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCOC(=O)c1c(C)cc(C(=O)O)c(NC(C)=O)c1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a mixture consisting of 1 g of 2-amino-4-ethoxycarbonyl-3,5-dimethylbenzoic acid, 20 ml of dry benzene, and 0.7 ml of pyridine in a flask cooled with ice water was added dropwise with stirring a solution of 450 mg of acetyl chloride in 5 ml of benzene. The reaction mixture was stirred overnight, and then shaken with dilute hydrochloric acid. The layers were separated. The acidic aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with water, and dried over sodium sulfate. The solvent was removed by distillation. The residue was recrystallized from ethyl acetate to afford 0.84 g of 2-acetylamino-4-ethoxycarbonyl-3,5-dimethylbenzoic acid melting at 164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].Br[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=1[O:36][CH3:37].C(=O)([O-])[O-].[K+].[K+]>>[CH3:33][O:32][C:30](=[O:31])[C:29]1[CH:34]=[CH:35][C:26]([CH2:25][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:2]([Cl:1])[CH:3]=2)=[C:27]([O:36][CH3:37])[CH:28]=1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(COc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)c(OC)c1

Procedure:
In analogy to Example 1, step 7, (3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (Example 19, Step 5) was reacted with methyl 4-(bromomethyl)-3-methoxy-benzoate and potassium carbonate to give the title compound as a colorless viscous oil. MS (m/e, ISP neg. ion)=542.1 [M−H+].
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].CS(O[CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=[CH:32][C:31]=1[CH:40]1[CH2:42][CH2:41]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:23]=[CH:22][C:6]2[N:7]([CH2:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=[CH:32][C:31]=3[CH:40]3[CH2:41][CH2:42]3)[C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2]
Reactant: CS(=O)(=O)OCc1c(C2CC2)cnc2ccccc12
Reactant: C[C@@H]1Nc2cc(C#N)ccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1Nc2cc(C#N)ccc2N(Cc2c(C3CC3)cnc3ccccc23)C(=O)[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 59.5 %

Procedure:
To a rt solution of tert-butyl(3S,4S)-7-cyano-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (155 mg, 490 μmol) in DMF (1.22 ml) was added (3-cyclopropylquinolin-4-yl)methyl methanesulfonate (149 mg, 539 μmol) and cesium carbonate (479 mg, 1.47 mmol). The reaction was stirred at rt for 2.5 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(3S,4S)-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (145 mg, 60%) as a white solid. MS m/z 498 (MH)+.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1.[CH:21]1[C:26]([OH:27])=[CH:25][CH:24]=[C:23]([CH3:28])[CH:22]=1>>[C:23]1([CH3:28])[CH:22]=[CH:21][C:26]([O:27][C:15]2[CH:16]=[CH:17][C:12]([C:11]([NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:2])=[O:20])=[O:19])=[CH:13][CH:14]=2)=[CH:25][CH:24]=1
Reactant: Cc1ccc(O)cc1
Reactant: COC(=O)c1ccccc1NC(=O)c1ccc(I)cc1
Product: Cc1ccc(Oc2ccc(C(=O)Nc3ccccc3C(=O)O)cc2)cc1

Procedure:
In analogy to example 2,2-(4-p-Tolyloxy-benzoylamino)-benzoic acid was prepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester [75541-84-3] and p-cresol. MS (m/e): 346.3 (M−H−, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[C:10]([C:11]#[N:12])[C:3]=12.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:10]([C:11]#[N:12])=[CH:9][N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N#Cc1cnc2[nH]cnc(Cl)c1-2
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C#N)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-chloro-1H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile D42 (60 mg) and potassium carbonate (282 mg, 2.04 mmol) were dissolved in DMF (6 ml), {2-[(chloromethyl)oxy]ethyl}(trimethyl)silane (69 mg, 0.41 mmol) was added dropwise. The reaction mixture was stirred at R.T. for 16 hours. The reaction mixture was poured onto water (30 ml), extracted with EtOAc (60 ml). Organic layer was washed with water (3×20 ml), brine (20 ml), dried (Na2SO4), filtered and concentrated in vacuo to obtain a yellow oil of desired product D43 in 105 mg. LCMS [MH+] 308.9@1.83 min (5 min run)
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[S:26](Cl)(=[O:28])=[O:27]>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[S:26]([NH:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=2)[N:14]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Product: O=S(=O)(Nc1cccc(COCc2ccc(F)cc2)n1)c1cc(F)ccc1F

Procedure:
This material was prepared in analogy to example 1 from 6-(4-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.058 g) and 2,5-difluoro-benzenesulfonyl chloride (0.058 g) as a light yellow gum (0.075 g). MS (ESI−): 407.2 ([M−H]−)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6]>C(Cl)Cl.CCOCC>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: OCc1cccc(I)c1
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1cccc(I)c1

Procedure:
Commercially available 3-iodobenzyl alcohol (5.32 mL, 41.9 mmol) was dissolved in 200 mL CH2Cl2. Upon completion, the reaction was diluted with 250 mL Et2O. The product was recovered as off-white crystals (8.1 g, 83.4%) mp: 48.0–55.0° C. TLC: Rf0.54 (3:1 hexanes/EtOAc). IR (neat): 3058, 2824, 2728, 1698, 1586, 1566. 1H-NMR (400 MHz, CDCl3): δ 9.93 (s, 1H, C1-H), 8.22 (t, 1H, J=1.6, C3-H), 7.96 (dt, 1H, J=7.7, 1.4, C5-H), 7.85 (dt, 1H, J=7.7, 1.3, C7-H), 7.29 (t, 1H, J=7.7, C6-H). 13C-NMR (125 MHz, CDCl3): δ 190.6, 143.1, 138.4, 138.0, 130.7, 128.8, 94.6. EI-MS m/z (rel int): 232 (M+, 100), 231 ([M−H]+, 25), 203 ([M−CHO]+, 14), 104 ([M−HI]+, 38).
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[C:10]([O:15][CH3:16])=[C:11]([NH2:14])[CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:21]([Cl:36])=[CH:20][N:19]=1.Cl.O1CCOCC1>C(O)(C)C>[Cl:36][C:21]1[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[N:23][C:18]([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[C:10]=2[O:15][CH3:16])=[N:19][CH:20]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCc2ccc(N)c(OC)c2CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)c2CC1

Procedure:
3-Ethyl-6-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (50.0 mg, (0.23 mmol) was dissolved in isopropanol (3 mL) and the mixture was treated with N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (58 mg, 0.17 mmol) and 4N HCl/Dioxane (0.056 mL, 0.20 mmol). The reaction was then irradiated at 140° C. for 20 minutes. The solution was reduced en vacuo and the product was isolated and purified by flash column chromatography (0% MeOH/DCM-15% MeOH/DCM) to afford 3.83 mg of N-{(1R,2R)-2-[5-Chloro-2-(3-ethyl-6-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a white foam, LC/MS (ESI)=523.39 (M+H). 1H NMR (400 MHz, DMSO, d6) δ 7.93 (s, 1H), 7.82 (m, 2H), 7.07 (d, 1H, J=8.59), 6.86 (m, 1H), 6.77 (m, 1H), 3.71 (m, 2H), 3.62 (s, 3H), 2.89 (s, 3H), 2.67 (m, 4H), 2.59 (m, 1H), 2.53 (m, 2H), 2.42 (m, 2H), 2.34 (m, 1H), 2.04 (m, 2H), 1.70 (m, 2H), 1.35 (m, 2H), 1.23 (m, 2H), 1.03 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=1O.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][C:34]2[C:33]([F:32])=[CH:38][CH:37]=[CH:36][C:35]=2[F:39])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Oc1c(F)cccc1F
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC(Oc2c(F)cccc2F)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 33.5 %

Procedure:
4-Hydroxycyclohexanecarboxylic acid ethyl ester (300 mg; 1.7 mmol), triphenylphosphine (1 g; 4.2 mmol) and 2,6-difluorophenol (340 mg; 2.6 mmol) were stirred in anhydrous toluene and chilled to 0° C. under nitrogen flow. Diethyl azodicarboxylate (2 mL; 4.3 mmol) was added to the mixture over 1 minute and warmed to room temperature. Reaction continued for 16 hours. Reaction was quenched with water, and mixture was extracted with 4×5 mL with ethyl acetate. Combined organics were washed with brine and dried over MgSO4. Oily residue was triturated with diethyl ether and solids filtered off. Filtrate was concentrated at reduced pressure and purified via flash chromatography using 5-20% ethyl acetate in hexanes to give 162 mg of title compound. (34% yield).
Reaction SMILES: [CH3:1][C:2]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([C:6](=[CH2:10])[CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].[CH2:16]([SnH:20]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>>[CH3:1][C:2]([O:11][Si:12]([CH3:13])([CH3:14])[CH3:15])([C:6](=[CH2:10])[CH2:7][CH2:8][CH3:9])[CH2:3]/[CH:4]=[CH:5]/[Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCC(C)(O[Si](C)(C)C)C(=C)CCC
Product: C=C(CCC)C(C)(C/C=C/[Sn](CCCC)(CCCC)CCCC)O[Si](C)(C)C
Reaction time: 1 h

Procedure:
A mixture of 26 g. of 4-methyl-5-methylene-4-trimethylsilyloxy-1-octyne, 200 mg. of azoisobutyrylnitrile and 41.1 g. of tri-n-butylstannane is stirred under argon in an oil bath at 140° C. The mixture is stirred at 140°-150° C. for one hour under argon, then at 140°-150° C. for 1.5 hours under vacuum to remove excess tri-n-butylstannane. The residue is distilled via a Kugelrohr (150° C., 0.05 mm.) giving the desired product as a colorless liquid.
Reaction SMILES: Br[C:2]1[C:3]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=23)=[O:10])=[N:4][N:5]([CH3:7])[CH:6]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[CH3:7][N:5]1[CH:6]=[C:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([F:32])([F:31])[F:20])[C:3]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=23)=[O:10])=[N:4]1
Reactant: Cn1cc(Br)c(NC(=O)c2cnn3cccnc23)n1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cn1cc(-c2ccccc2C(F)(F)F)c(NC(=O)c2cnn3cccnc23)n1
Yield: 3.9 %

Procedure:
To a stir-bar equipped microwave vial was added: N-(4-bromo-1-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (101 mg, 0.313 mmol, 1 eq), 2-trifluoromethylphenyl boronic acid (126.6 mg, 0.6666 mmol, 2.13 eq), bis(triphenylphosphine)palladium(II) chloride (26.8 mg, 0.0382 mmol, 0.12 eq), sodium carbonate (1.0 mL of a 2.0 M aqueous solution, 2 mmol, 6 eq), and 3 mL acetonitrile. The reaction mixture was subjected to microwave irradiation at 130° C. for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 4.7 mg (4%) of N-(1-methyl-4-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=387.1; 1H NMR (400 MHz, DMSO-d6) δ: 9.58 (s, 1H), 9.32 (d, 1H), 8.74 (d, 1H), 8.57 (s, 1H), 7.78 (s, 1H), 7.74 (d, 1H), 7.60 (t, 1H), 7.49 (m, 2H), 7.28 (d of d, 1H), 3.87 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.C(=O)(O)[O-].[Na+].[NH2:15][C:16]1[C:21]([C:22]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])=[O:23])=[CH:20][N:19]=[C:18](S(CC)(=O)=O)[N:17]=1.O>CN(C)C=O>[NH2:15][C:16]1[C:21]([C:22]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])=[O:23])=[CH:20][N:19]=[C:18]([NH:2][CH:3]2[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]2)[N:17]=1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2cc(F)ccc2OC)c(N)n1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCC(O)CC2)nc1N
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a stirred solution of trans-4-amino-cyclohexanol hydrochloride (108 mg, 0.71 mmol, Aldrich) in dimethylformamide, were added sodium bicarbonate(98 mg, 0.92 mmol) and (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone (201 mg, 0.59 mmol, Example 48) and the mixture was stirred at 90° C. for 1 hour. The mixture was poured into water and extracted with ethyl acetate. The extracts were dried with sodium sulfate and concentrated. The residue was chromatographed (2.5% methanol in dichloromethane) to give a white solid. 172 mg, 81%. MS(ES) (M+H)+=361.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Cl:12])[CH:6]=1)[OH:4].O=[C:14]([CH3:28])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:27][O:26][C:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH:14]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Cl:12])[CH:6]=2)[OH:4])[CH3:28])=[CH:22][CH:21]=1)=[O:25]
Reactant: NCC(O)c1ccc(F)c(Cl)c1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2ccc(F)c(Cl)c2)cc1
Yield: 52.9 %

Procedure:
Following a procedure similar to that described in Example 3, but using 3.0 g of 2-amino-1-(3-chloro-4fluorophenyl)ethanol (prepared as described in Preparation 40), 4.22 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 80 ml of benzene, 60 ml of absolute methanol and 3.5 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 3.31 g of the title compound were obtained having an Rf=0.22 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).