Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH:3]1([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[S:16]([NH2:19])(=[O:18])=[O:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(OCC)(=O)C>O.O.CC(C)=O.C(N(CC)CC)C.CO>[CH:3]1([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[S:16]([NH:19][C:27]([NH:26][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:28])(=[O:18])=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: NS(=O)(=O)c1cnccc1NC1CCCCC1
Reactant: O=C=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=C(NC1CCCCC1)NS(=O)(=O)c1cnccc1NC1CCCCC1
Yield: 50 %

Procedure:
0.01 mol of NaOH dissolved in a minimum of water is added to a solution of 0.01 mol of (4-(cyclohexylamino)pyrid-3-yl)sulfonamide in 80 ml of a water/acetone mixture (1:1). The mixture is stirred with a magnetic rod, and 0.015 mol of cyclohexylisocyanate is added. Stirring is continued, while the reaction is followed by TLC (silica gel 60F254, mobile phase: ethyl acetate 9, methanol 1, triethylamine 0.2). Gentle heating can accelerate the reaction. The mixture is evaporated under reduced pressure, and the residue is taken up in 100 ml of 0.2N NaOH. Any insoluble material is filtered out and the solution is corrected to pH 6.5-7 and left to crystallize for 1 hour in the refrigerator. The precipitate collected is suspended in 100 ml of a water/acetone mixture (4:1) saturated with NaHCO3. The mixture is stirred for 1 hour and then filtered, and the filtrate is brought back to pH 6.5-7 and left to crystallize in the refrigerator. The crystals are collected, washed in cold water and dried under vacuum at normal temperature. Yield is around 50-60%. Melting point: 165°-167° C.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].[C:9]([O:13][CH2:14][C@@H:15]([OH:21])[CH2:16][C:17](OC)=[O:18])([CH3:12])([CH3:11])[CH3:10].[Cl-].[NH4+].C(OCC)C>C(=O)=O.CC(C)=O.O1CCCC1>[C:9]([O:13][CH2:14][C@@H:15]([OH:21])[CH2:16][C:17](=[O:18])[CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)C[C@H](O)COC(C)(C)C
Agent: O=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC[C@@H](O)CC(=O)CC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
After completion of the dropwise addition, the mixture was stirred for 15 minutes to synthesize a lithium enolate of t-butyl acetate. The reaction mixture was cooled to -50° C. in dry ice-acetone, and a solution of 3.3 g (16.5 mmole) of methyl (3S)-4-t-butoxy-3-hydroxybutanoate as prepared in Example 1 in 15 ml of tetrahydrofuran was added to the mixture through the dropping funnel over 20 minutes, followed by stirred for an additional 1.5 hours. After confirming the completion of the reaction by gas chromatography, 30 ml of a saturated aqueous solution of ammonium chloride and 100 ml of diethyl ether were added to the reaction mixture to conduct extraction. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (diethyl ether/hexane: 1/1 by volume) to obtain 2.3 g (yield: 46%) of t-butyl (5S)-6-t-butoxy-5-hydroxy-3-oxohexanoate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[OH:20])[N:7]=1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O[C:43](=O)[C:44]([CH2:48][CH3:49])([CH3:47])[CH2:45][CH3:46])C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:43][C:44]([CH2:48][CH3:49])([CH3:47])[CH2:45][CH3:46])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(C)(CC)CC
Reactant: CCOC(=O)c1cc(C)n(Cc2cc(Br)ccc2O)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C)n(Cc2cc(Br)ccc2OCC(C)(CC)CC)n1
Temperature: 100 °C

Procedure:
A solution of 1-(5-bromo-2-hydroxy-benzyl)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester, 6 (0.20 g, 0.60 mmol), triphenylphosphine (0.31 g, 1.2 mmol), ditert-butylazodicarboxylate (0.27 g, 1.2 mmol) and 2-ethyl-2-methyl-butan-1-ol 20 (0.13 g, 1.2 mmol) in a mixture of THF (8 mL) was heated at 100° C. in an Emrys microwave reactor for 20 minutes. The volatiles were removed in vacuo and the crude product was purified on silica to yield 1-[5-bromo-2-(2-ethyl-2-methyl-butoxy)-benzyl]-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester, 22.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH2:26][CH3:27])=[CH:4][CH:3]=1.Cl[C:29]([O:31][CH3:32])=[O:30]>ClCCl>[CH3:32][O:31][C:29](=[O:30])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([OH:25])[CH2:23][CH2:24]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: CCn1cnc2c(Nc3ccc(N)cc3)nc(N[C@H]3CC[C@H](O)CC3)nc21
Reactant: COC(=O)Cl
Solvent: ClCCl
Product: CCn1cnc2c(Nc3ccc(NC(=O)OC)cc3)nc(N[C@H]3CC[C@H](O)CC3)nc21

Procedure:
trans 4-[6-(4-amino-phenylamino)-9-ethyl-9H-purin-2-yl-amino]-cyclohexanol (example 77, stage 1.2, 100 mg, 0.272 mmol) is suspended in 1 ml dichloromethane and treated with 21 μl (0.272 mmol) methyl chloroformate. The reaction mixture is stirred at RT for 20 h after which another equivalent of methyl chloroformate (21 μl, 0.272 mmol) is added. After additional 23 h at RT the reaction mixture is evaporated and the product purified by chromatography on silica gel (CH2Cl2/MeOH 95:5). {4-[9-ethyl-2-(trans-4-hydroxy-cyclo-hexylamino)-9H-purin-6-yl-amino]-phenyl}-carbamic acid methyl ester is obtained as tan crystals, 93 mg (81%). m.p. 131-135° C.; MS [M+H]+426; HPLC (System h) tR=4.84 min.
Reaction SMILES: [OH-].[K+].[I:3][C:4]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si](C)(C)C)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]>CO>[I:3][C:4]1[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: C[Si](C)(C)C#Cc1ccc(I)c(C(=O)O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccc(I)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
4.5 ml of aqueous potassium hydroxide solution (1 N) are added at 0° C. to a solution of 500 mg of 2-iodo-5-trimethylsilylethynylbenzoic acid (1.45 mmol, 1 eq.) in 30 ml of methanol. After stirring for 2 h at room temperature, the reaction medium is washed with 2×50 ml of CH2Cl2 and the aqueous phase is then reacidified to pH 2 by the addition of molar hydrochloric acid solution. After extraction with 2×50 ml of CH2Cl2, the organic phases are combined, dried and evaporated to give 383 mg of 2-iodo-5-ethynylbenzoic acid in the form of a yellow solid (yield: 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4]O.S(Cl)(Cl)=O.[CH3:16][NH:17][CH3:18]>C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:17]([CH3:18])[CH3:16]
Reactant: COc1ccc(N)c(CO)c1
Reactant: CNC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(N)c(CN(C)C)c1

Procedure:
2-Amino-N,N-dimethyl-5-methoxy-benzylamine was prepared from 2-amino-5-methoxy-benzyl alcohol, thionyl chloride and dimethylamine analogous to Example 1. Proof of structure by IR-, UV- and NMR-spectra. IR-spectrum (methylenechloride):
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:30]=[CH:29][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=O)[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=3)[CH:12]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[NH2:31][NH:32][C:33]([NH2:35])=[S:34].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH:1]([O:4][C:5]1[CH:30]=[CH:29][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[N:31][NH:32][C:33]([NH2:35])=[S:34])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=3)[CH:12]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: NNC(N)=S
Reactant: CC(C)Oc1ccc(C(=O)c2cccc(C(=O)c3ccc(OC(C)C)cc3)c2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC(C)Oc1ccc(C(=O)c2cccc(C(=NNC(N)=S)c3ccc(OC(C)C)cc3)c2)cc1
Yield: 26.9 %

Procedure:
1,3-bis-(4-isopropoxybenzoyl)benzene 21 (0.14 g, 0.39 mmol) was dissolved in anhydrous methanol (20 mL). The solution was heated at reflux for 15 min, and thiosemicarbazide (0.043 g, 0.47 mmol) and a catalytic amount of p-toluenesulfonic acid were added. After 10 h at reflux, the solvent was removed under vacuum and the resulting solid was further purified using flash chromatography (silica gel, hexanes:ethyl acetate, 50:50) to afford the desired 1,3-bis-(4-isopropoxybenzoyl)benzene thiosemicarbazone 22 as a white solid (0.05 g, 0.105 mmol, 27% yield); HRMS (ESI) calculated for C27H29N3O3SH+ (M+H) 476.2002, found 476.2005; HPLC retention time 18.440, 18.767 min.
Reaction SMILES: C(OC([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([CH2:17][CH2:18][CH3:19])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O)C.[OH-].[Na+]>>[CH2:17]([C:11]1[N:10]=[C:9]2[C:14]([C:15]([OH:16])=[CH:6][CH:7]=[N:8]2)=[CH:13][CH:12]=1)[CH2:18][CH3:19]
Reactant: CCCc1ccc2c(=O)c(C(=O)OCC)c[nH]c2n1
Agent: [Na+]
Agent: [OH-]
Product: CCCc1ccc2c(O)ccnc2n1
Yield: 100.4 %

Procedure:
The product from Example 2e (4.73 g, 18.1 mmol) was reacted with NaOH (756 mg, 18.9 mmol) following the procedure from Example 1c giving the title compound as a solid (3.42 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[O:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][N:32]3[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]3)=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][N:32]3[CH2:37][CH2:36][CH:35]([NH:38][CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9]4=[O:16])[CH2:34][CH2:33]3)=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1
Reactant: COC(=O)c1cc(=O)n(CC=O)c2cc(OC)ccc12
Reactant: NC1CCN(Cc2ccc3c(c2)OCCO3)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(=O)n(CCNC2CCN(Cc3ccc4c(c3)OCCO4)CC2)c2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To 10 mL of a chloroform solution containing 111 mg of methyl 7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-4-carboxylate and 93 mg of 1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperidin-4-ylamine, 23 μL of acetic acid was added and stirred at room temperature for 1 hour. To the reaction mixture, 132 mg of sodium triacetoxyborohydride was added and stirred for 0.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate:hexane=3:1], to give 134 mg of methyl 1-(2-(1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperidin-4-ylamino)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylate.
Reaction SMILES: C([O:3][C:4](=[O:51])[C@H:5]([C:11]1[C:12]([CH3:50])=[N:13][C:14]2[N:15]([N:28]=[C:29]([C:31]3[CH:32]=[C:33]([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=4[O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])[CH:34]=[CH:35][CH:36]=3)[CH:30]=2)[C:16]=1[N:17]1[CH2:22][CH2:21][C:20]([O:24][CH2:25][CH:26]=[CH2:27])([CH3:23])[CH2:19][CH2:18]1)[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])C.O[Li].O>CO.O>[CH2:25]([O:24][C:20]1([CH3:23])[CH2:19][CH2:18][N:17]([C:16]2[N:15]3[N:28]=[C:29]([C:31]4[CH:32]=[C:33]([C:37]5[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=5[O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])[CH:34]=[CH:35][CH:36]=4)[CH:30]=[C:14]3[N:13]=[C:12]([CH3:50])[C:11]=2[C@H:5]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:4]([OH:51])=[O:3])[CH2:22][CH2:21]1)[CH:26]=[CH2:27]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(-c4cccc(-c5ccc(F)cc5O[C@@H](C)CC=C)c4)nn23)CC1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3cc(-c4cccc(-c5ccc(F)cc5O[C@@H](C)CC=C)c4)nn23)CC1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 21.7 %

Procedure:
To a solution of (S)-ethyl-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′-fluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (32 mg, 0.048 mmol, 1 equiv) in MeOH (1.0 mL) and water (0.1 mL) was added LiOH.H2O (60 mg, 1.43 mmol, 30 equiv). The reaction was heated to 60° C. for 2 h. Upon cooling to ambient temperature, the reaction was then filtered and purified via preparative HPLC with the following conditions: Column. XBridge Phenyl, 19×mm, 5-1 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Product (7 mg, 23%) isolated. 1H NMR (600 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.89 (d, J=7.7 Hz, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.36-7.30 (m, 2H), 7.10 (d, J=11.6 Hz, 1H), 7.04 (s, 1H), 6.88-6.81 (m, 1H), 6.31 (d, J=6.1 Hz, 1H), 5.58 (s, 1H), 4.66-4.60 (m, 1H), 4.53 (q, J=7.0 Hz, 1H), 4.37 (t, J=12.1 Hz, 1H), 3.64-3.55 (m, 4H), 2.88 (br. s., 1H), 2.53 (s, 3H), 2.40-2.32 (m, 1H), 2.31-2.24 (m, 1H), 1.96-1.59 (m, 4H), 1.32 (s, 3H), 1.16 (s, 9H), 1.13 (d, J=6.1 Hz, 3H). LCMS (M+1)=643.5.
Reaction SMILES: [CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH2:24][CH:25]2[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]2)[CH:9]=1.[C:46]1(B(O)O)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>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.O>[CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH2:24][CH:25]2[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]2)[CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)C1CCC(Cc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(Cl)nc4)c3n2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C1CCC(Cc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Temperature: 140 °C

Procedure:
In a 2-5 mL microwave vial was charged ethyl 4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-chloropyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)cyclohexanecarboxylate (Int-4k, 300 mg, 0.45 mmol), phenylboronic acid (108 mg, 0.89 mmol), K3PO4 (189 mg, 0.89 mmol), and Pd(PPh3)4 (52 mg, 0.045 mmol). To this was added 3:1 1,4-dioxane:H2O (4 mL). The vial was flushed with argon and sealed. The reaction was heated to 140° C. for 20 minutes in a microwave synthesizer. The reaction was then diluted with DCM (30 mL) and washed with H2O. The organic phase was dried over Na2SO4 and the residue was purified via silica gel chromatography to yield the title compound. Yield=265 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][C:40]=1[F:41])[CH2:5][O:6][C:7]1([C:30]([NH:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[O:31])[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:26][C:25]([CH3:27])=[N:24][CH:23]=4)=[C:18]([O:28][CH3:29])[CH:17]=3)=[N:14][N:15]=[C:8]12.[C:42](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][C:40]=1[F:41])[CH2:5][O:6][C:7]1([C:30]([N:32]([CH3:42])[CH2:33][C:34]([F:37])([F:35])[F:36])=[O:31])[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:26][C:25]([CH3:27])=[N:24][CH:23]=4)=[C:18]([O:28][CH3:29])[CH:17]=3)=[N:14][N:15]=[C:8]12
Reactant: O=C([O-])[O-]
Reactant: COc1cc(-c2nnc3n2CCCC3(OCc2ccc(F)c(F)c2)C(=O)NCC(F)(F)F)ccc1-c1cnc(C)o1
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(-c2nnc3n2CCCC3(OCc2ccc(F)c(F)c2)C(=O)N(C)CC(F)(F)F)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a mixture of 8-[(3,4-difluorobenzyl)oxy]-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-N-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide (200 mg) in DMF (5 mL) were added cesium carbonate (169 mg) and methyl iodide (0.026 mL) at room temperature. After stirring at room temperature for 2 hr, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate/THF (2/1). The extract was washed with brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (75 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7](=[O:23])[N:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[S:9](=[O:18])(=[O:17])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:24]([NH:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7](=[O:23])[N:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[S:9](=[O:18])(=[O:17])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)N1C(=O)C(NCCCBr)=C(c2ccccc2)S1(=O)=O
Reactant: CCCCNCc1ccccc1
Product: CCCCN(CCCNC1=C(c2ccccc2)S(=O)(=O)N(C(C)(C)C)C1=O)Cc1ccccc1

Procedure:
The title compound was prepared from 4-[(3-bromopropyl)amino]-2-tert-butyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and N-benzylbutan-1-amine in a similar manner as described for Example 5. 1H NMR (500 MHz CDCl3): δ 7.52-7.44 (m, 2H), 7.42-7.38 (m, 3H), 7.33-7.30 (m, 2H), 7.30-7.24 (m, 3H), 6.36 (t, 1H), 3.48 (s, 2H), 2.86-2.78 (m, 2H), 2.40-2.12 (m, 4H), 1.76 (s, 9H), 1.56-1.44 (m, 4H), 1.36-1.24 (m, 2H), 0.91 (t, 3H); 13C NMR (125 MHz CDCl3): δ 159.8, 139.4, 135.6, 131.8, 129.4, 129.2, 128.9, 128.4, 127.2, 125.7, 106.3, 61.5, 59.2, 54.1, 52.0, 44.3, 29.2, 27.8, 26.3, 20.9, 14.3; Mass Spectrum: M+H+ 484.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.O>CS(C)=O>[C:5]([C:4]1[CH:3]=[C:2]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=1)#[N:6]
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Reactant: C1CNCCN1
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc(N2CCNCC2)cc(C(F)(F)F)c1
Yield: 89.2 %

Procedure:
2.42 g (13 mmol) 3-fluoro-5-trifluoromethyl-benzonitrile and 6.0 g (70 mmol) piperazine was dissolved in 50 ml dimethylsulfoxide and the solution was refluxed for one day. The mixture was poured into 200 ml of water and extracted with diethylether (3×100 ml). The organic layers were washed with saturated sodium chloride solution, then dried and evaporated to dryness in vacuo giving 2.96 g (yield 89.2%) of the title compound, melting at 85-7° C.
Reaction SMILES: C([O:4][CH2:5][CH:6]([C:22]1[CH:27]=[CH:26][C:25](Br)=[CH:24][C:23]=1[F:29])[N:7]1[CH2:21][CH2:20][C:10]2([O:15][CH2:14][C:13](=[O:16])[N:12]([CH:17]3[CH2:19][CH2:18]3)[CH2:11]2)[CH2:9][CH2:8]1)(=O)C.CC1(C)C(C)(C)OB([C:38]2[CH:47]=[C:46]3[C:41]([CH:42]=[CH:43][CH:44]=[N:45]3)=[CH:40][CH:39]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:17]1([N:12]2[CH2:11][C:10]3([CH2:9][CH2:8][N:7]([CH:6]([C:22]4[CH:27]=[CH:26][C:25]([C:38]5[CH:47]=[C:46]6[C:41]([CH:42]=[CH:43][CH:44]=[N:45]6)=[CH:40][CH:39]=5)=[CH:24][C:23]=4[F:29])[CH2:5][OH:4])[CH2:21][CH2:20]3)[O:15][CH2:14][C:13]2=[O:16])[CH2:18][CH2:19]1
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Reactant: CC(=O)OCC(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1COC2(CCN(C(CO)c3ccc(-c4ccc5cccnc5c4)cc3F)CC2)CN1C1CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
A solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl acetate (0.345 mmol) in 1,4-dioxane (1.5 mL) was treated with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.380 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.017 mmol), and 2M aq potassium carbonate (1.035 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120° C. for 15 min. The mixture was then concentrated to dryness in vacuo. The brown residue was diluted with ethanol (2 mL) and the solution was stirred in an oil bath at 50° C. overnight, after which the reaction was concentrated to dryness under a stream of nitrogen. The crude material was suspended in water (50 mL) and was extracted three times with ethyl acetate. The aqueous layer was further diluted with brine (20 mL) and was extracted once more with tetrahydrofuran. The organic layers (ethyl acetate and tetrahydrofuran) were combined, dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-6% methanol/dichloromethane) and chiral HPLC (Chromegachiral CC4, methanol) afforded the title compound as a white solid in >98% ee (21 mg, 12% yield). MS(ES)+ m/e 476.1 [M+H]+. αD=+ 20 deg (c=0.04, methanol).
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[C:3]1[O:7][CH:6]=[C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:4]=1.[F:15][C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[CH2:24][CH2:25][CH2:26]O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[F:15][C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[CH2:24][CH2:25][CH2:26][O:11][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[C:3]([Si:2]([CH3:1])([CH3:13])[CH3:14])[O:7][CH:6]=1
Reactant: C[Si](C)(C)c1cc(CCC(=O)O)co1
Reactant: OCCCc1cc(F)c(F)cc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[Si](C)(C)c1cc(CCC(=O)OCCCc2cc(F)c(F)cc2F)co1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 3-(5-trimethylsilyl-3-furyl)propionic acid (61.3 mg, 0.29 mmol), 3-(2,4,5-trifluorophenyl)propan-1-ol (55 mg, 0.29 mmol), 1,3-dicyclohexylcarbodiimide (66 mg, 0.32 mmol) and 4-dimethylaminopyridine (10 mg) in dichloromethane (3 ml) was stirred at room temperature overnight (17 hours). Most of the solvent was evaporated and the residue was purified by preparative TLC (20×20 cm, 1000μ silica plate; developed with 10% ethyl ether/hexane). The title ester was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH2:11][Cl:12])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O>C(#N)C>[Br:13][C:8]1[N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]2=[N:10][C:9]=1[CH2:11][Cl:12]
Reactant: ClCc1cn2cccc(Cl)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: ClCc1nc2c(Cl)cccn2c1Br
Temperature: 25 °C

Procedure:
Acetonitrile (8.5 ml) was added to 8-chloro-2-(chloromethyl)imidazo[1,2-a]-pyridine (341 mg, 1.7 mmol). N-bromosuccinimide (302 mg, 1.7 mL) was added and the mixture was stirred at rt until complete. The reaction mixture was partitioned with EtOAc and satd. aq. NaHCO3 solution. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was taken up in DCM and purified by chromatography on a 23 g silica gel column using 0 to 70% gradient of EtOAc in hexane. The desired fractions were combined and concentrated under reduced pressure to give 3-bromo-8-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine as a white crystalline solid.