Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:6]=1)=[O:4].[OH-].[Na+]>C1COCC1.O>[Cl:16][C:12]1[CH:11]=[C:10]([N:7]2[CH:8]=[N:9][C:5]([C:3]([OH:4])=[O:2])=[N:6]2)[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ncn(-c2cccc(Cl)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ncn(-c2cccc(Cl)c2)n1

Procedure:
14.8 g (62.3 mmol) 1-(3-chloro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid methyl ester was taken up in 70 mL THF and treated with 40 mL 4M aqueous NaOH solution at RT for 12 h. The reaction mixture was diluted with water, THF was removed by distillation, ice water was added and the mixture was acidified with 4 M aqueous HCl solution. The precipitated was filtered off, washed with water and triturated with diethyl ether.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([C:26]2([CH2:30][C:31]#[N:32])[CH2:29][NH:28][CH2:27]2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](Cl)(=[O:35])[CH3:34].C(N(CC)CC)C>C(Cl)Cl>[C:33]([N:28]1[CH2:29][C:26]([CH2:30][C:31]#[N:32])([N:23]2[CH:24]=[CH:25][C:21]([C:9]3[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:12]4[CH:13]=[CH:14][C:15]5[N:16]([C:17]([CH3:20])=[N:18][N:19]=5)[C:11]=4[CH:10]=3)=[N:22]2)[CH2:27]1)(=[O:35])[CH3:34]
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CNC5)n4)n3Cc3ccccc3)n12
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(CC#N)(n2ccc(-c3cc4c(ccc5nnc(C)n54)n3Cc3ccccc3)n2)C1
Reaction time: 0.08 h
Yield: 92.9 %

Procedure:
To {3-[3-(6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (8.0 mg, 0.019 mmol, from Example 90) was added acetyl chloride (1.6 μL, 0.022 mmol, Aldrich) in DCM (0.50 mL), followed by triethylamine (5.3 μL, 0.038 mmol). The reaction was complete in 5 minutes. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) afforded desired product (8.2 mg, 93%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C@@H:17]([NH:29]C(=O)OC(C)(C)C)[CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)[CH:15]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C@@H:17]([NH2:29])[CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=4)[CH:15]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)Cn1cc(-c2ccc3cnccc3c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccc(C(F)(F)F)cc1)Cn1cc(-c2ccc3cnccc3c2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
A mixture of tert-butyl(S)-3-(4-(isoquinolin-6-yl)-1H-pyrazol-1-yl)-1-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (90 mg, 0.18 mmol) and TFA (5.00 mL, 64 mmol) in DCM (5 mL) was stirred at room temperature for 2 hours. After concentration by vacuum distillation, the residue was purified by reverse-phase HPLC (Phenomenex Synergi 4m Max RP 80 A column, 150×21 mm, 20 mL/min, 10-95% CH3CN/H2O, 0.1% TFA, 10.5 minute gradient) to give the product as an off-white solid (41 mg, 57%). HRMS (TOF) Calcd for C22H20F3N4+: 397.1635, found: 397.1642.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C([O-])=O.[Na+].[O:12]=[C:13]1[C:21]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])([NH:22][C:23]([CH:25]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][NH:26]2)=[O:24])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]1[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)=O>[CH:1]([N:26]1[CH:25]([C:23]([NH:22][C:21]2([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:13]2=[O:12])=[O:24])[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)=[O:3]
Reactant: CCCCCN1C(=O)C(CCC(=O)OCC)(NC(=O)C2Cc3ccccc3CN2)c2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=CO
Product: CCCCCN1C(=O)C(CCC(=O)OCC)(NC(=O)C2Cc3ccccc3CN2C=O)c2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A mixture of 0.66 g of formic acid and 1.35 g of acetic acid anhydride was heated at 50° C. for 15 minutes. After cooling by dilution with 15 ml of anhydrous methylene chloride, 0.68 g of sodium formate and 15 ml of a methylene chloride solution of 1.70 g of ethyl 3-[2,3-dihydro-2-oxo-1-pentyl-3-(1,2,3,4-tetrahydro-3-isoquinolinyl)carbonylamino-1H-indol-3-yl]propionate were added to this mixed anhydride solution. The whole was stirred at room temperature overnight. The reaction mixture was neutralized with an aqueous saturated sodium hydrogen carbonate solution and then extracted with chloroform. The extract was washed, dried, filtered and then evaporated in vacuo to afford 1.72 g of ethyl 3-[3-(2-formyl-1,2,3,4-tetrahydro-3-isoquinolinyl)carbonylamino-2,3-dihydro-2-oxo-1-pentyl-1H-indol-3- yl]propionate as a pale yellow amorphous solid. IR (Nujol) (cm-1): 3280, 1720, 1655, 1610, FAB-MS (m/z): 506 (MH+) 160 (base).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.Br[CH:28]([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH:28]([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[N:9]=2)[CH:7]=1
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: COc1ccc(Cl)cc1-c1n[nH]cc1NC(=O)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(C(C)C(=O)OC(C)(C)C)cc1NC(=O)c1cnn2cccnc12
Temperature: 75 °C
Yield: 70.4 %

Procedure:
A suspension of N-(3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (1.0 g, 2.7 mmol, 1 equiv), tert-butyl 2-bromopropanoate (0.54 mL, 3.2 mmol, 1.2 equiv), and cesium carbonate (1.1 g, 3.2 mmol, 1.2 equiv) in N,N-dimethylformamide (15 mL) was heated at 75° C. for 3 h. The reaction mixture was concentrated, and the resulting residue was partitioned between half-saturated aqueous sodium chloride solution (50 mL) and ethyl acetate (50 mL). The aqueous was extracted with ethyl acetate (2×50 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (90% ethyl acetate in heptane) provided product (0.945 g, 70%). LCMS (ESI): M+H=497.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([OH:23])=[CH:8][C:9]([C:14]3[S:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=3)=[N:10]2)=[CH:5][CH:4]=1.O[C@@H:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[C@H:27]([C:41]([O:43][CH3:44])=[O:42])[CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:44][O:43][C:41]([CH:27]1[CH2:26][CH:25]([O:23][C:7]2[C:6]3[C:11](=[C:12]([CH3:13])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=[C:9]([C:14]3[S:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=3)[CH:8]=2)[CH2:30][CH2:29][N:28]1[C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])=[O:42]
Reactant: COc1ccc2c(O)cc(-c3nc(C(F)(F)F)cs3)nc2c1C
Reactant: COC(=O)[C@@H]1C[C@H](O)CCN1C(=O)OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1CC(Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a stirred solution of compounds 203b (1 g, 1 eq.) and 12 (1.39 g, 1.2 eq.), and triphenylphosphine (1.34 g, 1.5 eq.) in anhydrous THF (40 mL) at 0° C. was added DIAD (1.02 mL, 1.5 eq.). The reaction mixture was stirred at room temperature for 2 hrs. THF was then removed under reduced pressure and the residue was purified by chromatography on silica gel (petroleum ether/EtOAc) to yield compound 13 as a white solid in 52% yield. MS (ESI, EI+) m/z=616 (MH+).
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[C:16]([O:20][C:21]([N:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[CH3:28][C:29]1[CH:56]=[CH:55][CH:54]=[CH:53][C:30]=1[CH2:31][N:32]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH3:52])[C@@H:33]([CH2:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[CH:38]=1)[CH:34]=[O:35]>O1CCCC1>[C:16]([O:20][C:21]([N:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C@@H:34]([OH:35])[C@@H:33]([N:32]([CH2:31][C:30]1[CH:53]=[CH:54][CH:55]=[CH:56][C:29]=1[CH3:28])[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH3:52])[CH2:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[CH:38]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)n1cccc1
Reactant: Cc1ccccc1CN(Cc1ccccc1C)[C@H](C=O)Cc1cc(F)cc(F)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccccc1CN(Cc1ccccc1C)[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)c1cccn1C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 10 %

Procedure:
Add n-butyllithium (3.30 mL, 8.25 mmol, 2.5 M in hexanes) to a solution of 2,2,6,6-tetramethylpiperidine (1.40 mL, 8.18 mmol) in tetrahydrofuran (THF) (30 mL) at −78° C. over 2 min. Stir 5 min, then warm to −10° C. and stir 5 min, then cool to −78° C. Add N-tert-butoxycarbonylpyrrole (1.37 mL, 8.25 mmol) in THF (1.6 mL) over 3 min. Stir 30 min and add 2-(S)-[bis-(2-methylbenzyl)-amino]-3-(3,5-difluorophenyl)-propionaldehyde (2.96 g, 7.44 mmol) in THF (15 mL) over 5 min. Stir 60 min at −78° C., warm to 0° C. and stir 60 min. Cool −78° C. and quench with saturated aqueous ammonium chloride solution. Extract with ethyl acetate, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with hexanes and dichloromethane) to give the title compound as a foam (0.416 g, 10%).
Reaction SMILES: P(=O)(O)(O)O.O.O[CH2:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[C:17]([OH:20])([CH3:19])[CH3:18])[C:12]#[N:13]>C1(C)C=CC=CC=1>[CH3:19][C:17]1([CH3:18])[C:16]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=2[CH2:8][O:20]1
Reactant: CC(C)(O)c1ccc(C#N)cc1CO
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)OCc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of orthophosphoric acid (147.5 mL) and demineralized water (29.5 mL) is added to a stirred toluene solution (300 mL) of 3-hydroxymethyl-4-(1-hydroxy-1-methylethyl)benzonitrile (29.5 g, 0.154 mol) at 0-5° C. The reaction mixture is stirred at room temperature for 3.0 hrs. The toluene layer is separated and the aqueous layer is extracted with toluene (3×50 mL). Combined organic layers are washed with saturated sodium bicarbonate solution (1×40 mL) followed by demineralized water (1×40 mL). Evaporation of the toluene layer under reduced pressure gives a viscous liquid which is purified by column chromatography (silica gel 230-400 mesh,) to give 1,1-dimethyl-1,3-dihydro-2-benzofuran-5-carbonitrile.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][N:9]([C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([O:18]C)=[O:17])[C:8]2=[O:24])#[N:2].[OH-].[Na+]>>[C:1]([C:3]1[CH:4]=[C:5]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)[CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][N:9]([C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([OH:18])=[O:17])[C:8]2=[O:24])#[N:2]
Reactant: COC(=O)c1ccc(C)c(-n2cnc3c(C#N)cc(N4CCN(C)CC4)cc3c2=O)c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C(=O)O)cc1-n1cnc2c(C#N)cc(N3CCN(C)CC3)cc2c1=O

Procedure:
Using an analogous procedure to that described paragraph (C) in the portion of Example 1 which is concerned with the preparation of starting material methyl 3-[8-cyano-6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoate was hydrolysed with 1N NaOH to give 3-[8-cyano-6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid; Mass Spectrum: M+H+ 404.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]([CH:22]2[CH2:24][CH2:23]2)[CH2:20][CH3:21])[C:13]=1[NH2:25].[C:26](OC)(=[O:30])[C:27]([CH3:29])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]2[N:25]=[C:27]([CH3:29])[C:26](=[O:30])[N:18]([CH:19]([CH:22]3[CH2:24][CH2:23]3)[CH2:20][CH3:21])[C:14]=2[N:15]=[CH:16][CH:17]=1
Reactant: CCC(Nc1nccc(-c2ccc(OC(F)F)cc2Cl)c1N)C1CC1
Reactant: COC(=O)C(C)=O
Product: CCC(C1CC1)n1c(=O)c(C)nc2c(-c3ccc(OC(F)F)cc3Cl)ccnc21

Procedure:
4-(2-Chloro-4-difluoromethoxy-phenyl)-N2-(1-cyclopropyl-propyl)-pyridine-2,3-diamine (0.284 g, 0.77 mmol) and methyl pyruvate (140 μL, 1.54 mmol) were treated substantially as described in Part F of Example 113 to give 8-(2-Chloro-4-difluoromethoxy-phenyl)-4-(1-cyclopropyl-propyl)2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 115b): 1H NMR (300 MHz, CDCl3) δ 8.52–8.46 (2d, 1H, J=4.8), 7.37–7.32 (m, 2H), 7.26–7.14 (m, 2H), 6.85–6.37(t,1H, J=73.3 Hz), 5.09–4.95, 4.75–4.2 (2m, 1H), 2.48 (s, 3H), 2.4–2.25 (m, 1H), 2.23–2.16 (m, 1H), 2.13–1.93 (m, 1H), 0.90–0.85 (t, 3H, J=7.3 Hz), 0.80–0.67 (m, 1H), 0.57–0.42 (m, 1H), 0.40–0.29 (m, 1H), 0.24–0.18 (m, 1H). MS (AP) m/z 420.2 [(M+H)+, 100], 461.3 [(M+H+CH3CN)+, 20].
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:18]([Si:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)Cl)([CH3:21])([CH3:20])[CH3:19]>CN(C)C1C=CN=CC=1>[Si:22]([O:8][CH:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCC1CC=CCC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](OC=C1C=CCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 3-cyclohexene-1-methanol (Aldrich, 13.0 mL, 0.11 mol), N,N-diisopropylethylamine (43 mL, 0.244 mol) and 4-dimethylaminopyridine (2.70 g., 0.022 mol) in 375 mL of dry CH2CI2 under N2 at 25° C. was added tert-butyldiphenylchlorosilane (32 mL, 0.123 mol). The mixture was stirred at 25° C. for 48 hours. The reaction mixture was washed sequentially with 150 mL portions of 1N HCl, water, brine and dried over anhydrous MgSO4. The solvent was evaporated. The residue was loaded onto a 4"×4" column of silica and slowly eluted using hexanes as eluant. 3-(tert-butyldiphenylsilyloxymethylene)-1-cyclohexene, 33.6 g (86%), was obtained as a colorless oil which was homogenous by TLC (Rf=0.4, hexanes).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH3:22])[C:9]2[CH:13]([CH2:14][C:15]([O:17]CC)=[O:16])[O:12][B:11]([OH:20])[C:10]=2[CH:21]=1.[Li+].[OH-].[ClH:26]>C1COCC1.O.O>[ClH:26].[CH3:23][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH3:22])[C:9]2[CH:13]([CH2:14][C:15]([OH:17])=[O:16])[O:12][B:11]([OH:20])[C:10]=2[CH:21]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(OCCN(C)C)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCCN(C)C)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 15 %

Procedure:
To a solution of ethyl 2-(6-(2-(dimethylamino)ethoxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (crude) in 15 ml of THF/H2O (2/1) was added LiOH (42 mg, 1.0 mmol) in 5 ml H2O at 0° C. The reaction mixture was stirred at room temperature for 1.5 h and acidified by 1.0 N HCl to pH=6. The resulting mixture was extracted with EtOAc (3×20 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound as a white solid (35 mg, yield: 15%, two steps). 1H NMR (400 MHz, DMSO-d) δ9.15 (s, 1H), 7.08 (d, J=1.6 Hz, 1H), 6.89 (d, J=1.6 Hz, 1H), 5.46-5.43 (m, 1H), 4.24-4.22 (m, 2H), 4.09 (m, 1H), 3.24 (m, 2H), 3.16 (s, 3H), 3.05-3.01 (m, 1H), 2.65 (s, 6H), 2.26 (s, 3H), 2.09-2.02 (m, 1H); MS (ESI) m/z=294 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][C:10]=1[O:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][C:10]=1[O:11][CH2:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(COc1cc(OCc2ccccc2)ccc1OCc1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: OC(COc1cc(OCc2ccccc2)ccc1OCc1ccccc1)c1ccccc1
Temperature: 22 °C
Reaction time: 2 h

Procedure:
To the solution of 2-[2,5-bis(benzyloxy)phenoxy]-1-phenylethanone (0.14 g) in methanol (0.5 ml) and tetrahydrofuran (1.9 ml) was added at the 0° C. temperature sodium borohydride (6.5 mg). The reaction was stirred 15 minutes at 0° C. and 2 hrs at 22° C. temperature. After adding water (5 ml) methanol and tetrahydrofuran were evaporated off. After the residue was stirred at 22° C. 0.5 hr the product was filtered, washed with cold water and dried under reduced pressure. Yield is 0.09 g. 1H NMR (DMSO-d6) δ: 4.05 (m, 2H), 4.91 (m, 1H), 4.95 (s, 2H), 5.01 (s, 2H), 5.59 (d, J 4.7 Hz, 1H), 6.47 (dd, J 2.8, 8.8 Hz, 1H), 6.68 (d, J 2.8 Hz, 1H), 6.89 (d, J 8.8 Hz, 1H), 7.24-7.45 (m, 15H).
Reaction SMILES: [NH2:1]C1C(Cl)=C(C=CC=1)C(N)=O.[Br:12][C:13]1[C:14]([Cl:23])=[C:15]([C:19]([F:22])=[CH:20][CH:21]=1)[C:16](O)=[O:17]>>[Br:12][C:13]1[C:14]([Cl:23])=[C:15]([C:19]([F:22])=[CH:20][CH:21]=1)[C:16]([NH2:1])=[O:17]
Reactant: NC(=O)c1cccc(N)c1Cl
Reactant: O=C(O)c1c(F)ccc(Br)c1Cl
Product: NC(=O)c1c(F)ccc(Br)c1Cl

Procedure:
This compound was prepared using a method analogous to that of 3-amino-2-chlorobenzamide (A.1.2), 3-bromo-2-chloro-6-fluorobenzoic acid replacing 3-amino-2-chlorobenzoic acid;
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][NH:7][C:8](=[O:29])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:18]=[CH:17][C:16]=2[NH2:28])[CH:10]=1.[C:35]([O:39][C:40](=[O:54])[CH2:41][CH2:42][S:43][CH2:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=1)[C:48](O)=[O:49])([CH3:38])([CH3:37])[CH3:36].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:18]=[CH:17][C:16]=2[NH:28][C:48]([C:47]2[CH:46]=[C:45]([CH:53]=[CH:52][CH:51]=2)[CH2:44][S:43][CH2:42][CH2:41][C:40]([O:39][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:54])=[O:49])[CH:10]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Reactant: Nc1ccc(OC2CCOCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(OC3CCOCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.7 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(tetrahydro-2H-pyran-4-yloxy)phenyl)isonicotinamide (270 mg, 0.52 mmol, 1.00 equiv, 90%) in dichloromethane (10 mL), 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid (339 mg, 0.92 mmol, 2.00 equiv, 80%), EDC.HCl (220 mg, 1.15 mmol, 2.00 equiv), and 4-dimethylaminopyridine (140 mg, 1.15 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 25° C. The resulting solution was diluted with 150 mL of dichloromethane and was washed with 1×20 mL of aqueous NH4Cl, 1×20 mL of 10% sodium bicarbonate, and 1×20 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:1)˜dichloromethane:methanol (20:1). The product was obtained as 190 mg (42%) of a brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH2:16])[CH3:15].[CH3:18][C:19]1[O:23][C:22]([CH:24]=O)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH:16][CH2:24][C:22]1[O:23][C:19]([CH3:18])=[CH:20][CH:21]=1)[CH3:15]
Reactant: Cc1ccc(C=O)o1
Reactant: CC(C)(N)COc1ccc2ccccc2c1Cl
Product: Cc1ccc(CNC(C)(C)COc2ccc3ccccc3c2Cl)o1
Yield: 41 %

Procedure:
Prepared from 1-[(1-chloronaphthalen-2-yl)oxy]-2-methylpropan-2-amine and 5-methylfuran-2 carbaldehyde in 41% yield as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[O:15])[CH2:11][CH2:12][O:13][CH3:14])[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:6][C:5]=1[NH2:20].[C:22](Cl)(Cl)=[O:23]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[O:15])[CH2:11][CH2:12][O:13][CH3:14])[C:7]([C:16]([F:17])([F:19])[F:18])=[CH:6][C:5]=1[N:20]=[C:22]=[O:23]
Reactant: COCCC(=O)c1cc(C(=O)OC)c(N)cc1C(F)(F)F
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: COCCC(=O)c1cc(C(=O)OC)c(N=C=O)cc1C(F)(F)F
Yield: 100 %

Procedure:
In a dried flask purged with argon, a solution of 2-amino-5-(3-methoxy-propionyl)-4-trifluoromethyl-benzoic acid methyl ester (154 mg, 0.504 mmol) in dry toluene (4.7 mL) was cooled to 0° C. and treated dropwise with a solution of phosgene in toluene (20%, 4.9 mL). A slow stream of phosgene was introduced and the reaction mixture was heated to reflux for 2 h. Argon was blown through the yellow solution and the solvent distilled off leaving the title compound (168 mg, 100%) as an oily residue, sufficiently pure for the next step. 1H-NMR (CDCl3, 360 MHz): 8.20 (s, 1H), 7.45 (s, 1H), 4.00 (s, 3H), 3.75 (t, J=8 Hz, 2H), 3.35 (s, 3H), 3.10 (t, J=8 Hz, 2H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=2[C:9](=[O:17])[NH:8][C:7]2[CH:18]=[CH:19][CH:20]=[N:21][C:6]1=2)=[O:4].[CH2:22]([N:24]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1)[CH2:25][CH3:26])[CH3:23].C(OC(C)C)(C)C>C(#N)C>[CH2:22]([N:24]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=2[C:9](=[O:17])[NH:8][C:7]2[CH:18]=[CH:19][CH:20]=[N:21][C:6]1=2)=[O:4])[CH2:25][CH3:26])[CH3:23]
Reactant: CCN(CC)CC1CCCCN1
Reactant: Cc1ccc2c(c1)C(=O)Nc1cccnc1N2C(=O)CCl
Solvent: CC(C)OC(C)C
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2ccc(C)cc2C(=O)Nc2cccnc21
Yield: 54 %

Procedure:
Prepared in analogy to Example 2 from 11-(chloroacetyl)-5,11-dihydro-8-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[(diethylamino)methyl]piperidine, but using acetonitrile as solvent, in a yield of 54% of theory. M.p. 173-174° C. (diisopropylether).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3](Cl)=[O:4].[OH-].[NH4+:15]>>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([NH2:15])=[O:4]
Reactant: [NH4+]
Reactant: CCCCCCCCC(C)C(=O)Cl
Agent: [OH-]
Product: CCCCCCCCC(C)C(N)=O
Temperature: 25 °C
Yield: 85.5 %

Procedure:
2-Methyl decanoyl chloride (68.9 g, 336 mmol) was added dropwise to rapidly stirred ammonium hydroxide (200 ml) cooled in an ice bath. The resulting white slurry was stirred at room temperature for one-half hour, then filtered through a Buchner funnel. The filter cake was washed with 100 ml of ice water, air-dried overnight, then dried in a vacuum over at 55° C. for 2 hours to give 53 g (85.5% yield) of a white solid product, m.p. 80°-81° C. (lit. m.p. 81.4° C.).