Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C@@H:31]1[CH2:42][CH2:41][C@@H:40]([OH:43])[C:34]2=[N+:35]([O-:39])[CH:36]=[CH:37][CH:38]=[C:33]2[CH2:32]1>C(Cl)Cl>[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C@@H:31]1[CH2:42][CH2:41][C:40](=[O:43])[C:34]2=[N+:35]([O-:39])[CH:36]=[CH:37][CH:38]=[C:33]2[CH2:32]1
Reactant: [O-][n+]1cccc2c1[C@H](O)CC[C@@H](c1cccc(F)c1F)C2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CC[C@@H](c2cccc(F)c2F)Cc2ccc[n+]([O-])c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dess-MartinPeriodinane (1.227 g, 2.89 mmol) was added to the CH2Cl2 (8 mL) solution of (6R,9R)-6-(2,3-difluorophenyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine 1-oxide (0.7662 g, 2.63 mmol) at rt. The reaction was stirred at rt for 1 hour. The reaction was directly load to a column and separated with 10% methanol in CH2Cl2 (0 to 10% gradient) (0.54 g, 42%). MS(ESI)[M+H+]=290.03.
Reaction SMILES: C(OP([CH:9]([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[Br-].[Mg+2].[Br-].CCN(CC)CC.[CH2:26]([N:33]1[CH2:37][CH2:36][C@@H:35]([NH:38][C:39]2[C:46]([Cl:47])=[CH:45][C:42]([CH:43]=O)=[CH:41][N:40]=2)[CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.C(OCC)(C)=O.O>[CH2:26]([N:33]1[CH2:37][CH2:36][C@@H:35]([NH:38][C:39]2[N:40]=[CH:41][C:42](/[CH:43]=[C:9](\[F:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:45][C:46]=2[Cl:47])[CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=Cc1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)c(Cl)c1
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(F)=C/c1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)c(Cl)c1
Temperature: 7.5 °C
Yield: 81.6 %

Procedure:
To a mixture of ethyl (diethoxyphosphoryl)(fluoro)acetate (1.46 g) and magnesium bromide (1.33 g) in THF (20 ml) was added dropwise to a Et3N (0.92 ml) with stirring at 0-15° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at same condition for an hour. A solution of 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloronicotinaldehyde (1.36 g) in THF (10 ml) solution was added the above mixture and resultant mixture was stirred at 0-15° C. for 4 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-n-hexane (3:7). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2Z)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridinyl)-2-fluoroacrylate (1.42 g).
Reaction SMILES: CC(C)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:11](Br)/[CH:12]=[C:13](/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])\[CH3:14].[OH:22][C:23]1[CH:33]=[CH:32][C:26]2[N:27]=[C:28]([C:30]#[N:31])[S:29][C:25]=2[CH:24]=1>CCCCCCC.C(OCC)(=O)C>[CH2:11]([O:22][C:23]1[CH:33]=[CH:32][C:26]2[N:27]=[C:28]([C:30]#[N:31])[S:29][C:25]=2[CH:24]=1)/[CH:12]=[C:13](/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])\[CH3:14]
Reactant: N#Cc1nc2ccc(O)cc2s1
Reactant: CC(C)=CCC/C(C)=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)=CCC/C(C)=C/COc1ccc2nc(C#N)sc2c1
Reaction time: 20 h
Yield: 120 %

Procedure:
To a dry 25-ml round-bottomed flask containing acetone (5 mL), anhydrous potassium carbonate (1.2 g, 8.4 mmole), and geranyl bromide (1.5 mL, 7.3 mmole) was added 6-hydroxy-2-cyanobenzothiazole (1 g, 5.6 mmole). The mixture was refluxed under argon with stirring. Reaction progress was monitored by TLC analysis, developing with 2:1 heptane-ethyl acetate. After 20 h, the potassium carbonate was filtered from the cooled reaction mixture. The solution was concentrated in vacuo to yield 2.1 g of solid. The solid was further purified by flash chromatography using a mixture of 9:1 heptane-ethyl acetate. Appropriate fractions were pooled and evaporated to yield 0.84 g of solid. The structure was confirmed by 1H NMR analysis in DMSO-d6.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.ClCCl.Cl[Si](C)(C)C.[C:26](Cl)(=[O:30])[C:27]([CH3:29])=[O:28]>C(N(CC)CC)C>[O:30]=[C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)[C:27](=[O:28])[CH3:29]
Reactant: CC(=O)C(=O)Cl
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Yield: 44 %

Procedure:
Using the method for the preparation of the side chain acid in Example 3, 11.5 g (50 mmol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 500 ml of dichloromethane, 21.0 ml (150 ml) of triethylamine, 20 ml (158 mmol) of chlorotrimethylsilane, and 8.0 g (75 mmol) of pyruvic acid chloride, [J. Org. Chem., 35, 3972 (1970)] gives 6.6 g of 6-[4(1,2-dioxopropylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid after recrystallization from N,N-dimethylacetamide; mp>280°.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[CH3:8][O:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:30][C:31]([F:49])([F:48])[C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44](=O)[CH2:45][CH3:46])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1>C1(C)C=CC=CC=1>[CH3:8][O:9][CH:10]=[C:44]([C:41]1[CH:42]=[CH:43][C:38]([C:35]2[CH:36]=[CH:37][C:32]([C:31]([F:49])([F:48])[F:30])=[CH:33][CH:34]=2)=[CH:39][CH:40]=1)[CH2:45][CH3:46]
Reactant: CCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCC(=COC)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
To a an ambient temperature suspension of potassium tert-butoxide (670 mg, 5.39 mmol) in toluene (36 mL) is added (methoxymethyl)triphenylphosphonium chloride (1.85 g, 5.56 mmol) and is stirred at room temperature for 30 min. 1-(4′-trifluoromethylbiphenyl-4-yl)-propan-1-one (1 g, 3.59 mmol) is added, and the reaction mixture continues to stir at room temperature overnight. The reaction mixture is filtered, using dichloromethane to aid rinsing, concentrated to ⅓ volume, then loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 25% giving 4-(1-methoxymethylene-propyl)-4′-trifluoromethylbiphenyl (278 mg).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Cl:8][C:9]1[CH:16]=[C:15]([N:17]2[C:21](=[O:22])[CH2:20][C@@H:19]([OH:23])[C@@H:18]2[CH2:24][CH3:25])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12].IC.O>O1CCCC1>[Cl:8][C:9]1[CH:16]=[C:15]([N:17]2[C:21](=[O:22])[C@H:20]([CH3:1])[C@@H:19]([OH:23])[C@@H:18]2[CH2:24][CH3:25])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: CC(C)NC(C)C
Reactant: CC[C@H]1[C@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: CC[C@H]1[C@H](O)[C@@H](C)C(=O)N1c1ccc(C#N)c(Cl)c1
Reaction time: 1 h
Yield: 37 %

Procedure:
A solution of diisopropylamine (0.208 mL) in tetrahydrofuran (8 mL) was cooled to −78° C., n-butyllithium-hexane solution (0.885 mL, 1.6 mol/L) was added dropwise, and the mixture was stirred for 1 hr. A solution of 2-chloro-4-[(2S,3R)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]benzonitrile (145.5 mg) in tetrahydrofuran (2 mL) was added dropwise and the mixture was stirred at −78° C. for 1 hr. A solution of iodomethane (0.176 mL) in tetrahydrofuran (2 mL) was added dropwise at −78° C., and the mixture was stirred at −78° C. for 30 min and at 0° C. for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→1/3) to give the title compound as a colorless solid (yield: 57.0 mg, 37%).
Reaction SMILES: O[C:2]1[C:3]2[S:12][CH:11]=[CH:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.P(Cl)(Cl)([Cl:15])=O.CN(C)C1C=CC=CC=1>C(#N)C>[Cl:15][C:2]1[C:3]2[S:12][CH:11]=[CH:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1
Reactant: CSc1nc(O)c2sccc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: CSc1nc(Cl)c2sccc2n1
Yield: 90.5 %

Procedure:
4-Hydroxy-2-methylthiothiopheno[3,2-d ]pyrimidine (15.4 g, 78 mmol) was combined with 50 mL of dry acetonitrile and 29 mL (312 mmol) of phosphoryl chloride and 10 mL (78 mmol) of N,N-dimethylaniline were added with stirring. The mixture was heated to reflux with stirring for 2 hours. It was then allowed to cool and most of the acetonitrile was removed by evaporation under reduced pressure. The residue was poured slowly into 200 mL of cold water with cooling and agitation. The resulting mixture was extracted with 4×500 mL of ether and the combined ethereal extracts were dried over magnesium sulfate and concentrated by evaporation under reduced pressure. The 15.3 g of tan solid title compound obtained melted at 115°-118° C. and had a proton NMR spectrum consistent with the assigned structure.
Reaction SMILES: CN1CCOCC1.ClC(OCC(C)C)=O.[C:16]([O:20][C:21]([NH:23][C@H:24]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:25][C:26]([OH:28])=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].Cl.[F:40][C:41]([F:59])([F:58])[O:42][C:43]1[CH:57]=[CH:56][C:46]([CH2:47][CH:48]2[NH:54][CH2:53][CH2:52][CH2:51][NH:50][C:49]2=[O:55])=[CH:45][CH:44]=1>ClCCl>[C:16]([O:20][C:21]([NH:23][C@H:24]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:25][C:26]([N:54]1[CH2:53][CH2:52][CH2:51][NH:50][C:49](=[O:55])[C@H:48]1[CH2:47][C:46]1[CH:45]=[CH:44][C:43]([O:42][C:41]([F:58])([F:59])[F:40])=[CH:57][CH:56]=1)=[O:28])=[O:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: O=C1NCCCNC1Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCCNC(=O)[C@H]1Cc1ccc(OC(F)(F)F)cc1)Cc1cc(F)c(F)cc1F
Temperature: -20 °C
Reaction time: 2 h

Procedure:
N-Methylmorpholine (0.072 mL) and isobutyl chloroformate (0.039 mL) were added to a stirred solution of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (95 mg) in dichloromethane (5 mL) at −20° C. and the resultant mixture was stirred for 30 min. Hexahydro-3-[4-(trifluoromethoxy)benzyl]-2H-1,4-diazepin-2-one hydrochloride obtained in Step D (91 mg) and IV-methylmorpholine (0.036 mL) were added. The reaction mixture was stirred for 30 min at −20° C. and 2 h at ambient temperature and then evaporated. The residue was purified by preparative TLC (silica gel, methanol/saturated aqueous ammonium hydroxide/dichloromethane 4.4:0.1:95.5), and the isomers were subsequently resolved by HPLC (ChiralPAK OD, 7% ethanol/hexane) to provide the slower eluting (R,R)-isomer.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:13]CC)(=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[N:16]([CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)=[N+:17]=[N-:18]>C(O)C>[CH2:10]([O:9][C:7]([C:6]1[N:18]=[N:17][N:16]([CH2:19][C:20]2[CH:21]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=2)[C:5]=1[OH:13])=[O:8])[CH3:11]
Reactant: [N-]=[N+]=NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1O
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Combine a solution of sodium ethoxide (5.5 mL, 21 wt % in ethanol) and diethyl malonate (2.50 mL, 16.5 mmol) in ethanol (26 mL) with a solution of 1-azidomethyl-3,5-bis-trifluoromethyl-benzene (4.40 g, 16.3 mmol) in ethanol (6 mL) and heat to 80° C. After 7 hours, cool to RT. Concentrate mixture in vacuo and dissolve the viscous oil in H2O (20 mL). Add aqueous 1N HCl until solution reaches pH 2-3. Collect the white precipitate by filtration and dry under reduced pressure to give the title compound: MS (IS) 384.0 (M+H), MS (ES−) 382.1 (M−H); 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.92 (s, 2H), 5.41 (s, 2H), 4.15 (q, 2H, J=7.3), 1.22 (t, 3H, J=7.3).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.[CH3:29]C([O-])(C)C.[K+].CI>CN(C=O)C.C1COCC1>[CH3:29][O:1][CH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1
Reactant: CC(C)(C)[O-]
Reactant: Cc1c(CO)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCc1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C
Temperature: 0 °C

Procedure:
To a solution of compound 3B (9.0 mg, 0.025 mmol) in DMF:THF (1:1, 1 mL) at 0° C. was added KOtBu (1.5 M in THF, 0.025 mL, 0.038 mmol). After stirring for 45° min at 0° C., methyl iodide (2 μL, 0.025 mmol) was added and the reaction mixture was stirred for an additional 1h, warmed to 25° C., and stirred for 3h. No reaction was observed during this time. The reaction mixture was cooled once more to 0° C., additional KOtBu (1.5 M in THF, 0.25 mL, 0.38 mmol) was added and the reaction mixture was stirred for 30 min, after which time additional methyl iodide (20 μL, 0.25 mmol) was added. After stirring for an additional 2h at 0° C., the reaction was quenched by the addition of saturated aqueous NH4Cl (10 mL) and dichloromethane (10 mL). The layers were separated, the aqueous phase was extracted with dichloromethane (2×10 mL) and the combined organic extracts were dried over MgSO4, filtered concentrated, and purified by preparative HPLC (YMC S5 ODS 20×100 mm, eluting with 30-100% aqueous methanol over 15 min containing 0.1% TFA, 20 mL/min) to afford the desired product as a yellow semi-solid. HPLC: 100% at 4.27 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 200 nm). MS (ES): m/z 385.21 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6](=[O:8])[C:5]2[NH:9][CH:10]=[CH:11][C:4]=2[S:3]1(=[O:13])=[O:12].Br[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][N:9]1[C:5]2[C:6](=[O:8])[CH2:7][N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]=2[CH:11]=[CH:10]1
Reactant: CN1CC(=O)c2[nH]ccc2S1(=O)=O
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN1CC(=O)c2c(ccn2CCCCCl)S1(=O)=O
Yield: 100.1 %

Procedure:
A suspension of 400 mg (2 mmol) of Compound 12, 1.37 g (8 mmol) of 1-bromo-4-chlorobutane and 1.11 g (8 mmol) of potassium carbonate in 20 ml of 2-butanone was refluxed for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: ethyl acetate/hexane=1/2), whereby 582 mg of the title compound were obtained (yield: 100%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=4)=[CH:21][C:20]=3[F:33])=[O:17])=[CH:13][C:12]([C:34]([CH3:37])([CH3:36])[CH3:35])=[N:11]2)=[CH:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[C:34]([C:12]1[CH:13]=[C:14]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=3)=[CH:21][C:20]=2[F:33])=[O:17])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][CH:6]=2)[N:11]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: COC(=O)c1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(C)c3)cc2F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(CO)cc3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
To a solution of 4-(3-tert-butyl-5-{3-[2-fluoro-4-(2-methyl-pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzoic acid methyl ester (700 mg, 1.35 mmol) in anhydrous THF at 0° C. was slowly added a 1N solution of lithium aluminum hydride in THF (0.95 mL, 0.95 mmol). The mixture was stirred at room temperature for 15 minutes, and then water was added dropwise to quench the reaction. The mixture was extracted with EtOAc, and the combined organic phases were dried over MgSO4 and evaporated at reduced pressure. The residue was purified by HPLC (10% to 90% aq acetonitrile) to afford 600 mg (90%) of the title compound as a white solid. 1H-NMR (DMSO-d6) δ 8.97 (s, 1H), 8.79 (s, 1H), 8.29 (d, J=5.7 Hz, 1H), 8.13 (t, J=9.0 Hz, 1H), 7.46 (m, 4H), 7.18 (d, J=14.7 Hz, 1H), 6.95 (d, J=10.2 Hz, 1H), 6.76 (d, J=2.1 Hz, 1H), 6.71 (d, J=5.4 Hz, 1H), 6.36 (s, 1H), 5.30 (t, J=5.7 Hz, 2H), 2.38 (s, 3H), 1.25 (s, 9H); MS LC-MS [M+H]+=490.2, RT=2.41 min.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C3C=CC=CC=3)[C@@H:13]([O:14]C(=O)C)[C@@H:12]2[F:30])=[C:4]([NH2:31])[N:3]=1.CC#N.O.O.[OH-].[Li+]>C(O)(=O)C>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@@H:12]2[F:30])=[C:4]([NH2:31])[N:3]=1
Reactant: CC(=O)O[C@H]1[C@H](F)[C@H](n2cnc3c(N)nc(F)nc32)O[C@@H]1COC(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of 1f (430 mg, 0.99 mmol) in 1:1 MeCN-H2O (40 mL) was treated in one portion with solid lithium hydroxide monohydrate (125 mg, 2.97 mmol). The reaction became a clear solution after being stirred at room temperature for 20 minutes. A 3-h TLC aliquot showed the deblocking to be Glacial acetic acid (57 μl) was added, and the solution was evaporated until white solid deposited. After being chilled, the solid was collected, washed with cold water, and dried in vacuo at room temperature to give crude 1g, 252 mg. This solid was dissolved in 40 mL of water and applied to a water-equilibrated SM-4 Bio-Bead column (1.5×32 cm). After initial elution with water, the product was eluted with a stepwise gradient, 5% →20% EtOH in water. The residue from the combined, evaporated column fractions was crystallized from 25 mL of boiling water with charcoal treatment and dried in vacuo at 56° C. for 16 hours to give pure 1g: 178 mg (59%). Mp 207°-209° C.; TLC 5:1 CHCl3 -MeOH, Rf 0.50; HPLC 99%, 9:1 H2O-MeCN; MS, z/e 288 (M+1)+ ; UV λ max pH 1 261 (14.0), 268 (sh), pH 7 260 (15.1), 268 (sh), pH 13 261 (14.9), 268 (sh). Anal. Calcd. for C10H11F2N5O3 ·H2O: C, 39.35; H, 4.29; N, 22.94. Found: C, 39.51; H, 4.21; N, 22.94.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[Cl:33][C:34]1[CH:35]=[C:36]([C:40]2[N:45]=[CH:44][C:43]([NH2:46])=[CH:42][N:41]=2)[CH:37]=[CH:38][CH:39]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:46][C:43]3[CH:44]=[N:45][C:40]([C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([Cl:33])[CH:35]=4)=[N:41][CH:42]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: Nc1cnc(-c2cccc(Cl)c2)nc1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cnc(-c5cccc(Cl)c5)nc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.7 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation B; 45 mg, 0.12 mmol) was diluted with DCM (1 mL) followed by the addition of oxalyl chloride in DCM (2M) (66 μl, 0.13 mmol) and DMF (1 drop). 2-(3-chlorophenyl)pyrimidin-5-amine (25 mg, 0.12 mmol) and DIEA (52 μl, 0.30 mmol) were added and the reaction was stirred at ambient temperature for 4 hours. The reaction was loaded directly onto silica gel and eluted with 5% ethyl acetate/hexanes to 70% ethyl acetate/hexanes to yield the desired compound (45 mg, 0.080 mmol, 67% yield).
Reaction SMILES: Br[C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7](=[O:12])[CH2:8][N:9]([CH3:11])[CH2:10][C:4]=2[CH:3]=1.[C:15]([O:19]C(C)(C)C)(=[O:18])[CH:16]=[CH2:17].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:11][N:9]1[CH2:10][C:4]2[CH:3]=[C:2](/[CH:17]=[CH:16]/[C:15]([OH:19])=[O:18])[CH:14]=[N:13][C:5]=2[NH:6][C:7](=[O:12])[CH2:8]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CN1CC(=O)Nc2ncc(Br)cc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reaction time: 0.42 h
Yield: 97.1 %

Procedure:
A suspension of 7-bromo-4-methyl-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.63 g, 2.5 mmol) in propionitrile (10 mL) and DMF (3 mL) was de-oxygenated with Ar for 25 min. The mixture was treated with tert-butyl acrylate (1.5 mL, 10 mmol) and (i-Pr)2EtN (0.9 mL, 5 mmol) and was de-oxygenated with Ar for 10 min. Pd(OAc)2 (56 mg, 0.25 mmol) and P(o-tol)3 (150 mg, 0.49 mmol) were added simultaneously, and the mixture was de-oxygenated a third time for 5 min. The mixture was heated to reflux for 18 h, then allowed to cool. The resulting precipitate was isolated by filtration, dissolved in CH2Cl2, filtered through Celite, and the solvent was removed in vacuo to give the title compound (0.60 g, 80%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 8.63 (s, 1H), 8.41 (d, J=2.0 Hz, 1H), 7.62 (d, J=1.7 Hz, 1H), 7.52 (d, J=16.0 Hz, 1H), 6.37 (d, J=16.0 Hz, 1H), 3.96 (s, 2H), 3.77 (s, 2H), 2.49 (s, 3H), 1.53 (s, 9H); MS (ESI) m/e 304 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH3:15])[C:8]([S:13][CH3:14])=[C:9]([O:11][CH3:12])[CH:10]=1)C=C.[BH4-].[Na+]>C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:12][O:11][C:9]1[CH:10]=[C:5]([OH:4])[CH:6]=[C:7]([CH3:15])[C:8]=1[S:13][CH3:14]
Reactant: C=CCOc1cc(C)c(SC)c(OC)c1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(O)cc(C)c1SC
Temperature: 45 °C

Procedure:
The allyl ether from stage (i) (850 mg, 3.8 mmol) was dissolved in THF (38 mL) and treated with palladium tetrakis(triphenylphosphine) (440 mg, 0.38 mmol) and sodium borohydride (719 mg, 19 mmol). The reaction mixture was then heated to 45° C. for 18 h. After cooling to room temperature most of the THF was evaporated and the residue was partitioned between 2M NaOH (25 mL) and diethyl ether (25 mL). The aqueous layer was separated and the organic layer was re-extracted with 2M NaOH (25 mL). The combined aqueous layers were neutralised to pH 7–8 with concentrated HCl and extracted with EtOAc (2×25 mL). The combined organic extracts were dried (MgSO4) and evaporated to an orange solid of the title phenol (530 mg, 76%); δH (CDCl3, 400 MHz) 2.20 (3H, s), 2.41 (3H, s), 3.83 (3H, s), 6.26 (1H, s), 6.29 (1H, s); MS m/z (ES−) 183 (M−H+).