Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=C(OC)C=CC=1C(O)=O.COC([C@H]1C[C@H](N)CN1C(OC(C)(C)C)=O)=O.FC1C=CC(O)=C(B(O)O)C=1.[F:41][C:42]1[CH:43]=[CH:44][C:45]([OH:77])=[C:46]([C:48]2[N:57]=[C:56]([NH:58][C@@H:59]3[CH2:63][N:62](C(OC(C)(C)C)=O)[C@@H:61]([C:71](OC)=[O:72])[CH2:60]3)[C:55]3[C:50](=[CH:51][C:52]([O:75][CH3:76])=[CH:53][CH:54]=3)[N:49]=2)[CH:47]=1>>[F:41][C:42]1[CH:43]=[CH:44][C:45]([OH:77])=[C:46]([C:48]2[N:57]=[C:56]([NH:58][C@H:59]3[CH2:60][C@H:61]([CH2:71][OH:72])[NH:62][CH2:63]3)[C:55]3[C:50](=[CH:51][C:52]([O:75][CH3:76])=[CH:53][CH:54]=3)[N:49]=2)[CH:47]=1
Reactant: COC(=O)[C@H]1C[C@H](Nc2nc(-c3cc(F)ccc3O)nc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C
Agent: COC(=O)[C@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Agent: COc1ccc(C(=O)O)c(N)c1
Agent: OB(O)c1cc(F)ccc1O
Product: COc1ccc2c(N[C@@H]3CN[C@@H](CO)C3)nc(-c3cc(F)ccc3O)nc2c1

Procedure:
The title compound was prepared using methods analogous to those described in Synthesis 80-A, 30-A, 76-B and 89-B, replacing 2-amino-5-methoxybenzoic acid with 2-amino-4-methoxybenzoic acid in Synthesis 80-A, replacing (S)-(−)-1-boc-3-aminopyrrolidine with (2R,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in Synthesis 30-A, replacing 2-hydroxyphenylboronic acid with 5-fluoro-2-hydroxyphenylboronic acid in Synthesis 76-B (using the crude Boc-protected amine in Synthesis 89-B), and replacing (2R,4S)-1-tert-butyl 2-methyl 4-(2-(5-fluoro-2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1,2-dicarboxylate with (2R,4S)-1-tert-butyl 2-methyl 4-(2-(5-fluoro-2-hydroxyphenyl)-7-methoxyquinazolin-4-ylamino)pyrrolidine-1,2-dicarboxylate in Synthesis 89-B.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12](C(O)=O)[CH2:11][S:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1C[O:20][CH2:19]C1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH2:19][OH:20])[S:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CSCC1C(=O)O
Agent: B
Product: CC(C)(C)OC(=O)N1CSC(CO)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a stirred solution of 3-tert-butoxycarbonylthiazolidine4-carboxylic acid (2.3 g, 10.0 mmol) in THF (30 ml) was added BH3.THF(1.0 M solution in THF, 20.0 ml, 20.0 mmol) at 0° C. After stirred at room temperature for 1.0 h, the reaction mixture was heated under reflux for 1.0 hr. After cooled, the mixture was concentrated in vacuo. Water was added thereto at 0° C., and extracted with EtOAc. The extract was washed with water, then dried over Na2SO4, and concentrated in vacuo to give 3-tert-butoxycarbonyl-5-hydroxymethylthiazolidine (2.0 g , quant) as a a colorless oil. 1H-NMR (CDCl3) δ 1.48 (s, 9H), 2.80–2.85 (m, 1H), 3.13–3.17 (m, 1H), 3.20–3.30 (m, 1H), 3.64–3.70 (m, 2H), 4.34 (br s, 1H), 4.60 (br s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]([CH2:12][CH3:13])[C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH2:12][CH3:13])[C:8]([NH:10][CH3:11])=[O:9])=[CH:14][CH:15]=1
Reactant: CCC(Oc1ccc(O)cc1)C(=O)NC
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCC(Oc1ccc(OCc2cccc(Cl)c2)cc1)C(=O)NC

Procedure:
In analogy to the procedure described in Example 3b), the alkylation of (RS)-2-(4-hydroxy-phenoxy)-N-methyl-butyramide with 3-chloro-benzylbromide in 2-butanone using potassium carbonate as the base yielded the (RS)-2-[4-(3-chloro-benzyloxy)-phenoxy]-N-methyl-butyramide as a white solid; MS: m/e=334 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][CH:5]=1)=[C:2]=[S:3].Br.Br[CH2:19][CH2:20][NH2:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[S:3]1[CH2:19][CH2:20][N:21]=[C:2]1[NH:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH2:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:8][CH:9]=1
Reactant: NCCBr
Reactant: O=C1CCC(c2ccc(N=C=S)cc2)=NN1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCC(c2ccc(NC3=NCCS3)cc2)=NN1
Temperature: 80 °C
Yield: 73.9 %

Procedure:
A mixture of 0.57 g of 4,5-dihydro-6-[4-(isothiocyano)phenyl]-3(2H)-pyridazinone, 0.51 g of 2-bromoethylamine hydrobromide and 0.34 g of anhydrous K2CO3 in 12 ml of DMF is heated at 80° C. for four hours. The reaction mixture is cooled, filtered, and the filtrate is concentrated under reduced pressure. The residue is treated with water, neutralized, and filtered to give 0.5 g of 6-[4-[(4,5-dihydro-2-thiazolyl)amino]phenyl]-4,5-dihydro-3(2H)-pyridazinone, mp 217°-218° C.
Reaction SMILES: C([C:3]1[C:4]([C:16]([OH:18])=[O:17])=[C:5]([CH3:15])[N:6]([CH3:14])[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[OH-].[Na+]>CCO>[CH3:14][N:6]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][C:4]([C:16]([OH:18])=[O:17])=[C:5]1[CH3:15]
Reactant: CCc1c(C(=O)O)c(C)n(C)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(=O)O)cc(-c2ccccc2)n1C
Yield: 92.9 %

Procedure:
To the solution of Ethyl 1,2-dimethyl-5-phenyl-1H-pyrrole-3-carboxylic acid (3 g, 13 mmol) in EtOH (50 ml) was added NaOH (1.6 g, 39 mmol) at room temperature. The reaction mixture was refluxed for 1 day with LC-MS monitoring. After reaction complete, EtOH was evaporated under reduced pressure. Water (50 ml) was added and washed aqueous layer with diethyl ether twice. 1N HCl solution was added to aqueous layer until pH<3. And extraction was accomplished with EtOAc. Organic layer was dried with MgSO4 and evaporated in vacuo to provide title compound (2.6 g, 95%) as yellow soild. Without further purification, acid was used for the reaction of amide coupling.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:10][CH:9]([OH:11])[CH2:8][NH:7]1)=[O:5].Cl[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].Cl>C(#N)C>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([OH:11])[CH2:8][N:7]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])=[O:5]
Reactant: COC(=O)C1CC(O)CN1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: Cl
Solvent: CC#N
Product: COC(=O)[C@@H]1C[C@H](O)CN1c1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 22 h
Yield: 98.9 %

Procedure:
A suspension of 2S,4S)-4-hydroxy-pyrrolidine-2-carboxylic acid methyl ester hydrochloride (4.0 g, 1.0 eq) in acetonitrile (55 mL) was treated with TEA (3.8 g, 1.36 eq) and 1-chloro-2-nitrobenzene (4.1 g, 1.05 eq). A solution formed, followed by rapid formation of a white precipitate. The mixture was stirred at 60° C. for 22 h then poured over HCl 1N (60 mL) and extracted several times with ether. The combined organic extracts were dried over sodium sulfate and evaporated. Purification by flash chromatography on silica gel with an heptane/ethyl acetate gradient yielded the title compound as a white solid (5.8 g, 79%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1C1CCCCC=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]1([CH3:44])[CH2:33][CH2:32][C:31](=[O:34])[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29]1>>[C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:30]1[C:31](=[O:34])[CH2:32][CH2:33][C:28]([CH3:27])([CH3:44])[CH:29]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C(=O)CC1
Reactant: Cc1cc2ccccc2c(C2=CCCCC2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2ccccc2c(C2=CC(C)(C)CCC2=O)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-Butoxy-2-(1-(3,3-dimethyl-6-oxocyclohex-1-enyl)-3-methylnaphthalen-2-yl)acetic acid (11) was prepared following the procedure to make (S)-2-tert-butoxy-2-(1-cyclohexenyl-3-methylnaphthalen-2-yl)acetic acid of Example 6 except that 4,4-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-enone was used instead of cyclohexenylboronic acid. Atropisomers were separated by flash column chromatography. 1H-NMR: 400 MHz, (CD3OD) δ: 7.72 (d, J=8.2 Hz, 1H), 7.59 (s,1H), 7.39 (m, 2H), 7.37 (m, 1H), 7.02 (s, 1H), 5.42 (s,1H), 2.82 (m, 1H), 2.67 (m, 1H), 2.58 (s, 3H), 2.18 (m, 2H), 1.38 (s, 6H), 1.08 (s, 9H). LCMS-ESI+ (m/z): [M−H]− calcd for C25H29O4: 393.50. found: 393.0.
Reaction SMILES: C(S(N1CC(CC#N)([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)C1)(=O)=O)C.O.Cl.[OH-].[Na+]>O1CCCC1>[NH:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1
Reactant: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Temperature: 23 °C
Reaction time: 3.5 h
Yield: 82.1 %

Procedure:
To a suspension of crude 4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl) -7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (6), made as described above, in tetrahydrofuran (THF, 4.2 L) in the reactor was charged water (H2O, 20.8 L), and a 10% aqueous HCl solution (16.2 L, 45.89 mol, 3.44 equiv) at room temperature. The resulting reaction mixture was stirred at 16-30° C. for 2-5 h. When the reaction was deemed complete by HPLC analysis, the reaction mixture was treated with a 30% aqueous sodium hydroxide (NaOH) solution (4 L, 50.42 mol, 3.78 equiv) at room temperature. The resulting reaction mixture was stirred at room temperature for 1-2 h. The solids were collected by filtration and washed with water (2×5 L). The wet cake was charged back to the reactor with acetonitrile (21.6 L), and resulting suspension was heated to gentle reflux for 1-2 h. The clear solution was then gradually cooled down to room temperature with stirring, and solids were precipitated out from the solution with cooling. The mixture was stirred at room temperature for an additional 1-2 h. The solids were collected by filtration, washed with acetonitrile (2×3.5 L), and dried in oven under reduced pressure at 45-55° C. to constant weight to afford 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 3281.7 g, 3996.8 g theoretical, 82.1% yield) as white crystalline solids (99.5 area % by HPLC). For 5: 1H NMR (DMSO-d6, 400 MHz) δ 13.41 (br. s, 1H), 8.74 (s, 1H), 8.67 (br. s, 1H), 8.35 (br. s, 1H), 7.72 (d, 1H, J=3.7 Hz), 7.10 (d, 1H, J=3.7 Hz), 5.61 (s, 2H), 3.51 (t, 2H, J=8.2 Hz), 0.81 (t, 2H, J=8.2 Hz), 0.13 (s, 9H) ppm; C15H21N5OSi (MW, 315.45), LCMS (EI) m/e 316 (M++H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:16][C:17]([C:19]1[S:20][CH:21]=[C:22]([CH2:24]Cl)[N:23]=1)=[O:18])C>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([O:13][CH2:24][C:22]2[N:23]=[C:19]([C:17]([OH:18])=[O:16])[S:20][CH:21]=2)=[CH:11][CH:12]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)c1nc(CCl)cs1
Product: O=C(O)c1nc(COc2ccc(-c3ccccc3)cc2)cs1

Procedure:
4-(Biphenyl-4-yloxymethyl)-thiazole-2-carboxylic acid was prepared using general procedure B from 4-phenylphenol (available from Aldrich, Milwaukee, Wis.) and 4-chloromethyl-thiazole-2-carboxylic acid ethyl ester (Intermediate 4). Yield: 54 mg. Mass spectrum (ES) M-OH=294
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:7]=[C:8]([CH2:13][CH2:14][C:15]([OH:17])=O)[CH:9]=[C:10]([Cl:12])[CH:11]=1>C(Cl)Cl>[Cl:12][C:10]1[CH:9]=[C:8]2[C:7](=[C:6]([Cl:5])[CH:11]=1)[C:15](=[O:17])[CH2:14][CH2:13]2
Reactant: O=C(O)CCc1cc(Cl)cc(Cl)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1CCc2cc(Cl)cc(Cl)c21
Yield: 71.6 %

Procedure:
Thionyl chloride (45.2 g) was added dropwise at 40° C. to a solution of 3-(3,5-di-chlorophenyl)propionic acid (54.8 g) in methylene chloride (200 ml). After reaction was complete, excess thionyl chloride and the solvent were removed by distillation. The oily residue was added dropwise at 40° C. to a suspension of aluminium chloride (66.7 g) in methylene chloride (200 ml). The reaction mixture was added to dilute hydrochloric acid after 18 hours at 40° C. The aqueous phase was separated off and extracted once with methylene chloride (250 ml). The combined organic phases were freed from the solvent. The residue was recrystallized from cyclohexane. 36 g of a colorless solid (m.p.: 119-120° C.) were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:16]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:15][C:5]2[N:6]([CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:7]=[N:8][C:4]=2[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:30]N1C(=O)CCC1=O.[NH4+].[Cl-]>C1COCC1>[Cl:30][C:7]1[N:6]([CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[C:5]2[CH:15]=[C:16]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COCCOCn1cnc2cc(Cl)c(N3CCCC3)cc21
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCOCn1c(Cl)nc2cc(Cl)c(N3CCCC3)cc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
A solution of 5-chloro-1-(2-methoxy-ethoxymethyl)-6-pyrrolidin-1-yl-1H-benzoimidazole (0.221 g, 0.714 mmol) and THF (2.5 mL) was cooled to −78° C. in an acetone/dry ice bath. Lithium diisopropylamide (2.0M solution in THF/heptane/ethylbenzene, 0.90 mL, 1.8 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for 30 min. N-chlorosuccinimide (267 mg, 2.00 mmol) was added at −78° C. and the reaction mixture was warmed to 23° C. and stirred for 2 h. Saturated aqueous NH4Cl (20 mL) was added and the crude product was extracted into EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (0-100% EtOAc/hexanes) to yield the titled compound (0.240 g, 71%) as a mixture of regioisomers with purity of 70%. MS (ESI/CI): mass calcd. for C15H19Cl2N3O2, 343.1; m/z found, 344.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[C-:13]#[N:14].[Na+].CS(C)=O>O>[CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:13]#[N:14])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(CCl)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Cc1ccc(CC#N)cc1
Yield: 73.4 %

Procedure:
527 g of 4-isobutylbenzyl chloride, 153 g of sodium cyanide and 720 ml of dimethylsulfoxide are agitated for 6 hours at 40° C. The mixture is cooled and then diluted with water. An oily layer separates and is extracted with ether. The ether solution is subjected to fractionation and yields 367 g of 4-isobutylphenyl acetonitrile.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4]Cl.[F:13][C:14]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:15][OH:16].[OH-].[K+].ClCCl>CN(C)C=O>[F:13][C:14]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:15][O:16][CH2:4][C:3]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=1[CH3:1]
Reactant: Cc1ccc([N+](=O)[O-])cc1CCl
Reactant: OCC(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])cc1COCC(F)(F)C(F)(F)F
Reaction time: 8 h

Procedure:
In 16.5 ml of dimethylformamide, 5.00 g (0.027 mol) of 2-methyl-5-nitrobenzyl chloride and 21.3 g (0.135 mol) of 2,2,3,3,3-pentafluoropropanol were dissolved. The solution was then added with 2.29 g (0.041 mol) of KOH pellets and stirred overnight. Dichloromethane was added and the precipitated salts were filtered out. The filtrate was acidified with dilute hydrochloric acid and then the solvents were distilled off.
Reaction SMILES: [C@H:1]([NH:5][C:6]1[C:7]([C:20]#[N:21])=[CH:8][C:9]([C:16]([F:19])([F:18])[F:17])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])([CH2:3][CH3:4])[CH3:2].OO.C(=O)([O-])[O-:25].[K+].[K+]>CS(C)=O>[C@H:1]([NH:5][C:6]1[C:7]([C:20]([NH2:21])=[O:25])=[CH:8][C:9]([C:16]([F:19])([F:18])[F:17])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])([CH2:3][CH3:4])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC[C@@H](C)Nc1cc(C(=O)OC)c(C(F)(F)F)cc1C#N
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC[C@@H](C)Nc1cc(C(=O)OC)c(C(F)(F)F)cc1C(N)=O
Yield: 197.7 %

Procedure:
(R)-Methyl 5-(sec-butylamino)-4-cyano-2-(trifluoromethyl)benzoate (45 mg, 0.150 mmol) was dissolved in DMSO (1 mL) and was treated with 30% aqueous hydrogen peroxide (0.05 mL) and potassium carbonate (6 mg, 0.043 mmol) at ambient temperature for 2 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was dried over sodium sulfate, then filtered and concentrated to afford a yellow oil which was purified by column chromatography (silica gel, 10-40% ethyl acetate in hexanes) to afford (R)-methyl 5-(sec-butylamino)-4-aminocarbonyl-2-(trifluoromethyl)benzoate (27 mg, 0.085 mmol, 57% yield). (R)-M ethyl 5-(sec-butylamino)-4-aminocarbonyl-2-(trifluoromethyl)benzoate (27 mg, 0.085 mmol) was suspended in methanol (1 mL) and was treated with 1 M sodium hydroxide (0.2 mL, 0.2 mmol) at 45° C. for 1 h. Dichloromethane (0.5 mL) and 1M sodium hydroxide (0.2 mL, 0.2 mmol) was added and the mixture was stirred at 45° C. for a further 1.5 h. Dichloromethane (0.5 mL) and 1M sodium hydroxide (0.2 mL, 0.2 mmol) were added, and the mixture was stirred at 45° C. for a further 1 h and then at ambient temperature for 15 h. The reaction mixture was concentrated to afford an aqueous residue that was cooled in an ice bath, was acidified with 1N hydrochloric acid to pH ˜2, then extracted with ethyl acetate (2×). The organic portion was dried over sodium sulfate, then filtered and concentrated to provide 4-(aminocarbonyl)-5-{[(1R)-1-methylpropyl]amino}-2-(trifluoromethyl)benzoic acid (23 mg, 0.076 mmol, 89% yield). MS (EI) for C13H15F3N2O3: 305 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:31])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][CH:22]([CH2:25][C:26]([O:28]C)=[O:27])[CH2:21][CH2:20]4)=[CH:15][C:14]=3[F:30])[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1.[Li+].[OH-].Cl.C(O)(C)C.[NH3:39]>O1CCOCC1.C1COCC1.CO.O.C(Cl)Cl>[NH2:39][C:2]1[C:7]2[C:8](=[O:31])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:20][CH2:21][CH:22]([CH2:25][C:26]([OH:28])=[O:27])[CH2:23][CH2:24]4)=[CH:15][C:14]=3[F:30])[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: N
Reactant: COC(=O)CC1CCC(c2ccc(N3CCOc4ncnc(Cl)c4C3=O)c(F)c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Nc1ncnc2c1C(=O)N(c1ccc(C3CCC(CC(=O)O)CC3)cc1F)CCO2
Temperature: 23 °C
Reaction time: 16 h

Procedure:
The title compound was prepared as follows. A mixture of methyl 2-(4-(4-(4-chloro-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)-3-fluorophenyl)cyclohexyl)acetate (20 mg, 0.045 mmol), from Preparation 4, in 0.5M ammonia in dioxane was stirred at 50° C., in a tightly capped flask, for 3 hours. The reaction mixture was concentrated to give a white solid, which was carried on to the next step without further purification. LiOH (4.5 mg, 0.18 mmol) was added to a solution of the white solid in THF/methanol/water (2.4 mL, 3:2:1) and the resulting solution was stirred at 23° C. for 16 hours. 1M HCl solution was added to reaction solution to adjust the pH about 3. 20% i-propanol in DCM (30 mL) was added to extract reaction mixture. The organic layer was separated and dried over MgSO4 and concentrated to give a solid. Purification was done by chromatography (4 g, silica gel column) with methanol/DCM from 2-6% to give a white solid 12 mg as the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([N:14]([CH2:28][CH2:29][CH3:30])[C:15]([C:17]1[CH:18]=[C:19]([CH:24]=[C:25](I)[CH:26]=1)[C:20]([O:22][CH3:23])=[O:21])=[O:16])[CH2:12][CH3:13]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-].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]>[CH2:28]([N:14]([CH2:11][CH2:12][CH3:13])[C:15]([C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH:26]=1)[C:20]([O:22][CH3:23])=[O:21])=[O:16])[CH2:29][CH3:30]
Reactant: CCCN(CCC)C(=O)c1cc(I)cc(C(=O)OC)c1
Reactant: c1cocn1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-[(Dipropylamino)carbonyl]-5-iodobenzoic acid (12 g, 32 mmol) is dissolved in 20% methanol/benzene (480 mL), and 2M trimethylsilyldiazomethane in hexane (19 mL, 38 mmol) is added slowly. Upon completion of the addition, the solution is concentrated under reduced pressure to give methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate for use without further purification in the following reaction. To a −70° C. stirred solution of oxazole (120 mg, 1.7 mmol) in tetrahydrofuran (4 mL) is added n-butyllithium (1.6 M in hexanes, 1.2 mL, 1.9 mmol). After 30 min, zinc chloride (1 M in diethyl ether, 5.2 mL, 5.2 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is added a solution of methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate (643 mg, 1.6 mmol) in anhydrous tetrahydrofuran (3 mL) followed by palladium(0) tetrakis(triphenylphosphine) (80 mg, 0.07 mmol). The reaction mixture is heated at reflux for 3 h. The reaction mixture is cooled, diluted with ethyl acetate, filtered, washed with saturated sodium bicarbonate, water, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 60% ethyl acetate/hexane) provides the title compound in pure form. 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.27 (s, 1H), 8.14 (s, 1H), 7.80 (s, 1H) 7.32 (s, 1H), 3.52 (t, 2H), 3.22 (t, 2H), 1.75 (m, 2H), 1.30 (m, 2H), 0.97 (t, 3H), 0.79 (t, 3H).
Reaction SMILES: [CH:1]1[C:10]2[N:9]3[CH:11]=[CH:12][CH:13]=[C:8]3[C:7]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[O:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[F:26][C:27]([F:42])([F:41])[S+]1C2C=CC=CC=2C2C=CC=CC1=2.O>CN(C=O)C>[F:26][C:27]([F:42])([F:41])[C:11]1[N:9]2[C:10]3[CH:1]=[CH:2][CH:3]=[N:4][C:5]=3[O:6][C:7]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:8]2=[CH:13][CH:12]=1
Reactant: FC(F)(F)[s+]1c2ccccc2c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ncccc1-n1cccc12
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ncccc1-n1c(C(F)(F)F)ccc12
Yield: 51.6 %

Procedure:
A solution of tert-butyl spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate (134 mg, 0.393 mmol) and 5-(trifluoromethyl)dibenzothiophen-5-ium (99.4 mg, 0.393 mmol) in DMF (2 mL) was stirred at 80° C. for 1.5 hours. The mixture was poured into water and was extracted with EtOAc (3×). The organics were combined, washed with water and brine, dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography (1-30% EtOAc/hexanes) to give tert-butyl 9′-(trifluoromethyl)spiro-[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate (83 mg, 56%). ESI-MS m/z calc. 409.2. found 410.5 (M+1)+; Retention time: 1.92 minutes (3 min run).