Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([OH:18])=O)[C:5]2[C:10]([CH3:11])=[N:9][N:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=2[N:7]=1.[NH2:19][CH2:20][C:21]1[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=1[CH3:27].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:6]=2[N:7]=1
Reactant: Cc1nn(C(C)(C)C)c2nc(Cl)cc(C(=O)O)c12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C(C)(C)C)c(=O)[nH]1
Reaction time: 8 h

Procedure:
To a solution of 6-chloro-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (320 mg, 1.195 mmol) in DMSO(7 mL) were added 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (338 mg, 1.793 mmol), N-methylmorpholine (0.526 mL, 4.78 mmol), 1-hydroxy-7-azabenzotriazole (325 mg, 2.391 mmol) and EDC (458 mg, 2.391 mmol), and the reaction mixture was stirred overnight. The reaction mixture was quenched with water (20 mL) and stirred for 10 min. The precipitate was collected by filtration and further dried under high vacuum to give the product as a solid, 450 mg (94%). LCMS E-S (M+H)=402.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.71 (s, 9 H), 2.12 (s, 3 H), 2.22 (s, 3 H), 2.37 (s, 3 H), 4.33 (d, J=4.80 Hz, 2 H), 5.88 (s, 1 H), 7.09-7.21 (m, 1 H), 8.77 (t, J=4.93 Hz, 1 H), 11.53 (s, 1 H).
Reaction SMILES: CC([CH:5]1[CH2:10][N:9]([CH2:11][CH:12]([O:24][CH2:25][CH3:26])[C:13]2[CH:22]=[CH:21][C:16]3[C:17](=[O:20])[O:18][CH2:19][C:15]=3[C:14]=2[CH3:23])[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.[ClH:30]>O1CCOCC1>[ClH:30].[CH2:25]([O:24][CH:12]([C:13]1[CH:22]=[CH:21][C:16]2[C:17](=[O:20])[O:18][CH2:19][C:15]=2[C:14]=1[CH3:23])[CH2:11][N:9]1[CH2:10][CH2:5][NH:6][CH2:7][CH2:8]1)[CH3:26]
Reactant: CCOC(CN1CCN(C(=O)[O-])C(C(C)(C)C)C1)c1ccc2c(c1C)COC2=O
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(CN1CCNCC1)c1ccc2c(c1C)COC2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl-4-[2-(ethyloxy)-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate was treated with 4M HCl in dioxane (4 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness. Analysis by LC indicated complete removal of the Boc group and formation of 5-[1-(ethyloxy)-2-piperazin-1-ylethyl]-4-methyl-2-benzofuran-1(3H)-one hydrochloride.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Br:21])[CH:9]=[C:8]2[CH3:22])=[O:4]>O1CCOCC1.[OH-].[Na+]>[Br:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:10]1[CH:9]=[C:8]([CH3:22])[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[N:11]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3Br)cc(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(-c2ccccc2Br)nc2ccc(C(=O)O)cc12

Procedure:
Compound 471b (500 mg, 1.4 mmol) was refluxed in a mixture of 15 mL dioxane and 15 mL 1M aqueous NaOH for 1 h then it was evaporated to dryness, the residue dissolved in 50 mL water and acidified with 1M HCl solution to pH 4. The precipitate was filtered off, washed four times with water and dried. Yield: 361 mg (75%).
Reaction SMILES: [C:1]1([S:7]([N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:27])([C:23]([F:26])([F:25])[F:24])[C:18]#[C:19][C:20](O)=[O:21])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN.Cl.[CH3:35][N:36](C)CCCN=C=NCC>C(Cl)Cl>[CH3:35][NH:36][C:20](=[O:21])[C:19]#[C:18][C:17]([C:14]1[CH:15]=[CH:16][C:11]([N:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:12][CH:13]=1)([OH:27])[C:23]([F:26])([F:25])[F:24]
Reactant: CC(C)CN(c1ccc(C(O)(C#CC(=O)O)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)C#CC(O)(c1ccc(N(CC(C)C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.2 g of 4-[4-(benzenesulfonyl-isobutyl-amino)-phenyl]-5,5,5-trifluoro-4-hydroxy-pent-2-ynoic acid (see Example 69; 0.439 mmol) and 0.26 mL of methylamine (2M in THF) were combined in 3 mL of CH2Cl2 at rt. 0.1 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.527 mmol) was added. The resulting mixture was stirred at rt for 16 h. After addition of 80 mL of CH2Cl2 the resulting solution was washed with an aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate and brine. The organic layers were dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica(EtOAc:hexanes, 1:1) to give the title compound. 1H NMR (400 MHz, CDCl3) δ 0.90 (m, 6 H), 1.56 (m, 1 H), 2.91 (d, J=5.0 Hz, 3 H), 3.31 (m, 2 H), 3.72 (br s, 1 H), 6.26 (d, 5.0 Hz, 1 H), 7.11 (d, J=8.7 Hz, 2 H), 7.44-7.60 (m, 5 H), 7.64 (d, J=8.7 Hz, 2 H). Mass Spectrum (CI+) m/e=486 (M+18).
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[Br:9][C:10]1[CH:11]=[CH:12][C:13]([OH:17])=[N:14][C:15]=1[Cl:16]>CO>[Br:9][C:10]1[CH:11]=[C:12]([I:8])[C:13]([OH:17])=[N:14][C:15]=1[Cl:16]
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(Br)c(Cl)n1
Solvent: CO
Product: Oc1nc(Cl)c(Br)cc1I
Temperature: 45 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
NIS (7.38 g, 32.8 mmol) was added to a stirring solution of commercially available 5-bromo-6-chloropyridin-2-ol (5.70 g, 27.3 mmol) in MeOH (50 ml) at 45° C. The reaction was allowed to stir at 45° C. for 1 h. The amber colored solution was cooled to rt and then concentrated in vacuo. The resulting yellow solids were diluted with 25 mL DCM, triturated for 30 min, then collected filtering with minimal DCM to give 5-bromo-6-chloro-3-iodopyridin-2-ol (7.60 g, 22.7 mmol, 83% yield) as a white solid consistent by LCMS and NMR. LCMS: m/e 335 (M+H)+ LCMS retention time: 2.62 min. (Column: Phenomenex-Luna 50×2.0 mm 3u. Solvent A=90% Water: 10% Methanol: 0.1% TFA. Solvent B=10% Water: 90% Methanol: 0.1% TFA. Start % B=0. Final % B=100. Gradient Time=4 min. Flow Rate=0.8 mL/min.). 1H NMR (500 MHz, MeOD) δ ppm 8.26 (s, 1H).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][CH:27]2[CH2:29][CH2:28]2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][CH:27]2[CH2:29][CH2:28]2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(Sc2c(NCC3CC3)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(Sc2c(NCC3CC3)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
The mixture of 0.6 g of 4-(4-acetamidophenylmercapto)-3-cyclopropylmethylamino-5-sulfamoylbenzoic acid, 3 ml of water and 6 ml of 2 N aqueous sodium hydroxide is refluxed for 2 hours under nitrogen. After cooling it is filtered, the filtrate acidified with glacial acetic acid to pH 4-5, the precipitate separated, washed with water and recrystallized from 66% aqueous ethanol, to yield the 4-(4-aminophenylmercapto)-3-cyclopropylmethylamino-5-sulfamoylbenzoic acid melting at 221°-223°.
Reaction SMILES: IC.CN([CH2:6][CH:7]1[CH2:19][S:18][C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]1=[O:20])=[CH:16][CH:15]=[CH:14][CH:13]=3)C.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:21][C:22]1[N:23]([CH2:6][CH:7]2[CH2:19][S:18][C:10]3[NH:11][C:12]4[C:17]([C:9]=3[C:8]2=[O:20])=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:24]=[CH:25][N:26]=1
Reactant: CN(C)CC1CSc2[nH]c3ccccc3c2C1=O
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1nccn1CC1CSc2[nH]c3ccccc3c2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.60 ml (0.09 mol) of iodomethane are added to a solution of 23.43 g (0.09 mol) of 3-[(dimethylamino)methyl]-4-oxo-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole (hydrochloride) in 250 ml of dimethylformamide. The mixture is stirred at room temperature for 1 hour, a solution of 22.17 g (0.27 mol) of 2-methylimidazole in 50 ml of dimethylformamide is then added and the reaction medium is thereafter heated to 100° C. for 36 hours. After the mixture is cooled, 500 ml of 2N aqueous sodium carbonate solution are added and the resulting mixture is extracted three times with ethyl acetate. The organic phases are combined, washed with water (200 ml), dried and concentrated under vacuum. The product is chromatographed on silica, eluting with a methylene chloride/ethanol/ammonia solution mixture (92:8:0.5). The residue is recrystallized in acetonitrile.
Reaction SMILES: OCCNS(C1C=CC(C2NC(=O)C(=CC=2)C(O)=O)=CC=1)(=O)=O.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[OH:47][CH2:48][CH2:49][N:50](CCO)[S:51]([C:54]1[CH:59]=[CH:58][C:57]([C:60]2[NH:61][C:62](=[O:76])[C:63](=[CH:74][CH:75]=2)[C:64]([O:66][N:67]2[C:71](=[O:72])[CH2:70][CH2:69][C:68]2=[O:73])=[O:65])=[CH:56][CH:55]=1)(=[O:53])=[O:52]>CN(C)C=O>[OH:47][CH2:48][CH2:49][NH:50][S:51]([C:54]1[CH:59]=[CH:58][C:57]([C:60]2[NH:61][C:62](=[O:76])[C:63](=[CH:74][CH:75]=2)[C:64]([O:66][N:67]2[C:68](=[O:73])[CH2:69][CH2:70][C:71]2=[O:72])=[O:65])=[CH:56][CH:55]=1)(=[O:53])=[O:52]
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(-c2ccc(S(=O)(=O)N(CCO)CCO)cc2)[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)c1ccc(-c2ccc(S(=O)(=O)NCCO)cc2)[nH]c1=O
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: O=C(ON1C(=O)CCC1=O)c1ccc(-c2ccc(S(=O)(=O)NCCO)cc2)[nH]c1=O

Procedure:
From 3.8 g. of 6-[4-[(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinic acid and 1.34 g. of N-hydroxysuccinimide in 60 ml. of dimethylformamide, and 2.56 g. of N,N'-dicyclohexylcarbodiimide in 5 ml. of dimethylformamide, following the procedure of (a) above, there is obtained 6-[4-[(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinic acid, 2,5-dioxo-1-pyrrolidinyl ester; m.p. 203.5°-205° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.[CH:9]1([O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH:18]=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.C([O-])(=O)C.[Na+].C([BH3-])#N.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH:9]1([O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:18][NH:1][C:2]2[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=2)[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: N#Cc1c[nH]nc1N
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CNc2n[nH]cc2C#N)cc1OC1CCCC1
Reaction time: 24 h

Procedure:
A solution of 3-amino-4-cyanopyrazole (5.0 g, 0.16 mol), 3-cyclopentyloxy-4-methoxybenzaldehyde (10.0 g, 0.045 mol) and sodium acetate (0.2 g, 2.4 mol) in methanol (70 mL) was placed in a stirred reaction flask equipped with a pH stat controlling a syringe pump and syringe filled with 3N acetic acid in methanol. The pH stat was set to maintain pH 7. After 24 hours, more 3-cyclopentyloxy-4-methoxybenzaldehyde (7.0 g, 0.031 mol) was added and the reaction was continued. After 48 hours, more 3-cyclopentyloxy-4-methoxybenzaldehyde (4.0 g, 9.0 mmol) and soduim cyanoborohydride (0.5 g, 7.9 mmol) was added and the reaction was continued. After 72 hours, more sodium cyanoborohydride (0.5 g, 7.9 mmol) was added and after 96 hours, the reaction was stopped and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (75 mL) and water (50 mL). The ethyl acetate layer was washed with water (2×50 mL) and evaporated. The crude product was chromaotgraphed over 200 g of flash chromatography silica gel. Elution with 2% methanol/methylene chloride removed some impurities including 3-cyclopentyloxy-4-methoxybenzyl alcohol. Continued elution with methanol/methylene chloride mixtures of increasing methanol concentration afforded 8 g (56%) of nearly pure title compound. Pure 3-(3-cyclopentyloxy-4-methoxy-benzylamino)-4-cyanopyrazole, mp 159-160° was obtained by recrystallization from methanol.
Reaction SMILES: COC[O:4][C:5]1[C:6]([C:15](=[O:17])[CH3:16])=[CH:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:10]=1.Cl>CC(O)C.C1COCC1>[OH:4][C:5]1[C:6]([C:15](=[O:17])[CH3:16])=[CH:7][C:8]([C:11]([F:14])([F:12])[F:13])=[N:9][CH:10]=1
Reactant: COCOc1cnc(C(F)(F)F)cc1C(C)=O
Agent: Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(=O)c1cc(C(F)(F)F)ncc1O
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(5-(methoxymethoxy)-2-(trifluoromethyl)pyridin-4-yl)ethanone (3.2 g, 13 mmol) and 5N HCl (40 ml) in i-PrOH/THF (1:1, 40 ml) was stirred at 45° C. overnight. The mixture was cooled, concentrated, taken up in H2O, neutralized with saturated NaHCO3, and extracted with DCM (3×). The organic layers were combined, dried over Na2SO4, and concentrated to give the title compound as a tan solid. MS (m+1): 206.2
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].N[C@H](C(O)=O)CC(=O)N.N[C@@H](C(O)=O)CC(=O)N.N[C@H](C(O)=O)CCC(=O)O.N[C@@H](C(O)=O)CCC(=O)O.N[C@H](C(O)=O)CC(=O)O.N[C@@H](C(O)=O)CC(=O)O>>[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: NC(=O)CC[C@@H](N)C(=O)O
Agent: NC(=O)C[C@@H](N)C(=O)O
Agent: NC(=O)C[C@H](N)C(=O)O
Agent: N[C@@H](CC(=O)O)C(=O)O
Product: NC(=O)CC[C@H](N)C(=O)O

Procedure:
replace with: D-Gln, Asn, D-Asn, Glu, D-Glu, Asp, D-Asp;
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[N:17]=[N:18][N:19]([CH2:21][CH2:22][NH:23]C(OC(C)(C)C)=O)[N:20]=3)[CH2:15][C@@:9]1([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C@H:10]([O:31][CH2:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.ClCCl>[NH2:23][CH2:22][CH2:21][N:19]1[N:18]=[N:17][C:16]([C@@H:14]2[CH2:15][C@:9]3([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C@H:13]2[CH2:12][CH2:11][C@H:10]3[O:31][CH2:32][C:33]2[CH:34]=[C:35]([C:43]([F:44])([F:45])[F:46])[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=2)=[N:20]1
Reactant: CC(C)(C)OC(=O)NCCn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Yield: 96.6 %

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-{2-[2-(t-butoxycarbonylamino)ethyl]-2H-tetrazol-5-yl}-1-phenyl-8-azabicyclo[3.2.1 ]octane (Example 140; 0.54 g) was stirred in 20% trifluoroacetic acid/dichloromethane for 90 minutes. The mixture was concentrated in vacuo. The residue was partitioned between saturated sodium carbonate and dichloromethane. The organic layer was separated, dried (MgSO4), filtered and concentrated to yield the title compound (0.45 g, 96%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([C:8]1[C:16]2[C:11](=[N+:12]([O-])[CH:13]=[CH:14][CH:15]=2)[NH:10][N:9]=1)[CH3:7]>ClC(Cl)C>[Cl:3][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:10][N:9]=[C:8]([CH2:6][CH3:7])[C:16]=12
Reactant: CCc1n[nH]c2c1ccc[n+]2[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: CCc1n[nH]c2nccc(Cl)c12
Reaction time: 0.5 h
Yield: 47 %

Procedure:
Phosphorus oxychloride (11.1 mL) was added to a suspension solution of compound (3b) (19.5 g) in dichloroethane (240 mL) at room temperature, followed by stirring for 30 min. The solvent of the reaction solution was distilled away, and then acetonitrile (40 mL), methanol (40 mL), and water (80 mL) were added to the residue. After adjustment of pH to 9 with an aqueous sodium hydroxide solution, water (400 mL) was added thereto. The precipitate was collected by filtration, washed by sprinkling methanol (40 mL), water (300 mL), ether (60 mL), and hexane (30 mL), sequentially, and dried under reduced pressure to obtain compound (3c) (10.2 g, 47%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]([CH3:12])([CH3:11])[O:9][C:8](=[O:13])[NH:7][C:6]=2[CH:14]=1.[CH3:15][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>CN(C=O)C.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]([CH3:11])([CH3:12])[O:9][C:8](=[O:13])[N:7]([CH3:15])[C:6]=2[CH:14]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC1(C)OC(=O)Nc2cc(Br)ccc21
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)OC(C)(C)c2ccc(Br)cc21
Reaction time: 0.5 h

Procedure:
Into the solution of 7-bromo-4,4-dimethyl-1H-benzo[d][1,3]oxazin-2(4H)-one 7.37 (1.35 g) in DMF (20 mL) was added 1M solution of NaHMDS in THF (7 mL) at rt. After 30 min., MeI (0.85 g) was added. After overnight stirring, the reaction mixture was extracted with ethyl acetate and washed with brine, and dried with dry agent. After removal of the solvent, the residue was crystallized from mixture of DCM and Hexane to provide 1.2 g of 7-bromo-1,4,4-trimethyl-1H-benzo[d][1,3]oxazin-2(4H)-one 7.38 was synthesized.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].CO.[BH4-].[Na+]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1cc(C2CCC(=O)CC2)ccc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNC(=O)c1cc(C2CCC(O)CC2)ccc1N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2-amino-5-(1,4-dioxaspiro[4.5]dec-8-yl)-N-methylbenzamide (Compound 139B, 333 mg, 1.15 mmol) in THF (10 mL, 200 mmol) was treated with aqueous 3N HCl (2 mL) and allowed to stir at rt for 3.5 hours. The mixture was cooled to 0° C. and basified with dropwise addition of 50% aq. NaOH to pH-10 and then was diluted with EtOAc (30 mL). The organic layer was separated, washed with brine (2×10 mL), dried over anhydrous sodium sulfate. The solvents were evaporated under reduced pressure and the crude ketone was purified on the ISCO Combiflash eluting with 80-100% EtOAc in hexane then 5% DCM/MeOH to isolate the ketone intermediate as 235 mg of a white solid. MS (ES+): m/z=247.07 (100) [M+1]. LCMS: tR=2.29 min (ZQ3, polar—5 min). A solution of 2-amino-N-methyl-5-(4-oxocyclohexyl)benzamide in MeOH (7 mL, 200 mmol) was cooled to 0° C. and treated with sodium borohydride (43 mg, 1.1 mmol). The mixture was stirred at 0° C. for 1 hour then quenched with sat. aq. NH4Cl (1 mL). The crude residue obtained from concentrating the reaction mixture in vacuo was taken up in 1 mL H2O and EtOAc (30 m). The layers were separated. The aqueous layer was saturated with salt and washed again with −20 mL of EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude solid was taken up in DCM/MeOH, treated with silica and concentrated. This silica was loaded into an sample column and purified on an ISCO Combiflash (0-5% Then 10% MeOH/DCM) to isolate 201 mg of the desired product as an 80:20 mixture of cis/trans isomers. Major product (trans): MS (ES+): m/z=249.07 (100) {M+1]; HPLC: tR=2.10 min (ZQ3, polar—5 min). Minor product (cis): MS (ES+): m/z=249.10 (100) [M+1]; HPLC: tR=2.28 minutes (ZQ3, polar—5 min). The mixture was used in the next step.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]=3[CH:18]=2)[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-].Cl>CO>[CH3:16][C:13]1([CH3:17])[C:12]2[CH:18]=[C:8]([C:5]3([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]3)[CH:9]=[CH:10][C:11]=2[O:15][CH2:14]1
Reactant: COC(=O)C1(c2ccc3c(c2)C(C)(C)CO3)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)COc2ccc(C3(C(=O)O)CC3)cc21
Temperature: 40 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
To a solution of 1-(3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-cyclopropanecarboxylic acid methyl ester (1.0 g, 4.0 mmol) in MeOH (10 mL) was added LiOH (0.40 g, 9.5 mmol). The mixture was stirred at 40° C. overnight. HCl (10%) was added slowly to adjust the pH to 5. The resulting mixture was extracted with ethyl acetate (10 mL×3). The extracts were washed with brine and dried over Na2SO4. The solvent was removed under vacuum and the crude product was purified by preparative HPLC to give 1-(3,3-dimethyl-2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxylic acid (0.37 g, 41%). 1H NMR (400 MHz, CDCl3) δ 7.11-7.07 (m, 2H), 6.71 (d, J=8 Hz, 1H), 4.23 (s, 2H), 1.66-1.63 (m, 2H), 1.32 (s, 6H), 1.26-1.23 (m, 2H).
Reaction SMILES: [C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2].OC([C:10]1[NH:15][C:14](=[O:16])[CH:13]=[CH:12][N:11]=1)C>O1CCOCC1>[C:1]([O:4][C@@H:5]([C:10]1[NH:15][C:14](=[O:16])[CH:13]=[CH:12][N:11]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(O)c1nccc(=O)[nH]1
Reactant: C=COC(C)=O
Solvent: C1COCCO1
Product: CC(=O)O[C@H](C)c1nccc(=O)[nH]1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of vinyl acetate (4.3 g, 50 mmol) in dioxane (63 mL) was added 2-(1-hydroxy-ethyl)-3H-pyrimidin-4-one (prepared according to the method of Preparation Twelve, 2.1 g, 15.1 mmol), and the mixture was heated to 50° C. To the resulting solution was added lipase P30 (0.21 g, 10 wt %) and the heating was continued for 24 h. The reaction mixture was filtered and the filtrate was evaporated to obtain a thick syrupy liquid residue. The residue was purified by flash column chromatography (95:5 dichloromethane:methanol) to give the title compound as a colorless liquid, 0.97 g (92% of theory). 1H NMR (CDCl3, 300 MHz) δ 1.61 (d, 3H), 2.20 (s, 3H), 5.65 (q, 1H), 6.35 (d, 1H), 7.97 (d, 1H), 11.94 (s, 1H); [α]D+39.9 (c 1.0, MeOH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8](Br)[C:7]([F:11])=[CH:6][C:5]=1[O:12][CH3:13].C([O-])([O-])=O.[K+].[K+].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>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.OO>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]([F:11])=[CH:6][C:5]=1[O:12][CH3:13])=[O:14]
Reactant: COC(=O)c1cc(Br)c(F)cc1OC
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OO
Product: COC(=O)c1cc(-c2ccccc2)c(F)cc1OC
Temperature: 110 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a flame dried flask containing degassed toluene (15.2 mL, 0.5 M) was added 5-bromo-4-fluoro-2-methoxy-benzoic acid methyl ester (2.0 g, 7.6 mmol), anhydrous K2CO3 (2.1 g, 15.2 mmol), phenylboronic acid (3.7 g, 30.4 mmol), and Pd(PPh3)4 (0.88 g, 0.76 mmol). Using a reflux condenser, the stirring mixture was heated to 110° C. for 3.5 h. The mixture was then cooled to room temperature, placed in an ice bath and H2O2 (30%, 10 mL) was slowly added. The ice bath was removed and the reaction was allowed to stir at room temperature for one hour. The mixture was then diluted with ether and washed successively with 2 N HCl and saturated aq NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated to afford a brown oil. Purification by MPLC (10-100% ethyl acetate in heptane, 23 mL/min, 75 min) provided 6-fluoro-4-methoxy-biphenyl-3-carboxylic acid methyl ester (1.8 g, 91%) as a pale yellow solid: Rf 0.5 (40% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 8.00 (d, J=9.0 Hz, 1H), 7.53-7.33 (m, 5H), 6.79 (d, J=12.6 Hz, 1H), 3.94 (s, 3H), 3.89 (s, 3H).