Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:19]([F:20])=[CH:18][C:10]3[NH:11][C:12](S(C)(=O)=O)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.[Br:27][C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1>N1C=CC=CC=1.CCOC(C)=O>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:19]([F:20])=[CH:18][C:10]3[NH:11][C:12]([O:34][C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([Br:27])[CH:29]=4)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1
Reactant: Oc1cccc(Br)c1
Reactant: CS(=O)(=O)c1nc2cc(-c3ccc(-c4ccccc4)cc3)c(F)cc2[nH]1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Fc1cc2[nH]c(Oc3cccc(Br)c3)nc2cc1-c1ccc(-c2ccccc2)cc1
Reaction time: 48 h

Procedure:
To a solution of compound 13-6 (1.53 g, 4.2 mmol) in 20 mL in pyridine was added 3-bromo-phenol (1.4 g, 8.4 mmol). The reaction mixture was heated to reflux and allowed to stir for 48 h. The reaction mixture was diluted with EtOAc (150 mL) and washed three times with 100 mL portions of saturated aqueous ammonium chloride. The combined organic layers were dried over MgSO4 filtered and concentrated in vacuo. The crude was purified on ISCO (EtOAc/Hexanes=1/1) to yield the title compound 13-7 along with recovered starting material 13-6.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH:24][C:25](=[O:27])[CH3:26])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1)=O.[C:28]([CH:33]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:30][CH2:31][CH3:32])=[O:29].[CH:53](Cl)(Cl)Cl>>[C:25]([NH:24][C:11]1[S:12][C:13]([C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=2)=[C:9]([C:6]2[CH:5]=[CH:4][C:3](/[CH:53]=[CH:33]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:8][CH:7]=2)[N:10]=1)(=[O:27])[CH3:26]
Reactant: ClC(Cl)Cl
Reactant: CC(=O)Nc1nc(-c2ccc(C=O)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)/C=C/c1ccc(-c2nc(NC(C)=O)sc2-c2ccc(S(C)(=O)=O)cc2)cc1
Reaction time: 1 h

Procedure:
To a suspension of N-{4-(4-formylphenyl)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide (360 mg) in chloroform (7 ml) was added (carbethoxymethylene)triphenylphosphorane (626 mg) at 20° C., and the mixture was stirred for 1 h. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel (150 ml) with hexane/ethyl acetate (1:1-1:2) as an eluent to give ethyl(2E)-3-(4-{2-(acetylamino)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-4-yl}phenyl)acrylate as a pale yellow solid.
Reaction SMILES: [K].[Cl:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[OH:11].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Cl:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[O:11][CH2:16][CH2:15][CH2:14][CH2:13][Br:12]
Reactant: COc1ccc(O)c(Cl)c1
Reactant: BrCCCCBr
Agent: [K]
Product: COc1ccc(OCCCCBr)c(Cl)c1

Procedure:
The intermediate 4-(2-chloro-4-methoxyphenoxy)butyl bromide was prepared from the potassium salt of 2-chloro-4-methoxyphenol and 1,4-dibromobutane.
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH2:24])=[N:13][N:14]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:10][CH:9]=1>ClCCl.C(N(CC)CC)C>[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH:24][C:1](=[O:5])[CH2:2][CH:3]=[CH2:4])=[N:13][N:14]2[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2ccc(Cl)cc21
Reactant: C/C=C/C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC(=O)Nc1nn(C(=O)OC(C)(C)C)c2cc(Cl)ccc12
Temperature: 19 °C
Reaction time: 16 h

Procedure:
0.45 cm3 of predistilled crotonyl chloride is added to 1 g of 6-chloro-1-[(1,1-dimethylethoxy)carbonyl]-1H-indazole-3-amine described previously, in 40 cm3 of dichloromethane and 1.05 cm3 of triethylamine. The mixture is stirred at about 19° C. for 16 hours. The medium is then concentrated under reduced pressure (20 kPa; 40° C.). The residue is taken up in 100 cm3 of ethyl acetate and 50 cm3 of distilled water. The organic phase is then washed with 50 cm3 of saturated aqueous sodium chloride solution. The resulting solution is dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under the conditions already described previously. The residue is purified by chromatography under an argon pressure of 50 kPa, on silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a cyclohexane/ethyl acetate mixture (90/10 by volume) and collecting 15 cm3 fractions. The fractions containing the expected product are combined and then evaporated under reduced pressure (2 kPa; 40° C.). After drying (90 Pa; 45° C.), 120 mg of N-(6-chloro-1-[(1,1-dimethylethoxy)carbonyl]-1H-indazol-3-yl)-3-butenamide are obtained in the form of a yellow solid.
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:5][CH:4]([CH2:6][CH:7]([NH:10][C:11](=[O:19])[O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH2:8]O)[CH2:3]1.C[CH2:22][N:23](C(C)C)C(C)C.CS(Cl)(=O)=O.[CH3:35][C:36]([O:39][C:40]([O:42]C(OC(C)(C)C)=O)=O)([CH3:38])[CH3:37]>C(Cl)Cl>[CH3:16][Si:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][O:12][C:11]([NH:10][CH:7]([CH2:8][N:23]([C:40]([O:39][C:36]([CH3:38])([CH3:37])[CH3:35])=[O:42])[CH3:22])[CH2:6][CH:4]1[CH2:5][C:2]([F:20])([F:1])[CH2:3]1)=[O:19]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCOC(=O)NC(CO)CC1CC(F)(F)C1
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CN(CC(CC1CC(F)(F)C1)NC(=O)OCC[Si](C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.1 %

Procedure:
2-(Trimethylsilyl)ethyl 3-(3,3-difluorocyclobutyl)-1-hydroxypropan-2-ylcarbamate (240 mg, 0.776 mmol) was dissolved in CH2Cl2 (4 mL) and the solution was cooled to 0° C. DIEA (301 mg, 2.32 mmol, 3.0 equiv) was added followed by MsCl (133 mg, 1.16 mmol, 1.5 equiv) and the mixture was stirred for 30 min at 0° C. LC-MS analysis showed consumption of the alcohol and formation of the desired mesylate. The reaction was quenched by addition of aq citric acid (10% by weight). The layers were separated and the aqueous phase was extracted with additional CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and solvent was removed. The residue was taken up in methylamine solution (30 wt % in ethanol, 10 mL). Methanol was added dropwise to aid dissolution. The mixture was divided into three 4 mL portions. Each portion was separately heated to 150° C. for 7 min in a CEM microwave reactor. The four reaction mixtures were combined and volatile materials were removed. The residue was dissolved in acetonitrile (7 mL) and 1.0 M aq NaOH (2.0 mL) was added, followed by Boc2O (186 mg, 0.854 mmol, 1.1 equiv). After 1 h starting amine was still observed by LC-MS and additional Boc2O (1.1 equiv) was added. After 1 h all the amine was converted into the Boc derivative. The solvent was removed in vacuo and the residue was taken up in EtOAc and water. The layers were separated and the organic layer was washed with sat'd aq NaHCO3, brine and evaporated. The diamine was purified by flash chromatography on 12 g of silica, eluting with a 0 to 50% EtOAc in hexanes gradient. The fractions which stained with ninhydrin were combined and evaporated to yield 2-(2-(trimethylsilyl)ethoxycarbonylamino)-1-(3,3-difluorocyclobutyl)-3-(N-(t-butoxycarbonyl)-N-methylamino)-propane (56 mg, 15%) of the deprotected amine. 1H and 19F NMR were consistent with the desired product.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(N=C=NCCCN(C)C)C.[NH2:22][CH2:23][C:24]1[N:29]=[C:28]2[S:30][C:31]3[CH2:32][N:33]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:34][CH2:35][C:36]=3[C:27]2=[C:26]([C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([O:52][CH3:53])[CH:45]=2)[C:25]=1[Cl:54].[N:55]1([CH2:60][C:61](O)=[O:62])[CH:59]=[N:58][CH:57]=[N:56]1>O.CN(C)C=O>[CH2:37]([N:33]1[CH2:34][CH2:35][C:36]2[C:27]3[C:28]([S:30][C:31]=2[CH2:32]1)=[N:29][C:24]([CH2:23][NH:22][C:61](=[O:62])[CH2:60][N:55]1[CH:59]=[N:58][CH:57]=[N:56]1)=[C:25]([Cl:54])[C:26]=3[C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([O:52][CH3:53])[CH:45]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(O)Cn1cncn1
Reactant: COc1ccc(-c2c(Cl)c(CN)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2c(Cl)c(CNC(=O)Cn3cncn3)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
N-hydroxybenotriazole (HOBt) (0.427 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC) (0.535 g) were added to an ice-cooled mixture of the compound (1.0 g) obtained in Example 18B, (1,2,4-triazol-1-yl)acetic acid (0.325 g) and N,N-dimethylformamide (DMF) (20 ml), the mixture was stirred at room temperature for 8 hours, poured over water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (20:1, v/v) to yield 7-benzyl-3-chloro-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro-2-(1,2,4-triazol-1-ylacetylaminomethyl)thieno[2,3-b:5,4-c']dipyridine (0.55 g, 50%), which was then recrystallized from ethyl acetate-hexane to yield a colorless powder having a melting point of 101 to 102° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[C:14]([S:20][CH3:21])=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19])=[O:11].[SH:22][C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[O:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[S:22][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[C:14]([S:20][CH3:21])=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19])=[O:11]
Reactant: CSc1nccc(C)c1NC(=O)CCCCCCCCBr
Reactant: Sc1nc2ccccc2o1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nccc(C)c1NC(=O)CCCCCCCCSc1nc2ccccc2o1
Temperature: 80 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
Triethylamine (302 mg, 2.99 mmol) was added to a chloroform (4 ml) solution of this aminopyridine (307 mg, 1.99 mmol), and a chloroform (4 ml) solution of 9-bromononanyl chloride (2.99 mmol) was then slowly added thereto dropwise while being cooled with ice. The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 125 g, eluent—hexane:ethyl acetate=3:1→2:1) to obtain 261 mg (yield 35%) of 9-bromo-N-(4-methyl-2-methylthio-3-pyridyl)nonanamide as a colorless powdery crystal (melting point: 77 to 78° C.). To a DMF (5 ml) solution of this amide (114 mg, 0.31 mmol) and 2-mercaptobenzoxazole (46 mg, 0.31 mmol) were added 18-crown-6 (8 mg, 0.03 mmol) and potassium carbonate (51 mg, 0.37 mmol), and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through preparative thin-layer chromatography (eluent—chloroform:methanol=20:1) to obtain 89 mg (yield 66%) of the desired compound as a colorless powdery crystal.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[O:15][C:14](=[O:16])[C:9]3[CH2:10][NH:11][CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1.C(N(CC)CC)C.Cl.ClCC[N:29]1[CH2:36][CH:35]2[CH2:37][CH:31]([CH2:32][CH2:33][CH2:34]2)[CH2:30]1>>[CH:31]12[CH2:37][CH:35]([CH2:34][CH2:33][CH2:32]1)[CH2:36][N:29]([CH:12]1[NH:11][CH2:10][C:9]3[C:14](=[O:16])[O:15][C:5]4[CH:4]=[C:3]([CH3:17])[C:2]([Cl:1])=[CH:7][C:6]=4[C:8]=3[CH2:13]1)[CH2:30]2
Reactant: ClCCN1CC2CCCC(C2)C1
Reactant: Cc1cc2oc(=O)c3c(c2cc1Cl)CCNC3
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cc2oc(=O)c3c(c2cc1Cl)CC(N1CC2CCCC(C2)C1)NC3
Yield: 64.4 %

Procedure:
Prepared by the method described for Example 13 from 9-chloro-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (1.2 g, 0.005 moles), triethylamine (1.4 ml, 0.010 moles), and 3-(2-chloroethyl)-3-azabicyclo[3.3.1]nonane hydrochloride (1.1 g, 0.005 moles). Recrystallization from methanol gave the product (1.2 g), mp 147°-149° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:12]([O:14]C)=[O:13])=[CH:5][C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1.[OH-].[Na+].C(O)C>O>[CH3:1][O:2][C:3]1[C:4]([C:12]([OH:14])=[O:13])=[CH:5][C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1
Reactant: COC(=O)c1cc2c(cc1OC)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc2c(cc1C(=O)O)OCO2
Yield: 85.7 %

Procedure:
A mixture of methyl 6-methoxy-1,3-benzodioxole-5-carboxylate (3 g, 14 mmol), prepared as in Example 1, 20% sodium hydroxide (50 mL) and ethanol (25 mL) was heated 1 hour at reflux and then diluted with water, washed with diethyl ether (2×), treated with concentrated hydrochloric acid and cooled in an ice-bath. The solids were collected, washed with water (2×) and dried under vacuum at 70° C. to give 6-methoxy-1,3-benzodioxole-5-carboxylic acid (2.3 g, 12 mmol), m.p. 151° C.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[NH:10][NH2:11].[BH3-]C#N.[Na+]>CO.C([O-])(O)=O.[Na+].CCOC(C)=O>[C:14]([O:13][C:9]([NH:10]/[N:11]=[CH:1]/[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: C=CCCCCC=O
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C=CCCCC/C=N/NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
To a solution of 46 (68 mg, 0.610 mmol) and tert-butyl carbazate (81 mg, 0.613 mmol) in MeOH (5 mL) was added ground molecular sieves (115 mg, 3A). The mixture was stirred for 3 h after which it was filtered through celite and evaporated. The residue was dissolved in dry THF (3 mL) and AcOH (3 mL). NaBH3CN (95 mg, 1.51 mmol) was added and the solution was stirred over night. The reaction mixture was diluted with saturated NaHCO3 solution (6 mL) and EtOAc (6 mL). The organic phase washed with brine, saturated NaHCO3, brine, dried over MgSO4 and evaporated. The cyanoborane adduct was hydrolyzed by treatment with MeOH (3 mL) and 2 M NaOH (1.9 mL). The mixture was stirred for 2 h and the MeOH was evaporated. H2O (5 mL) and DCM (5 mL) were added and the water phase was extracted three times with DCM. The combined organic phases were dried and evaporated. Purification by flash column chromatography (toluene/ethyl acetate 9:1 with 1% triethylamine and toluene/ethyl acetate 6:1 with 1% triethylamine) provided 47 (85 mg, 61%) as an oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:28]([C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])=[CH:27][C:24]=1[CH:25]=O.C(OC(N1CCC[C@H](NCC2C=C(C(F)(F)C)C=CC=2OC(F)(F)F)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:25][C:24]2[CH:27]=[C:28]([C:31]([F:36])([F:37])[C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:30][C:23]=2[O:22][CH3:21])[C@@H:3]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc(C(F)(F)C(F)(F)F)cc1C=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC[C@H](NCc2cc(C(C)(F)F)ccc2OC(F)(F)F)[C@@H]1c1ccccc1
Product: COc1ccc(C(F)(F)C(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This Compound was prepared from Compound 12 and Compound 40 in the same manner of Compound 26. This was employed in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[NH2:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][CH:7]=1.[CH3:37][CH:38]([CH2:41][CH2:42][CH3:43])[CH:39]=O>ClCCCl>[CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[NH:34][CH2:37][CH:38]([CH3:39])[CH2:41][CH2:42][CH3:43])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:11]=1.[Cl:33][C:31]1[CH:30]=[CH:29][C:28]([NH:34][CH2:37][CH:38]([CH3:39])[CH2:41][CH2:42][CH3:43])=[C:27]([CH:32]=1)[C:26]([NH:25][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:11]=1)[C:3]([OH:2])=[O:36])=[O:35]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Cl)ccc1N
Reactant: CCCC(C)C=O
Solvent: ClCCCl
Product: CCCC(C)CNc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)C(=O)O
Product: CCCC(C)CNc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)C(=O)OC

Procedure:
(2S)-[5-chloro-2-(2-methyl-pentylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester was prepared following procedure G using (2S)-(2-amino-5-chloro-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionicacid methyl ester (100 mg, 0.2 mmol) prepared in Example 10, 2-methyl-pentanal (30 mg, 0.25 mmol) in DCE (4 mL). Purification by flash chromatography (ethyl acetate/hexanes 1:3) gave the title compound as a thick liquid, which was hydrolyzed according to Procedure C yielding the title compound (85 mg). LC/MS (m/z): 571 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][O:6][CH2:5][C@:4]2([C:20]3[CH:19]=[C:18]([OH:21])[N:17]=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][C:10]([Br:22])=[CH:11][CH:12]=3)[N:3]=1.[F-].[Cs+].C(#N)C.[F:28][C:29]([F:41])(S(F)(=O)=O)C(O[Si](C)(C)C)=O>CCOC(C)=O>[Br:22][C:10]1[CH:9]=[C:8]2[C@:4]3([N:3]=[C:2]([NH2:1])[CH2:7][O:6][CH2:5]3)[C:20]3[CH:19]=[C:18]([O:21][CH:29]([F:41])[F:28])[N:17]=[CH:16][C:15]=3[O:14][C:13]2=[CH:12][CH:11]=1
Reactant: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(O)cc12
Reactant: C[Si](C)(C)OC(=O)C(F)(F)S(=O)(=O)F
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(OC(F)F)cc12
Reaction time: 0.25 h
Yield: 19.7 %

Procedure:
A flask was charged with (S)-5′-amino-7-bromo-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-3-ol (0.250 g, 0.690 mmol), cesium fluoride (9.17 mg, 0.069 mmol), and acetonitrile (6.90 mL). Trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.272 mL, 1.381 mmol) was added slowly and the reaction was stirred for 15 minutes. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (0-10% MeOH/DCM), to afford (S)-7-bromo-3-(difluoromethoxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.056 g, 0.136 mmol, 19.68% yield) as a light yellow solid. [M+H]+=411.9
Reaction SMILES: O.CC(C)([O-])C.[K+].[CH:8]1([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH2:29][CH3:30])[CH:26]=4)[N:21]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)[C:20]=3[C:40]([O:42]CC)=[O:41])=[CH:15][CH:14]=2)[CH2:10][CH2:9]1.Cl>C(OCC)C.C(OCC)(=O)C>[CH:8]1([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH2:29][CH3:30])[CH:26]=4)[N:21]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)[C:20]=3[C:40]([OH:42])=[O:41])=[CH:15][CH:14]=2)[CH2:10][CH2:9]1
Reactant: CCOC(=O)c1c(-c2ccc(OCC3CC3)cc2)c2cc(OCC)ccc2n1Cc1cccc(OC)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOc1ccc2c(c1)c(-c1ccc(OCC3CC3)cc1)c(C(=O)O)n2Cc1cccc(OC)c1
Temperature: 0 °C
Yield: 14.3 %

Procedure:
Water (5 uL) was added to a cooled (0° C.) and stirred suspension of potassium t-butoxide (90 mg, 0.80 mmol) in ethyl ether (5 mL). The slurry was stirred for 5 min and then a solution of ethyl 3-[4-(cyclopropylmethoxy)phenyl]-5-ethoxy-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 144, 52 mg, 0.10 mmoL) in ethyl ether (2+1 mL rinse) was added. The mixture was warmed to rt and stirred for 16 h. The solution was adjusted to pH=7 with 1 M hydrochloric acid and diluted with ethyl acetate (50 mL). This mixture was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative TLC, using 1:1 ethyl acetate/hexane as the eluent, to afford 7.0 mg (14%) of desired product. The product had: 1H NMR (300 MHz, acetone-D6) δ 7.45-7.37 (m, 3 H), 7.18 (t, 1 H), 6.99-6.91 (m, 4 H), 6.77 (dd, 1 H), 6.70 (m, 2 H), 5.85 (d, 2 H), 3.99-3.86 (m, 4 H), 3.69 (s, 3 H), 1.36-1.28 (m, 4 H), 0.63-0.59 (m, 2 H), 0.39-0.37 (m, 2 H); mass spectroscopy gave MH+=472.2 (calcd exact mass for C29H29NO5=471.20).
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14][OH:15])[CH2:3]1.CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:15][CH2:14][C@@H:4]1[CH2:3][C:2]([F:1])([F:16])[CH2:6][N:5]1[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a CH2Cl2 (22 ml) solution of (S)-tert-butyl 4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.65 g, 11.2 mmol) and Et3N (2.3 ml, 16.8 mmol), at 0° C., methylsulfonyl chloride (0.95 ml, 12.3 mmol) was added dropwise over ˜2 minutes, ice bath was removed after 15 minutes, and stirring was continued at room temperature for another 30 minutes. Reaction went to completion as monitored by LC-MS. The reaction mixture was cooled to 0° C. and was quenched by addition of saturated aqueous solution of NaHCO3 (˜30 ml), stifling was continued at 0° C. for 5 minutes and at room temperature for 15 minutes. Two layers were separated, aqueous layer was extracted with CH2Cl2 (˜30 ml). Organic layers were combined, washed with brine (˜25 ml), dried (Na2SO4), filtered, solvent was removed in vacuo. Compound ((S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)methyl methanesulfonate was obtained as a very light yellow oil: 3.40 g (96% crude yield).
Reaction SMILES: [F-:1].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11](I)[CH:12]=1)[C:9](=[O:14])[N:8]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH2:7]2.COC(=O)[C:26](Cl)([F:28])[F:27]>CN(C=O)C.[Cu]I>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([C:26]([F:28])([F:1])[F:27])[CH:12]=1)[C:9](=[O:14])[N:8]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH2:7]2
Reactant: O=C1c2c(I)cc(Cl)cc2CN1Cc1ccc(F)cc1
Reactant: [F-]
Reactant: COC(=O)C(F)(F)Cl
Agent: [Cu]I
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2c(cc(Cl)cc2C(F)(F)F)CN1Cc1ccc(F)cc1
Temperature: 140 °C
Reaction time: 18 h
Yield: 19.7 %

Procedure:
CuI (0.076 g, 0.4 mmol) and potassium fluoride (0.023 g, 0.4 mmol) were added under an N2 atmosphere to a solution 5-chloro-2-(4-fluoro-benzyl)-7-iodo-2,3-dihydro-isoindol-1-one (0.149 g, 0.37 mmol) and chloro-difluoro-acetic acid methyl ester (0.046 mL, 0.43 mmol) in DMF (4 mL). The mixture was stirred at 140° C. for 18 h. The reaction was cooled and the solvent evaporated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-chloro-2-(4-fluoro-benzyl)-7-trifluoromethyl-2,3-dihydro-isoindol-1-one (0.025 g, 20%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.37 (s, 2H), 4.76 (s, 2H) 7.05 (m, 2H), 7.26 (m, 2H), 7.56 (s, 1H), 7.78 (s, 1H). GC-MS: m/z 343 (M)+, 322 (M−21)+.