Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1.Cl[C:13]1[N:18]=[CH:17][NH:16][C:15]2=[N:19][CH:20]=[CH:21][C:14]=12>O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:13]2[C:14]3[CH:21]=[CH:20][NH:19][C:15]=3[N:16]=[CH:17][N:18]=2)=[CH:6][CH:5]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: OCc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc(COc2ncnc3[nH]ccc23)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 24.8 %

Procedure:
To a 0.375 M solution of aqueous potassium hydroxide (26.2 mL, 9.83 mmol) was added (4-chlorophenyl)methanol (464 mg, 3.26 mmol) and the mixture was heated to 80° C. for 30 min. Then 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (500 mg, 3.26 mmol) was added and the mixture was refluxed at 130° C. After 6 h, additional (4-chlorophenyl)methanol (100. g, 0.701 mmol) was added and the solution was heated to 115° C. overnight. The reaction was cooled to rt and diluted with water. The solution was then extracted with EtOAc (2×) and DCM (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude oil was purified by silica gel chromatography eluting with a gradient of 5 to 30% EtOAc in DCM to afford the product as a white solid (210 mg, 25%). LC/MS: Rt=1.72 min, ES+ 260. (FA standard).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH2:35])[CH2:30]1)[CH3:28]>C(O)C>[CH2:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:30]1)[CH3:28]
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: CCN1CCCC(N)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCN1CCCC(NCC(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1

Procedure:
7.2 gm of 11-chloroacetyl-5,11-dihydro-6H-pyrido [2,3-b][1,4]benzodiazepin-6-one, 2.8 gm of sodium carbonate and 3.8 gm of 1-ethyl-3-amino-piperidine were refluxed in 100 ml of ethanol for 5 hours. Then the hot mixture was suction-filtered, the filtrate was evaporated in vacuo to dryness, and the residue was purified on a silica gel column. The evaporation residue of the eluate was recrystallized from ethyl acetate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)([O-])=O>C(O)C.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc([N+](=O)[O-])c2)CC1
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(N)c2)CC1
Reaction time: 8 h
Yield: 100 %

Procedure:
tert-Butyl 4-(3-nitrophenoxy)piperidine-1-carboxylate (prepared as described in WO-A-2003/068760) (10.764 g; 33.39 mmol) is dissolved in 430 ml of ethanol, Raney nickel (7.2 g) is then added and the reaction medium is placed under hydrogen (pressure: 50 bar) at room temperature overnight. The reaction medium is filtered through Celite and evaporated to dryness to give quantitatively (9.76 g) the expected product in the form of a beige-coloured oil.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH3:5].[H-].[Na+].[OH:8][C:9]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1.O>CN(C)C=O>[CH2:2]([O:8][C:9]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1)[C:3]#[C:4][CH3:5]
Reactant: Cc1ccccc1C1(O)CN(C(=O)OC(C)(C)C)C1
Reactant: CC#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOC1(c2ccccc2C)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
1 ml (11.4 mmol) of 1-bromo-2-butyne is added to a suspension of 1.4 g (34.2 mmol) of sodium hydride at 60% in 14 ml of dimethylformamide cooled beforehand to 0° C. After stirring for 1 h, 3 g (11.4 mmol) of tert-butyl 3-hydroxy-3-o-tolylazetidine-1-carboxylate in 20 ml of dimethylformamide are added dropwise and the reaction mixture is then stirred for 1 h 30. After hydrolysis with water and with a saturated aqueous solution of ammonium chloride, the reaction medium is extracted with a 1/1 heptane/ethyl acetate mixture. The organic phase is dried over sodium sulphate, filtered and concentrated. The residue obtained is purified by silica gel chromatography, elution being carried out with a 80/20 heptane/ethyl acetate mixture. 2.9 g of tert-butyl 3-but-2-ynyloxy-3-o-tolylazetidine-1-carboxylate are obtained in the form of a yellow oil with a yield of 81%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[CH3:12][C:13]([S@@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14].O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])/[CH:5]=[N:18]/[S@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: COc1ccc(C=O)cc1F
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(/C=N/[S@@](=O)C(C)(C)C)cc1F
Temperature: 65 °C
Yield: 89.7 %

Procedure:
To a solution of 3-fluoro-4-methoxybenzaldehyde (2.0 g, 13 mmol) in THF (40 mL) was added (S)-2-methylpropane-2-sulfinamide (2.84 g, 23.4 mmol) and Ti(OEt)4 (5.92 g, 26.0 mmol). The reaction mixture was heated at 65° C. for 12 h. After cooling to RT, the mixture was poured into water. The solid was filtered, and the filtrate was extracted with EtOAc (3×100 mL). The filtrate was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with EtOAc/petroleum ether (1:4) to afford 3.0 g (90%) of (S,E)-N-(3-fluoro-4-methoxybenzylidene)-2-methylpropane-2-sulfinamide (66). LCMS (ESI) m/z: 258.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[N:28][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:23][C:24]2[CH:29]=[N:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)=[N:3][CH:4]=1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: N#Cc1ccc(N)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1CCOC1
Product: N#Cc1ccc(Nc2ncc(Cl)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cn1
Temperature: 120 °C
Yield: 70 %

Procedure:
A solution of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.300 g, 0.892 mmol) in THF (2.5 mL) containing 5-amino-2-pyridinecarbonitrile (0.213 g, 1.78 mmol), Cs2CO3 (0.872 g, 2.67 mmol), Xantphos (0.021 g, 0.036 mmol) and palladium (II) acetate (4 mg, 0.018 mmol) was heated under microwave irradiation for 30 minutes at 120° C. The reaction mixture was adsorbed onto silica gel and purified by silica column chromatography (Combiflash Rf, 12 g SiO2 Cartridge, 0-10% MeOH in DCM) to give the title compound 31 as a cream solid (0.262 g, 70%). LCMS-B: rt 7.13 min; m/z 419 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[S:27]>O1CCCC1>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[NH:25][C:26]([NH:1][C:2]1[C:3]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[S:27]
Reactant: COC(=O)c1cccc(N)c1NCCCO
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: COC(=O)c1cccc(NC(=S)Nc2ccc(Cl)cc2Cl)c1NCCCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of methyl 3-amino-2-[(3-hydroxypropyl)amino]benzoate (1.00 g, 4.46 mmol) in tetrahydrofuran (12 mL) was added 2,4-dichlorophenyl isothiocyanate (910 mg, 4.46 mmol), and the mixture was stirred at room temperature for 3 hr. The mixture was concentrated and the residue was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a brown solid (1.87 g, 4.37 mmol, 98%).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH:14]([CH3:16])[CH3:15]>>[I:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH:14]([CH3:16])[CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)Br
Reactant: Oc1cccc2ccc(I)nc12
Product: CC(C)Oc1cccc2ccc(I)nc12
Yield: 84 %

Procedure:
Reaction of 2-iodo-quinolin-8-ol 8 with 2-bromopropane following the method described in Example 8 gave 2-iodo-8-isopropoxyquinoline 9 in 84% yield. 9:
Reaction SMILES: [C:1]([CH:4]1[CH:9]([C:10]#[N:11])[CH2:8][CH:7]2[CH2:12][CH:5]1[C:6]2([CH3:14])[CH3:13])(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[OH:3][CH:1]([CH:4]1[CH:9]([C:10]#[N:11])[CH2:8][CH:7]2[CH2:12][CH:5]1[C:6]2([CH3:13])[CH3:14])[CH3:2]
Reactant: CC(=O)C1C(C#N)CC2CC1C2(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)C1C(C#N)CC2CC1C2(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-Acetyl-6,6-dimethyl-bicyclo[3.1.1]heptane-3-carbonitrile (551 mg, 2.88 mmol) was dissolved in methanol (20 ml) under an atmosphere of dry N2. The reaction was then cooled to 0° C. to which sodium borohydride (203 mg, 5.37 mmol) was added. After stirring at 0° C. for two hours, the reaction was concentrated under vacuum and partitioned between saturated NaHCO3 and CH2Cl2. The CH2Cl2 layer was dried over Na2SO4, filtered and concentrated under vacuum to give 2-(1-hydroxy-ethyl)-6,6-dimethyl-bicyclo[3.1.1]heptane-3-carbonitrile as a mixture of diastereomers. The mixture was then dissolved in anhydrous DMF (10 ml) under an atmosphere of dry N2. To this reaction was added 1,1'-thiocarbonyl-diimidazole (990 mg, 5.00 mmol). After stirring at ambient temperature for 16 hours, the reaction was then partitioned between 1.0% sodium bisulfate solution and ethyl ether. The ethyl ether layer was washed twice with water, once with brine, dried over MgSO4, filtered and concentrated under vacuum to give imidazole-1-carbothioic acid-O-[1-(3-cyano-6,6-dimethyl-bicyclo(3.1.1]hept-2-yl)-ethyl] ester as a mixture of diastereomers. The mixture was then dissolved in anhydrous toluene (10 ml) under an atmosphere of dry N2. To this mixture was added α,α'-azo-isobutyronitrile (250 mg, 1.52 mmol) and tributyltin hydride (2.0 ml, 7.21 mmol). The reaction was then heated to 100° C. . After stirring at 100° C. for 3 hours, the reaction was concentrated under vacuum to give an oil. The oil was chromatographed on silica gel using hexanes to remove the bulk of the tin containing species and then eluting with 1% ethyl acetate in hexanes to give 288 mg of the titled compound: 1H NMR (CDCl3)δ 2.72 (dt, J=6.8, 9.8 Hz, 1H), 2.37-2.47 (m, 2H), 2.13-22 (m, 2H) 2.00 (m, 2H), 1.60 (m, 1H), 1.21-1.38 (m, 2H), 1.20 (s, 3H), 0.98 (t, J=7.2 Hz, 3H), 0.91 (s, 3H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cccc(Cl)c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(c1cccc(Cl)c1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
254 mg (0.449 mmol) of (2R*,4S*)-2-benzyl-1-(3-chlorobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 68 mg (1.80 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR62## is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.29, FD-MS: M+ =470.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[CH:25]=[C:26]([SH:31])[CH:27]=[CH:28][C:29]=1[Cl:30]>CS(C)=O>[Cl:1][C:2]1[C:3]([S:31][C:26]2[CH:27]=[CH:28][C:29]([Cl:30])=[C:24]([Cl:23])[CH:25]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(Sc2ccc(Cl)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.4 %

Procedure:
tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation 160, 416 mg, 1.68 mmol) was added to a mixture of potassium carbonate (694 mg, 5.02 mmol), 3,4-dichlorothiophenol (300 mg, 1.77 mmol) in DMSO (16.7 mL) and the reaction stirred at room temperature for 18 hours. The reaction was quenched by addition of 0.5 N aqueous NaOH (20 mL) and EtOAc (30 mL) and the mixture partitioned. The aqueous was further extracted with EtOAc (3×10 mL), the organics combined, washed with brine (10 mL), dried (MgSO4), filtered and evaporated to give a yellow solid. Silica gel column chromatography eluting with 9:1 DCM:heptanes resulted in isolation of the title compound as a white solid (571 mg, 83%).
Reaction SMILES: [CH3:1][C:2]([CH3:35])([O:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]2=[C:18]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[C:19]3[CH:20]=[CH:21][C:22]([C:25]([O:27]C)=[O:26])=[CH:23][C:24]=3[N:10]2[CH2:9][CH2:8]1)=[O:6])[CH3:3]>CO.C1COCC1.[OH-].[Na+]>[CH3:3][C:2]([CH3:35])([O:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]2=[C:18]([CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][C:24]=3[N:10]2[CH2:9][CH2:8]1)=[O:6])[CH3:1]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(C(=O)OC(C)(C)C)c1ccccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccccc21
Temperature: 50 °C
Yield: 96.5 %

Procedure:
A solution of methyl 5-[(1,1-dimethylethoxy)carbonyl]-13-cyclohexyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-carboxylate (1.08 g, 2.28 mmol) in MeOH (40 mL), THF (30 mL) and 5N aqueous NaOH (2 mL) was heated at 50° C. overnight. Additional 10N aqueous NaOH (6 mL) was added and the reaction mixture was again heated at 50° C. for 5 h. The reaction was cooled, concentrated under vacuum and partitioned between EtOAc (60 mL) and ½ saturated aqueous NH4Cl (30 mL). The organic layer was washed with brine (10 mL) and the combined aqueous layers were extracted with EtOAc (40 mL). The combined organic layers were dried (MgSO4), filtered, concentrated to yield 5-[(1,1-dimethylethoxy)carbonyl]-13-cyclohexyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-carboxylic acid (1.01 g, 2.20 mmol, 96%) as a yellow solid. 1HNMR (500 MHz, Acetone-d6) δ 8.23 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.60–7.51 (m, 3H), 7.48–7.41 (m, 1H), 4.81 (br s, 1H), 4.66 (br s, 1H), 3.86 (br s, 1H), 3.59 (br s, 1H), 3.12–2.97 (m, 1H), 2.15–1.67 (m, 6H), 1.52–1.20 (m, 4H), 1.18 (s, 9H). LCMS: m/e 461 (M+H)+, ret time 2.26 min, column C, 2 minute gradient, start at 0% B.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[N:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:14]=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].[Cl-].[NH4+]>CN(C)C=O.O>[C:27]([O:26][C:24](=[O:25])[CH2:23][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)c1cccc(NC(=O)OC(C)(C)C)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a solution of sodium hydride (mineral oil 55% dispersion) (15.7 g, 0.360 mol) in N,N-dimethylformamide (362 ml) was added dropwise a solution of ethyl 6-tert-butoxycarbonylaminopyridin-2-carboxylate (see WO 2006/074884A) (81.2 g, 0.305 mol) in N,N-dimethylformamide (300 ml) over 20 minutes under ice cooling in an argon atmosphere, followed by stirring at room temperature for 1 hour. tert-Butyl bromoacetate (54.0 ml, 0.366 mol) was then added dropwise over 10 minutes under ice cooling, followed by further stirring at room temperature for 1 hour. After completion of the reaction, to the reaction solution was added an aqueous solution in which ammonium chloride (1.77 g, 33.0 mmol) was dissolved in water (300 ml), followed by extraction with toluene. The separated organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=9:1→4:1 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (108 g) as a pale yellow liquid. (Yield: 93%)
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][CH:23]=[C:22](Cl)[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:32][C:33]1([F:37])[CH2:36][NH:35][CH2:34]1.C(=O)(O)[O-].[Na+].O>CS(C)=O>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][CH:23]=[C:22]([N:35]4[CH2:36][C:33]([F:37])([F:32])[CH2:34]4)[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Reactant: FC1(F)CNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CC(F)(F)C2)ccc1Br
Temperature: 150 °C
Reaction time: 8 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 24, 2.2 g, 4.25 mmol) in DMSO (25 mL) under nitrogen, were added 3,3-difluoroazetidine hydrochloride (2.75 g, 21.3 mmol) and sodium bicarbonate (2.14 g, 25.5 mmol). The resulting mixture was stirred at 150° C. overnight. Water was added and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate in hexanes to afford the titled compound. 1H NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.78 (s, 2H), 7.63 (d, J=8.7 Hz, 1H), 6.24 (d, J=8.7 Hz, 1H), 5.75 (d, J=8.4 Hz, 1H), 4.87 (d, J=17.1 Hz, 1H), 4.23-4.40 (m, 6H), 0.79 (d, J=7.6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]=[CH:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH2:15][C:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:18])[CH3:17].C(OC(=O)NC(C)(C)CC1C2C(=C(CCS(C)(=O)=O)C=CC=2)NC=1)(C)(C)C>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH2:15][C:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:18])[CH3:17]
Reactant: COC(=O)C=Cc1cccc2c(CC(C)(C)NC(=O)OC(C)(C)C)c[nH]c12
Agent: CC(C)(Cc1c[nH]c2c(CCS(C)(=O)=O)cccc12)NC(=O)OC(C)(C)C
Product: COC(=O)CCc1cccc2c(CC(C)(C)NC(=O)OC(C)(C)C)c[nH]c12

Procedure:
3-[3-(2-tert-Butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl]-propionic acid methyl ester is prepared from 3-[3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl]-acrylic acid methyl ester as described below for the preparation of {2-[7-(2-methanesulfonyl-ethyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester (80%). FDMS m/e=375.2 (M++1).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13]([OH:15])=[O:14])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.[O:26]1C[CH:27]1[C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:39]=[C:38]([C:40]3[O:44][N:43]=[C:42]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:41]=3[C:51]([F:54])([F:53])[F:52])[O:37][N:36]=2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[OH:26][CH:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:39]=[C:38]([C:40]3[O:44][N:43]=[C:42]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:41]=3[C:51]([F:54])([F:53])[F:52])[O:37][N:36]=2)=[CH:31][CH:30]=1)[CH2:6][N:8]1[CH2:9][CH:10]([CH2:12][C:13]([OH:15])=[O:14])[CH2:11]1
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(C3CO3)cc2)no1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC1CN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Yield: 1.6 %

Procedure:
2-(1-(tert-Butoxycarbonyl)azetidin-3-yl)acetic acid (53.9 mg, 0.250 mmol) was treated with TFA/DCM for 1 hour. Solvents were removed in vacuo and the resulting material was dried. The solids were dissolved in 2-propanol (5 mL) and 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole (50 mg, 0.125 mmol) and cesium carbonate (245 mg, 0.751 mmol) were added. The reaction mixture was treated at 90° C. overnight. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. After concentration, the material was repurified by HPLC to yield 1 mg of 2-(1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)azetidin-3-yl)acetic acid as a TFA salt. MS (m+1)=515. HPLC Peak RT=3.24 minutes(Analytical Method A). Purity=95%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][NH:7][C:6](=O)[C:5]=2[CH:4]=[CH:3]1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:6]1[C:5]2[CH:4]=[CH:3][N:2]([CH3:1])[C:10]=2[C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1c[nH]c(=O)c2ccn(C)c12
Product: COC(=O)c1cnc(Cl)c2ccn(C)c12
Reaction time: 0.83 h

Procedure:
A suspension of methyl 1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (47.4 g) in phosphorus oxychloride (64.4 ml) was heated to reflux and stirred for 50 minutes then allowed to cool. The phosphorus oxychloride was removed in vacuo and the residue partitioned between dichloromethane (600 ml) and saturated sodium carbonate (600 ml). The aqueous layer was separated and further extracted with dichloromethane (600 ml). The organic layers were combined, dried (MgSO4) and the solvent removed. The residue was purified by column chromatography on a Biotage silica column (800 g) eluting with dichloromethane to yield the title compound as a white solid (42.7 g).