Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19][NH:20][C:21]([NH2:23])=[O:22]>C(O)(=O)C>[CH3:19][N:20]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:23][C:21]1=[O:22]
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Reactant: CNC(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: Cn1c(-c2ccccc2)cc(-c2ccccc2)nc1=O
Reaction time: 8 h

Procedure:
A solution of 15 g. of dibenzoylmethane and 43.5 g. of M-methylurea in 250 ml. of glacial acetic acid is refluxed for 8 hours while dry hydrogen chloride gas is bubbled through the reaction mixture. An additional amount of 5 equivalents of N-methylurea is then added and refluxing continued for another 8 hours while bubbling hydrogen chloride through the reaction system. The N-methylurea addition is again repeated and refluxing procedure continued for a further 8 hours. The resulting mixture is filtered and the filtrate evaporated in vacuo to dryness. The residue is taken up with methylene chloride, treated with 2N. sodium hydroxide and the methylene chloride layer separated. The aqueous layer is extracted three times with methylene chloride. All methylene chloride fractions are combined and extracted several times with water, dried, filtered and evaporated in vacuo to dryness. The residue is crystallized from methylene chloride/diethyl ether to obtain 1-methyl-4,6-diphenylpyrimidin-2(1H)-one, m.p. 183°-185°C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH2:22][CH2:21][C:7]=3[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1.[F:33][C:34]([F:49])([F:48])[C:35]1[CH:36]=[CH:37][C:38]([C:41]2[CH:46]=[CH:45][NH:44][C:43](=[O:47])[CH:42]=2)=[N:39][CH:40]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[O:47]=[C:43]1[CH:42]=[C:41]([C:38]2[CH:37]=[CH:36][C:35]([C:34]([F:49])([F:33])[F:48])=[CH:40][N:39]=2)[CH:46]=[CH:45][N:44]1[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH2:22][CH2:21][C:7]=3[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cn2)cc[nH]1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(Br)cc42)CN(C(=O)OC(C)(C)C)CCC3)cc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(-n5ccc(-c6ccc(C(F)(F)F)cn6)cc5=O)cc42)CN(C(=O)OC(C)(C)C)CCC3)cc1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
tert-Butyl 8-bromo-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.20 g, 0.39 mmol), 4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (0.10 g, 0.43 mmol) and Cs2CO3 (0.14 g, 0.43 mmol) were suspended in DMSO (2.3 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (985 mg, 0.50 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The solution was cooled, diluted with 5:1 MeOH/NH4OH (15 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH2Cl2 (50 mL). The resulting solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was diluted with CH2Cl2 and washed with brine (3×25 mL). The organic solution was dried over Na2SO4, filtered and concentrated to dryness. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 5 column volumes; increased to 0:100 over 10 column volumes and held for 8 column volumes) gave the title compound (98 mg, 37%) as a yellow film: 1H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.40-8.38 (m, 2H), 8.23-8.18 (m, 1H), 7.93 (d, J=7.2 Hz, 1H), 7.75-7.65 (m, 3H), 7.39-7.33 (m, 4H), 7.12 (dd, J=7.2, 1.8 Hz, 1H), 4.48 (s, 2H), 3.61-3.60 (m, 2H), 3.33-3.27 (m, 2H), 2.31 (s, 3H), 1.89-1.88 (m, 2H), 1.30-1.08 (m, 9H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH:14]([CH3:16])[C:13](=O)[NH:12][C:11]=3[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20]>N1C=CC=CC=1.O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH:14]([CH3:16])[C:13](=[S:20])[NH:12][C:11]=3[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1Oc2ccc(-c3ccccc3)cc2NC1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: c1ccncc1
Product: CC1Oc2ccc(-c3ccccc3)cc2NC1=S
Yield: 100 %

Procedure:
1.62 g of 6-phenyl-2-methyl-1,4-benzoxazin-3-one is heated with 0.5 g of phosphorus pentasulfide in 6 ml of pyridine p.a. The product is diluted with water, extracted 3 times with ethyl acetate, the organic phase is washed with brine and dried with magnesium sulfate. It is concentrated by evaporation. The crude product corresponds to a yield of 100%. Column chromatography with a hexane/ethyl acetate mixture yields pure product.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+].O>CS(C)=O>[CH3:10][O:11][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: COc1cccnc1Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cccnc1OC
Temperature: 80 °C

Procedure:
To a solution of 2-chloro-3-methoxy-pyridine (110 g) in DMSO (1 L) was added sodium methoxide (124 g). The reaction mixture was heated to 80° C. overnight. The reaction mixture was poured into 3 L water and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[CH2:17][CH:18]([OH:23])[CH:19]([CH3:22])[CH2:20][CH3:21])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[CH2:17][CH:18]([OH:23])[CH:19]([CH3:22])[CH2:20][CH3:21]
Reactant: CCC(C)C(O)Cc1cc(OC)c(Cl)cc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)C(O)Cc1cc(OC)c(Cl)cc1N
Reaction time: 9 h
Yield: 95.9 %

Procedure:
To a solution of tert-butyl[5-chloro-2-(2-hydroxy-3-methylpentyl)-4-methoxyphenyl]carbamate (873 mg) in dichloromethane (12.2 mL) was added dropwise trifluoroacetic acid (3.76 mL) under ice-cooling, and this mixture was stirred for 9 hours. The reaction mixture was concentrated under reduced pressure. To the residue were added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution to separate the organic layer. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (603 mg). 1H-NMR (CDCl3) δ ppm: 0.75-1.75 (9H, m), 2.45-2.85 (2H, m), 3.30-4.10 (6H, m), 6.60-6.80 (2H, m). ESI-MS (m/z): 258, 260 (M+H)+
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[NH:23][CH:24]=O>C1COCC1>[CH3:24][NH:23][C:17]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=1[C:8]1[NH:7][C:15]2[C:10]([CH:9]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: O=CNc1ccc(Cl)cc1-c1cc2ccccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1ccc(Cl)cc1-c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
A total of 123 ml 1M LiAlH4 in THF was added portionwise to a solution of 15.37 g N-[2-(1H-indol-2-yl)-4-chlorophenyl]formamide in 230 ml THF, during which the temperature was maintained below 20° C. The resulting mixture was stirred three hours at room temperature and then quenched with a saturated NH4Cl solution (140 ml). This was then filtered through celite, dried (MgSO4), and concentrated to yield a solid. Purification by HPLC using CH2Cl2 /hexane (2:3) as eluent yielded 7.43 g solid, m.p. 123°-126°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]2[CH:17]=[CH:18][S:19][C:12]=12)C(OCC)=O)[CH3:2].O.[Cl-].[Li+]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:11]1[CH:16]=[CH:15][N:14]=[C:13]2[CH:17]=[CH:18][S:19][C:12]=12)[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccnc2ccsc12
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1ccnc2ccsc12
Temperature: 110 °C
Yield: 53.9 %

Procedure:
Dissolve 2-(thieno[3,2-b]pyridin-7-yl)malonic acid diethyl ester (12.90 g, 44.0 mmol) in dimethyl sulfoxide (295 mL). Add water (0.79 mL) and lithium chloride (3.73 g, 87.9). Heat the solution to 110° C. for 3 hours. Quench the reaction with saturated brine (3 L) and extract with ethyl acetate (3×1 L). Rewash the organic layers with saturated brine (1 L). Treat the organic layers with magnesium sulfate, filter and concentrate. The residue was purified on silica using 25% ethyl acetate/hexanes to yield the desired compound (5.25 g, 54%).
Reaction SMILES: Cl.[CH2:2]([NH:9][C:10]1[C:11]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][C:12]=2[N:13]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[O:27][CH:26]=[N:25][CH:24]=3)=[CH:19][CH:18]=2)[N:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[CH2:2]([NH:9][C:10]1[C:11]2[CH2:31][CH2:30][NH:29][CH2:28][C:12]=2[N:13]=[C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[O:27][CH:26]=[N:25][CH:24]=3)=[CH:21][CH:22]=2)[N:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(nc(Nc3ccc(-c4cnco4)cc3)nc2NCc2ccccc2)C1
Agent: Cl
Solvent: CO
Product: c1ccc(CNc2nc(Nc3ccc(-c4cnco4)cc3)nc3c2CCNC3)cc1
Temperature: 76 °C
Yield: 47.7 %

Procedure:
Hydrogen chloride (2 mL, 0.20 mmol, 2M aq) was added to a solution of tert-butyl 4-(benzylamino)-2-(4-(oxazol-5-yl)phenylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (0.1 g, 0.20 mmol, Example 5a) in MeOH (5 mL) and heated in an open reaction vessel to 76° C. for 1 h. The residual solvent was removed under reduced pressure, the crude product was redissolved in DMSO and purified by preparative HPLC to give N4-benzyl-N2-(4-(oxazol-5-yl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine (38 mg, 47.5%). MS (ESI+)/(ESI−) m/z 399/397
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]([CH3:16])=[O:15].[OH-].[Na+].O>C(O)C>[C:1]1([CH:11]=[CH:13][C:14](=[O:15])[CH:16]=[CH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1cccc2ccccc12)C=Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37.7 %

Procedure:
1-Naphthaldehyde (22, 1.36 ml, 10.0 mmol) and acetone (19, 0.37 ml, 5.0 mmol) were combined in ethanol (10 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.40 g, 10.0 mmol) and water (10 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, filtered and evaporated to afford a solid. The crude solid was recrystallized from ethyl acetate to give 0.63 g (38%) of a yellow solid: mp 132-133° C. [expected mp 128° C.]; 1H NMR: δ 7.24 (d, 2H, J=15.7 Hz), 7.57 (m, 6H), 7.92 (m, 6H), 8.28 (d, 2H, J=8.0 Hz), 8.65 (d, 2H, J=15.5 Hz); 13C NMR: δ 123.4, 125.1, 125.4, 126.2, 126.9, 128.1, 128.7, 130.7, 131.7, 132.2, 133.7, 140.3, 188.5.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[C:26]1([NH:36]N)[C:35]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=2[CH:29]=[CH:28][N:27]=1.C1(N)C2CCCCC=2C=CN=1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[C:26]1([N:36]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[C:35]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=2[CH:29]=[CH:28][N:27]=1
Reactant: NNc1nccc2c1CCCC2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Agent: Cl[Sn]Cl
Agent: Nc1nccc2c1CCCC2
Agent: O=N[O-]
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1nccc2c1CCCC2

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (5,6,7,8-tetrahydro-isoquinolin-1-yl)-hydrazine (prepared from the commercial 5,6,7,8-tetrahydro-isoquinolin-1-ylamine using sodium nitrite and tin(II) chloride in analogy to that described in J. Med. Chem. 2003, 46, 4676-4686) according to example 43 gave the desired product. MS: M=400.0 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([CH3:11])[CH2:10][C:5]2=[C:4]([C:12]([NH:14][C@@H:15]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:16]([NH:18][CH3:19])=[O:17])=[O:13])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCOCC1.O.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.[Pd]>[CH3:11][N:9]1[CH2:8][CH2:7][N:6]2[C:2]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:3][C:4]([C:12]([NH:14][C@@H:15]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:16]([NH:18][CH3:19])=[O:17])=[O:13])=[C:5]2[CH2:10]1
Reactant: OB(O)c1ccccc1
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)c1nc(Br)n2c1CN(C)CC2
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)[C@H](CC(C)C)NC(=O)c1nc(-c2ccccc2)n2c1CN(C)CC2
Temperature: 100 °C

Procedure:
A mixture of intermediate 20D (50 mg, 0.13 mmol), potassium carbonate (32 mg, 0.23 mmol), phenylboronic acid (0.20 mmol) and palladium tetrakis (8 mg) in dioxane (1.0 mL) and water (0.5 mL) was heated at 100° C. in a sealed vial overnight. After cooling down to room temperature, the mixture was passed through a thiol-based palladium scavenger. The residue was concentrated to dryness, to which MeOH (0.5 mL) was added. The solution was filtered to remove insoluble material and purified by preparative LC-MS using a gradient of 5% MeCN/water to 95 MeCN/water (0.1% formic acid) in 15 min. Pure fractions were evaporated with a Savant speedvac. The resulting oil was taken up in DCM (1.0 mL) and diluted with hexane (1.0 mL). Evaporation under air flow with mild heating gave Compound 275 as a white solid product (56% yield). LCMS (+ESI) m/z 384.1 [M+H]+.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:29])([F:28])[F:27])[O:12][N:11]=2)=[CH:6][CH:5]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH:31]1[CH2:36][C:37]([O:39]CC)=[O:38]>C(O)C>[OH:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:28])([F:27])[F:29])[O:12][N:11]=2)=[CH:8][CH:9]=1)[CH2:3][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH:31]1[CH2:36][C:37]([OH:39])=[O:38]
Reactant: CCOC(=O)CC1COCCN1
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(C3CO3)cc2)no1
Solvent: CCO
Product: O=C(O)CC1COCCN1CC(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Temperature: 80 °C

Procedure:
To a mixture of 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole, Preparation 28C (30 mg, 0.075 mmol) in ethanol (2 mL) was added ethyl 2-(morpholin-3-yl)acetate (52.1 mg, 0.301 mmol). The resulting mixture was heated at 80° C. overnight. Solvent was removed in vacuo. The residue was treated with 6N HCl/MeCN at 50° 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. Isolated fractions with correct mass were freeze-dried overnight to yield 18 mg of 2-(4-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)morpholin-3-yl)acetic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.23 (2H, d, J=7.91 Hz), 7.72 (2H, dd, J=8.35, 2.20 Hz), 7.68 (2H, d, J=7.03 Hz), 7.53-7.65 (3H, m), 5.22-5.30 (1H, m), 3.61-4.21 (7H, m), 3.35-3.55 (2H, m), 2.88-3.10 (2H, m). MS (m+1)=545. HPLC Peak RT=3.23 minutes (Analytical Method A). Purity=93%.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:16][C:9]=1[C:10]([NH:12][CH:13]1[CH2:15][CH2:14]1)=O>C1COCC1>[Cl:7][C:8]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:16][C:9]=1[CH2:10][NH:12][CH:13]1[CH2:14][CH2:15]1
Reactant: COCCCc1ccc(Cl)c(C(=O)NC2CC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCCc1ccc(Cl)c(CNC2CC2)c1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
LiAlH4 (5.70 g, 151 mmol) was added in portions to a sol. of 2-chloro-N-cyclopropyl-5-(3-methoxy-propyl)-benzamide (10 g, 37.7 mmol) in THF (230 mL) at 0° C. The ice bath was removed, and the mixture was heated to reflux for 4 h. The mixture was allowed to cool to rt, and was cooled to 0° C. Water (7.5 mL), aq. 15% NaOH (17 mL), and water (5.7 mL) were carefully added. The mixture was filtered, and the precipitate was washed with EtOAc. The filtrate was evaporated under reduced pressure. The residue was diluted with EtOAc, and the resulting mixture was washed with water, and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:4→1:3→1:2) yielded the title compound (5.60 g, 59%). LC-MS: tR=0.86 min; ES+: 254.19.
Reaction SMILES: N12CCCN=C1CC[CH2:4][CH2:3][CH2:2]2.[Cl:12][C:13]1[CH:14]=[C:15]([CH2:19][CH:20]([OH:39])/[CH:21]=[CH:22]/[C@H:23]2[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[N:24]2[CH2:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][C:36]([OH:38])=[O:37])[CH:16]=[CH:17][CH:18]=1.IC(C)C>CC(C)=O>[CH:3]([O:37][C:36](=[O:38])[CH2:35][O:34][CH2:33][CH2:32][CH2:31][CH2:30][N:24]1[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][C@@H:23]1/[CH:22]=[CH:21]/[CH:20]([OH:39])[CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[CH:14]=1)([CH3:4])[CH3:2]
Reactant: O=C(O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1cccc(Cl)c1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC(C)I
Solvent: CC(C)=O
Product: CC(C)OC(=O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1cccc(Cl)c1
Reaction time: 0.08 h
Yield: 49.9 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 16 μL, 0.11 mmol) was added to a solution of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-hydroxy-but-1-enyl]-6-oxo-piperidin-1-yl}-butoxy)-acetic acid (29 mg, 0.071 mmol) in acetone (0.5 mL). After 5 min, 2-iodopropane (35 μL, 0.35 mmol) was added. After 17 h, the reaction mixture was concentrated in vacuo, EtOAc (15 mL) was added and the resultant mixture was washed with 0.5 M aqueous HCl (5 mL), saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic phase was then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2<5% MeOH/CH2Cl2, gradient) afforded 16 mg (50%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:33]=[CH:32][C:24]3[C:25](=O)[O:26]C(C)(C)[O:28][C:23]=3[CH:22]=2)=[C:16]([F:34])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[NH3:36]>C(O)(C)C>[C:1]([O:5][C:6](=[O:35])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:33]=[CH:32][C:24]([C:25](=[O:26])[NH2:36])=[C:23]([OH:28])[CH:22]=2)=[C:16]([F:34])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CCN(Cc1ccc(Oc2ccc3c(c2)OC(C)(C)OC3=O)c(F)c1)C(=O)OC(C)(C)C
Reactant: N
Solvent: CC(C)O
Product: CC(C)CCN(Cc1ccc(Oc2ccc(C(N)=O)c(O)c2)c(F)c1)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
[4-(2,2-Dimethyl-4-oxo-4H-benzo[1,3]dioxin-7-yloxy)-3-fluoro-benzyl]-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-1d-1: 20 g) was dissolved in 35 mL of a 2 M solution of ammonia in isopropanol. The resulting solution was then treated with 50 mL of a saturated aqueous ammonia solution and the resulting mixture heated at 80° C. After 8 hours, the reaction mixture was cooled to ambient temperature and concentrated with a rotary evaporator. The residue was diluted with ethyl acetate and the organic solution was washed twice with water, once with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with 50% ethyl acetate in heptane to afford the title compound (I-1e-1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10]Cl)[CH2:7][C:6]=2[CH:12]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:7][C:6]=2[CH:12]=1
Reactant: ClCC1Cc2cc(Cl)ccc2O1
Reactant: C1CNCCN1
Product: Clc1ccc2c(c1)CC(CN1CCNCC1)O2
Temperature: 135 °C
Reaction time: 15 h
Yield: 65.1 %

Procedure:
To 5-chloro-2-(chloromethyl)-2,3-dihydro-1-benzofuran (1.6 g, 7.9 mmol) was added piperazine (2.72 g, 31.6 mmol, 4 eq) with stirring for 15 hours at 135° C. in an oil bath. The crude material was purified by silica gel chromatography using 3% dichloromethane in methanol to elute. The product-containing fractions were combined and concentrated under vacuum to afford 1-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine as a light yellow solid (1.3 g, 65%); (ES, m/z): [M+H]+ 253; 1H NMR (300 MHz, CDCl3): δ 7.03-7.11 (m, 2H), 6.68 (d, J=8.4 Hz, 1H), 4.93-5.03 (m, 1H), 3.20-3.29 (m, 1H), 2.88-2.99 (m, 6H), 2.72-2.79 (m, 1H), 2.49-2.63 (m, 5H).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[NH2:17][CH2:18][C:19]1[O:23][C:22]([C:24]([OH:26])=[O:25])=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+].Cl>O.C(COC)OC.C(N(CC)CC)C>[C:24]([C:22]1[O:23][C:19]([CH2:18][NH:17][C:2]2[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:20][CH:21]=1)([OH:26])=[O:25]
Reactant: CS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1Cl
Reactant: NCc1ccc(C(=O)O)o1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: COCCOC
Product: CS(=O)(=O)c1cc(C(=O)O)c(NCc2ccc(C(=O)O)o2)cc1Cl
Reaction time: 24 h

Procedure:
A mixture of 2,4-dichloro-5-methylsulfonylbenzoic acid (3.50 g.; 0.013 mole), 5-aminomethyl-2-furancarboxylic acid hydrochloride (4.83 g.; 0.027 mole), triethylamine (11.5 ml.), and glyme (25 ml.) is heated to 140°-150° C. for 24 hours. Solid sodium bicarbonate (5.0 g.) is added and refluxing is continued for another 24 hours. The mixture is poured into water (150 ml.) and acidified by the addition of 6N hydrochloric acid. The tan solid is collected, washed with water, and dried, 1.20 g., m.p. 269°-272° C. Recrystallization from acetonitrile gives 2-(5-carboxyfurfurylamino)-4-chloro-5-methylsulfonylbenzoic acid, m.p. 263.5°-265.5° C. (dec.).