Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[CH:5]2.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.CCN(C(C)C)C(C)C.[CH2:63]([SH:70])[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:63]([S:70][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[CH:5]2)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: Fc1cc2[nH]ncc2cc1Br
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Fc1cc2[nH]ncc2cc1SCc1ccccc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A solution of 5-bromo-6-fluoro-1H-indazole (1-1, 1.0 g, 5.08 mmol, 1.0 equiv), Xantphos (0.294 g, 0.508 mmol, 0.1 equiv), and Pd2(dba)3 (0.465 g, 0.508 mmol, 0.1 equiv) was made in dioxane (25 mL) followed by the addition of DIEA (1.77 mL, 10.15 mmol, 2.0 equiv) and benzylmercaptan (0.630 mL, 5.33 mmol, 1.05 equiv) and the reaction was stirred at 120° C. overnight. The reaction mixture concentrated in vacuo and purified using normal phase chromatography. ESI+ MS [M+H]+ C14H11FN2S: 259.9 found, 259.3 required.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4](Cl)[N:3]=1.[CH2:9]([NH:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH3:10].C[O:17][C:18](=[O:30])/[CH:19]=[CH:20]/[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>ClCCl.CN(C=O)C.CO>[CH2:9]([NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:2]1[N:3]=[C:4]([C:23]2[CH:22]=[C:21](/[CH:20]=[CH:19]/[C:18]([OH:30])=[O:17])[CH:26]=[CH:25][CH:24]=2)[CH:5]=[N:6][CH:7]=1)[CH3:10]
Reactant: COC(=O)/C=C/c1cccc(B(O)O)c1
Reactant: CCNCCCN
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CCNCCCNc1cncc(-c2cccc(/C=C/C(=O)O)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3 %

Procedure:
2,6-Dichloropyrazine (298 mg, 2.0 mmol) was dissolved in 25 mL dichloromethane. 1,5,7-triazabicyclo[4.4.0]dec-5-ene polystyrene (PS-TBD) (2.0 g, 5.0 mmol) was added followed by N-ethyltrimethylenediamine (194 mg, 1.90 mmol). The resulting mixture was agitated at room temperature overnight. The resin was filtered and the mother liquors were concentrated to a solid H (429 mg, 100%, mixture of isomers), which was used directly. [3-(E-3-methoxy-3-oxo-1-propen-1-yl)phenyl]boronic acid (618 mg, 3.0 mmol) and bistriphenylphosphinepalladium(II)chloride (35 mg, 0.05 mmol) were dispersed in 5 mL DMF in a reaction tube. Subsequently 1.5 mL of 2M Na2CO3 was added followed by intermediate H prepared above (429 mg, 2.0 mmol) as a solution in 5 mL DMF. The tube was sealed and the reaction mixture was heated at 85° C. for 72 hours. The reaction mixture was then filtered through a plug of celite, and the mother liquors were treated with a silica-bound sulfonic acid (Si-tosic acid), (9.5 g, 8.36 mmol). The resulting mixture was agitated for 24 hours, then the silica was isolated by filtration and washed with methanol. Intermediate I (150 mg, 88%, mixture of isomers) was eluted from the silica with 7N ammonia in methanol, and isolated by concentration of the eluant. The mixture was used directly. Intermediate I prepared above (140 mg, 0.41 mmol) was dissolved in 15 mL methanol. Amberlyst A26 (OH form) (1.5 g, 2.16 mmol) was added and the resulting mixture was agitated at room temperature for 72 hours. The resin was isolated by filtration and washed with methanol. The product was eluted from the resin using 20% formic acid in methanol, and isolated by concentration of the eluant (105 mg, 73%, mixture of isomers). The mixture was purified by preparative HPLC to provide the title compound (18.4 mg, 13%); MS analysis electrospray, 327 (M+H).
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:31]1[C:39]2[C:34](=[N:35][CH:36]=[C:37]([C:40]3[CH:41]=[C:42]([CH:46]=[CH:47][C:48]=3[Cl:49])[C:43]([OH:45])=[O:44])[CH:38]=2)[O:33][C:32]=1[C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1.[C:57]([O:60][CH2:61]C)(=[O:59])C>CO.CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:49][C:48]1[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][C:40]=1[C:37]1[CH:38]=[C:39]2[C:31]([C:57]([O:60][CH3:61])=[O:59])=[C:32]([C:50]3[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=3)[O:33][C:34]2=[N:35][CH:36]=1
Reactant: CCOC(C)=O
Reactant: O=C(O)c1ccc(Cl)c(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CS(C)=O
Product: COC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cc(C(=O)O)ccc3Cl)cc12
Reaction time: 8 h
Yield: 67 %

Procedure:
1,3-bis(diphenylphosphino)propane (28 mg, 0.067 mmol) was added to a stirring solution of palladium(II) acetate (7.5 mg, 0.034 mmol) and 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-chlorobenzoic acid (75 mg, 0.17 mmol) in MeOH (0.6 mL) and DMSO (1.1 mL) at 80° C. in a Parr bomb which was charged with 150 psi CO (g) and allowed to stir overnight. The mixture was diluted with ethyl acetate and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product 4-chloro-3-(2-(4-fluorophenyl)-3-(methoxycarbonyl)furo[2,3-b]pyridin-5-yl)benzoic acid (75 mg, 0.113 mmol, 67% yield) by LCMS. LC-MS retention time: 2.28 min; m/z (MH+): 427. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][C:2]1C=[CH:5][NH:4][C:3]=1C=O.Cl.[NH2:10][OH:11].[C:12]([O-])(=O)[CH3:13].[Na+]>CO>[CH3:5][N:4]1[CH:3]=[CH:2][CH:1]=[C:12]1[CH:13]=[N:10][OH:11]
Reactant: CC(=O)[O-]
Reactant: NO
Reactant: Cc1cc[nH]c1C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cn1cccc1C=NO
Yield: 88.1 %

Procedure:
Methyl-2-pyrrolecarboxaldehyde (5 g), hydroxylamine hydrochloride (9.55 g) and sodium acetate (11.28 g) were dissolved in methanol (100 ml) and the solution was refluxed for 12 hours. Aftre confirming the completion of the reaction using TLC, the resulting mixture was purified by column-chromatography (ethyl acetate/hexane=3/1) to yield the compound (5.01 g, 88%) as a brown solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].Cl.Cl[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>>[OH:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[N:9]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[C:8]1=[O:21]
Reactant: COc1ccc(COn2c(=O)[nH]c3c(sc4ccccc43)c2=O)c(OC)c1
Reactant: ClCc1ccccn1
Agent: Cl
Product: O=c1c2sc3ccccc3c2n(Cc2ccccn2)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was alkylated with 2-chloromethylpyridine hydrochloride and subsequently deprotected to provide the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:13])=[C:7]([Cl:22])[CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:23][NH:24][CH2:25][CH2:26][CH2:27][NH:28][CH3:29]>C(#N)C>[ClH:1].[ClH:1].[Cl:22][C:7]1[CH:6]=[CH:5][C:4]2[N:3]=[C:2]([N:24]([CH3:23])[CH2:25][CH2:26][CH2:27][NH:28][CH3:29])[CH:11]=[CH:10][C:9]=2[C:8]=1[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:13]
Reactant: O=C(NCC1CCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CNCCCNC
Solvent: CC#N
Product: CNCCCN(C)c1ccc2c(C(=O)NCC3CCCCC3)c(Cl)ccc2n1
Product: Cl
Temperature: 100 °C

Procedure:
A stirred suspension of 2,6-dichloro-N-(cyclohexylmethyl)quinoline-5-carboxamide (Example 43 (a)) (250 mg) and N,N′-dimethyl-1,3-propanediamine (0.80 mL) in acetonitrile (3 mL) was heated at 100° C. in a microwave for 2 hours after which it was cooled to room temperature and concentrated. The residue was purified by recrystallisation (methanol:ethyl acetate). The resultant product was converted to the dihydrochloride salt by treatment with hydrochloric acid (4M in 1,4-dioxane). Recrystallisation (methanol/ethyl acetate) afforded the title compound as a solid (110 mg).
Reaction SMILES: C1COCC1.[CH2:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:22]([C:24](=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])#[N:23]>C1(C)C=CC=CC=1>[CH2:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][CH:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:24]([C:22]#[N:23])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(C#N)=Cc1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)C(Cc1ccc(OCc2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
835 mg of Mg are suspended in 5 ml of abs. THF. A solution of 2.0 g of 4-benzyloxybenzyl chloride in 5 ml of abs. tetrahydrofuran is subsequently added dropwise. When the addition is complete, the cloudy solution is stirred at room temperature for a further 1 hour, a solution of 1.73 g of ethyl 2-cyano-3-phenylacrylate in 10 ml of abs. toluene is subsequently added, and the mixture is refluxed for 16 hours. The solvent is removed, and conventional work-up gives ethyl 4-(4-benzyloxyphenyl)-2-cyano-3-phenylbutyrate (“AA”).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:28])=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[C:7]([N+:22]([O-:24])=[O:23])=[C:8]([CH:18]=[C:19]([F:21])[CH:20]=1)[NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[F:17].[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[F:21][C:19]1[CH:18]=[C:8]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:7]([N+:22]([O-:24])=[O:23])=[C:6]([CH:20]=1)[O:5][C:4]1[C:3]([CH3:28])=[C:2]([NH:1][S:31]([CH2:29][CH3:30])(=[O:33])=[O:32])[CH:27]=[CH:26][CH:25]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1c(N)cccc1Oc1cc(F)cc(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2[N+](=O)[O-])c1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 118 %

Procedure:
1.18 g 3-(3-amino-2-methylphenoxy)-5-fluoro-N-(2-fluoro-4-iodophenyl)-2-nitroaniline (2.3 mmol, 1 eq.) were dissolved in 9.6 mL pyridine, cooled to 0° C., treated with 292 μL ethyl sulfonyl chloride (3.1 mmol, 1.2 eq.) and stirred at 0° C. for 3 hours. The reaction mixture was diluted with toluene and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The aqueous layer was reextracted with ethyl acetate. The combined organic layers were dried, filtered and concentrated in vacuo to yield 1.6 g of the crude product, which was taken up in toluene and again concentrated in vacuo. The crude product was used in the subsequent transformations without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Cl:25][CH2:26][CH2:27][CH2:28][C:29]([NH:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1)=[O:30]
Reactant: O=C(Cl)CCCCl
Reactant: COC(=O)c1ccc(-c2ccc(N)nc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2ccc(NC(=O)CCCCl)nc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
A stirred suspension of methyl 4-(6-amino-2-methylpyridin-3-yl)benzoate (D7, 1.0 g, 4.1 mmole) in dichloromethane (80 ml) was treated with pyridine (0.66 ml, 8.2 mmole), followed by 4-chlorobutyryl chloride (0.47 ml, 4.3 mmole). The resulting solution was stirred at 25° C. for 2 h, then treated with 5% Na2CO3 solution and after 30 minutes, the organic layer was separated, dried (Na2SO4) and concentrated in vacuo to leave a pale yellow solid. This was recrystallised from ethyl acetate/60-80 petrol to afford the title compound as a beige solid (1.13 g, 80%).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[C:38]1[S:39][C:40]([CH3:43])=[N:41][N:42]=1.C(O)C>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.C1(C)C=CC=CC=1>[CH3:3][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:38]3[S:39][C:40]([CH3:43])=[N:41][N:42]=3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:1]
Reactant: Cc1nnc(Br)s1
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3nnc(C)s3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Reaction time: 2 h
Yield: 28.8 %

Procedure:
A flask was charged with 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 52) (223 mg, 0.536 mmol), potassium carbonate (222 mg, 1.607 mmol), tetrakis(triphenylphosphine)palladium(0) (61.9 mg, 0.054 mmol) and 2-bromo-5-methyl-1,3,4-thiadiazole (125 mg, 0.696 mmol) then filled with ethanol (3 mL) and toluene (3 mL). The resulting mixture was degassed for 15 min under house vacuum (with several quenches with nitrogen) then stirred at 100° C. for 2 h before being cooled to room temperature and left stand still for 16 h. The insoluble material was filtered off and rinsed with AcOEt. Most of the solvent was removed in vacuo and the residue was dissolved in AcOEt. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 25 G silica cartridge (gradient: 25 to 100% AcOEt in hexanes) gave a material which was then further purified by MDAP (modifier: ammonium bicarbonate) to give 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(5-methyl-1,3,4-thiadiazol-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (60 mg, 0.154 mmol, 28.8% yield) as a white foam.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:25]([O:27][CH3:28])=[O:26])=[C:9]([CH3:24])[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[N:11]2)=[CH:6][C:5]=1F)[CH3:2].[CH2:30]([S-:32])[CH3:31].[Na+].IC>CS(C)=O.O>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:25]([O:27][CH3:28])=[O:26])=[C:9]([CH3:24])[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[CH:15]=3)=[N:11]2)=[CH:6][C:5]=1[S:32][CH2:30][CH3:31])[CH3:2]
Reactant: CC[S-]
Reactant: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)OC)c2cc1F
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CS(C)=O
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)OC)c2cc1SCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 7-(ethyloxy)-6-fluoro-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (9.35 g, 22.95 mmol) in dimethyl sulfoxide (150 mL) was added sodium ethanethiolate (6.44 g, 68.9 mmol) and the resulting mixture was stirred at room temperature overnight. Iodomethane (7.18 mL, 115 mmol) was added, and the mixture was stirred for 2 h. The mixture was diluted with water and extracted with methylene chloride. The organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford methyl 7-(ethyloxy)-6-(ethylthio)-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used without further purification. MS (m/z) 450.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>C(Cl)Cl>[C:35]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10])[C:16]1[O:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)=[N:19][N:20]=1)(=[O:38])[CH2:36][CH3:37]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)O[C@@H](C)[C@@H](Nc1ccc(C#N)c(Cl)c1C)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 19 h
Yield: 52 %

Procedure:
To a 50 mL round bottomed flask was added 2-chloro-4-((1R,2S)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile (200 mg, 0.508 mmol, pyridine (1 mL, 12.41 mmol) and methylene chloride (15 mL). Propionyl chloride (0.22 mL, 2.54 mmol) was then added dropwise and the mixture was stirred at room temperature for 19 h. The reaction mixture was then quenched with 10% aq HCl (15 mL) and methylene chloride (30 mL) was added. The phases were partitioned and the aqueous phase extracted with methylene chloride (30 mL) (×2). The combined organics were washed with a saturated solution of sodium hydrogen carbonate, dried (Na2SO4) and concentrated to furnish a yellow oil (0.116 g, 52%). 1H NMR (Acetone d6, 400 MHz) δ 8.23 (d, J=9 Hz, 2 H), 8.00 (d, J=9 Hz, 2 H), 7.53 (d, J=9 Hz, 1 H), 7.02 (d, J=9 Hz, 1 H), 5.73 (d, J=9 Hz, 1 H), 5.69-5.64 (m, 1 H), 5.48 (dd, J=5 and 8 Hz, 1H), 2.37 (s, 3 H), 2.34 (q, J=7 Hz, 1 H), 1.47 (d, J=6 Hz, 3 H) and 1.02 (t, J=8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[C:17](=[O:32])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:20]=1)[CH2:5][NH:6][C:7](=[O:13])OC(C)(C)C.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[C:17](=[O:32])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:20]=1)[CH2:5][NH:6][C:7](=[O:13])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.[NH2:6][CH2:5][C:4]1[CH:14]=[CH:15][C:16]([C:17]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH:20]=2)=[O:32])=[C:2]([Cl:1])[CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1)c1ccccn1

Procedure:
75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-((tert-butoxycarbonylamino)methyl)-2-chlorobenzoic acid via Procedure G to yield tert-butyl 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate. Tert-butyl 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate was subsequently treated with 4N HCl in Dioxane to remove the Boc protecting group and form the HCl salt of 4-(aminomethyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. 54 mg of the crude HCl salt of 4-(aminomethyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was coupled to picolinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N-(3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)picolinamide. MS (Q1) 477.3 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:4]([Cl:12])[CH:3]=1.[H-].[Na+].[CH3:15]I.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:11][CH3:15])([CH3:10])[CH3:9])=[C:4]([Cl:12])[CH:3]=1
Reactant: CC(C)(O)c1ccc(Br)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(C)(C)c1ccc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 370 mg (1.48 mmol) of 2-(4-bromo-2-chloro-phenyl)-propan-2-ol in 2 ml DMF was added to a suspension of sodium hydride (65 mg, ˜60% dispersion in oil) in 2 ml DMF at 0° C. The mixture was stirred at 0° C. for 30 min and then 111 μl (1.78 mmol) of methyl iodide were added. The reaction mixture was then warmed to rt and stirring was continued overnight. Then water was added and the mixture was extracted with ether. The organic phase was washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo to give a residue which was purified by flash column chromatography (1:9 ether/pentane). The title compound was obtained as a colorless liquid (310 mg, 79%). 1H NMR (CDCl3, 300 MHz): δ 1.64 (s, 6H), 3.13 (s, 3H), 7.35 (m, 2H), 7.54 (d, J=1.7 Hz, 1H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][CH2:14][C:15]([CH3:50])([CH3:49])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])=[CH:19][CH:18]=1>O.C(OCC)(=O)C>[OH:13][CH2:14][C:15]([CH3:49])([CH3:50])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])=[CH:19][CH:18]=1
Reactant: [NH3+]O
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
A mixture of hydroxylammonium chloride (0.68 g), sodium hydrogen carbonate (0.98 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-({1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.49 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.19 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.14 g, 26%).