Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25](=[O:36])[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].O>CCO>[F:35][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[F:34])[CH2:27][NH:26][C:25]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)[N:12]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:11]=1[CH:22]([CH3:24])[CH3:23])=[O:36]
Reactant: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3cccnc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)O)cc2n1Cc1cccnc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following General Procedure F, ethyl3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-3-ylmethyl)-1H-indole-6-carboxylate (Compound 46, 439 mg, 0.896 mmol) ) in EtOH (12 ml) was added NaOH (179 mg, 4.48 mmol) and H2O (1 ml). The reaction was stirred at 25° C. for 12 h, concentrated in vacuo to an oil then acidified to PH=5 with 10% HCl, diluted with EtOAc, washed organic with H2O, brine, dried over Na2SO4 and concentrated in vacuo to yield the title compound as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Cl)=[C:9]([NH2:12])[C:8]([F:13])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:6]=1)=[O:4].[CH2:21]([Sn](CCCC)(CCCC)C=C)[CH2:22]CC>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH:21]=[CH2:22])=[C:9]([NH2:12])[C:8]([F:13])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(-c2ccc(Cl)cc2)c(F)c(N)c1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: C=Cc1c(C(=O)OC)nc(-c2ccc(Cl)cc2)c(F)c1N
Temperature: 110 °C
Yield: 9.4 %

Procedure:
4-Amino-3-chloro-6-(4-chlorophenyl)-5-fluoropyridine-2-carboxylic acid methyl ester (0.5 g, 1.59 mmol), tributyl(vinyl)tin (1.01 g, 3.17 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.111 g, 0.159 mmol), and tetrabutylammonium triphenyldifluorosilicate (1.71 g, 3.17 mmol) were combined in acetonitrile (3 ml) and heated to 110° C. for 15 min in a CEM microwave reactor. The cooled reaction mixture was concentrated onto silica gel and purified by flash chromatography on silica gel (hexane/ethyl acetate gradient) twice to yield the title compound (46 mg, 5% yield) as an off-white solid, mp 81-83° C. 1H NMR (CDCl3) δ 7.9 (m, 1H), 7.43 (m, 1H), 6.89 (dd, 1H), 5.7 (dd, 1H), 5.57 (dd, 1H), 4.72 (br s, 2H), 3.93 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1>>[OH:28][C@@H:25]1[CH2:26][CH2:27][N:23]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:24]1
Reactant: O[C@@H]1CCNC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CC[C@@H](O)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-pyrrolidin-3-ol (1.2 equiv) to give 176 (16.8 mg, M+1 383.1)
Reaction SMILES: [CH3:1][N:2]([CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)[C:3](=[O:25])[CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH3:24].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[NH2:28][CH2:27][CH2:26][N:2]([CH3:1])[C:3](=[O:25])[CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH3:24]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)N(C)CCNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)N(C)CCN
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
To a solution of tert-butyl 2-((4Z,7Z,10Z,13Z,16Z,19Z)—N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethylcarbamate (1.71 g, 3.5 mmol)) in dichloromethane (50 mL) at 0° C. was slowly added TFA (17 mL). The mixture was stirred (0° C., 2 h) basified to pH 10 with saturated aqueous Na2CO3 and extracted with EtOAc (3×150 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to afford (4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-aminoethyl)-N-methyldocosa-4,7,10,13,16,19-hexaenamide (1.31 g, 97%) as a light yellow oil.
Reaction SMILES: [CH:1]12[CH2:9][CH:4]([CH:5]([CH:7]=O)[CH2:6]1)[CH:3]=[CH:2]2.[CH:10]([CH:12]1CCC[CH:14](CCC=O)[CH2:13]1)=O.C(C1CCC(CCC=O)CC1)=O.C(C1CCCC(C(C)C=O)C1)=O.C(C1CCC(C(C)C=O)CC1)=O.C(C1CCCCC=1)=C.C1(C=O)CCCCC(C=O)CCCC(C=O)CC1.C=CC=C>>[CH:2]1[CH2:3][CH2:4][CH2:9][CH:1]=[CH:6][CH2:5][CH2:7][CH:10]=[CH:12][CH2:13][CH:14]=1
Reactant: O=CC1CC2C=CC1C2
Reactant: O=CCCC1CCCC(C=O)C1
Agent: C=CC1=CCCCC1
Agent: C=CC=C
Agent: CC(C=O)C1CCC(C=O)CC1
Product: C1=CCCC=CCCCC=CC1

Procedure:
Examples of suitable cyclic polyaldehydes are trans-1,3-cyclohexanedicarboxaldehyde; cis-1,3-cyclohexanedicarboxaldehyde; trans-1,4-cyclohexanedicarboxaldehyde; cis-1,4-cyclohexanedicarboxaldehyde; a mixture of 1,3-cyclohexanedicarboxaldehydes and 1,4-cyclohexanedicarboxaldehydes, preferably a 1-to-1 mixture thereof; exo,exo-2,5-norbornanedicarboxaldehyde; exo,exo-2,6-norbornanedicarboxaldehyde; exo,endo-2,5-norbornanedicarboxaldehyde; exo,endo-2,6-norbornanedicarboxaldehyde; endo,endo-2,5-norbornanedicarboxaldehyde; endo,endo-2,6-norbornanedicarboxaldehyde product (endo and exo mixture); 3-(3-formylcyclohexyl)propanal; 3-(4-formylcyclohexyl)propanal; 2-(3-formylcyclohexyl)propanal; 2-(4-formylcyclohexyl)propanal; and cyclododecane-1,4,8-tricarbaldehyde. The trans-1,3-cyclohexanedicarboxaldehyde; cis-1,3-cyclohexanedicarboxaldehyde; trans-1,4-cyclohexanedicarboxaldehyde; and cis-1,4-cyclohexanedicarboxaldehyde can be prepared by a process comprising hydroformylating 3-cyclohexene-1-carboxaldehyde using the hydroformylating conditions described later. The 1:1 mixture of 1,3- and 1,4-cyclohexanedicarboxaldehydes can be prepared by a process comprising reacting acrolein and 1,3-butadiene in a Diels-Alder reaction to give 3-cyclohexenecarboxaldehyde (also called 1,2,3,6-tetrahydrobenzaldehyde), and hydroformylating the 3-cyclohexenecarboxaldehyde. The exo,exo-2,5-norbornanedicarboxaldehyde; exo,exo-2,6-norbornanedicarboxaldehyde; exo,endo-2,5-norbornanedicarboxaldehyde; exo,endo-2,6-norbornanedicarboxaldehyde; endo,endo-2,5-norbornanedicarboxaldehyde; and endo,endo-2,6-norbornanedicarboxaldehyde product (endo and exo mixture) can be prepared by a process comprising reacting acrolein and cyclopentadiene in a Diels-Alder reaction to give a 2-norbornene-5-carboxaldehyde, and hydroformylating the 2-norbornene-5-carboxaldehyde. The 3-(3-formylcyclohexyl)propanal; 3-(4-formylcyclohexyl)propanal; 2-(3-formylcyclohexyl)propanal; and 2-(4-formylcyclohexyl)propanal can be prepared by a process comprising hydroformylating vinyl cyclohexene. The cyclododecane-1,4,8-tricarbaldehyde can be prepared by a process comprising trimerizing 1,3-butadiene to give 1,4,8-cyclododecatriene, and hydroformylating the 1,4,8-cyclododecatriene.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[Br:10][C:11]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:12]=1[CH:13]=[O:14].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[Br:10][C:11]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)=[CH:15][C:12]=1[CH:13]=[O:14]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(Br)c(C=O)c2)nc1
Temperature: 80 °C
Yield: 78 %

Procedure:
To a solution of 6-chloro-nicotinonitrile (3.5 g, 25.0 mmol, 1.0 eq.), 2-bromo-5-hydroxy-benzaldehyde (5.0 g, 25.0 mmol, 1.0 eq.) in DMF (40.0 mL) was added K2CO3 (4.1 g, 30.0 mmol, 1.2 eq.) under nitrogen atmosphere. The mixture was heated at 80° C. overnight. After cooling to room temperature, the mixture was poured into EtOAc (30 mL) and H2O (30 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×20 mL). Combined organic extracts was washed with brine (30 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give 6-(4-bromo-3-formyl-phenoxy)-nicotinonitrile as a white solid. 1H NMR(CHLOROFORM-d) δ: 10.35 (s, 1H), 8.43 (dd, J=2.3, 0.6 Hz, 1H), 7.98 (dd, J=8.6, 2.3 Hz, 1H), 7.69-7.77 (m, 2H), 7.30 (dd, J=8.6, 3.0 Hz, 1H), 7.12 (dd, J=8.6, 0.8 Hz, 1H). Amount obtained, 5.92 g, 78% yield.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.[CH2:20]([O:22][C:23]([C:25]1[N:26]=[CH:27][NH:28][C:29]=1[NH2:30])=[O:24])[CH3:21]>C(O)(=O)C>[CH2:20]([O:22][C:23]([C:25]1[N:26]=[CH:27][N:28]2[C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)=[N:30][C:29]=12)=[O:24])[CH3:21]
Reactant: CCOC(=O)c1nc[nH]c1N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Yield: 43.5 %

Procedure:
A mixture of 4,4,4-trifluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (10.0 g, 35.2 mmol) and 5-amino-1H-imidazole-4-carboxylic acid ethyl ester (5.0 g, 32.2 mmol) in acetic acid (120 mL) was refluxed for 24 h and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate/heptane) and crystallization (diethyl acetate/hexane) to yield 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine -8-carboxylic acid ethyl ester (5.65 g, 43%) as a yellow solid. MS (EI) 403.1 [(M)+]; mp 243° C.
Reaction SMILES: S([N:11]=[S:12]1(=[O:20])[CH2:17][CH2:16][CH2:15][S:14](=[O:19])(=[O:18])[CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.S(=O)(=O)(O)O>>[NH:11]=[S:12]1(=[O:20])[CH2:17][CH2:16][CH2:15][S:14](=[O:19])(=[O:18])[CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)N=S2(=O)CCCS(=O)(=O)C2)cc1
Agent: O=S(=O)(O)O
Product: N=S1(=O)CCCS(=O)(=O)C1

Procedure:
The method of claim 61 which includes the additional step of reacting said 1-tosylimino-1,3-dithiane-1,3,3-trioxide with concentrated sulfuric acid at 25° to 90° C to yield the corresponding 1-imino-1,3-dithiane-1,3,3-trioxide.
Reaction SMILES: [C:1]1([C:7]2([C:12]([OH:14])=O)[CH2:11][CH2:10]CC2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([C@@H:21]([N:23]2[CH2:27][C@H:26]3[CH:28]([NH2:31])[CH2:29][CH2:30][C@H:25]3[CH2:24]2)[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[C:1]1([C@H:7]([CH2:11][CH3:10])[C:12]([NH:31][C@H:28]2[C@H:26]3[C@H:25]([CH2:24][N:23]([C@H:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH3:22])[CH2:27]3)[CH2:30][CH2:29]2)=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: C[C@@H](c1ccccc1)N1C[C@@H]2CCC(N)[C@@H]2C1
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: CC[C@H](C(=O)N[C@@H]1CC[C@H]2CN([C@@H](C)c3ccccc3)C[C@H]21)c1ccccc1

Procedure:
The title compounds were prepared by substituting (S)-2-phenylbutanoic acid for 1-phenylcyclopentanecarboxylic acid and (3aS,6aR)-2-((S)-1-phenylethyl)octahydrocyclopenta[c]pyrrol-4-amine for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Examples 1 and 2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[OH:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ClCCl.C(#N)C>[CH:11]1([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:21]4[CH:22]=[C:17]([OH:16])[CH:18]=[CH:19][CH:20]=4)[CH:3]=3)[NH:8][CH:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OB(O)c1cccc(O)c1
Reactant: Brc1cnc2[nH]cc(C3CCCC3)c2c1
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: ClCCl
Product: Oc1cccc(-c2cnc3[nH]cc(C4CCCC4)c3c2)c1
Yield: 13.5 %

Procedure:
A mixture of 5-bromo-3-cyclopentyl-1H-pyrrolo[2,3-b]pyridine (31.8 mg, 0.12 mmol), 3-hydroxyphenylboronic acid (33.1 mg, 0.24 mmol) and 4.2 mg (5 mol %) of dichlorobis(triphenylphosphino)palladium(II) were placed in a vial and 0.8 ml of acetonitrile and 0.8 ml of a 2M aqueous solution of sodium carbonate were added and the mixture irradiated in a Personal Chemistry® microwave reactor to 150° C. for 900 seconds. The resulting mixture was distributed between 15 mL of a saturated aqueous solution of sodium bicarbonate and 30 mL of dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The crude was purified via silica gel chromatography using a gradient of ethyl acetate in hexanes to give 3-(3-Cyclopentyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenol (4.5 mg, 14% yield) as off white powder. 1H NMR (500 MHz, CD3OD) δ 8.36 (s, 1H), 8.14 (d, 2 Hz, 1H), 7.29 (t, 8 Hz, 1H), 7.19 (s, 1H), 7.10 (d, 7 Hz, 1H), 7.06 (s, 1H), 6.79 (dd, 2 Hz, 8 Hz, 1H), 2.1 (m, 2H), 1.94 (m, 2H), 1.8 (m, 4H), 1.37 (m, 1H). MS: m/z 279.1 [MH+].
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:12]2=[CH:13][N:14]=[C:15]([CH3:17])[CH:16]=[C:11]2[C:10]([C:18](=[O:20])[CH3:19])=[N:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:18]([C:10]1[C:11]2[C:12](=[CH:13][N:14]=[C:15]([CH3:17])[CH:16]=2)[N:8]([CH2:7][C:6]([OH:21])=[O:5])[N:9]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1nn(CC(=O)OC(C)(C)C)c2cnc(C)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1nn(CC(=O)O)c2cnc(C)cc12

Procedure:
A solution of (3-acetyl-5-methyl-pyrazolo[3,4-c]pyridin-1-yl)-acetic acid tert-butyl ester (126 mg, 0.37 mmol) and TFA (0.171 mL, 2.22 mmol) in CH2Cl2 (5 mL) was stirred at RT for 24 h. Solvents were removed under reduced pressure, Et2O was added and the precipitate was filtered, washed with Et2O and dried under high vacuum. The material thus obtained was used without further purification in the next step. MS (UPLC/MS): 234 [M+H]+, 232 [M−H]−, 465 [2M−H]−; tR (HPLC conditions f): 0.53 min.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[NH:28]1[CH:32]=[CH:31][N:30]=[N:29]1.CC([O-])(C)C.[Na+].CNCCNC>CN1C(=O)CCC1.CCOC(C)=O.[Cu]I>[CH2:24]([C:21]1[CH:20]=[N:19][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([C@H:10]3[CH2:11][C@H:9]3[CH2:8][O:7][CH2:6][C:5]3[CH:26]=[CH:27][C:2]([N:28]4[CH:32]=[CH:31][N:30]=[N:29]4)=[CH:3][CH:4]=3)[CH2:13][CH2:14]2)=[N:23][CH:22]=1)[CH3:25]
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(Br)cc3)CC2)nc1
Reactant: c1c[nH]nn1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: CNCCNC
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(-n4ccnn4)cc3)CC2)nc1
Temperature: 25 °C

Procedure:
The product of example 54 (step A) (100 mg, 0.232 mmol), CuI (44 mg, 0.232 mmol), triazole (48 mg, 0.697 mmol), NaOtBu (67 mg, 0.697 mmol) and N,N′-dimethylethylene diamine (61 mg, 0.697 mmol) in NMP (1 mL) was heated at 130° C. for 15 h. The reaction was cooled to room temperature, diluted with EtOAc and washed with H2O (×3). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum to leave a residue which was purified by silica gel column chromatography (elution with 2:1 hexane:ethyl acetate) to yield the title compound. MS (ESI) m/z 419 [M+H]+. GPR119 Human EC50: 0.3 nM
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[Br:16]Cl>C(Cl)CCl.CCOCC>[Br:16][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:15])=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=1
Reactant: ClBr
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Solvent: CCOCC
Solvent: ClCCCl
Product: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of 2,6-di-tert-butylphenol (2.06 g, 10 mmol) in EDC (50 mL) in a 200-mL round bottom flask, was added the stabilized BrCl brominating reagent (12 mL, about 11 mmol) dropwise, with stirring at room temperature. Initially, the orange reddish color of the reagent disappeared quickly. The color from the last 1 mL persisted for several minutes. The reaction mixture was allowed to stand for 30 minutes before being quenched with a few drops of sodium sulfite solution. After phase separation, it was diluted with EDC (50 mL), washed with water (100 mL) and dried (Na2SO4). The organic layer was concentrated under reduced pressure to afford a glue-like material. The material was redissolved in ether (10 mL) and after solvent removal, a crystalline solid 4-bromo-2,6-di-tert-butylphenol product (2.63 g, 92% recovered yield) was obtained in high purity (>98% by GC).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:16]([OH:18])=[O:17])=[C:4]2[CH:3]=[CH:2]1.N[C:20]1C=C(C)SC=1C(OC)=O>>[CH3:20][C:14]1[S:13][C:12]([C:16]([OH:18])=[O:17])=[C:11]([NH:10][C:9]2[CH:8]=[CH:7][N:6]=[C:5]3[NH:1][CH:2]=[CH:3][C:4]=23)[CH:15]=1
Reactant: O=C(O)c1sccc1Nc1ccnc2[nH]ccc12
Reactant: COC(=O)c1sc(C)cc1N
Product: Cc1cc(Nc2ccnc3[nH]ccc23)c(C(=O)O)s1

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid using methyl 3-amino-5-methylthiophene-2-carboxylate instead of methyl 3-aminothiophene-2-carboxylate. LCMS (ESI) 274 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.60 (1H, br. s.) 9.66 (1H, s) 8.06 (1H, d, J=4.49 Hz) 7.30-7.38 (1H, m) 6.95 (1H, d, J=5.47 Hz) 6.42 (1H, d, J=1.76 Hz) 2.50 (3H, s)
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][CH2:17]3)=[CH:12][N:11]=2)=[CH:5][C:4]([C:26]2[CH:27]=[N:28][CH:29]=[C:30]([N:34]3[C:46](=[O:47])[C:45]4[S:44][C:43]5[CH2:42][CH2:41][CH2:40][CH2:39][C:38]=5[C:37]=4[CH:36]=[N:35]3)[C:31]=2[CH:32]=[O:33])=[CH:3]1.[BH4-].[Na+]>CO>[OH:33][CH2:32][C:31]1[C:30]([N:34]2[C:46](=[O:47])[C:45]3[S:44][C:43]4[CH2:42][CH2:41][CH2:40][CH2:39][C:38]=4[C:37]=3[CH:36]=[N:35]2)=[CH:29][N:28]=[CH:27][C:26]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH2:18][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:20][CH2:21]3)=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: Cn1cc(-c2cncc(-n3ncc4c5c(sc4c3=O)CCCC5)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2cncc(-n3ncc4c5c(sc4c3=O)CCCC5)c2CO)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
To a solution of 116b (46 mg, 0.07 mmol) at 0° C. in methanol (4 mL) was added sodium borohydride (20 mg, 0.7 mmol) and stirred for 30 minutes. Then the reaction mixture was quenched with water (1.0 mL) and concentrated. The residue was purified by reverse-phase prep-HPLC to afford 116 (12 mg, 28%) as a yellow solid. LCMS: [M+H]+ 653. 1H NMR (500 MHz, DMSO) δ 8.60 (s, 1H), 8.59 (s, 1H), 8.56 (d, J=2.0, 1H), 8.50 (s, 1H), 8.44 (s, 1H), 7.87 (d, J=3.0, 1H), 7.38-7.36 (m, 2H), 7.24-7.22 (m, 1H), 4.90 (m, 1H), 4.56-4.53 (m, 2H), 4.46-4.44 (m, 4H), 3.59 (s, 3H), 3.44-3.42 (m, 1H), 3.06 (t, J=4.5, 4H), 2.94-2.93 (m, 2H), 2.85-2.84 (m, 2H), 2.38 (t, J=4.0, 4H), 1.89-1.84 (m, 4H)
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C([O-])(=O)C.[Na+].[CH3:10][C:11]([NH:14][S:15]([C:18]1[CH:22]=[CH:21][N:20](C)[C:19]=1[CH:24]=O)(=[O:17])=[O:16])([CH3:13])[CH3:12].O>CO>[CH3:13][C:11]([NH:14][S:15]([C:18]1[CH:22]=[CH:21][NH:20][C:19]=1[CH:24]=[N:4][O:3][CH3:2])(=[O:17])=[O:16])([CH3:10])[CH3:12]
Reactant: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1C=O
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CON=Cc1[nH]ccc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Yield: 96.2 %

Procedure:
To a suspension of 3.91 g (46.8 mmol) of methoxyamine hydrochloride in 60 mL of methanol was added 3.84 g (46.8 mmol) of sodium acetate. After stirring the white suspension for ca. 15 minutes 5.72 g (23 mmol) of N-(1,1-dimethylethyl)-2-formyl-1-methyl-1H-pyrrole-3-sulfonamide was added in one portion. The white suspension was heated at a gentle reflux overnight ca. 16 hours. The reaction mixture was cooled to room temperature and poured into 500 mL of water. The aqueous mixture was extracted with four 100 mL, portions of methylene chloride. The combined extracts were washed with water, dried (MgSO4) and concentrated in vacuo yielding 5.74 g of the title compound as a white solid, m.p. 99°-101° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O=S(Cl)Cl.[CH3:18]O>>[Br:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Br
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc([N+](=O)[O-])cc1Br

Procedure:
2-Bromo-4-nitrobenzoic acid (6.2 g, 25.3 mmol) was dissolved in MeOH (120 mL), and SOCl2 (5.5 mL, 75.9 mmol) was added dropwise at 0° C. The reaction mixture was refluxed for 6 h. The reaction solvent was concentrated to dryness. Residual SOCl2 was removed by co-evaporation with CH2Cl2 (×3). The solid was dried under vacuum to afford methyl 2-bromo-4-nitrobenzoate in 99.5% (6.52 g) yield as a light yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.50 (1H, s, Ar), 8.21 (1H, d, J=8.4 Hz, Ar), 7.91 (1H, d, J=8.4 Hz, Ar), 3.97 (3H, s, OCH3); 13C-NMR (CDCl3, 100 MHz) δ 165.2, 149.2, 137.9, 131.7, 129.1, 122.1, 122.0, 53.1; MS (ESI) m/z Calcd for C8H6BrNO4 (M+): 259.0, Found: 260.1 (M+H+). Next, the nitro group of methyl 2-bromo-4-nitrobenzoate (6.38 g, 24.6 mmol) was chemoselectively reduced with 5 nCl2.2H2O (27.8 g, 123.2 mmol) in a manner similar to that described for compound 6 to deliver methyl 4-amino-2-bromobenzoate in 96.0% (5.41 g) yield as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 7.74 (1H, d, J=8.8 Hz, Ar), 6.90 (1H, d, J=1.6 Hz, Ar), 6.55 (1H, dd, J=8.8 Hz, 1.6 Hz, Ar), 4.06 (2H, s, NH2), 3.83 (3H, s, OCH3); 13C-NMR (CDCl3, 100 MHz) δ 165.9, 150.4, 133.6, 124.1, 119.7, 119.6, 112.7, 51.8; MS (ESI) m/z Calcd for C8H8BrNO2 (M+): 229.0, Found: 230.1 (M+H+). Finally, a solution of sulfuric acid (98%, 6 mL) in H2O (75 mL) was added to methyl 4-amino-2-bromobenzoate (1.23 g, 5.38 mmol) and the resulting suspension was heated to 90° C., then stirred for 5 h at this temperature. The reaction mixture was cooled to 0° C. and a solution of NaNO2 (384 mg, 5.57 mmol) in H2O (5 mL) was added dropwise, then the reaction was allowed to warm to ambient temperature. The reaction mixture was then added to a solution of sulfuric acid (98%, 6 mL) in H2O (75 mL) that had been preheated to 90° C. The reaction mixture was stirred at 90° C. for 1 h, and then allowed to cool. The reaction mixture was partitioned between EtOAc (200 mL) and aqueous solution. The organic layer was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (35% EtOAc in hexanes) to afford compound 10 in 41.1% (508 mg) yield as a light brown solid. 1H-NMR (CDCl3, 400 MHz) δ 7.76 (1H, d, J=8.8 Hz, Ar), 7.09 (1H, s, Ar), 6.75 (1H, d, J=8.8 Hz, Ar), 3.84 (3H, s, OCH3); 13C-NMR (CDCl3, 100 MHz) δ 166.2, 160.3, 133.5, 123.4, 122.1, 121.4, 114.3, 52.1; MS (ESI) m/z Calcd for C8H7BrO3 (M+): 230.0, Found: 231.0 (M+H+).