Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[O:6][C:7]2[C:13]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:4].CC1C=CC(S(O[CH2:32][CH2:33][C:34]2[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[CH:36][N:35]=2)(=O)=O)=CC=1>>[CH3:41][O:40][C:39]1[C:34]([CH2:33][CH2:32][N:17]2[CH2:18][CH2:19][N:14]([C:13]3[C:7]4[O:6][C:5]([C:3]([N:2]([CH3:20])[CH3:1])=[O:4])=[CH:9][C:8]=4[CH:10]=[CH:11][CH:12]=3)[CH2:15][CH2:16]2)=[N:35][CH:36]=[CH:37][CH:38]=1
Reactant: CN(C)C(=O)c1cc2cccc(N3CCNCC3)c2o1
Reactant: COc1cccnc1CCOS(=O)(=O)c1ccc(C)cc1
Product: COc1cccnc1CCN1CCN(c2cccc3cc(C(=O)N(C)C)oc23)CC1

Procedure:
The compound was prepared according to the procedure disclosed in Example 46 starting from N,N-dimethyl-7-(piperazin-1-yl)benzofuran-2-carboxamide (0.085 g, 0.31 mmol) (Example 39d) and 2-(3-methoxypyridin-2-yl)ethyl 4-methylbenzenesulfonate (0.092 g, 0.31 mmol). The product was purified by preparative HPLC to give the title compound.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CN1CCCC1=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:5]2[N:6]=[C:2]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[S:3][C:4]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1sc(Br)nc1Cc1ccc(Cl)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)cc1
Yield: 80.8 %

Procedure:
To a solution of ethyl 2-bromo-4-(4-chlorobenzyl)thiazole-5-carboxylate (4.19 g, 11.6 mmol, prepared as described in Example 10) in N-methylpyrrolidinone (12.2 mL) was added potassium carbonate (3.21 g, 23.2 mmol) and morpholine (1.52 mL, 17.4 mmol) and the resulting mixture was heated to 130 degrees for 90 minutes. The reaction was cooled and the volatiles were removed by concentration at 65 degrees under oil pump vacuum. The residue was taken up in DCM (100 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with DCM (50 mL). The combined DCM layers were dried over MgSO4, filtered, and concentrated to give the crude product, which was purified by silica gel chromatography (ethyl acetate/hexane=0/100→35/65) to give 3.44 g of the title compound as a white solid. (80% yield). LC/MS (FA) ES+ 367. 1H NMR (300 MHz, CDCl3) δ: 7.32-7.27 (m, 2H), 7.24-7.20 (m, 2H), 4.28 (s, 2H), 4.27 (q, 2H, J=7.2 Hz), 3.80-3.76 (m, 4H), 3.53-3.48 (m, 4H), 1.32 (t, 3H, J=7.2 Hz).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:15][CH:16]=[CH2:17].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[Si:18]([O:1][C:2]1[C:3]([CH2:15][CH:16]=[CH2:17])=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[CH2:12][CH:13]=[CH2:14])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: C=CCc1cc(C(=O)OC)cc(CC=C)c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCc1cc(C(=O)OC)cc(CC=C)c1O[Si](C)(C)C(C)(C)C
Yield: 97.2 %

Procedure:
The product of Step B (3.1 g, 13.36 mmol) was treated with tert-butyldimethylsilyl chloride (2.22 g, 1.1 equiv), triethylamine (3 mL) and DMAP (0.1 equiv) in dichloromethane overnight. The mixture was concentrated and flash chromatographed with 5% and then 10% ethyl acetate in hexane to furnish 4.5 g (97%) of the title compound.
Reaction SMILES: [C:1]1(=[O:24])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)[C:4](=[O:19])[C:3]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]12.Cl.[CH3:26][O:27][C:28](=[O:31])[CH2:29][NH2:30].C([O-])(=O)C.[Na+]>C(O)(=O)CC>[CH3:26][O:27][C:28]([CH2:29][N:30]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]1[CH2:6][N:5]1[C:4](=[O:19])[C:3]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]2[C:1]1=[O:24])=[O:31]
Reactant: COC(=O)CN
Reactant: O=C(CCC(=O)c1ccccc1)CN1C(=O)c2ccccc2C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCC(=O)O
Product: COC(=O)Cn1c(CN2C(=O)c3ccccc3C2=O)ccc1-c1ccccc1

Procedure:
9.6 g (0.03 mol) of 5-phthalimido-1-phenyl-1,4-pentanedione, 5.0 g (0.04 mol) of glycine methyl ester hydrochloride and 3.2 g (0.04 mol) of anhydrous sodium acetate are stirred in 80 ml of propionic acid at 60° C. for 20 hours. Purification is by column chromatography. Solid phase: "Silica-Woelm", particle size 0.1 to 0.2 mm; manufacturer: Messrs. Woelm, Eschwege, Germany; mobile phase: methylene chloride.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]1[CH2:15]O.[CH:17]1([N:20]2[C:28]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[NH:22][C:21]2=[O:29])[CH2:19][CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1COCC1>[CH:17]1([N:20]2[C:28]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[N:22]([CH2:15][C:7]3[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][F:1])[C:14]4[C:9]([N:8]=3)=[N:10][CH:11]=[CH:12][CH:13]=4)[C:21]2=[O:29])[CH2:19][CH2:18]1
Reactant: O=c1[nH]c2cnccc2n1C1CC1
Reactant: OCc1nc2ncccc2n1CCCCF
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1n(Cc2nc3ncccc3n2CCCCF)c2cnccc2n1C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.3 %

Procedure:
To a suspension of (1-(4-fluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)methanol 42-5 (958 mg, 4.3 mmol), 1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one 10-d (950 mg, 5.15 mmol) and triphenylphosphine (1350 mg, 5.15 mmol) in 30 ml dry THF was added (E)-diisopropyl diazene-1,2-dicarboxylate (1.26 ml, 6.43 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The precipitate was filtered off and washed with some diethyl ether to obtain the title product as a white powder (1036 mg, 63%).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[F:18])[NH:14][N:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=1[CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)[N:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(CO)c2C1
Reactant: Fc1cc2[nH]ncc2cc1SCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2cccc(Cn3ncc4cc(SCc5ccccc5)c(F)cc43)c2C1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5-(benzylthio)-6-fluoro-1H-indazole (1-2, 0.35 g, 1.35 mmol, 1.0 equiv) and tert-butyl 8-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.53 g, 2.03 mmol, 1.5 equiv) in THF (6.77 mL) at 0° C. was added polymer supported triphenylphosphine (0.71 g, 2.71 mmol, 2.0 equiv) followed by di-tertbutylazodicarboxylate (0.62 g, 2.71 mmol, 2.0 equiv) and the reaction mixture was stirred at 0° C. for 2.5 hours. The reaction was concentrated and purified using normal phase chromatography to yield the desired regioisomer. ESI+ MS [M+H]+ C29H30FN3O2S: 504.3 found, 504.6 required.
Reaction SMILES: C(O[C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:28])[CH2:12][N:13]2[C:21]3[CH:20]=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[C:15]3[CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][C:14]2=3)=[CH:7][CH:6]=1)C.[OH-].[NH4+:31]>O>[CH3:27][N:24]1[CH2:25][CH2:26][C:14]2[N:13]([CH2:12][CH:11]([C:8]3[CH:7]=[CH:6][C:5]([C:4]([NH2:31])=[O:29])=[CH:10][CH:9]=3)[OH:28])[C:21]3[CH:20]=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[C:15]=2[CH2:23]1
Reactant: [NH4+]
Reactant: CCOC(=O)c1ccc(C(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(C(N)=O)cc2)CCN(C)C1
Temperature: 25 °C

Procedure:
A solution of 4-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-benzoicacid ethyl ester (90 mg, 0.229 mmol) in 25% ammonium hydroxide solution (5 mL) was stirred at 120° C. for 1 h. The progress of reaction was monitored by NMR and LCMS. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc (3×30 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 4-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-benzamide (3 mg) which was separated by chiral preparative HPLC to obtain 139a and 139b. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.18 (t, 2H), 7.4 (d, 1H), 7.31 (d, 2H), 7.23 (s, 1H), 7.03 (t, 1H), 5.08 (t,1H), 4.64 (dd, 1H), 4.33 (m, 2H), 4.21 (dd, 1H), 3.71 (t, 1H), 3.45 (bs, 1H), 3.12 (m, 1H), 3.09 (d, 3H), 2.6 (d, 1H), 2.41 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7].[Br:15]Br>CC(O)=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]([O:13][CH3:14])=[CH:11][C:10]=1[Br:15]
Reactant: BrBr
Reactant: COC(=O)c1ccc(OC)c(OC)c1
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC)c(OC)cc1Br
Reaction time: 0.75 h
Yield: 63.6 %

Procedure:
To 10.00 g (51 mmol) of methyl 3,4 dimethoxybenzoate (6) in 50 mL of AcOH at 0° C. was added 8.90 g (56 mmol) of Br2 in 50 mL of AcOH over 1.5 h. The ice bath was removed and the mixture stirred 45 min. The reaction was quenched by pouring into 700 mL of H2O, stirred 30 min, left quiescent for 1 h, and filtered. The collected solid was washed with H2O and washed with sat. aq. Na2S2O3. The solid was partially dried, dissolved in 300 mL hot MeOH, and the resultant solution was cooled. The cool methanolic solution of product was treated with 200 mL of H2O and the white solid filtered to give 8.92 g (64% yield) of methyl-2-bromo-4,5-dimethoxybenzoate (7) as a white powder. The compound matched the physical and spectral properties of the known compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:17]=3[N:18]=2)[C:7]([NH:10][CH2:11][CH2:12][CH3:13])=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[Cl:31]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20]([C:27]4[CH:28]=[CH:29][C:30]([Cl:31])=[C:25]([CH3:24])[CH:26]=4)=[CH:19][C:17]=3[N:18]=2)[C:7]([NH:10][CH2:11][CH2:12][CH3:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1cc(B(O)O)ccc1Cl
Reactant: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)ccc2o1
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccc(Cl)c(C)c3)ccc2o1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-6-propylaminophenyl)-5-bromobenzoxazole (400 mg, 1.59 mmol) and 3-methyl-4-chlorophenylboronic acid (271 mg, 1.59 mmol) the subtitle compound was obtained (230 mg, 34%). The product was used directly in the next step without purification.
Reaction SMILES: [C:1]1([N:11]=[C:12]=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[CH:16]([OH:22])[CH2:15]2>>[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[CH:16]([O:22][C:12](=[O:13])[NH:11][C:1]1[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=1)[CH2:15]2
Reactant: O=C=Nc1cccc2ccccc12
Reactant: OC1CN2CCC1CC2
Product: O=C(Nc1cccc2ccccc12)OC1CN2CCC1CC2

Procedure:
1-Naphthylisocyanate and 3-quinuclidinol were used. The title compound was isolated as a white solid (34%): mp 186-188° C.; FAB LRMS m /z 297 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:26]1([CH2:32][CH2:33][SH:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[OH-].[Na+]>O1CCOCC1.O>[CH2:33]([S:34][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)[CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(Cl)nn2)CC1
Reactant: SCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(SCCc3ccccc3)nn2)CC1
Temperature: 105 °C
Yield: 44.1 %

Procedure:
A mixture of [4-(6-chloro pyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone (0.089 g, 0.240 mmol), 2-phenylethanethiol (0.049 g, 0.36 mmol) and sodium hydroxide (9.6 mg) in 5 mL 1,4-dioxane was heated at 100-110° C. overnight. The reaction mixture was cooled to room temperature, diluted with 20 mL of water, and then extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulphate, then concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a white solid (50 mg, 43.7% yield). 1H NMR (400 MHz, CDCl3) δ 7.65, 7.52-7.55, 7.47-7.48, 7.27, 7.12-7.22, 7.03, 6.76, 3.89-3.94, 3.79-3.84, 3.54-3.61, 3.49-3.51, 3.45, 3.17-3.25, 2.97.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][NH2:9])=O)=[CH:2]1.Cl[C:11]1[CH:12]=[CH:13][C:14]([C:20]#[N:21])=[C:15]([N:17]=[C:18]=[S:19])[CH:16]=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:21]=[C:20]3[N:9]([C:18]([SH:19])=[N:17][C:15]4[CH:16]=[CH:11][CH:12]=[CH:13][C:14]=43)[N:8]=2)=[CH:2]1
Reactant: N#Cc1ccc(Cl)cc1N=C=S
Reactant: NNC(=O)c1ccoc1
Product: Sc1nc2ccccc2c2nc(-c3ccoc3)nn12

Procedure:
As in Example 39, 3-furoic acid hydrazide is reacted with 5-chloro-2-cyanophenyl isothiocyanate to produce 2-(3-furyl)-5-mercapto-[1,2,4]triazolo[1,5-c]quinazoline, mp>300°, which is converted to the 5-methylthio compound and thence to 9-chloro-2-(3-furyl)-5-imino-5,6-dihydro[1,2,4]triazolo[1,5-c]quinazoline, purified as the methanesulphonate salt, mp 290°-292°.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15]>O>[CH2:12]([N:16]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Product: CCCCN1C(=O)c2ccccc2C1=O
Temperature: 200 °C
Yield: 95 %

Procedure:
A 10-gallon stainless steel reactor equipped with a turbine blade impeller, cooling coil, distilling condenser, azeotropic separator, thermocouple probe and means to maintain a nitrogen atmosphere, was charged with 15.335 kg (103.53 moles) phthalic anhydride. N-butylamine (7.663 kg, 104.57 moles) from a pressure vessel was slowly added to the reactor which was at room temperature, e.g., about 25° C. The resulting exothermic reaction between the amine and phthalic anhydride was continued until the temperature in the reactor rose to 90° C., at which time addition of amine was complete. The reaction mixture was then heated, with removal of water, for a 5 hour period until the temperature of the mixture reached 200° C. The reaction mixture then was maintained at 200° C. for 2 hours. The resulting product was vacuum distilled at a temperature ranging from 150-155° C. and at a pressure of 20 mm, to afford a liquid which solidified. The melting point of the solid was about 34 to 35° C. and was produced at a 95% yield.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1)N.[CH3:13][CH:14]([C:23](=O)[CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>C(O)(=O)C>[CH3:24][C:23]1[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])([CH3:13])[C:8]2[C:3](=[CH:4][CH:5]=[C:6]([S:9]([OH:12])(=[O:11])=[O:10])[CH:7]=2)[N:1]=1
Reactant: NNc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)C(C)CCCCCC(=O)O
Solvent: CC(=O)O
Product: CC1=Nc2ccc(S(=O)(=O)O)cc2C1(C)CCCCCC(=O)O

Procedure:
4-Hydrazinobenzenesulfonic acid (1.88 g, 10 mmol), 7-methyl-8-oxononanoic acid (2.8 g, 15 mmol) and glacial acetic acid (10 ml) were mixed and heated under reflux for 6 hrs. The solvent was then evaporated under vacuum and the residue triturated with diethyl ether until a solid was obtained. This was dried under vacuum to give crude product, 3.4 g (100%). This was purified by preparative HPLC as required (RPC18. Water+0.1% TFA→MeCN+0.1% TFA gradient). UV/Vis (Water+0.1% TFA): 274, 229, 204 nm. 1H-nmr (D2O) δ 0.6-0.9 (2H, broad m), 1.10-1.25 (2H, broad m), 1.35-1.50 (2H, m), 1.60 (3H, s), 2.10-2.40 (2H, broad m+2H, t), 7.77 (1H, d), 7.97 (1H, dd) and 8.06 (1H, d) MS (MALDI-TOF) MH+340.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1.Cl[C:16]1[C:17]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[C:30]([CH3:35])=[N:31][N:32]([CH3:34])[CH:33]=3)[CH2:24][CH2:23]2)=[N:18][CH:19]=[CH:20][N:21]=1.CN(C)C(=O)C.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:34][N:32]1[CH:33]=[C:29]([CH2:28][N:25]2[CH2:24][CH2:23][N:22]([C:17]3[C:16]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:14])([F:13])[F:1])[CH:5]=4)=[N:21][CH:20]=[CH:19][N:18]=3)[CH2:27][CH2:26]2)[C:30]([CH3:35])=[N:31]1
Reactant: Cc1nn(C)cc1CN1CCN(c2nccnc2Cl)CC1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
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: CC(=O)N(C)C
Solvent: O
Product: Cc1nn(C)cc1CN1CCN(c2nccnc2-c2cccc(OC(F)(F)F)c2)CC1
Temperature: 110 °C
Yield: 35.9 %

Procedure:
Charge a carousel tube with 3-(trifluoromethoxy)benzeneboronic acid (140 mg, 0.68 mmol), 3′-chloro-4-(1,3-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (173 mg, 0.56 mmol) and N,N-dimethylacetamide (1 mL). Add N,N-dimethylacetamide (3 mL) and potassium carbonate (190 mg, 1.35 mmol) and purge with nitrogen for about 45 min. Add water (2 mL, purged with nitrogen for 1 hr.), then tetrakis(triphenylphosphine)palladium(0) (0.004 g, 0.0034 mmol), purge the reaction for about 30 min., and then heat overnight at 110° C. Cool to room temperature, add water and extract with DCM (3×30 mL). Concentrate the combined DCM extracts and purify using silica gel chromatography followed by reverse phase HPLC to give the title compound (0.087 g, 30%). MS (ES): m/z=433.1 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]([CH3:19])[C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([NH:2][C:3]1[N:4]([CH3:19])[C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)(=[O:22])[CH3:21]
Reactant: Cn1c(N)c(-c2ccc(Cl)cc2)c2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1c(-c2ccc(Cl)cc2)c2ccccc2n1C

Procedure:
To ten grams of 2-amino-3-(p-chlorophenyl)-1-methylindole hydrochloride in 80 ml. of pyridine, 5.4 ml. acetic anhydride are added under stirring at 20°-25° C. After five hours the pyridine is distilled off in vacuo at 40°-45° C and the oily residue solidifies with water. The product is crystallized from methanol. Yield 7.9 g. M.p. 196°-197° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.Cl.[N:26]1[CH:31]=[CH:30][C:29]([C:32](Cl)=[O:33])=[CH:28][CH:27]=1>>[N:26]1[CH:31]=[CH:30][C:29]([C:32]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:33])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1
Agent: Cl
Product: O=C(Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1)c1ccncc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.011 mL (0.061 mMol) 4-pyridinecarbonyl chloride hydrochloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([N:28]1[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]1)(=[O:27])=[O:26].[ClH:41]>C(OCC)(=O)C>[ClH:41].[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([N:28]1[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]1)(=[O:26])=[O:27]
Reactant: CCOC(=O)c1c(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(S(=O)(=O)N2CCNCC2)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
Through a solution of ethyl 5-bromo-3-{[4-(tert-butoxycarbonyl)-piperazin-1-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate (44 mg, 0.067 mmol) in 5 mL of ethyl acetate at 0° C. was bubbled HCl gas for 2 minutes. After stirring an additional 30 minutes, the reaction was concentrated in vacuo to provide the titled product as a white solid. ESI+MS: 556.0 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-])=O)=[CH:5][N:4]=1)#[N:2].[Cl-].[NH4+].C(OCC)(=O)C>O.[Zn]>[NH2:10][C:6]1[C:7]([CH3:9])=[CH:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: Cc1cc(C#N)ncc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C#N)ncc1N
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a suspension of 2-cyano-4-methyl-5-nitropyridine (1.86 g) and ammonium chloride (3.05 g) in water (50 mL) was added zinc (7.46 g) under ice-cooling over 10 minutes, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added ethyl acetate (50 mL), and the resulting mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration, and the organic layer of the filtrate was separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residual solids were suspended in a mixed solvent (n-hexane/ethyl acetate=1/1), and collected by filtration. The collected solids were dried under reduced pressure to give the title compound (0.7 g).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([OH:7])=O)[CH3:3].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[C:16]([C@@H:20]([NH2:22])[CH3:21])[CH:17]=[CH:18][CH:19]=2)[CH:9]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:1][N:2]([CH3:3])[CH2:4][C:5]([NH:22][C@H:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[CH:9]=[N:8][CH:13]=[CH:12][CH:11]=2)[CH:15]=1)[CH3:21])=[O:7]
Reactant: CN(C)CC(=O)O
Reactant: C[C@H](N)c1cccc(-c2cccnc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)CN(C)C)c1cccc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of dimethylamino-acetic acid (0.083 mmol), (S)-1-(3-pyridin-3-yl-phenyl)-ethylamine (12.7 mg, 0.064 mmol), EDAC.HCl (18.4 mg, 0.096 mmol), HOBT (13 mg, 0.096 mmol) and diisopropylethylamine (33 μL, 0.192 mmol) in DMF (2 mL) was stirred at room temperature for 18 h, and the reaction mixture was purified by preparative HPLC (5 mM NH4OAc buffer; gradient 0% to 100% B in 10 min (A: 10% CH3CN/H2O ; B: 90% CH3CN/H2O; column: Primesphere C18 HC 21.2×100 mm) to afford the title product.