Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:11]([C:12]2[S:13][C:14]3[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][C:19]=3[N:20]=2)[N:10]=[C:9]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])[S:8]1)=[N+:2]=[N-:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:11]([C:12]2[S:13][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][C:19]=3[N:20]=2)[N:10]=[C:9]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])[S:8]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCCN=[N+]=[N-])c3ccccc3)sc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nc2c(s1)CNCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of tert-butyl 2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (0.313 g, 0.524 mmol) in 10.0 mL of DCM at 0° C. was added TFA (1 mL). The mixture was stirred for 1 hour at 0° C. then at room temperature for 1 hour. The reaction was then concentrated to dryness and partitioned between EtOAc (30 mL) and saturated NaHCO3 solution (30 mL). The aqueous layer was extracted with EtOAc (2×20 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo to afford the desired product as a yellow gum (0.251 g, 96%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Cl)[CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10]2=[O:20])=[CH:5]1.BrC1C=C(C=CC=1)[C:28]#[N:29]>>[NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[C:28]#[N:29])=[C:11]2[C:6]([N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10]2=[O:20])=[CH:5]1
Reactant: N#Cc1cccc(Br)c1
Reactant: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(CCN)cc2n(C)c1=O
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCN)cc2n(C)c1=O

Procedure:
The title compound was prepared analogously to Intermediate B by replacing 1-bromo-3-chlorobenzene with 3-bromobenzonitrile.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:9]1[N:10]=[C:3]2[C:2]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([C:21]([F:32])([F:31])[F:20])[CH:27]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: COc1ccccc1Nc1nc2c(Br)cccn2n1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: COc1ccccc1Nc1nc2c(-c3cccc(C(F)(F)F)c3)cccn2n1

Procedure:
(2-Methoxy-phenyl)-[8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(2-methoxy-phenyl)-amine (50.0 mg, 0.157 mmol) and (3-trifluoromethylphenyl)boronic acid (33.0 mg, 0.174 mmol) with Pd(dppf)Cl2 (0.012 g) as the catalyst in a manner analogous to Step 2c. The reaction product was isolated as a white solid (0.042 g, 70%). MP=137-141° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (dd, J=6.7, 0.9 Hz, 1H), 8.43 (dd, J=8.0, 1.3 Hz, 1H), 8.34 (s, 1H), 8.25 (d, J=7.4 Hz, 1H), 7.71-7.58 (m, 4H), 7.08-6.98 (m, 4H), 3.93 (s, 3H). MS=385 (MH)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:13]2[N:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[CH3:48][C:49]1[CH:54]=[CH:53][C:52]([S:55]([NH:58][CH2:59][C:60](O)=[O:61])(=[O:57])=[O:56])=[CH:51][CH:50]=1>CN(C)C1C=CN=CC=1.ClCCl.CCCCCC>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:13]2[N:18]=[CH:17][C:16]([CH2:19][NH:20][C:60](=[O:61])[CH2:59][NH:58][S:55]([C:52]3[CH:53]=[CH:54][C:49]([CH3:48])=[CH:50][CH:51]=3)(=[O:57])=[O:56])=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)NCC(=O)O)cc1
Reactant: NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NCC(=O)NCc2ccc(C(c3cc(F)ccc3F)S(=O)(=O)c3ccc(Cl)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
To a dichloromethane (6 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine hydrochloride (40 mg, 0.0898 mmol) obtained in Example 66 were added triethylamine (45 μl, 0.324 mmol), 4-dimethylaminopyridine (5 mg, 0.0449 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21 mg, 0.108 mmol) and N-p-tosylglycine (25 mg, 0.108 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was then washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and then, concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=2.3 eluate was concentrated under reduced pressure to give the title compound (41 mg, 0.0661 mmol, 73%) as a white powder.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[NH2:25][CH2:26][C:27]1([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:41]=2[Cl:47])[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]1>>[Cl:47][C:41]1[C:42]([Cl:46])=[CH:43][CH:44]=[CH:45][C:40]=1[C:27]1([CH2:26][NH:25][C:22](=[O:24])[C:3]2[C:2]([F:1])=[C:7]([S:8][C:9]3[S:13][C:12]([NH:14][C:15]4[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=4)=[N:11][CH:10]=3)[CH:6]=[CH:5][N:4]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2cccc(Cl)c2Cl)CC1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5cccc(Cl)c5Cl)CCNCC4)c3F)s2)c1

Procedure:
Following the amide bond forming procedure given in example 37, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1) and tert-butyl 4-(aminomethyl)-4-(2,3-dichlorophenyl)piperidine-1-carboxylate (amine intermediate “J”) were reacted to give the title compound. LC/MS (M+H)+: 703. Ret. time: 2.01 min. (Condition M).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:19]([CH:28]([NH2:30])[CH3:29])=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)[CH:15]=[N:16][CH:17]=1.C(N(CC)C(C)C)(C)C>C(O)C>[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:19]([CH:28]([NH:30][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)[CH3:29])=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)[CH:15]=[N:16][CH:17]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1ccc2cccnc2c1-c1cncc(F)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1ccc2cccnc2c1-c1cncc(F)c1

Procedure:
A mixture of 6-bromo-9H-purine (0.1072 g, 0.54 mmol), 1-[8-(5-fluoropyridin-3-yl)quinolin-7-yl]ethanamine (0.072 g, 0.27 mmol), and N,N-diisopropylethylamine (0.05630 mL, 0.32) in ethanol (0.9 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/minute) to give the desired product as a tris-TFA salt. LCMS calculated for C21H17FN7(M+H)+: m/z=386.2; found: 386.1. 1H NMR (DMSO-d6, 400 MHz) δ 9.40 (1H, s), 8.81 (1H, m), 8.65 (1H, s), 8.62 (1H, s), 8.50 (1H, s), 8.41 (2H, m), 8.11 (1H, d, J=8.8 Hz). 7.97˜7.84 (2H, m), 7.55 (1H, dd, J=8.4 and 4.4 Hz), 5.25 (1H, m), 1.58 (3H, d, J=6.8 Hz) ppm. 19F NMR (DMSO-d6, 376.28 MHz) δ −75.0 ppm.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=O)C.[O:28]=[S:29]1(=[O:43])[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=2)[CH2:31][CH2:30]1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[O:43]=[S:29]1(=[O:28])[CH2:30][CH2:31][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=4[F:22])=[CH:14][CH:15]=3)=[O:3])=[N:40][CH:41]=2)[CH2:33][CH2:34]1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cn1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCS(=O)(=O)CC4)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), 5-(1,1-dioxothiomorpholin-4-ylmethyl)-pyridin-2-ylamine (Step 104.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 6 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. Title compound: ESI-MS: 570.0 [M+H]+; tR=3.86 min (System 1); TLC: Rf=0.10 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:5])C.[NH:16]([C:18]1[N:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)[NH2:17].O>ClCCl.CO>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[N:16]([C:18]3[N:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[N:17]=[C:4]([CH3:5])[N:6]=2)=[CH:13][CH:12]=1
Reactant: NNc1ccc(S(N)(=O)=O)cn1
Reactant: CCOC(C)=NC(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Cc1nc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cn2)n1
Reaction time: 8 h
Yield: 61 %

Procedure:
N-(1-ethoxy-ethylidene)-4-chloro-benzamide 472 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 6-hydrazinopyridine-3-sulfonic acid amide 433 mg (2.23 mmol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 6-[5-(4-chloro-phenyl)-3-methyl-[1,2,4]triazole-1-yl]-pyridine-3-sulfonic acid amide (446 mg, yield: 61%) was obtained as a solid phase.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH:12](OCC)(OCC)OCC>>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][CH:12]=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: CCOC(OCC)OCC
Product: Clc1ccc(-c2nnco2)cc1

Procedure:
A stirred solution of 8.1 grams (0.048 mole) of 4-chlorobenzoic acid hydrazide in 300 ml of triethyl orthoformate was heated under reflux for 16 hours. The excess triethyl orthoformate was removed by distillation and the residual solid was stirred with petroleum ether to yield 7.7 grams of 2-(4-chlorophenyl)-1,3,4-oxadiazole; m.p. 129° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]1[NH:13][CH2:14][CH2:15][N:16]=1.[C:17]([Zn]C#N)#[N:18]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CN(C=O)C>[NH:13]1[CH2:14][CH2:15][N:16]=[C:12]1[CH:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:2]([C:17]#[N:18])[C:3]=2[CH2:4][CH2:5][O:6]1
Reactant: Clc1cccc2c1CCOC2C1=NCCN1
Reactant: N#C[Zn]C#N
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Product: N#Cc1cccc2c1CCOC2C1=NCCN1
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-(5-chloroisochroman-1-yl)-4,5-dihydro-1H-imidazole (50 mg), dicyanozinc (25 mg), bis(tri-t-butylphosphine)palladium(0) (3 mg) and DMF (2 ml) was stirred in microwave reactor at 160° C. for 30 minutes. The title compound was purified with separation methods F and G. (Yield 22 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][C:30]([C:26]([CH3:28])([CH3:27])[CH3:29])=[CH:31][CH:32]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(NC(=O)c2ccccc2O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2ccccc2OC(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
To a solution of N-(4-methoxyphenyl)-2-hydroxybenzamide (0.484 g, 2.00 mmol) in methylene chloride (35 mL) cooled to 0° C. was added 0.28 mL triethylamine (0.28 mL, 2.0 mmol), followed by the dropwise addition of a solution of 4-tert-butylbenzoyl chloride (0.393 mL, 2.00 mmol) in methylene chloride (15 mL). The reaction mixture was allowed to warm to room temperature over 16 h and washed with cold water. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. Trituration with hexane provided 0.488 g (61%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]3=[CH:6][C:5]=2[C:4](=[O:15])[N:3]1[CH2:16][CH2:17][C@@H:18]([NH:22][C@H:23]([C:28]([NH:30][CH2:31]C1C=CC=C(C(F)(F)F)C=1)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])[C:19]([OH:21])=[O:20].CC(C([C@H](N[C@@H](CC(C)C)C(NC[C:72]1[CH:80]=[CH:79][C:75]([C:76]([OH:78])=[O:77])=[CH:74][CH:73]=1)=O)CCN1C(=O)C2C=C3C=CC=CC3=CC=2C1=O)=O)(C)C>>[C:19]([C@H:18]([NH:22][C@@H:23]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:28]([NH:30][CH2:31][C:72]1[CH:80]=[CH:79][C:75]([C:76]([OH:78])=[O:77])=[CH:74][CH:73]=1)=[O:29])[CH2:17][CH2:16][N:3]1[C:2](=[O:1])[C:10]2[CH:9]=[C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]3=[CH:6][C:5]=2[C:4]1=[O:15])([OH:21])=[O:20]
Reactant: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)C(C)(C)C)C(=O)NCc1ccc(C(=O)O)cc1
Reactant: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)O)C(=O)NCc1cccc(C(F)(F)F)c1
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)O)C(=O)NCc1ccc(C(=O)O)cc1

Procedure:
Prepared as described for Example 1, Part (b) by hydrolysis of the product of Part (a) above to give the title compound as a solid; 20 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16]([CH3:21])=[C:17]([CH:19]=[O:20])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Mg]I>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][C:16]([CH3:21])=[C:17]([CH:19]([OH:20])[CH3:22])[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1sc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1C=O
Reactant: C[Mg]I
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1sc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1C(C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-formyl-5-methyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.31 g, 1 mmol) in THF (10 mL) was added MeMgI (1 mL, 3 mmol) in Et2O at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was washed with H2O and brine. After drying over Na2SO4, the solvent was removed. The residue was purified by flash chromatography on silica gel to afford the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=O.[NH:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([Cl:23])=[N:15][N:14]=1)[NH2:12].C(N(CC)CC)C>O1CCOCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[N:14]2[N:15]=[C:16]([Cl:23])[C:17]3[C:22]([C:13]2=[N:11][N:12]=1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: NNc1nnc(Cl)c2ccccc12
Reactant: O=C(Cl)c1ccccc1Br
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Clc1nn2c(-c3ccccc3Br)nnc2c2ccccc12
Yield: 60 %

Procedure:
A solution of 2-bromobenzoyl chloride (0.12 mole) in dioxane (50 ml) is added to a mixture of 1-hydrazino-4-chlorophthalazine (0.1 mole), triethylamine (0.12 mole) and dioxane (200 ml). The reaction mixture is refluxed for five hours then the solvent is evaporated off and the obtained residue is washed with a small amount of water and crystallized from methanol giving the compound of the title in 60% yield. M.p. 203°-04° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[N:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[C:4](=[S:23])[N:3]1[C:24]1[CH:25]=[C:26]([C:32]([F:35])([F:34])[F:33])[C:27]([C:30]#[N:31])=[N:28][CH:29]=1.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[C:30]([C:27]1[N:28]=[CH:29][C:24]([N:3]2[C:2](=[O:1])[C:6]3([CH2:9][CH2:8][CH2:7]3)[N:5]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH:17]4[CH2:22][CH2:21][N:20]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:19][CH2:18]4)=[CH:12][CH:11]=3)[C:4]2=[S:23])=[CH:25][C:26]=1[C:32]([F:34])([F:33])[F:35])#[N:31]
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(OC4CCNCC4)cc3)C2=S)cc1C(F)(F)F
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CN1CCC(Oc2ccc(N3C(=S)N(c4cnc(C#N)c(C(F)(F)F)c4)C(=O)C34CCC4)cc2)CC1

Procedure:
The title compound was synthesized as described in Example 27 using 5-(8-oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile and ethyl 2-bromoacetate as starting materials. LCMS [M+1]+ 588.1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CCOC(=O)CCc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCc1nccn1-c1ccc(F)cc1[N+](=O)[O-]
Yield: 47.8 %

Procedure:
1,4-Difluoro-2-nitrobenzene 239 mg, ethyl 3-(1H-imidazol-2-yl)propanoate 252 mg, potassium carbonate 415 mg and N,N-dimethylacetamide 10 mL were heated at 100° C. for 64 hours. The reaction liquid was diluted with ethyl acetate and filtered. The filtrate was condensed under reduced pressure and subjected to silica gel chromatography (ethyl acetate) to provide 220 mg of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[S:4].[CH3:19][I:20]>CC(C)=O>[IH:20].[CH3:19][S:4][C:3](=[N:2][CH3:1])[NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: CI
Reactant: CNC(=S)Nc1c(C)cccc1N1CCOCC1
Solvent: CC(C)=O
Product: CN=C(Nc1c(C)cccc1N1CCOCC1)SC
Product: I

Procedure:
A mixture of N-methyl-N'-(6-methyl-2-morpholinophenyl)thiourea (11.5 g), methyl iodide (6.75 g) and acetone (100 ml) was heated under reflux for 2.5 hours to give 2-methyl-1-(6-methyl-2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (m.p. 187°-188° C.).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].[I:21][C:22]1[CH:23]=[C:24]2[C:40]([C:41]([NH:43][CH3:44])=[O:42])=[C:39]([C:45]3[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=3)[O:38][C:25]2=[N:26][C:27]=1[N:28]([CH2:33][CH2:34][CH2:35][CH:36]=[O:37])[S:29]([CH3:32])(=[O:31])=[O:30]>C1COCC1>[OH:37][CH:36]([CH2:35][CH2:34][CH2:33][N:28]([C:27]1[N:26]=[C:25]2[O:38][C:39]([C:45]3[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=3)=[C:40]([C:41](=[O:42])[NH:43][CH3:44])[C:24]2=[CH:23][C:22]=1[I:21])[S:29]([CH3:32])(=[O:31])=[O:30])[C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCC=O)S(C)(=O)=O)c(I)cc12
Reactant: CCOC(=O)C(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)C(O)CCCN(c1nc2oc(-c3ccc(C)cc3)c(C(=O)NC)c2cc1I)S(C)(=O)=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of diisopropylamine (1.4 eq., 18 μl) in THF (0.5 ml) cooled at 0° C. was added n-BuLi (1.6 M in hexane, 1.2 eq., 68 μl). The resultant solution was stirred at 0° C. for 10 min and cooled to −78° C., and then a solution of ethyl isobutyrate (1 eq., 10.5 mg) in THF (0.5 ml) was added. After the reaction mixture was stirred at −78° C. for 1 h, a solution of 5-iodo-N-methyl-6-(N-(4-oxobutyl)methylsulfonamido)-2-p-tolylfuro[2,3-b]pyridine-3-carboxamide (1 eq., 50.0 mg) in THF (1 ml) was introduced. The reaction mixture was stirred at −78° C. for 1 h, quenched with saturated aqueous NH4Cl, and extracted with diethyl ether. The combined ethereal layers were washed with brine, dried over MgSO4, filtered, and concentrated to yield the crude title compound which was used in next step without purification.
Reaction SMILES: [N:1]12[CH2:9][CH:5]([C:6](=[O:8])[CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[C:10]12([CH2:20][S:21]([OH:24])(=[O:23])=[O:22])[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][C:11]2=[O:12]>O>[C:10]12([CH2:20][S:21]([OH:24])(=[O:22])=[O:23])[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][C:11]2=[O:12].[N:1]12[CH2:9][C@H:5]([C:6](=[O:8])[CH2:7]1)[CH2:4][CH2:3][CH2:2]2
Reactant: O=C1CN2CCCC1C2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: O
Product: O=C1CN2CCC[C@@H]1C2

Procedure:
This compound was made in exactly the same manner as described in example 1 using (±) 1-azabicyclo[3.2.1]octan-6-one and (−) camphorsulfonic acid. M.p. 267-268° C. (decomp.) [α]D=−48° (water).
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[OH-].[Na+].S(OC)(O[CH3:17])(=O)=O>>[Cl:1][C:2]1[N:6]([CH3:17])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: COS(=O)(=O)OC
Reactant: Clc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(Cl)nc2ccccc21

Procedure:
To a solution of 2-chloro-1H-benzo[d]imidazole (3.0019 g, 19.67 mmol, Sigma-Aldrich Chemical Company, Inc.) in 2.5 M sodium hydroxide solution (19.67 ml, 49.2 mmol, J. T. Baker) at 0° C. was added dimethyl sulfate (3.01 ml, 31.5 mmol, Riedel de Haen AG) dropwise. The reaction was allowed to stir for 1½ h. White precipitate was noted to form. The white precipitate was filtered, washed with water, and dried to give the title compound. LCMS showed product peak at 1.47 min (m+1=167.0). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.80 (s, 3 H) 7.21-7.28 (m, 1 H) 7.28-7.35 (m, 1 H) 7.59 (d, J=3.72 Hz, 1 H) 7.61 (d, J=3.72 Hz, 1 H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[N:8]=[C:9]([C:11]([CH3:15])([CH3:14])[CH2:12][F:13])[CH:10]=1)=[O:5])[CH3:2].C(Cl)[Cl:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[N:8]=[C:9]([C:11]([CH3:15])([CH3:14])[CH2:12][F:13])[C:10]=1[Cl:18])=[O:5])[CH3:2]
Reactant: ClCCl
Reactant: CCOC(=O)c1cc(C(C)(C)CF)nn1C
Product: CCOC(=O)c1c(Cl)c(C(C)(C)CF)nn1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-(2-fluoro-1,1-dimethyl-ethyl)-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (722 mg, 3.16 mmol, prepared as described in the previous step) was dissolved in DCM (5 mL) and SO2Cl2 (0.256 mL, 3.16 mmol) was added dropwise to the stirred solution. The resulting mixture was stirred at room temperature for 16 h and then the solvent was removed under reduced pressure. The resulting residue was chromatographed on a 40-g SiO2 pre-packed column eluting with 0:1-1:4 EtOAc/heptane to yield 4-chloro-5-(2-fluoro-1,1-dimethyl-ethyl)-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester. 1H-NMR (400 MHz, CDCl3) δ: 4.59 (d, J=47 Hz, 2H), 4.40 (q, J=7.1 Hz, 2H), 4.08 (s, 3H), 1.43 (d, J=1.7 Hz, 6H), 1.41 (t, J=7.2 Hz, 3H).