Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[CH:30]([CH:33]([CH3:36])[CH2:34]O)([CH3:32])[CH3:31]>C(Cl)Cl>[CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH2:31][CH:30]([CH:33]([CH3:36])[CH3:34])[CH3:32])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC(C)C(C)CO
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Solvent: ClCCl
Product: CC(C)C(C)COC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[Z-2-carboxy-ethenyl]-cyclopropanecarboxylate in 30 ml of methylene chloride was added to a mixture of 3 ml of 1-dimethylamino-1-chloro-2-methyl-propen-1-yl [J. Org. Chem., Vol. 35 (1970), p. 3970] in 3 ml of methylene chloride and the mixture was stirred at room temperature for 15 minutes. After cooling the mixture to 5° C., 5 ml of 2-isopropyl-propanol were added thereto and the mixture was stirred at room temperature for 16 hours, was washed with water, with aqueous sodium chloride solution, was dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 9-1 cyclohexane-ethyl acetate mixture to obtain 2.25 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis)2,2-dimethyl-3-[Z-2-(2-isopropyl-propyloxycarbonyl)-ethenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+61.5°±2.5° (c=0.5% in benzene).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)[C:7]1=[NH:24].[Br:29]Br.C([O-])(O)=O.[Na+]>ClCCl>[F:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[F:22])[CH2:15][N:8]1[C:9]2[CH:14]=[CH:13][C:12]([Br:29])=[CH:11][C:10]=2[N:6]([CH2:5][C:4]2[CH:25]=[CH:26][C:27]([F:28])=[C:2]([F:1])[CH:3]=2)[C:7]1=[NH:24]
Reactant: N=c1n(Cc2ccc(F)c(F)c2)c2ccccc2n1Cc1ccc(F)c(F)c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N=c1n(Cc2ccc(F)c(F)c2)c2ccc(Br)cc2n1Cc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,3-Bis(3,4-difluorobenzyl)-1,3-dihydrobenzoimidazol-2-ylideneamine, prepared by Procedure A, was dissolved in dichloromethane, added bromine (2 eq) and stirred overnight at rt. Saturated aqueous NaHCO3 was added and the mixture extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered, concentrated in vacuo and purified by preparative LCMS to give the title compound as the free base (solid, mp 88-89.5° C.). MS(ES+) m/z 465 ([M+1]+, 100). 1NMR (DMSO-d6) δ 5.05 (s, 4H), 6.08 (br s, 1H), 6.85-6.93 (m, 1H), 6.98-7.23 (m, 4H), 7.35-7.45 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:44])([C:40]([F:43])([F:42])[F:41])[CH2:38][NH2:39]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C:21]([CH3:25])([CH3:26])[C:22]([NH:39][CH2:38][C:37]([F:44])([F:36])[C:40]([F:43])([F:42])[F:41])=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: NCC(F)(F)C(F)(F)F
Product: CC(C)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2,2-dimethyl-malonamic acid and 2,2,3,3,3-pentafluoropropylamine, the title compound was prepared in the same manner as described for example 1c. White solid (76%). MS: m/e=604(M+H+).
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[C:10]([NH:13][NH2:14])([NH2:12])=[NH:11].[ClH:15]>CO.C(O)(=O)C>[ClH:15].[NH2:9][C:8]1[N:13]([C:10]([NH2:12])=[NH:11])[N:14]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:7]=1
Reactant: N=C(N)NN
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(N)n(C(=N)N)n1
Yield: 33.8 %

Procedure:
A solution of 1.26 g of pivaloylacetonitrile and 1.37 g of aminoguanidine hydrochloride in 15 ml of methanol and 15 ml of acetic acid was heated under reflux for 5 hours. The solvents were removed by distillation under reduced pressure, and the resulting residue was purified by silica gel chromatography (eluent: chloroform/methanol=5/1) and then recrystallized from ethanol-ether to obtain 0.74 g of 5-amino-3-(1,1-dimethylethyl)-1H-pyrazole-1-carboxamidine hydrochloride having the following physico-chemical properties:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:34]([NH:36][C@H:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:35])[NH:16]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCCC1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:34]([NH:36][C@H:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:35])[NH2:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC[C@@H]1NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)[C@@H]1CCC[C@@H]1NC(=O)[C@@H](N)CCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 98.3 %

Procedure:
To a mixture of tert-butyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-[(9H-fluorene -9-ylmethoxy)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate (4.0 g) and chloroform(80 ml) was added piperidine (6.0 ml) under ice-cooling, followed by stirring at room temperature for 13 hours. The reaction mixture was washed with a saturated sodium bicarbonate solution, water, and saturated brine in this order, and the organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1, and then 0→2→5% methanol/chloroform) to obtain tert-butyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate (2.6 g).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]([C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:24])[NH2:22]>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:22][NH:21][C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:24])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)NN
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Yield: 80 %

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and (S)-tert-butyl 2-(hydrazinecarbonyl)piperidine-1-carboxylate (634 mg, prepared following a procedure analogous to Reference Example 5 and Reference Example 6), 567 mg of the title compound was afforded (yield 80%).
Reaction SMILES: [CH2:1]([N:8]([S:18]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19])[C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([NH2:30])([CH3:29])[CH3:28]>>[CH2:1]([N:8]([S:18]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)(=[O:19])=[O:20])[C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(N(Cc2ccccc2)S(=O)(=O)c2cccnc2)c1
Reactant: CC(C)N
Product: CC(C)NC(=O)c1cccc(N(Cc2ccccc2)S(=O)(=O)c2cccnc2)c1

Procedure:
3[Benzyl-(pyridine-3-sulfonyl)-amino]-N-isopropyl-benzamide was prepared from 3-[benzyl-(pyridine-3-sulfonyl)-amino]-benzoic acid and isopropylamine according to the method described for Example 2. HPLC retention time 5.46 min. Mass spectrum (APCI+) m/z 410 (M+H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:19](=O)[CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH:19](=[N:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=1)[CH2:20][CH3:21]
Reactant: CCC=O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC=Nc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To a solution of 4-trifluoromethylaniline (3.3 g, 20.5 mmol) and triethylamine (8.3 g, 83 mmol) in 100 mL of dichloromethane, cooled in an ice/water bath, was added slowly titanium tetrachloride (11.4 mL of a 1.0M solution in dichloromethane, 11.4 mmol). After 25 min, propionaldehyde (1.8 g, 25.6 mmol) was added slowly as a solution in dichloromethane. After an additional hour of stirring in the ice/water bath, an aqueous potassium carbonate solution was added (˜100 mL of a 1M solution). The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude title product which was used without further purification. 1H NMR (CDCl3) δ 1.2 (t, 3H), 2.5 (dq, 2H), 7.05 (d, 2H), 7.56 (d, 2H), 7.84 (t, 1H, J=4.4 Hz).
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH2:10][C:11]1[C:12]([CH3:23])=[N:13][O:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35]([C:19]3[CH:20]=[CH:21][C:16]([C:15]4[O:14][N:13]=[C:12]([CH3:23])[C:11]=4[CH2:10][CH2:9][S:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:17][CH:18]=3)=[CH:34][CH:33]=2)[CH2:30][CH2:31]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CCSCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCSCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 4-(2-benzylsulfanyl-ethyl)-5-(4-bromo-phenyl)-3-methyl-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11]([NH:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[O:12])=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[NH:26][C:25]2=[O:33])[CH2:20][CH2:19]1.[CH:34]1(N2C(C(O)=O)=NC3C2=NC=NC=3N2CCC(N3C4C=CC=CC=4NC3=O)CC2)C[CH2:35]1.C1(N)CC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[CH:1]1([N:2]2[C:10]([C:11]([NH:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[O:12])=[N:9][C:8]3[C:3]2=[N:4][CH:5]=[N:6][C:7]=3[N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[NH:26][C:25]3=[O:33])[CH2:20][CH2:19]2)[CH2:35][CH2:34]1
Reactant: O=C(O)c1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n1C1CC1
Reactant: Cn1c(C(=O)NCC2CC2)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CC1)c1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n1C1CC1

Procedure:
9-Cyclopropyl-N-(cyclopropylmethyl)-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxamide was prepared in the same manner as 9-methyl-N-(cyclopropylmethyl)-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxamide. The 9-cyclopropyl-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxylic acid (0.09 g, 0.21 mmol) was treated with cycloproplyamine (0.305 g, 0.429 g mmol, 0.037 mL), HATU (0.163 g, 0.429 mmol), diisopropylethylamine (0.110 g, 0.858 mmol, 0.149 mL) and DMA (8 mL) at room temperature for 18 hours. Purification by preparative reverse phase HPLC (eluting with 0.01% aqueous ammonium acetate and acetonitrile) yielded 0.057 g of 9-cyclopropyl-N-(cyclopropylmethyl)-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxamide as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.50 (broad s, 1H), 8.63 (t, 1H), 8.07 (s, 1H), 6.98 (m, 1H), 6.6.716 (m, 3H), 5.11 (broad s, 2H), 4.30 (m, 1H), 3.38 (m, 1H), 3.13 (dd, 1H), 2.93 (t,4H), 2.07 (t, 2H), 1.63 (m, 2H), 0.83 (m, 4H), 0.18 (m, 2H), 0.02 (m, 2H).MS (EI) for C25H28N8O2: 473 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:8]([NH:11][CH2:12][CH:13]=[CH2:14])[CH:9]=[CH2:10].[OH-].[Na+]>>[CH2:8]([N:11]([CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH:9]=[CH2:10]
Reactant: C=CCNCC=C
Reactant: Clc1ccncc1
Agent: [Na+]
Agent: [OH-]
Product: C=CCN(CC=C)c1ccncc1

Procedure:
4-Chloropyridine (13.24 g) was refluxed with excess diallylamine (28.04 g) under a nitrogen atmosphere for 3 days. The product mixture was neutralized with aqueous NaOH and extracted with ether. After drying, the ether was removed by simple distillation and the product purified by fractional distillation under reduced pressure. The pure 4-(diallylamino)pyridine (DAAP) was characterized by elemental analysis, FTIR, 13C NMR, and GC.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=1)=[O:10].[C:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>>[C:18]([C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=2)=[O:10])(=[O:29])=[O:28])=[CH:25][CH:26]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(C(=O)c2cc(Cl)ccc2N)ccn1
Product: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccnc(C)c2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and 4-acetyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3) δ 8.50 (d, J=4.8 Hz, 1H) 7.67-7.25 (m, 5H) 7.20-6.85 (m, 4H) 2.52 (s, 3H) 2.45 (s, 3H). MS: (ES) m/z=429.0 (M++1).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:23]([NH2:25])=[O:24])[CH:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])[CH3:27].C(N(CC)CC)C>C(Cl)Cl>[CH2:26]([S:28]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:23]([NH2:25])=[O:24])[CH:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1)(=[O:30])=[O:29])[CH3:27]
Reactant: NC(=O)c1cc(-c2cccnc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccnc4)cc23)CC1

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus 3-(4-piperidinyl)-5-(3-pyridinyl)-1H-indazole-7-carboxamide hydrochloride (Intermediate 21) (0.09 mmol) was reacted with ethane sulfonyl chloride (0.01 mL, 0.217 mmol) in the presence of triethylamine (0.04 mL, 0.468 mmol) in methylene chloride (10 mL) to give the title compound (4.9 mg, 13% for the last two steps)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:12])[N:8]=[CH:9]2)=[CH:4][N:3]=1.[C:13]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br)#[N:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]([CH2:18][C:17]1[CH:16]=[C:15]([CH:22]=[CH:21][CH:20]=1)[C:13]#[N:14])[C:7](=[O:12])[CH:6]=2
Reactant: N#Cc1cccc(CBr)c1
Reactant: Oc1cc2cnc(Br)cc2cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(Cn2cc3cc(Br)ncc3cc2=O)c1

Procedure:
The alkylation of 7-bromo-3-hydroxy-6-azaisoquinoline (1.00 g, 4.40 mmol) using 3-cyanobenzyl bromide (1.31 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethylformamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product.
Reaction SMILES: [NH2:1]CCC1C2C(=CC=CC=2)NC=1.[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.O>C1(C)C=CC=CC=1>[C:13]1(=[O:18])[NH:1][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1NC(=O)c2ccccc21
Reaction time: 12 h

Procedure:
A solution of 3.20 g (20.0 m mol) of tryptamine and 3.10 g (20.0 m mol) of phthalic anhydride in 40 ml of toluene was refluxed under a Dean-Stark water separator for 12 h. Cooling, filtration and concentration of the filtrate gave a crude phthalimide which was recrystallized from ethanol to produce 4.85 g (84%), of phthalimide, mp 164°-165° C.; reported 164°-165° C.3
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N[C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1N)[C:9]([OH:11])=[O:10].O.Cl>C(O)CCCC>[N:1]1[C:2](=[O:3])[N:4]=[C:13]2[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[CH:7]=[CH:6][C:14]=12
Reactant: NC(N)=O
Reactant: Nc1ccc(C(=O)O)cc1N
Agent: Cl
Solvent: O
Solvent: CCCCCO
Product: O=C1N=c2ccc(C(=O)O)cc2=N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
Urea (1.20 g, 0.0200 mol) and 3,4-diaminobenzoic acid (3) (3.04 g, 0.0200 mol) in pentan-1-ol (10 mL) was vigorously stirred and heated to reflux under a nitrogen atmosphere. The heating was discontinued after 4 hours and on cooling to room temperature, water (30 mL) was added. The pH was adjusted to 1 with conc. HCl. The resultant dark solid was filtered off, washed with further water (2×20 mL) and dried to give 3.00 g (84% yield) of benzimidazol-2-one-5-carboxylic acid (4) as a black powder,
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:23])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11](Br)=[CH:12][CH:13]=1)=[O:8].[CH2:24]([O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)[CH3:25]>>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:23])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH2:24][CH3:25])[CH:32]=2)=[CH:12][CH:13]=1)=[O:8]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: CS(=O)(=O)Nc1c(F)cc(CNC(=O)c2ccc(Br)s2)cc1F
Product: CCOc1cccc(-c2ccc(C(=O)NCc3cc(F)c(NS(C)(=O)=O)c(F)c3)s2)c1
Yield: 62 %

Procedure:
5-Bromo-thiophene-2-carboxylic acid 3,5-difluoro-4-methanesulfonylamino-benzylamide (80 mg, 0.19 mmol) was reacted with 3-ethoxy phenyl boronic acid (37.5 mg, 0.23 mmol) to give the title compound (55 mg, 62%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9](N)[CH:10]=1)=[O:4].N(OCCC(C)C)=O.[I:27]CI>N1CCCCC1.CC#N>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9]([I:27])[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: CC#N
Solvent: C1CCNCC1
Product: COC(=O)c1cc(I)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A mixture of 5-amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester (10.9 g, 45.2 mmol), iso-amyl nitrite (36.5 ml, 271.4 mmol) and diiodomethane (23 ml, 271.4 mmol) was stirred at room temperature for 1 hour. The mixture was then heated to 65° C. and kept at this temperature for 8 hours. The reaction mixture to room temperature and then added to a stirred solution of piperidine/CH3CN (V:V=90 ml: 90 ml). A vigorous exothermic reaction ensued. The excess volatile reagents were removed by rotary evaporation. The residue was diluted with ethyl acetate, washed with 10% hydrochloric acid, water, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with n-hexane, followed by n-hexane/ethyl acetate (20:1), giving 5-Iodo-4′-methyl-biphenyl-3-carboxylic acid methyl ester as white yellow solid (10.5 g, 66%).
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[CH2:16]([NH:23][CH2:24][CH2:25]O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:16]([N:23]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:8])[CH2:24][CH2:25][O:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCCNCc1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(OCCN(Cc1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.1 %

Procedure:
Triflic anhydride (11.18 g, 6.5 ml, 39 mmol) dissolved in 90 ml of DCM was added drop by drop to a well stirred solution of N-benzyl ethanol amine (2 g, 13.2 mmol) and diisopropylethyl amine (5.1 g, 6.9 ml, 39.7 mmol) in dichloromethane (160 ml) at 0° C. and stirred at room temperature for 1 h under nitrogen atmosphere. The reaction mixture was quenched with water and extracted with dichloromethane. Organic layer was washed with water and dried under sodium sulfate. Solvent evaporation under reduced pressure afforded 500 mg of the title compound as a an oil
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1C(OC(C)(C)C)=O>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:18]1[CH2:19][CH2:20][CH2:21][C@@H:17]1[C:9]1[O:8][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nc2ccccc2o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2oc([C@H]3CCCN3)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 16 mL flask, trifluoroacetic acid (4 mL) was added to a mixture of tert-butyl(2R)-2-(1,3-benzoxazol-2-yl)pyrrolidine-1-carboxylate (88 mg, 0.31 mmol; which may be prepared as described in Step 2) dissolved in dichloromethane (4 mL) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was concentrated to dryness and the residue used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH:21]C(OCC3C=CC=CC=3)=O)[CH2:10][C@H:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:32][CH3:33])=[O:4].C1CCCCC=1>[Pd].C(O)C>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH2:21])[CH2:10][C@H:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:32][CH3:33])=[O:4]
Reactant: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](NC(=O)OCc2ccccc2)C[C@@H]1C
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](N)C[C@@H]1C
Temperature: 25 °C
Yield: 90.9 %

Procedure:
cis-4-Benzyloxycarbonylamino-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1,7-dicarboxylic acid 1-ethyl ester 7-methyl ester (322 mg, 0.71 mmol), 10% palladium on carbon (32 mg) and cyclohexene (9 ml) in 16 ml ethanol was heated to 80° C. for 1.25 h. The reaction mixture was cooled to room temperature, filtered through Celite®, and concentrated in vacuo. Purification by silica gel chromatography using 1% isopropanol-dichloromethane afforded the title product (208 mg, 91%). 1H NMR (DMSO-d6) δ 1.02 (d, 3H), 6.68 (s, 1H).