Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=2[O:21][CH3:22])=[CH:9][CH:8]=1.[I-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:34]1[CH2:38][CH2:37][CH2:36][C@H:35]1[CH2:39][C:40]([OH:42])=[O:41]>[Cu]I.CS(C)=O>[F:20][C:16]1[C:17]([F:19])=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]3[CH:3]=[C:2]([N:34]4[CH2:38][CH2:37][CH2:36][C@H:35]4[CH2:39][C:40]([OH:42])=[O:41])[CH:25]=[CH:24][CH:23]=3)=[CH:8][CH:9]=2)=[C:14]([O:21][CH3:22])[CH:15]=1
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(Br)c2)cc1
Reactant: O=C(O)C[C@@H]1CCCN1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(N3CCC[C@H]3CC(=O)O)c2)cc1
Yield: 46 %

Procedure:
4′-(3-Bromo-benzyloxy)-4,5-difluoro-2-methoxy-biphenyl (142 mg, 0.35 mmol), copper(I) iodide (40 mg, 0.21 mmol), sodium iodide (105 mg, 0.70 mmol), cesium carbonate (687 mg, 2.1 mmol) and (S)-pyrrolidin-2-yl-acetic acid (106 mg, 0.78 mmol) and DMSO (0.35 ml) were reacted as above to yield 73 mg of {(S)-1-[3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-phenyl]-pyrrolidin-2-yl}-acetic acid as a white solid. LC-MS (ES) calculated for C26H25F2NO4, 453.18; found m/z 454 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([OH:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(C(C)C)CC)(C)C>O1CCCC1>[Br:1][CH2:2][C:3]([O:24][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:4]
Reactant: O=C(Br)CBr
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCCOC(=O)CBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
A solution of bromoacetyl bromide (0.49 ml; 5.65 mmol) in tetrahydrofuran (12 ml) is added, at 0° C., to a mixture of oleyl alcohol (1.00 ml; 3.77 mmol) and diisopropylethylamine (0.88 g; 5.65 mmol) in tetrahydrofuran (38 ml). The mixture is stirred for 2 h at 0° C. and then for 1 h at room temperature; it is then washed with 1N hydrochloric acid solution (20 ml) which is extracted with ether (50 ml). The combined organic phases are washed with saturated sodium carbonate solution (20 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by chromatography on a column of silica gel (eluent: 99/1 hexane/ether) to give oleyl 2-bromoacetate (1.31 g; 89%) in the form of a colorless oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[I:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1>>[CH3:1][N:2]([CH3:3])[C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:5]([I:4])=[CH:6][CH:7]=1
Reactant: CNC
Reactant: O=C(Cl)c1ccc(I)cc1
Product: CN(C)C(=O)c1ccc(I)cc1

Procedure:
A total of 20 ml of a 40% aqueous solution of dimethylamine was reacted with a solution of 5.4 g p-iodobenzoyl chloride as described in Example 3 and recrystallized from a benzene/hexane mixture to yield 4.9 g N, N-dimethyl-p-iodobenzamide as white crystals, m.p. 113°-115°, Rf 0.69.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:27](Cl)(=[O:29])[CH3:28]>C(Cl)Cl>[C:27]([N:15]1[CH:16]2[CH:21]([CH:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:19][CH2:18][CH2:17]2)[N:12]([C:10](=[O:11])[CH2:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:14]1)(=[O:29])[CH3:28]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C2C(N3CCCC3)CCCC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under N2, 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (113 mg, 0.29 mmol) was dissolved in absolute CH2Cl2 (14 ml) and acetyl chloride (27 mg, 0.34 mmol) was added dropwise. The mixture was stirred at room temperature overnight and then evaporated in vacuo. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH3 9.5:0.5:0.05, l=15 cm, V=5 ml). A yellowish resin was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C@@H:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[C@H:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: C[C@H]1NCCc2ccccc21
Product: C[C@@H]1c2ccccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-(R)-Methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[CH2:6][C:5]2=[O:13].[N+:14]([O-])([OH:16])=[O:15]>CCOCC>[CH3:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[CH3:1])[C:5](=[O:13])[CH:6]([N+:14]([O-:16])=[O:15])[C:7]2=[O:12]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc2c(cc1C)C(=O)CC2=O
Solvent: CCOCC
Product: Cc1cc2c(cc1C)C(=O)C([N+](=O)[O-])C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5,6-dimethyl indane-1,3-dione (0.52 g; 0.003 mole) suspended in anhydrous ether (5 ml.) was stirred at 10°C during the dropwise addition of fuming nitric acid (1.0 ml.). After the addition was complete the mixture was stirred at ambient temperature for 1 hr. and the precipitated yellow solid filtered. m.p. (water, hydrochloric acid) 111°-113°C. (Found: C, 60.11; H, 4.10; N, 6.14; C11H9NO4 requires: C, 60.28; H, 4.14; N, 6.39%).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-].[Cl:22][C:23]1[CH:24]=[C:25]([S:30]([N:33]([CH2:50][P:51](=[O:58])([O:55][CH2:56][CH3:57])[O:52][CH2:53][CH3:54])[C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][C:35]=2[C:44]#[C:45][Si](C)(C)C)(=[O:32])=[O:31])[CH:26]=[C:27]([Cl:29])[CH:28]=1.O>O1CCCC1>[Cl:22][C:23]1[CH:24]=[C:25]([S:30]([N:33]([CH2:50][P:51](=[O:58])([O:52][CH2:53][CH3:54])[O:55][CH2:56][CH3:57])[C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][C:35]=2[C:44]#[CH:45])(=[O:31])=[O:32])[CH:26]=[C:27]([Cl:29])[CH:28]=1
Reactant: CCOP(=O)(CN(c1c(C#C[Si](C)(C)C)ccc2ccccc12)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc2ccccc2c1N(CP(=O)(OCC)OCC)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
115 mg tetrabutylammonium fluoridetrihydrate are added to 155 mg diethyl {[(3,5-dichloro-phenylsulphonyl)-(2-trimethylsilanylethynyl-naphthalen-1-yl)-amino]-methyl}-phosphonate in 4 ml of tetrahydrofuran at ambient temperature. The reaction mixture is stirred for 15 minutes at ambient temperature, then it is mixed with water and extracted with ethyl acetate. The combined extracts are dried on magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with cyclohexane/ethyl acetate (50:50) as eluant.
Reaction SMILES: [N:1]1([S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16]3)(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[O:23]=[C:24]1[C:29]2=[CH:30][NH:31][C:32]([CH:33]=O)=[C:28]2[CH2:27][CH2:26][O:25]1>>[N:1]1([S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[C:16]3=[CH:33][C:32]2[NH:31][CH:30]=[C:29]3[C:24](=[O:23])[O:25][CH2:26][CH2:27][C:28]=23)(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1Cc2cc(S(=O)(=O)N3CCc4ccccc43)ccc2N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: O=C1Nc2ccc(S(=O)(=O)N3CCc4ccccc43)cc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
5-(2,3-Dihydro-indole-1-sulfonyl)-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][N:11]1[CH:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]=O>>[CH2:1]([N:8]([CH3:28])[CH2:9][CH2:10][N:11]1[CH:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNCCN2Cc3ccccc3CC2Cc2ccccc2)cc1
Reactant: C=O
Product: CN(CCN1Cc2ccccc2CC1Cc1ccccc1)Cc1ccccc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 1-g) using N-benzyl-2-[3-benzyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine obtained in Example 1 as a starting material and using paraformaldehyde to obtain a title compound as a pale yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[N:9][N:10]=[C:6]2[C:5]([N+:11]([O-])=O)=[C:4]([NH:14][CH2:15][CH2:16][CH2:17][OH:18])[C:3]=1[CH3:19]>[Pd].C(#N)C>[NH2:11][C:5]1[C:6]2[N:7]([N:8]=[N:9][N:10]=2)[C:2]([CH3:1])=[C:3]([CH3:19])[C:4]=1[NH:14][CH2:15][CH2:16][CH2:17][OH:18]
Reactant: Cc1c(NCCCO)c([N+](=O)[O-])c2nnnn2c1C
Agent: [Pd]
Solvent: CC#N
Product: Cc1c(NCCCO)c(N)c2nnnn2c1C
Reaction time: 16 h
Yield: 98.2 %

Procedure:
A mixture of 3-[(5,6-dimethyl-8-nitrotetraazolo[1,5-α]pyridin-7-yl)amino]propan-1-ol (4.00 g, 15.0 mmol) and 10% palladium on carbon (0.40 g) in acetonitrile (75 mL) was hydrogenated at 50 psi (3.5×105 Pa) on a Parr apparatus for 16 hours. The mixture was filtered through CELITE filter agent, which was rinsed with methanol. The filtrate was concentrated under reduced pressure to yield 3.48 g of 3-[(8-amino-5,6-dimethyltetraazolo[1,5-α]pyridin-7-yl)amino]propan-1-ol.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1>CC(O)C>[CH2:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@H:1]([OH:11])[CH2:2]1
Reactant: O=C1CCCc2ccccc21
Solvent: CC(C)O
Product: O[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 96.9 %

Procedure:
Tetralone (200 ml, 1.5 mol) was charged to the catalyst solution, followed by 2-propanol (0.5 l). The pressure was reduced (28.5 mmHg) and then a sodium 2-propoxide solution (120ml of 0.1M solution in 2-propanol) was charged. The mixture was stirred at ambient temperature under nitrogen for 4.5 h, at hourly intervals the flask was back filled with nitrogen and sufficient 2-propanol charged to compensate for the volume removed by distillation. This gave (R)-1-tetralol Yield 96.9%, ee 86.9%. The turnover number, integrated over 1 h, was 358 h−1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][CH2:28][O:29][C:22]=3[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][CH2:28][O:29][C:22]=4[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc4c(c3)OCCO4)c2c1C
Reactant: c1cn[nH]c1
Product: Cc1sc2nc(-n3cccn3)nc(NCc3ccc4c(c3)OCCO4)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6-dimethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6-dimethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[C:10]([O:19]C)(=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O-:17])=[O:16]>>[C:10]([OH:19])(=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: COC(=O)CCCCC(=O)[O-]
Agent: C[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)CCCCC(=O)O

Procedure:
The electrolytic condensation was conducted in the same manner as described in Example 2 except for changing the neutral salt group from sodium methylate to sodium carbonate by using monomethyl adipate obtained by the half esterification of adipic acid. Electrolytic cell voltage was 7.8 volts. Current efficiency was 67.2% and material yield was 80.2%.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C([Li])CCC.[CH2:15]1[O:23][C:22]2[CH:21]=[CH:20][C:19]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:18][C:17]=2[O:16]1.[CH:30]1([CH:36]=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1.CCCCCC>[CH2:15]1[O:23][C:22]2[CH:21]=[CH:20][C:19]([CH:24]([CH:36]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[OH:37])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:18][C:17]=2[O:16]1
Reactant: O=CC1CCCCC1
Reactant: CCOC(=O)Cc1ccc2c(c1)OCO2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(c1ccc2c(c1)OCO2)C(O)C1CCCCC1
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To a solution of N,N-diisopropyl-N-ethylamine (4.49 g) in tetrahydrofuran (50 ml) was added with stirring 1.6M n-butyl lithium in n-hexane solution (27.6 ml) below 0° C. under a nitrogen atmosphere. After the mixture was stirred in an ice-bath for 30 minutes, a solution of ethyl 3,4-methylenedioxyphenylacetate (3.85 g) in tetrahydrofuran (40 ml) was added at −78° C. The mixture was stirred for 30 minutes and cyclohexanecarbaldehyde (2.49 g) was added. After being stirred for 15 minutes at the same temperature, the mixture was quenched by saturated aqueous ammonium acetate. The mixture was extracted with diethyl ether (100 ml), and the solution was washed with 1M hydrochloric acid and brine successively, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=6:1) to give ethyl (2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionate (4.45 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:8][CH2:9][C:10]3[N:11]([N:12]=[C:13]([C:15]([N:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[O:16])[N:14]=3)[C:5]=2[S:4][C:3]=1[CH3:29].ClC1C=CC=CC=1C1C2C=C(CC)SC=2N2N=C(C(N)=[O:53])N=C2CN=1.ClC1C=CC=C(C(OO)=O)C=1>>[CH3:1][C:2]1[C:6]2[C:7]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[N+:8]([O-:53])[CH2:9][C:10]3[N:11]([N:12]=[C:13]([C:15]([N:17]4[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]4)=[O:16])[N:14]=3)[C:5]=2[S:4][C:3]=1[CH3:29]
Reactant: Cc1sc2c(c1C)C(c1ccccc1)=NCc1nc(C(=O)N3CCCCC3)nn1-2
Reactant: CCc1cc2c(s1)-n1nc(C(N)=O)nc1CN=C2c1ccccc1Cl
Agent: O=C(OO)c1cccc(Cl)c1
Product: Cc1sc2c(c1C)C(c1ccccc1)=[N+]([O-])Cc1nc(C(=O)N3CCCCC3)nn1-2

Procedure:
Each of 7,8-dimethyl-6-phenyl-2-piperdinocarbonyl-4H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]diazepine and 6-(2-chlorophenyl)-8-ethyl-4H-thieno[3,2-f]-s-triazolo[1,5-a]-[1,4]diazepine-2-carboxamide is treated with 70% m-chloroperbenzoic acid in the same manner as in a) to give 7,8-dimethyl-6-phenyl-2-piperidinocarbonyl-4H-thieno[3,2-f]-s-triazolo-[1,5-a][1,4]diazepine-5-oxide, as colorless prisms melting at 213° to 214° C. and 2-carbamoyl-6-(2-chlorophenyl)-8-ethyl-4H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]diazepine-5-oxide as colorless needles melting at 247° to 248° C, repectively.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1>Br.C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1
Reactant: COc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Agent: Br
Solvent: CC(=O)O
Product: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A solution of 5-methoxy-3-(1-methylpiperidin-4-yl)indole (2.30 g, 9.4 mmol) in 30 mL of 30% hydrobromic acid in acetic acid was heated in a sealed tube at 105° C. for 72 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water, and the pH was adjusted to about 13 with 5N aqueous sodium hydroxide. The mixture was concentrated in vacuo, and the residue was chromatographed on a silica gel column, eluting with 20% 2M ammonia in methanol/dichloromethane. After concentrating in vacuo, the residue was dissolved in methanol, charged with Dowex® 50X8-200 ion-exchange resin (25 g) and stirred overnight at room temperature. The mixture was filtered, and the resin was washed with water and methanol. The Dowex® resin was stirred overnight in 100 mL of 2M ammonia in methanol and filtered. The filtrate was concentrated in vacuo to provide 1.84 g (85%) of the title compound, which was used without further purification in Preparation 17. EA calculated for C13H17N3O: C, 67.53; H, 7.36; N, 18.18. Found: C, 67.24; H, 7.37; N, 18.38.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25]1[N:29]([C:30]2[S:31][C:32]([CH2:44][CH3:45])=[CH:33][C:34]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[CH:28]=[N:27][N:26]=1.[C:46](Cl)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:35]([C:34]1[CH:33]=[C:32]([CH2:44][CH3:45])[S:31][C:30]=1[N:29]1[CH:28]=[N:27][N:26]=[C:25]1[CH2:24][NH:23][C:46](=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:43]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2cnnc2CN)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2cnnc2CNC(=O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) [1,2,4]triazole di-p-toluenesulfonate (2.0 g) was dissolved in dimethylformamide (20 ml), and benzoyl chloride (0.42 ml) and triethylamine (1.5 ml) were added under ice-cooling. The mixture was stirred at room temperature for 8 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous citric acid solution and saturated brine, and dried over magnesium sulfate. After the solvent was evaporated, the residue was recrystallized from ethyl acetate to give 0.3 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) [1,2,4]triazol-3-ylmethyl)benzamide.
Reaction SMILES: Cl.[CH:2]1([CH2:6][NH2:7])[CH2:5][CH2:4][CH2:3]1.[C:8](Cl)(Cl)=[O:9]>>[CH:2]1([CH2:6][NH:7][C:8]([NH:7][CH2:6][CH:2]2[CH2:5][CH2:4][CH2:3]2)=[O:9])[CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Cl)Cl
Reactant: NCC1CCC1
Agent: Cl
Product: O=C(NCC1CCC1)NCC1CCC1
Yield: 37 %

Procedure:
In the manner of step (a) of Example 1, cyclobutanemethylamine hydrochloride (Buchman and Howton, J. Amer. Chem. Soc. 1948, 70:2517; 7.96 g, 80.5 mmol) was reacted with phosgene to give 1,3-bis(cyclobutylmethyl)urea as white powder (5.20 g, 37%), m.p. 153°-155° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=3)[CH2:22][CH2:21]2)[CH:12]=[CH:11]1>>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH2:19][N:20]3[CH2:21][CH2:22][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=4)[CH2:24][CH2:25]3)[CH:12]=[CH:11]2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(I)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4cc[nH]c34)CC2)c1
Product: COc1cccc(-n2ccc3cccc(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)c32)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-3-methoxybenzene and N-{3-[1-(1H-indol-7-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 482.3 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH:13][C:14]2[NH:18][C:17]3[CH:19]=[C:20]([O:26][CH2:27][CH3:28])[CH:21]=[C:22]([C:23]([OH:25])=O)[C:16]=3[N:15]=2)=[O:12])[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.S(O)(O)(=O)=O.[NH2:67][C:68]1[NH:69][CH:70]=[CH:71][N:72]=1>CN(C=O)C.[Cl-].[Na+].O>[CH2:27]([O:26][C:20]1[CH:21]=[C:22]([C:23](=[O:25])[NH:67][C:68]2[NH:69][CH:70]=[CH:71][N:72]=2)[C:16]2[NH:15][C:14]([NH:13][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:12])=[N:18][C:17]=2[CH:19]=1)[CH3:28]
Reactant: CCOc1cc(C(=O)O)c2nc(NC(=O)c3cc4ccccc4cn3)[nH]c2c1
Reactant: Nc1ncc[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(=O)Nc2ncc[nH]2)c2[nH]c(NC(=O)c3cc4ccccc4cn3)nc2c1
Yield: 22.7 %

Procedure:
100 mg (0.3 mmol) of 2-[(isoquinoline-3-carbonyl)-amino]-6-ethoxy-1H-benzoimidazole-4-carboxylic acid and 200 mg (0.53 mmol) of HBTU were dissolved in 1.0 mL of DMF and 0.5 mL of DIEA and reacted with 132 mg (1.0 mmol) of 2-aminoimidazole sulfate as described in general procedure A. Upon completion, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc, and dried under vacuum to produce 30 mg (23%) of isoquinoline-3-carboxylic acid [5-ethoxy-7-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 443 (M+1)+.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[N:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)([O:3][CH2:4][CH3:5])=[O:2].[CH2:16]([O:18][CH:19](OC(=O)C)OCC)[CH3:17].C(OCC)C>C(O)(=O)C>[C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[N:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:19][O:18][CH2:16][CH3:17])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(OCC)OC(C)=O
Reactant: CCOC(=O)c1cnc2c(c1)CC(=O)N2
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC=C1C(=O)Nc2ncc(C(=O)OCC)cc21
Temperature: 110 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
5-Carboethoxy-7-azaoxindole (0.040 g, 0.19 mmol) and diethoxymethylacetate (0.16 mL, 0.97 mmol) were combined and dissolved in acetic acid (1 mL). The reaction was warmed to 110° C. and stirred at this temperature for 1 h. The reaction was cooled to room temperature and diethyl ether was added to precipitate a beige solid that was collected by filtration (35 mg, 69% yield). 1H NMR 400 MHz (DMSO-d6) δ 11.30 (s, 1H); 8.58 (s, 1H); 8.05 (s, 1H); 7.93 (s, 1H); 4.44 (m, 2H); 4.28 (m, 2H); 1.35 (m, 3H); 1.28 (m, 3H).
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[S-:10][C:11]#[N:12].[NH4+].[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CC(C)=O>[CH:14]1([NH:20][C:11]([NH2:12])=[S:10])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1CCCCC1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Product: NC(=S)NC1CCCCC1
Temperature: 0 °C

Procedure:
295.5 g (2.1 mol) of benzoyl chloride were added dropwise over the course of 10 minutes to a solution of 165.0 g (2.2 mol) of ammonium thiocyanate in 500 ml of absolute acetone. After refluxing for 10 minutes, 198.9 g (2.0 mol) of cyclohexylamine were added dropwise, and the mixture was refluxed for a further 20 minutes. It was then stirred into 4 1 of ice-water, and the water was decanted off the oily product. The residue was dissolved in a hot mixture of 2 1 of 10% strength sodium hydroxide solution and 500 ml of ethanol and refluxed for 30 minutes. The reaction mixture was then diluted with ice-water, and the pH was adjusted initially to 1 with concentrated hydrochloric acid and then to 9 with solid sodium bicarbonate. The resulting precipitate was filtered off with suction, washed with water and dried at 80° C. under reduced pressure.