Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[C:6]2=[N:7][CH:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:10]=[C:5]2[N:4]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=3)[N:20]=[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:18]=2[CH3:34])[CH2:3]1.C1C(=O)N([Br:43])C(=O)C1>C(#N)C>[Br:43][C:8]1[N:7]=[C:6]2[C:2]([CH3:35])([CH3:1])[CH2:3][N:4]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]=[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:18]=3[CH3:34])[C:5]2=[CH:10][C:9]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2nc(Br)c(N3CCOCC3)cc21
Reaction time: 0.25 h

Procedure:
To a stirred solution of 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(2-pyridinyl)quinoline (250 mg, 0.489 mmol) in acetonitrile (6 mL) at 0° C. was added dropwise via syringe over 5 min a solution of n-bromosuccinimide (76 mg, 0.426 mmol) in acetonitrile (4 mL). The reaction was stirred at this temperature for 15 min. After this time the reaction was partitioned between EtOAc (40 mL) and water (15 mL). The separated organic layer was washed with NaHCO3 (15 mL, saturated aqueous solution) and Na2S2O3 (15 mL, saturated aqueous solution) and dried over MgSO4, filtered and evaporated in vacuo to give 4-(5-bromo-3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(2-pyridinyl)quinoline. 1H NMR (400 MHz, chloroform-d) δ ppm 8.64-8.82 (1H, m), 7.85-7.97 (3H, m), 7.75 (1H, dd, J=9.2, 5.9 Hz), 7.40-7.45 (1H, m), 7.31 (1H, ddd, J=9.3, 8.0, 2.6 Hz), 5.97 (1H, s), 3.71-3.90 (6H, m), 2.77-2.94 (4H, m), 2.38 (3H, s), 1.58 (3H, s), 1.52 (3H, s). Mass Spectrum (ESI) m/e=548.0 [(M+1) (79Br)] and 550.0 [(M+1) (81Br)]
Reaction SMILES: CS(O[C@H:6]1[C:25]2[C@:20]([CH3:27])([CH2:21][CH2:22][C:23](=[O:26])[CH:24]=2)[C@@H:19]2[C@H:8]([C@H:9]3[C@:16]([CH3:28])([CH2:17][CH2:18]2)[C@@:12]([O:29][C:30](=[O:32])[CH3:31])([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]3)[C@H:7]1OS(C)(=O)=O)(=O)=O.[N-:38]=[N+:39]=[N-:40].[Na+].C(O)(=O)C>CO>[N:38]([C:6]1[C:25]2[C@:20]([CH3:27])([CH2:21][CH2:22][C:23](=[O:26])[CH:24]=2)[C@@H:19]2[C@H:8]([C@H:9]3[C@:16]([CH3:28])([CH2:17][CH2:18]2)[C@@:12]([O:29][C:30](=[O:32])[CH3:31])([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]3)[CH:7]=1)=[N+:39]=[N-:40]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@@H](OS(C)(=O)=O)[C@@H](OS(C)(=O)=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(N=[N+]=[N-])C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
In a manner similar to that described in Example 6C, treat 6β,7β-dimethanesulfonyloxy-17α-acetoxy-4-pregnene-3,20-dione with sodium azide in aqueous methanol in the presence of acetic acid. Isolate and purify the resultant product in a manner similar to that described to obtain 6-azido-17α-acetoxy-4,6-pregnadiene-3,20-dione.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][N+:7]3[CH2:20][CH2:19][C:18]4[C:13](=[CH:14][C:15]5[O:23][CH2:22][O:21][C:16]=5[CH:17]=4)[C:8]=3[CH:9]=2)[C:4]=1[O:24][CH3:25].[Cl-].[C:27]([Mg]Br)#[C:28][CH3:29]>C(OCC)C>[CH3:25][O:24][C:4]1[C:5]2[CH:6]([C:27]#[C:28][CH3:29])[N:7]3[CH2:20][CH2:19][C:18]4[C:13]([C:8]3=[CH:9][C:10]=2[CH:11]=[CH:12][C:3]=1[O:2][CH3:1])=[CH:14][C:15]1[O:23][CH2:22][O:21][C:16]=1[CH:17]=4
Reactant: COc1ccc2cc3[n+](cc2c1OC)CCc1cc2c(cc1-3)OCO2
Reactant: CC#C[Mg]Br
Agent: [Cl-]
Solvent: CCOCC
Product: CC#CC1c2c(ccc(OC)c2OC)C=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.9 %

Procedure:
To a suspension of berberine hydrochloride (500 mg, 1.3 mmol) in anhydrous diethyl ether (100 mL) at 0° C. was added 1-propynylmagnesium bromide solution (0.5 M in tetrahydrofuran, 26 mL, 13 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 9,10-dimethoxy-8-prop-1-ynyl-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (190 mg, 37%). LC/MS m/e calcd for C23H21NO4 (M+H)+: 376.43, observed: 376.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.68 (d, J=2.02 Hz, 3 H) 2.76-2.86 (m, 2 H) 3.21-3.30 (m, 2 H) 3.80 (d, J=3.03 Hz, 6 H) 5.39-5.43 (m, 1 H) 6.01 (d, J=5.31 Hz, 2 H) 6.15 (s, 1 H) 6.76 (d, 2 H) 6.90 (d, J=8.34 Hz, 1 H) 7.32 (s, 1 H).
Reaction SMILES: [C:1]1(CO)[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.C(O)(=O)CC[C:14](C)=[O:15].C(N=C=NC(C)C)(C)C>CN(C1C=CN=CC=1)C.ClCCl>[C:3]1([CH2:14][OH:15])[C:4]([CH2:7][OH:8])=[CH:5][CH:6]=[CH:1][CH:2]=1
Reactant: OCc1ccc(CO)cc1
Reactant: CC(=O)CCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: OCc1ccccc1CO
Reaction time: 8 h
Yield: 191 %

Procedure:
In a flask with dichloromethane (ca. 25 ml), 1,4-phenylenedimethanol (5 g, 0.036 mol) and levulinic acid (8.36 g, 0.072 mol) were mixed. The flask was then cooled in an ice water bath. Diisopropyl carbodiimide (9.09 g, 0.072 mol) and the catalyst DMAP (ca. 100 mg) were then added slowly to the solution. The mixture was allowed to come to room temperature and was stirred overnight. The mixture was then filtered and washed with 1M HCL brine. It was then dried over MgSO4 and concentrated in vacuo to afford a white solid as the product (9.5 g). Its purity was ascertained using 1H NMR (300 MHZ in CDCL3): δ 7.34 (s, 4H), 5.11 (s, 4H), 2.77 (t, 4H), 2.62 (t, 4H), 2.18 (s, 6H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[OH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[OH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:7]([C:6]2[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:21][CH2:20]1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: OC1CCNCC1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)CC1
Yield: 70 %

Procedure:
Prepared in analogy to Example 1 from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 4-hydroxypiperidine. The crude material was purified by flash chromatography (methanol/dichloromethane) to yield the title compound as an amorphous yellow solid (yield 70%). MS (m/e): 342.3 (M+H+, 100%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15]O)[CH2:10][CH2:9]1)=[O:7].S(Cl)([Cl:19])=O>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][Cl:19])[CH2:10][CH2:9]1)=[O:7]
Reactant: O=C(c1ccco1)N1CCN(CCO)CC1
Reactant: O=S(Cl)Cl
Product: O=C(c1ccco1)N1CCN(CCCl)CC1
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
Dissolved in 20 ml of thionyl chloride was 1.76 g of 1-(2-furanylcarbonyl)-4-(2-hydroxyethyl)piperazine. The resulting mixture was stirred at room temperature for 7.5 hours. The thionyl chloride was distilled off under reduced pressure and the residue was poured into cold water. After alkalinization of the resulting aqueous solution with sodium carbonate, the solution was extracted with benzene and the benzene layer was washed with water. The benzene layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure to give 1.2 g of an oily substance. The reaction product was provided for the next step in its unpurified form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]2[CH2:27][C:26]([CH3:29])([CH3:28])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30]([O:32]CC)=[O:31])[CH:24]=3)[NH:19]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[OH-].[Li+].[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]2[CH2:27][C:26]([CH3:28])([CH3:29])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30]([OH:32])=[O:31])[CH:24]=3)[NH:19]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1ccccc1NS(=O)(=O)c1ccc(F)cc1)N2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2ccc(F)cc2)Nc2ccc(C(=O)O)cc21
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 2-(2-(4-fluorophenylsulfonamido)phenyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (crude 0.62 mmol) in ethanol was added a solution of lithium hydroxide monohydrate (129 mg, 3.08 mmol) and sodium hydroxide (50 mg, 1.23 mmol) in water (1.5 mL) at room temperature. The reaction mixture was stirred at 85° C. overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water, adjusted pH=3˜4 by 1M aqueous hydrochloric acid, extracted with ethyl acetate. The combined organic layer was washed by brine, dried over anhydrous Sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give 2-[2-(4-fluoro-benzenesulfonylamino)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid. LC/MS m/e obsd. (ESI+) [(M+H)+] 455.20.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4](NC2CCCCCC2)[N:3]=1.[Cl:26]C1N=C(NC2C=CC(OC)=C(Cl)C=2)N=C(NC2C=CC(OCC)=C(Cl)C=2)N=1>>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([Cl:26])[N:3]=[C:2]([Cl:1])[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: CCOc1ccc(Nc2nc(Cl)nc(Nc3ccc(OC)c(Cl)c3)n2)cc1Cl
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Product: COc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1Cl

Procedure:
A 1 kg campaign was conducted to develop a process which avoids multiple column purifications and employs a suitable recrystallisation method to produce compound 137. This scheme was stabilized for the campaign, however the scale up of compound 133 by one pot synthesis resulted in the formation of an impurity, which was carried over to the final step and was difficult to remove. The impurity was isolated and characterized to be 6-chloro-N-(3-chloro-4-methoxyphenyl)-N′-(3-chloro-4-ethoxyphenyl)[1,3,5]triazine-2,4-diamine. To avoid the impurity, the single pot reaction was avoided and compound 101 was isolated and purified by recrystallisation in ethylacetate.
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][C@@H:16]3[C@@:21]4([CH3:27])[CH2:22][CH2:23][C@H:24]([OH:26])[CH2:25][C:20]4=[CH:19][CH2:18][C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)=[O:8].[Si:29](OS(C(F)(F)F)(=O)=O)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>CN(C)C=O>[CH3:33][C:32]([Si:29]([CH3:31])([CH3:30])[O:26][C@@H:24]1[CH2:25][C:20]2[C@@:21]([CH3:27])([C@@H:16]3[C@@H:17]([CH2:18][CH:19]=2)[C@H:12]2[C@@:13]([CH3:28])([C@@H:9]([C:7](=[O:8])[CH3:6])[CH2:10][CH2:11]2)[CH2:14][CH2:15]3)[CH2:22][CH2:23]1)([CH3:35])[CH3:34]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Imidazole (ImH) can be added to a solution of pregnenolone (compound 3, see Scheme 1) in anhydrous dimethylformamide (DMF). Tert-butyldimethylsilyltrifluoromethanesulfonate can then be added to the solution. The reaction product can be purified to obtain compound 4, 1-((3S,8S,9S,10R,13S,14S,17S)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3-[(1,1-dimethylethyl)dimethylsilyloxy]-10,13-dimethyl-1H-cyclopenta[α]phenanthren-17-yl) ethanone, as shown in Scheme 2.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:12]=[C:11]([O:13]C)[C:10](=[O:15])[CH:9]=[C:8]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:2]=1.B(Br)(Br)Br>C(Cl)Cl>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:12]=[C:11]([OH:13])[C:10](=[O:15])[CH:9]=[C:8]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:2]=1
Reactant: COc1cn(-c2cccc(-c3ccccc3)c2)c(-c2ccccc2)cc1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1cc(-c2ccccc2)n(-c2cccc(-c3ccccc3)c2)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
1-(Biphenyl-3-yl)-5-methoxy-2-phenylpyridin-4(1H)-one (20 mg, 0.056 mmol) was treated with BBr3 (0.5 mL of a 1 M solution in CH2Cl2) and stirred at room temperature. After 1 h, the reaction mixture was cooled to 0° C. and quenched with dropwise addition of MeOH (0.1 mL), before being concentrated under a stream of N2, diluted with MeOH (0.8 mL) and purified by reversed phase HPLC (2 cm×5 cm C18, acetonitrile-water gradient, 0.05% TFA added) to provide (99%) of 1-(biphenyl-3-yl)-5-hydroxy-2-phenylpyridin-4(1H)-one. 1H NMR (499 MHz, DMSO): δ 7.88 (s, 1 H); 7.64-7.60 (m, 2 H); 7.53 (d, J=7.7 Hz, 2 H); 7.46-7.40 (m, 3 H); 7.40-7.36 (m, 1 H); 7.30-7.26 (m, 6 H); 6.58 (s, 1 H). HRMS (ES) Calc (M+H)+ 340.1332 found 340.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]2[N:11]3[C:12](=[O:24])[NH:13][C:14]3[C:15]2=[N:21][NH:22][CH:23]=3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)CCC.[C:30](#[N:34])[CH2:31][CH2:32]C.C1(N)CC1>C1(C)C=CC=CC=1>[CH:30]1([NH:34][C:12]([NH:13][C:14]2[C:15]([C:16]3[NH:17][C:18]4[CH:19]=[CH:20][C:8]([CH2:7][N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[CH:9][C:10]=4[N:11]=3)=[N:21][NH:22][CH:23]=2)=[O:24])[CH2:32][CH2:31]1
Reactant: CCCC#N
Reactant: O=c1[nH]c2c[nH]nc2c2nc3ccc(CN4CCOCC4)cc3n12
Agent: NC1CC1
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)NC1CC1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
7-Morpholin-4-ylmethyl-2,4-dihydro-1,2,4,5a,10-pentaaza-cyclopenta[α]fluoren-5-one (1.0 wt, prepared as outlined above in Example 66A) and a solvent such as n-butanol, butyronitrile, glycol or toluene (3.0 vol) can be charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. Cyclopropylamine (0.351 wt) can be added at temperature such as 15 to 30° C. under an inert atmosphere e.g. nitrogen. The contents can be heated to 40 to 105° C., in particular 40-80° C. and stirred at this temperature for 16 to 24 hours. Reaction completion can be determined by 1H NMR analysis. The reaction mixture can then be cooled to 10 to 20° C. The product can then be isolated by organic-aqueous extraction method as outlined above in Example 66A, or an alternative method of isolation may be employed such as the addition of an anti-solvent, for example n-heptanes, to the reaction mixture. This could allow the reaction product to precipitate with subsequent isolation by filtration. The solid can then be dried under vacuum at 35 to 45° C. to yield 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea. At this stage the solid can be purified by recrystallisation from an appropriate solvent, preferably a Class 2 or 3 solvent1. In addition, alternative methods of purification aside from recrystallisation may be employed for purification of the product such as flash column chromatography or filtration through a plug of silica gel or reverse-phase silica gel. 1 Class 3 and Class 2 solvents are as outlined Q3C—Tables and List in Guidance for Industry Q3C Impurities: Residual Solvents (November 2003, CDER, CBER, FDA, ICH) and as further outlined in Impurities: Guideline for Residual Solvents (1997, ICH).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].[CH3:41][NH:42][CH2:43][CH3:44]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:43]([N:42]([CH2:41][CH3:2])[CH2:9][CH2:8][N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:37])=[O:38])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:44]
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Reactant: CCNC
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Yield: 44.5 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting N,N-diethyl-N′-methyl-1,2-ethanediamine (130 mg, 1.0 mmol) for N-methylethanamine to afford 30.0 mg of the title compound (44.5%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:4]([C:21]#[N:22])[N:3]=1.[NH2:23][CH2:24][CH2:25][CH:26]=[CH2:27]>C(O)(C)C>[CH2:24]([NH:23][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:4]([C:21]#[N:22])[N:3]=1)[CH2:25][CH:26]=[CH2:27]
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3cccc(F)c3)c2c1
Reactant: C=CCCN
Solvent: CC(C)O
Product: C=CCCNc1nc(C#N)c(-c2cccc(F)c2)c2cc(OC)ccc12
Temperature: 25 °C

Procedure:
To a suspension of 1-chloro-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile (150 mg) in 15 mL isopropanol was added to 6 mL of a 0.81 M solution of 4-amino-1-butene. The mixture was heated to reflux for 4 days, then cooled to room temp and partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic solutions were washed with brine (1×), dried over MgSO4, and concentrated. Flash chromatography (3% to 50% EtOAc in hexanes) provided 146 mg of 1-(but-3-enylamino)-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile as a tan solid.
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:14][N:15]([CH3:32])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]2[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[CH:18][CH:17]=1>>[CH3:14][N:15]([CH3:32])[C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]([C:24]2[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])=[CH:20][CH:21]=1
Reactant: O=C(O)C1CCCc2ccccc21
Reactant: COc1ccc(NCc2ccc(N(C)C)cc2)cn1
Product: COc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3ccccc32)cn1
Yield: 68.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.70 g) and [(4-dimethylaminophenyl)methyl](6-methoxypyridin-3-yl)amine (0.49 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.54 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:23]1[CH:24]=[C:25]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:26]=[N:27][CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:23]4[CH:24]=[C:25]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:26]=[N:27][CH:28]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1cncc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (147 mg, 0. 5 mmol) and 5-bromo-pyridine-3-sulfonic acid amide (119 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (177 mg, 79%). MS (ISP) 449.9 [(M+H)+]; mp 252–254° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:35])[N:12]([CH2:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH3:9])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:58][O:59][C:60](=[O:64])[CH2:61][CH2:62][NH2:63].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:58][O:59][C:60](=[O:64])[CH2:61][CH2:62][NH:63][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([CH2:25][N:12]([C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[CH:17][CH:18]=2)[C:11]([NH:10][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH3:9])=[O:35])=[CH:27][CH:28]=1
Reactant: C[C@H](NC(=O)N(Cc1ccc(C(=O)O)cc1)c1ccc(C2CCCCC2)cc1)c1ccc(Cl)cc1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)c1ccc(CN(C(=O)N[C@@H](C)c2ccc(Cl)cc2)c2ccc(C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
4-[3-[1(S)-(4-Chlorophenyl)ethyl]1-(4-cyclohexylphenyl)ureidomethyl]benzoic acid (1.0 g, 2.04 mmol) was dissolved in DMF (8 ml) and HOBt (410 mg, 3.05 mmol), and EDAC (580 mg, 3.05 mmol) were added. The solution was stirred at room temperature for 30 min. A solution of 3-aminopropionic acid methyl ester hydrochloride (310 mg, 3.05 mmol) and N,N-diisopropylethylamine (530 μl, 3 mmol) in DMF (2 ml) was added, and the reaction mixture was stirred at ambient temperature over night. The reaction mixture was partitioned between ethyl acetate (70 ml) and water (3×50 ml). The organic phase was dried with anhydrous sodium sulfate and evaporated to dryness to afford 1.17 g (99%) of 3-{4-[3-[1(S)-(4-chloro-phenyl)ethyl]1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}propionic acid methyl ester. HPLC-MS (method A): m/z=576 (M+1); Rt=5.47 min.
Reaction SMILES: C([O:5][C:6](=[O:53])[C:7]([O:10]/[N:11]=[C:12](/[C:40]1[N:41]=[C:42]([NH:45]C(OC(C)(C)C)=O)[S:43][CH:44]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][C:26]1[CH:30]=[C:29]([CH2:31][NH:32]C(OC(C)(C)C)=O)[O:28][N:27]=1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:32][CH2:31][C:29]1[O:28][N:27]=[C:26]([CH2:25][C@@H:17]2[C@H:16]([NH:15][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:53])=[O:5])/[C:40]3[N:41]=[C:42]([NH2:45])[S:43][CH:44]=3)[C:19](=[O:20])[N:18]2[S:21]([OH:24])(=[O:22])=[O:23])[CH:30]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cc1cc(CN)on1)c1csc(N)n1)C(=O)O
Yield: 22.8 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((5-(((tert butoxycarbonyl)amino)methyl)isoxazol-3-yl)methyl)-4-oxoazetidine-1-sulfonic acid (10.9 mg, 14 μmol), TFA (70 μl, 0.91 mmol), and DCM (0.2 mL). The crude residue was purified by reverse phase prep HPLC (Xselect CSH, 19×100 mm, 5 μM, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min) to afford the title compound (1.7 mg, 17%). LCMS: Rt=0.48 min, m/z=532.1 (M+1). Method 2m_acidic_polar. 1H NMR (400 MHz, D2O) δ 6.85 (s, 1H), 6.52 (s, 1H), 5.38 (d, J=5.6 Hz, 1H), 4.26 (s, 2H), 3.22 (dd, J=16.2, 7.1 Hz, 2H), 3.10 (dd, J=16.2, 6.0 Hz, 1H), 1.33 (s, 3H), 1.29 (s, 3H).