Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8]I)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CC(N(C)C)=O.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:27][C:28]([C@H:30]2[CH2:35][CH2:34][C@H:33]3[C@H:36]4[C@H:46]([CH2:47][CH2:48][C@:31]23[CH3:32])[C@:44]2([CH3:45])[C:39]([CH:40]=[C:41]([C:49]([O-:51])=[O:50])[CH2:42][CH2:43]2)=[CH:38][CH2:37]4)=[O:29])([CH3:26])[CH3:25])=[CH:20][CH:19]=1.[Na+].[OH-].[Na+]>C(OCC)(=O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:27][C:28]([C@H:30]2[CH2:35][CH2:34][C@H:33]3[C@H:36]4[C@H:46]([CH2:47][CH2:48][C@:31]23[CH3:32])[C@:44]2([CH3:45])[C:39]([CH:40]=[C:41]([C:49]([O:51][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:50])[CH2:42][CH2:43]2)=[CH:38][CH2:37]4)=[O:29])([CH3:25])[CH3:26])=[CH:20][CH:19]=1
Reactant: COc1ccc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C(=O)[O-])CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1ccc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C(=O)OCOC(=O)C(C)(C)C)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Reaction time: 1 h

Procedure:
1 ml of pivaloyloxymethyl iodide was added, whilst ice-cooling, to 15 ml of a dimethylacetamide solution containing 196 mg of sodium 17β-{N-[1(4-methoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylate (prepared by reacting the compound obtained as described in Example 2 with sodium hydroxide in a conventional salification process). The resulting solution was then stirred for 1 hour, whilst ice-cooling, after which it was diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography using a gradient elution method, with solutions of from 1 to 3% by volume of acetone in methylene chloride as the eluent, to give 157 mg of the title compound.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][N:17]([CH3:42])[C@@H:18]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:38][CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[C:34](O)[CH:35]=4)[C:30]3=[O:40])=[CH:25][C:24]=2[F:41])[CH2:19]1.N1C=CC=CC=1>ClCCl>[CH3:16][N:17]([CH3:42])[C@@H:18]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:38][CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[C:34]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[CH:35]=4)[C:30]3=[O:40])=[CH:25][C:24]=2[F:41])[CH2:19]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CN(C)[C@@H]1CCN(c2ccc(N3CCc4cc(O)ccc4C3=O)cc2F)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)[C@@H]1CCN(c2ccc(N3CCc4cc(OS(=O)(=O)C(F)(F)F)ccc4C3=O)cc2F)C1
Reaction time: 0.5 h

Procedure:
Trifluoromethanesulfonic anhydride (2.06 g) was added to a solution of 2-[4-((R)-3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-6-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (1.5 g) and pyridine (0.64 g) in dichloromethane (40 mL) at 0° C. After 30 minutes, the mixture was partitioned between water and dichloromethane, and the organic phase was dried over magnesium sulfate and concentrated. The product with the molecular weight of 501.50 (C22H23F4N3O4S) was obtained in this way; MS (ESI): 502 (M+H+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][N:13]=2)[CH2:8]1.[CH:24]#[C:25][CH3:26]>ClCCl.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:2][C:3]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:24]#[C:25][CH3:26])=[CH:14][N:13]=2)[CH2:8]1
Reactant: C#CC
Reactant: Clc1ccc(CNC2CCN(c3ccc(I)cn3)C2)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#Cc1ccc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Reaction time: 8 h

Procedure:
Dissolve (2,4-dichlorobenzyl)-[1-(5-iodopyridin-2-yl)-pyrrolidin-3-yl]-amine hydrochloride (130 mg, 0.27 mmol) in dichloromethane (10 mL) and triethylamine (10 mL). Add trans-dichlorobis(triphenylphosphine)palladium (II) (10 mg, 0.014 mmol) and copper(I) iodide (3 mg, 0.016 mmol). Bubble propyne into the mixture for 1 min. Stir the mixture overnight, filter it through a pad of Celite®, concentrate and chromatograph on silica gel, eluting with 10:90 to 1:1 ethyl acetate:hexanes, to give the title compound as a residue. Dissolve the residue in methanol, add 1 N HCl in methanol (1 mL). Concentrate and dry in vacuum oven at 60° C. to give the title compound as its hydrochloride salt as a light yellow solid (95 mg, 89%). δ 1H NMR (400 MHz, MeOH-d4) δ 8.03 (d, 1H, J=1.6 Hz), 7.84 (d, 1H, J=8.8 Hz), 7.69-7.68 (m, 2H), 7.49 (dd, 1H, J=8.0, 2.2 Hz), 6.95 (d, 1H, J=9.6 Hz), 4.53-4.45 (m, 2H), 4.28-4.23 (m, 1H), 4.10-4.06 (m, 1H), 3.90-3.83 (m, 2H), 3.72-3.66 (m, 1H), 2.73-2.65 (m, 1H), 2.50-2.41 (m, 1H), 2.03 (s, 3H), MS (ES): m/z=360 [M+H].
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([OH:8])=[CH:6][CH:7]=1.[O:10]1[CH2:15][CH2:14][CH:13](O)[CH2:12][CH2:11]1>>[Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([O:8][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: Cc1nc(O)ccc1Br
Reactant: OC1CCOCC1
Product: Cc1nc(OC2CCOCC2)ccc1Br

Procedure:
The title compound was prepared from 3-bromo-6-hydroxy-2-methylpyridine and tetrahydro-4H-pyran-4-ol in analogy to Example 9c): colorless solid.
Reaction SMILES: S(O[CH2:12][CH2:13][CH:14]1[O:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16][CH2:15]1)(C1C=CC(C)=CC=1)(=O)=O.[NH:24]1[CH2:29][CH2:28][CH:27]([N:30]2[CH2:34][CH2:33][NH:32][C:31]2=[O:35])[CH2:26][CH2:25]1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[O:19]1[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16][CH2:15][CH:14]1[CH2:13][CH2:12][N:24]1[CH2:25][CH2:26][CH:27]([N:30]2[CH2:34][CH2:33][NH:32][C:31]2=[O:35])[CH2:28][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3O2)cc1
Reactant: O=C1NCCN1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C1NCCN1C1CCN(CCC2COc3ccccc3O2)CC1

Procedure:
The mixture of 4.9 g of 2-(2-tosyloxyethyl)-1,4-benzodioxan, 2.54 g of 1-(4-piperidyl)-2-imidazolidinone, 5 g of anhydrous sodium carbonate and 100 ml of 4-methyl-2-pentanone is stirred and refluxed for 3 days. It is filtered, evaporated and the residue recrystallized from isopropanol, to yield the 1-[1-[2-(1,4-benzodioxan-2-yl)-ethyl]-4-piperidyl]-2-imidazolidinone of the formula ##STR9## melting at 125°.
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10]([NH:12][C@H:13]1[CH2:17][CH2:16][C@@H:15]([C:18]([OH:20])=O)[CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C[O:22][C:23](=[O:73])[C@@H:24]([NH:40][C:41]([C@@H:43]1[CH2:52][C:51]2[CH:50]=[C:49]3[O:53][CH2:54][C@H:55]([C:57]4[CH:62]=[CH:61][C:60]([O:63][CH2:64][C:65]5[CH:70]=[CH:69][C:68]([Cl:71])=[C:67]([Cl:72])[CH:66]=5)=[CH:59][CH:58]=4)[O:56][C:48]3=[CH:47][C:46]=2[CH2:45][NH:44]1)=[O:42])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[C:33]=2[CH3:39])=[CH:28][CH:27]=1>C(Cl)Cl>[C:5]([O:9][C:10]([NH:12][C@H:13]1[CH2:17][CH2:16][C@@H:15]([C:18]([N:44]2[C@H:43]([C:41]([NH:40][C@@H:24]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[C:33]=4[CH3:39])=[CH:30][CH:31]=3)[C:23]([OH:73])=[O:22])=[O:42])[CH2:52][C:51]3[CH:50]=[C:49]4[O:53][CH2:54][C@H:55]([C:57]5[CH:62]=[CH:61][C:60]([O:63][CH2:64][C:65]6[CH:70]=[CH:69][C:68]([Cl:71])=[C:67]([Cl:72])[CH:66]=6)=[CH:59][CH:58]=5)[O:56][C:48]4=[CH:47][C:46]=3[CH2:45]2)=[O:20])[CH2:14]1)=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)C1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)[C@@H]3CC[C@H](NC(=O)OC(C)(C)C)C3)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C
Reaction time: 0.67 h

Procedure:
EDC (3 eq.) and (1R,3S)-3-tert-butoxycarbonylamino-cyclopentanecarboxylic acid (6 eq.) were dissolved in DCM and stirred for 40 minutes. To this solution was added (S)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (25 mg) and stirred for 12 hours. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 950.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][C:25]=2[CH:32]=O)=[CH:20][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][C:25]=2[CH2:32][N:5]2[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]2)=[CH:20][CH:19]=1
Reactant: CC1(C)CCC(c2ccc(Cl)cc2)=C(C=O)C1
Reactant: O=C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(CN2CCC(=O)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.3 %

Procedure:
A suspension of the hydrochloride salt of 4-oxopiperidine (273 mg, 2.01 mmol) and DIPEA (351 μL, 2.01 mmol) was stirred in DCE (9.0 mL) at room temperature for 10 minutes. 2-(4-Chlorophenyl)-5,5-dimethylcyclohex-1-enecarbaldehyde (500 mg, 2.01 mmol) was then added, followed by NaBH(OAc)3 (426 mg, 2.01 mmol) and activated molecular sieves (˜1 g). The resulting suspension was stirred at room temperature for 16 hours. The reaction mixture was then filtered through a plug of Celite, rinsing with EtOAc. The filtrate was washed sequentially with saturated aqueous NaHCO3, water, and brine. The organic layer was dried over MgSO4 and concentrated. The crude residue was purified by flash chromatography on silica gel to afford the title compound (262 mg, 40% yield). MS (ESI) m/e (M+H+): 331.88
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]3[N:23]4[CH:24]=[CH:25][C:26]([C:28](=O)[CH3:29])=[CH:27][C:22]4=[N:21][CH:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1.Cl.[NH2:32][OH:33].N1C=CC=CC=1>CCO>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]3[N:23]4[CH:24]=[CH:25][C:26]([C:28](=[N:32][OH:33])[CH3:29])=[CH:27][C:22]4=[N:21][CH:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: NO
Reactant: CC(=O)c1ccn2c(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)cnc2c1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NO)c1ccn2c(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)cnc2c1
Temperature: 90 °C
Yield: 55.6 %

Procedure:
To a stirred solution of 1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)ethanone (40 mg, 0.095 mmol) from Example 200 in EtOH (2 mL) at rt were added hydroxylamine hydrochloride (120 mg, excess) and pyridine (200 μL, excess). The mixture was heated at 90° C. for 1 h, and then cooled to rt. Purification by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH), CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase afforded 1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)ethanone oxime (23 mg, 61%) as yellow powder. 1H NMR (500 MHz, DMSO-d6) δ 11.46 (br s, 1H), 8.13 (d, J=7.4 Hz, 1H), 7.90 (d, J=7.4 Hz, 1H), 7.72 (s, 1H), 7.51 (s, 1H), 7.45 (s, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.44-6.58 (m, 1H), 5.89 (s, 1H), 4.78 (d, J=2.5 Hz, 1H), 4.29 (s, 2H), 3.50 (br s, 1H), 2.18 (s, 3H), 2.04 (d, J=12.3 Hz, 1H), 1.87 (d, J=10.8 Hz, 1H), 1.56-1.67 (m, 2H), 1.15-1.32 (m, 4H). LCMS (ESI) m/z 436 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:18])=[N:5][CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1.Br[C:20]1[N:21]=[C:22]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:24]=1[Br:25]>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:25][C:24]1[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:22]([N:34]2[CH2:35][CH2:36][NH:37][CH2:38][CH2:39]2)=[N:21][C:20]=1[C:7]1[CH:8]=[C:3]([O:2][CH3:1])[C:4]([NH2:18])=[N:5][CH:6]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N
Reactant: C[Si](C)(C)CCOCn1c(N2CCNCC2)nc(Br)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(-c2nc(N3CCNCC3)n(COCC[Si](C)(C)C)c2Br)cnc1N
Temperature: 115 °C

Procedure:
A mixture of 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (56.2 mg, 0.225 mmol) and 1-(4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)piperazine (90 mg, 0.204 mmol) in DME (2.1 ml) and 2M aqueous Na2CO3 (0.7 ml) was sparged with Ar for 2 min. Pd(Ph3P)4 (23.6 mg, 0.02 mmol) was added. The mixture was sparged with Argon for an additional 2 min and was heated in a sealed tube in a microwave reactor at 115° C. for 15 min. The reaction mixture was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude materials of both reactions were combined and purified by preparative TLC (SiO2, 1.0 mm, 90:10 DCM-MeOH) to furnish 5-(5-bromo-2-(piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3-methoxypyridin-2-amine was isolated as a white solid which was directly used in the next step: LCMS (m/z): 485.2 (MH+), tR=0.56 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9]C(=O)OCC2C=CC=CC=2)=[N:7][CH:8]=1)[CH3:2].[H][H]>C(O)C.[Pd]>[NH2:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=1
Reactant: CCc1ccc(NC(=O)OCc2ccccc2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(N)nc1
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A suspension of benzyl (5-ethyl-2-pyridyl)carbamate (1.9 g., 7.43 mmoles) and 10% palladium-on-carbon (0.4 g.) in ethanol (100 ml.) was shaken with hydrogen at a pressure of 3.5 kg./cm2 for 2 hours. The catalyst was removed by filtration and the filtrate concentrated to yield 2-amino-5-ethylpyridine (0.9 g., 99.4%) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:9]2[CH2:12][NH:13][C@@H:14]([CH:17]3[CH:22]4[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]4)[CH2:18]3)[C:15](=[O:16])[N:7]3[C:8]=2[C:4]=1[CH:5]=[CH:6]3.[C:25](OC(=O)C)(=[O:27])[CH3:26]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:25]([O:1][CH2:2][C:3]1[CH:11]=[CH:10][C:9]2[CH2:12][NH:13][C@@H:14]([CH:17]3[CH:22]4[CH2:21][CH2:20][N:19]([CH2:24][CH2:23]4)[CH2:18]3)[C:15](=[O:16])[N:7]3[C:8]=2[C:4]=1[CH:5]=[CH:6]3)(=[O:27])[CH3:26]
Reactant: O=C1[C@H](C2CN3CCC2CC3)NCc2ccc(CO)c3ccn1c23
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OCc1ccc2c3c1ccn3C(=O)[C@H](C1CN3CCC1CC3)NC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
4-(Dimethylamino)pyridine (13 mg, 0.05 mmol) was added to a solution of (S)-7-(hydroxymethyl)-2-(quinuclidin-3-yl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-1(2H)-one from Step B above in a mixture of acetic anhydride (0.1 ml, 1.2 mmol) and pyridine (3 ml). The mixture was stirred overnight at room temperature, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (silica gel, 90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide) to afford (S)-(1-oxo-2-(quinuclidin-3-yl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-7-yl)methyl acetate (124 mg, 71%) as a white solid: MS (ESI+) m/z 368 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[N:13]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][NH:24][S:25]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>>[Cl:8][C:7]1[C:2]([N:24]([CH2:23][C:19]2[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=2)[N:13]=[CH:14][CH:15]=[CH:16]3)[S:25]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=2)(=[O:26])=[O:27])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3ncccc3c2)cc1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3ncccc3c2)c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-(quinolin-6-ylmethyl)sulfamoyl)benzoate (step-1 of Example 39).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[C:7]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]([OH:35])[CH2:25][N:26]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][CH:17]=3)=[O:15])[C:6]=2[CH:36]=1.N1C=CC=CC=1.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[CH2:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:44]([CH3:43])(=[O:46])=[O:45])=[CH:36][C:6]=2[C:7]=1[C:14](=[O:15])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]([OH:35])[CH2:25][N:26]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:18][CH:17]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1oc2ccc(N)cc2c1C(=O)c1ccc(OCC(O)CN(CCCC)CCCC)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(OCC(O)CN(CCCC)CCCC)cc1
Temperature: 32.5 °C
Reaction time: 2 h

Procedure:
0.3 g of (5-amino-2-butyl-1-benzofuran-3-yl) {4-[3-(dibutylamino)-2-hydroxy-propoxy]-phenyl}methanone (III) was dissolved in 10 ml of dichloromethane. The solution was warmed to 30-35° C. and 0.06 g of pyridine was added at this temperature. After this 0.093 g of methanesulfonyl chloride was added and the mixture was stirred at 30-35° C. for 2 hours. The mixture was cooled to 20-25° C., washed with 2×15 ml of water, 2×15 ml of sodium hydrogencarbonate solution of 5%, 1×15 ml of water. The phases were sepatated and the dichloromethane phase was evaporated.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(SC(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@@H]1CCNC1
Product: O=C(Nc1ccc(SC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 9.2 using 5-bromo-6-chloro-N-(4-((chlorodifluoromethyl)thio)phenyl)nicotinamide (Stage 18.2) and (R)-pyrrolidin-3-ol to afford an off-white crystalline solid. HPLC (Condition 4) tR=5.97 min, UPLC-MS (Condition 3) tR=1.19 min, m/z=478.2/480.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[F:13].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O.O>[F:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[NH:1][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)c1ccc(N)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC)cc1F
Temperature: 150 °C
Reaction time: 20 h

Procedure:
A mixture of 4.0 g of ethyl 4-amino-3-fluorobenzoate, 6.66 g of hexadecyl bromide and 3.0 g of potassium carbonate in 25 ml of hexamethyl phosphoramide is stirred at 150° C. for 20 hr. The mixture is cooled, diluted with water and extracted with ether. The ether extract is washed with water, dried, and the ether evaporated. The residue is recrystallized from hexane to yield ethyl 3-fluoro-4-(hexadecylamino)benzoate as a white solid.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:28][C:29]1[N:34]=[C:33]([N:35]2[C:43](=[O:44])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]2=[O:45])[CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>CC#N>[O:45]=[C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43](=[O:44])[N:35]1[C:33]1[N:34]=[C:29]([CH2:28][N:11]([CH:9]2[C:10]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7][CH2:8]2)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:30]=[CH:31][CH:32]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(CBr)n1
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1CCCCN(Cc1cccc(N2C(=O)c3ccccc3C2=O)n1)C1CCCc2cccnc21

Procedure:
Using General Procedure A: Reaction of 2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione, 2-(6-bromomethyl-pyridin-2-yl)-isoindole-1,3-dione (Goswami, S. et al. J. Am. Chem. Soc. 1989, 111, 3425-6), and DIPEA in CH3CN gave 2-{4-[[6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pyridin-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione as a tan solid. Deprotection with hydrazine following General Procedure E gave the free base. Conversion to the HBr salt using General Procedure D gave COMPOUND 355 as a white solid. 1H NMR (D2O) δ 1.51-1.55 (m, 4H), 1.71-1.85 (m, 1H), 1.91-2.03 (m, 1H), 2.13-2.18 (m, 1H), 2.32-2.36 (m, 1H), 2.46-2.54 (m, 1H), 2.67-2.74 (m, 1H), 2.90-2.99 (m, 4H), 3.98 (s, 2H), 4.38 (dd, 1H, J=5.7, 10.8 Hz), 6.90-6.96 (m, 2H), 7.80-7.86 (m, 2H), 8.30(br d, 1H, J=8.1 Hz), 8.58 (br d, 1H, J=5.7 Hz); 13C NMR (D2O) δ 20.00, 20.43, 25.14, 25.26, 27.63, 39.57, 51.24, 52.88, 59.64, 113.08, 113.21, 125.70, 139.29, 140.38, 145.05, 146.08, 147.71, 151.86, 154.94; ES-MS m/z 326 (M+H). Anal. Calcd. for C19H27N5.3.4HBr.1.8H2O: C, 36.05; H, 5.41; N, 11.06; Br, 42.92. Found: C, 35.93; H, 5.24; N, 10.91; Br, 43.14.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:24])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(N(CC)CC)C>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([C:33]([O:32][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:34])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:24])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1sc2c(c1C(=O)c1ccc(-c3ccccc3)cc1)CCNC2
Solvent: CCN(CC)CC
Product: Nc1sc2c(c1C(=O)c1ccc(-c3ccccc3)cc1)CCN(C(=O)OCc1ccccc1)C2

Procedure:
2-Amino-3-(4-phenylbenzoyl)-4,5,6,7-tetrahydrothieno(2,3-c)pyridine was reacted with benzyloxycarbonyl chloride and triethylamine to afford the title compound as a solid (mp 83-85° C.). 1H NMR (CDCl3) 2.05 (m, 2H); 3.45 (m, 2H); 4.46 (s, 2H); 5.15 (s, 2H); 6.72 (bs, 2H) 7.35-7.66 (m, 14H)