Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]([CH3:24])=[CH:11][C:10]=1[F:25])=[O:7].FC(F)(F)S(O[C:34]1[C:45]([CH3:46])=[N:44][C:37]2[N:38]=[C:39]([S:42][CH3:43])[N:40]=[CH:41][C:36]=2[CH:35]=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH3:27][C:2]([CH3:1])([CH3:26])[CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:34]2[C:45]([CH3:46])=[N:44][C:37]3[N:38]=[C:39]([S:42][CH3:43])[N:40]=[CH:41][C:36]=3[CH:35]=2)[C:12]([CH3:24])=[CH:11][C:10]=1[F:25])=[O:7]
Reactant: CSc1ncc2cc(OS(=O)(=O)C(F)(F)F)c(C)nc2n1
Reactant: Cc1cc(F)c(NC(=O)NCCC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)C)c(F)cc3C)c(C)nc2n1
Temperature: 100 °C
Yield: 56.4 %

Procedure:
Combine 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (0.669 g, 1.768 mmol), 7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl trifluoromethanesulfonate (0.6 g, 1.768 mmol), K2CO3 (0.733 g, 5.30 mmol) and Pd(PPh3)4 (0.102 g, 0.088 mmol) in dioxane (8 mL) and water (2 mL) in a pressure tube, sparge with argon, seal and heat at 100° C. overnight. Cool the mixture to RT, treat with saturated aqueous. NaHCO3 and extract with EtOAc (3×). Dry the combined organics over MgSO4, concentrate to dryness and purify via silica gel chromatography (5-100% EtOAc/Hexanes) to afford the title compound (440 mg, 56%). MS (m/z): 442.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](Cl)=[O:10])=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:29]3[C:24](=[N:25][CH:26]=[N:27][C:28]=3[NH2:30])[N:23]([C@H:31]3[CH2:36][CH2:35][C@H:34]([N:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)[CH2:33][CH2:32]3)[N:22]=2)=[CH:17][C:16]=1[O:44][CH3:45]>N1C=CC=CC=1>[NH2:30][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[N:23]([C@H:31]3[CH2:36][CH2:35][C@H:34]([N:37]4[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]4)[CH2:33][CH2:32]3)[N:22]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]([NH:14][C:9](=[O:10])[C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=4)=[C:16]([O:44][CH3:45])[CH:17]=3)[C:29]=12
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(Trifluoromethyl)-1-benzenecarbonyl chloride (262 mg, 1.256 mmol) in dichloromathane (1 mL) was added to a solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.145 mmol) in pyridine (8 mL) at 0° C. After 30 minutes, the ice bath was removed the the reaction mixture was stirred at room temperature for 1.5 hour. Solvent was evaporated and the residue was purified by flash column chromatography using dichloromethane/methanol (80:20) as mobile phase to give trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethyl)benzamide (516 mg, 74%). 1H NMR (CDCl3-d) δ 1.55 (m, 2H), 1.74 (m, 2H), 2.10-2.27 (m, 6H), 2.30 (s, 3H), 2.51 (m, 4H), 2.66 (m, 3H), 3.96 (s, 3H), 4.04 (s, 3H), 4.78 (m, 1H), 5.57 (bs, 2H), 7.30 (m, 2H), 7.79 (d, J=8.25 Hz, 2H), 8.04 (d, J=8.05 Hz, 2H), 8.38 (s, 1H), 8.64 (s, 1H), 8.68 (d, J=8.20 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[C:6]([F:11])=[CH:5][C:3]=1[NH2:4].[CH3:12][S:13][CH3:14].ClN1C(=O)CCC1=O.[OH-].[Na+]>C(N(CC)CC)C.ClCCl>[F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[C:6]([F:11])=[C:5]([CH2:12][S:13][CH3:14])[C:3]=1[NH2:4]
Reactant: CSC
Reactant: Cc1c(F)c(N)cc(F)c1F
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCc1c(N)c(F)c(C)c(F)c1F
Reaction time: 0.5 h

Procedure:
To anhydrous dichloromethane (170 ml) are added 2,4,5-trifluoro-3-methylaniline (16.89 g) and dimethyl sulfide (11 ml). Thereto N-chlorosuccinimide (17.2 g) is added gradually below 5° C. After stirring for 30 minutes, triethylamine (21 ml) is added dropwise and the mixture is refluxed over night. After the mixture is cooled and made alkaline with 5% aqueous sodium hydroxide solution, the resultant is extracted with dichloromethane, and the extract is washed with water and dried. The solvent is distilled off under reduced pressure and the residue is purified by silica-gel column-chromatography (dichloromethane : n-hexane =1 : 1) to give 2,4,5-trifluoro-3-methyl-6-methylthiomethylaniline (8.3 g).
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]([OH:56])[CH2:6][C:5]1=[O:57])[CH:2]=[CH2:3].C(Cl)(Cl)=O.C1(C)C=CC=CC=1>C(#N)C>[CH3:32][C@H:27]1[CH2:28][C:29]([CH3:31])=[CH:30][C@@H:4]([CH2:1][CH:2]=[CH2:3])[C:5](=[O:57])[CH2:6][C@H:7]([OH:56])[C@@H:8]([CH3:55])[C@@H:9](/[C:43](/[CH3:54])=[CH:44]/[C@H:45]2[CH2:46][C@@H:47]([O:52][CH3:53])[C@H:48]([OH:51])[CH2:49][CH2:50]2)[O:10][C:11](=[O:42])[C@H:12]2[N:17]([CH2:16][CH2:15][CH2:14][CH2:13]2)[C:18](=[O:41])[C:19](=[O:40])[C@:20]2([OH:39])[O:35][C@@H:24]([C@@H:23]([O:36][CH3:37])[CH2:22][C@H:21]2[CH3:38])[C@@H:25]([O:33][CH3:34])[CH2:26]1
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: O=C(Cl)Cl
Solvent: CC#N
Solvent: Cc1ccccc1
Product: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Reaction time: 1.5 h

Procedure:
17-Allyl-1,14-di-hydroxy-12-[2-(4-hydroxy-3-methoxy-cyclohexyl)-1-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (FK506; 8.04 mg, 0.01 mmol) was dissolved in acetonitrile (CH3CN; 100 μl), a solution of phosgene (COCl2) in toluene (1.24 mmol/ml; 8 μl, 0.01 mmol) was added at room temperature, and this was followed by stirring for 1.5 hours. After the reaction solution was concentrated under reduced pressure, TOYO-Pearl resin (TSKgel AF-amino, 100 μl, free amino group (available amino group) 0.01 mmol; manufactured by Tosoh Corporation) and acetonitrile (CH3CN; 500 μl) were added, and this was followed by stirring at room temperature for 1.5 hours. After completion of the reaction, the resin was washed with DMF two times and with water two times, a saturated aqueous solution of sodium hydrogen carbonate (1 ml) was added, and this was followed by stirring for 1 minute. After the resin was washed with water two times and with DMF two times, acetic anhydride (100 μl) and DMF (400 μl) were added, and this was followed by stirring at room temperature for 5 minutes. Subsequently, the resin was washed with DMF three times and with 20% aqueous ethanol two times, and the TOYO Pearl resin with FK506 obtained was used in the binding experiment described below.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH3:25])=O)C.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:4](=[O:3])[C:6]2[CH:7]=[N:8][C:9]3[C:10]([O:24][CH3:25])=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]=2[N:16]([CH:17]2[CH2:18][CH2:19][CH:20]([CH3:23])[CH2:21][CH2:22]2)[C:34]1=[O:35]
Reactant: O=C=Nc1ccccc1Cl
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCC(C)CC1
Product: COc1cccc2c1ncc1c(=O)n(-c3ccccc3Cl)c(=O)n(C3CCC(C)CC3)c12
Yield: 67.8 %

Procedure:
3-(2-Chloro-phenyl)-7-methoxy-1-(4-methyl-cyclohexyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (50 mg) was prepared from 8-methoxy-4-(4-methyl-cyclohexylamino)-quinoline-3-carboxylic acid ethyl ester (0.164 mmol) and 1-chloro-2-isocyanato-benzene (0.25 mmol) following general procedure C. LCMS: m/z 450 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.58 (s, 1H), 7.62 (m, 1H), 7.54-7.59 (m, 1H), 7.52 (m, 2H), 7.06 (m, 2H), 6.42 (m, 1H), 4.91 (m, 1H), 4.06 (s, 3H), 2.71 (m, 1H), 1.98 (m, 1H), 1.65 (m, 4H), 1.56 (m, 1H), 1.08 (d, 3H) ppm.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17](=[O:34])[NH:18][C:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[N:22]=[C:21]([CH3:33])[N:20]=2)[CH2:12]1)=O)C1C=CC=CC=1>CO.CCOCC.[OH-].[OH-].[Pd+2]>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]1[N:22]=[C:21]([CH3:33])[N:20]=[C:19]([NH:18][C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]2)=[O:34])[CH:24]=1
Reactant: COc1ccccc1-c1cc(NC(=O)C2CCCN(C(=O)OCc3ccccc3)C2)nc(C)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: COc1ccccc1-c1cc(NC(=O)C2CCCNC2)nc(C)n1
Reaction time: 8 h
Yield: 83.7 %

Procedure:
3-[6-(2-Methoxy-phenyl)-2-methyl-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XXXVII) (0.270 g, 0.586 mmol) was taken in methanol (5 ml) to which 10% Pd(OH)2 (0.125 g) was added and the mixture was stirred overnight under an atmosphere of hydrogen. The reaction was monitored by TLC. After completion, the reaction mixture was filtered through a celite bed and concentrated to get a viscous oil which was stirred in ether to precipitate a white solid. Filtration provided 0.160 g of piperidine-3-carboxylic acid [6-(2-methoxy-phenyl)-2-methyl-pyrimidin-4-yl]-amide (compound #22A).
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[NH4+:15]>>[CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:15])=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [NH4+]
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Agent: [OH-]
Product: CCCCc1ccc(C(N)=O)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
To a stirred solution of 200 ml of aqueous ammonium hydroxide was added dropwise 35 ml of 4-butylbenzoyl chloride. The resulting mixture was stirred at room temperature for several hours. The white solid was collected by filtration, washed with water, then hexane, and dried in vacuo at 60° C. to give 33.4 g (99% yield) of the desired product, mp 135°-136° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[N:6][CH:7]=[N:8][CH:9]=1)([O-:3])=[O:2].Cl[C:19]1[O:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>CN1CCCC1=O.O>[O:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[NH:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[CH:7][N:6]=2)=[CH:12][CH:13]=1
Reactant: Clc1nc2ccccc2o1
Reactant: Nc1ccc(Nc2ncncc2[N+](=O)[O-])cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cncnc1Nc1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 120 °C
Reaction time: 0.75 h
Yield: 42.9 %

Procedure:
A mixture of N-(5-nitropyrimidin-4-yl)benzene-1,4-diamine (256 mg), 2-chloro-1,3-benzoxazole (110 mg) in N-methylpyrrolidone (3 mL) was stirred at 120° C. for 45 min. After this time, the reaction mixture was cooled to ambient temperature, diluted with water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) then brine (50 mL), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:3 ethyl acetate/methylene chloride) to afford N-1,3-benzoxazol-2-yl-N′-(5-nitropyrimidin-4-yl)benzene-1,4-diamine (107 mg) as a red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:22](O)=[O:23])[CH:18]=4)[N:13]=3)=[CH:10][C:9]([C:25]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:67]([O:69][C:70](=[O:85])[C:71]1[CH:76]=[CH:75][C:74]([NH:77][CH:78]2[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]2)=[C:73]([NH2:84])[CH:72]=1)[CH3:68]>CN(C=O)C>[CH2:67]([O:69][C:70](=[O:85])[C:71]1[CH:76]=[CH:75][C:74]([NH:77][CH:78]2[CH2:79][CH2:80][CH2:81][CH2:82][CH2:83]2)=[C:73]([NH:84][C:22]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([C:11]2[C:6]([C:5]4[CH:32]=[CH:33][C:2]([Cl:1])=[CH:3][CH:4]=4)=[CH:7][CH:8]=[C:9]([C:25]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:26])[CH:10]=2)[CH:21]=[CH:20]3)=[O:23])[CH:72]=1)[CH3:68]
Reactant: O=C(O)c1ccc2nc(-c3cc(C(=O)N4CCCC4)ccc3-c3ccc(Cl)cc3)ccc2c1
Reactant: CCOC(=O)c1ccc(NC2CCCCC2)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(NC2CCCCC2)c(NC(=O)c2ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(Cl)cc4)ccc3c2)c1
Reaction time: 8 h

Procedure:
Compound 24 (270 mg, 0.59 mmol) in 4 mL of DMF was activated with 246.6 mg (0.65 mmol) of HATU and 226 μL (1.30 mmol) of DIEA at room temperature for 15 minutes. Compound 11 (170 mg, 0.65 mmol) was added as solid and the mixture was stirred overnight. The DMF was evaporated; the remaining oil was solidified by trituration with water. The solid Compound 25 was filtered off, dried and used without further purification. MS: 701.34 (M+H+).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:15][Si:16]([CH3:19])([CH3:18])Cl>C1(C)C=CC=CC=1>[CH3:15][Si:16]([CH3:19])([CH3:18])[N:5]1[C:4](=[O:6])[CH2:3][CH2:2][C:1]1=[O:7]
Reactant: O=C1CCC(=O)N1
Reactant: C[Si](C)(C)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N1C(=O)CCC1=O
Temperature: 25 °C

Procedure:
To 400 g (4 moles) of succinimide and 900 ml of triethylamine in 2700 ml of toluene 780 ml of trimethylchlorosilane were added in two hours with vigorous stirring. After refluxing and stirring for an additional hour the mixture was allowed to cool to room temperature. The precipitate was filtered off, washed with 1 l of toluene and 1 l of light petrol (40°-60° C.) and the combined filtrate and washings concentrated to about 700 ml. N-trimethylsilylsuccinimide was isolated by distillation at diminished pressure. The yield was 573 g (3.35 moles) or 83.5%; boiling point 62° C./0.3 mm Hg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[NH2:6])[CH3:2].[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=1)[C:23](O)=[O:24].O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:18])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[NH:6][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][N:28]=[C:20]([Br:19])[CH:21]=1)[CH3:2]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(OC)c(OC)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(OC)c(OC)c1)NC(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To methylene chloride (120 ml) are added 3-(3,4-dimethoxyphenyl)alanine ethyl ester (12.4 g), 2-bromoisonicotinic acid (10.9 g), 1-hydroxybenzotriazole monohydrate (8.23 g) and 1,3-dicyclohexylcarbodiimide (11.1 g), and the mixture is stirred at room temperature overnight. The insoluble materials are removed by filtration, and the filtrate is concentrated. The residue is purified by silica gel chromatography (solvent; chloroform:acetone=10:1) to give N-(2-bromoisonicotinoyl)-3-(3,4-dimethoxyphenyl)alanine ethyl ester (13.9 g) as an oily product.
Reaction SMILES: CO[C:3](=[O:27])[CH:4]([NH:11][C:12](=[O:26])[CH:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:28][NH2:29]>CCO.C1COCC1>[C:22]([O:21][C:19](=[O:20])[NH:18][CH:13]([C:12](=[O:26])[NH:11][CH:4]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:3](=[O:27])[NH:29][CH3:28])[C:14]([CH3:17])([CH3:15])[CH3:16])([CH3:24])([CH3:25])[CH3:23]
Reactant: CN
Reactant: COC(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C1CCCCC1
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C1CCCCC1
Yield: 95 %

Procedure:
To compound 63 in EtOH-THF 1:2 was added a large excess of methylamine (30% in water) and left at rt. for 2 weeks. The solution was concentrated to dryness and the residue subjected to a short silica gel column eluted with 2% MeOH in dichloromethane to give a pure (>95%) product M+H+384.5.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[C:32]3[C:27](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=3)[CH2:26][N:25]([CH3:35])[CH2:24]2)[CH:18]=1)(=[O:16])=[O:15].[CH3:36][C:37]([CH3:58])([C:48]([O:50]N1C(=O)CCC1=O)=O)[C:38]([O:40]N1C(=O)CCC1=O)=O>>[Cl:33][C:30]1[CH:31]=[C:32]2[C:27](=[C:28]([Cl:34])[CH:29]=1)[CH2:26][N:25]([CH3:35])[CH2:24][CH:23]2[C:19]1[CH:18]=[C:17]([S:14]([NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:48](=[O:50])[C:37]([CH3:36])([CH3:58])[C:38]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]3[C:32]4[C:27](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=4)[CH2:26][N:25]([CH3:35])[CH2:24]3)[CH:18]=2)(=[O:16])=[O:15])=[O:40])(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Reactant: CC(C)(C(=O)ON1C(=O)CCC1=O)C(=O)ON1C(=O)CCC1=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)C(C)(C)C(=O)NCCOCCOCCOCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1

Procedure:
Compound 182 was prepared from compound 28 and bis(2,5-dioxopyrrolidin-1-yl) 2,2-dimethylmalonate (prepared using the methods outlined in example 168) following the procedure outlined in example 175. The crude product (250 mg) was purified by Prep-HPLC with the following conditions: Column, C18 silica gel; mobile phase, MeCN/H2O/CF3COOH=39/100/0.05; Detector, UV 254 nm. This resulted in 152.3 mg (47%) of a TFA salt of N1,N3-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,2-dimethylmalonamide as a white solid. 1H-NMR (300 MHz, CDCl3, ppm): δ 7.92˜7.89 (d, J=8.1 Hz, 2H), 7.79 (s, 2H), 7.6˜97.64 (m, 2H), 7.57˜7.55 (d, J=7.5 Hz, 4H), 3.68 (s, 2H), 4.87˜4.75 (m, 4H), 4.5˜44.49 (m, 2H), 3.90˜3.88 (m, 2H), 3.67˜3.45 (m, 20H), 3.3˜93.32 (m, 4H), 3.31 (s, 6H), 3.17˜3.05 (m, 4H), 1.41 (s, 1H). MS (m/z): 1189 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:35])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:34])[CH2:12][CH2:13][C@@:14]3([CH2:31][CH2:32][NH2:33])[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:37])[CH3:36])(=[O:3])[CH3:2].[O:38](C(OC(C)(C)C)=O)[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=O>ClCCl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:35])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:34])[CH2:12][CH2:13][C@@:14]3([CH2:31][CH2:32][NH:33][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:38])[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:36])[CH3:37])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5(CCN)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Solvent: ClCCl
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5(CCNC(=O)OC(C)(C)C)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Temperature: 20 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
To a solution of (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-aminoethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (34) (5.3 g, 10.36 mmol), TEA (2.165 mL, 15.53 mmol) and TEA (2.165 mL, 15.53 mmol) in dichloromethane (DCM) (100 mL) stirred at room temp was added BOC2O (2.404 mL, 10.36 mmol). The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was poured into ice water (300 ml) and the solids were collected and dried to give (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((tert-butoxycarbonyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (35) (5.8 g, 8.34 mmol, 81% yield) as a white foam. This was ssed crude in next reaction without further purification. 1H NMR (400 MHz, CHLOROFORM-d) b=4.58-4.37 (m, 2H), 3.26-2.96 (m, 4H), 2.93-2.72 (m, 2H), 2.28 (d, J=18.8 Hz, 1H), 2.11-0.71 (m, 53H); LC/MS: m/z calculated 611.5. found 634.3 (M+Na)+.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]3[O:20][CH2:21][O:22][C@H:17]3[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([C@:25]1([OH:33])[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1)#[CH:24].C(N(CC)CC)C.N>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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:24]#[C:23][C@:25]2([OH:33])[CH:30]3[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]3)[CH2:26]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]3[O:20][CH2:21][O:22][C@H:17]3[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Reactant: Ic1ccc(N2C[C@@H]3OCO[C@@H]3C2)nc1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O[C@]1(C#Cc2ccc(N3C[C@@H]4OCO[C@@H]4C3)nc2Cc2ccccc2)CN2CCC1CC2
Temperature: 75 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
A mixture of 116 mg of 2-benzyl-6-(cis-3,4-methylenedioxypyrrolidine-1-yl)-3-iodopyridine, 47 mg of (3R)-3-ethynyl-3-quinuclidinol, 33 mg of tetrakis(triphenylphosphine)palladium (0), 3 mg of cuprous iodide, 0.12 ml of triethylamine and 3.0 ml of N,N-dimethylformamide was heated under stirring at 75° C. for 4 hours in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia, and then extracted with ethyl acetate. The extract was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (20:1), to give 38 mg of the target compound.