Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[N:4]=1.Cl.[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])=[CH:35][CH:34]=[C:33]([NH:43][CH2:44][CH2:45][NH2:46])[N:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[ClH:2].[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:39])([F:41])[F:40])=[CH:35][CH:34]=[C:33]([NH:43][CH2:44][CH2:45][NH:46][C:3]2[N:8]3[N:9]=[C:10]([CH:12]4[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]4)[N:11]=[C:7]3[CH:6]=[C:5]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[N:4]=2)[N:32]=1
Reactant: NCCNc1ccc(C(=O)C(F)(F)F)c(N)n1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)nc(NCCNc4ccc(C(=O)C(F)(F)F)c(N)n4)n3n2)CC1
Temperature: 130 °C

Procedure:
55 mg (0.14 mmol) of 5-chloro-7-(2,4-difluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 53A), 48.9 mg (0.17 mmol) of 1-{2-amino-6-[(2-aminoethyl)amino]pyridin-3-yl}-2,2,2-trifluoroethanone hydrochloride (Example 13A) and 0.147 ml (0.84 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 21 mg (23% of theory) of the product as a solid.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][N:22]1[C:15](=[O:17])[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N2CCc3ccccc3C2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1,2,3,4-tetrahydro-isoquinoline via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a yellow oil. MS (ES) for C21H23NO5 [M+H]+: 370.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[O:22]=[C:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[CH:29]=2)[NH:24]1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=[C:31]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[CH:29]=2)[NH:24][C:23]1=[O:22]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Reactant: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Product: CC(=O)Nc1ccc2c(c1)C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCOCC1)CC3)C(=O)N2
Yield: 71.2 %

Procedure:
The title compound was prepared under the same conditions as described in Example 15 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide as starting materials to give N-{3-[3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-acetamide (60 mg, 71.2%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[N:14]=[CH:13][C:12]2[CH:11]=[CH:10][C:9]3[C:15]([C:19]([O:21]CC)=O)=[N:16][N:17]([CH3:18])[C:8]=3[C:7]=2[N:6]=1)=[O:3].CO.C[N:27](C)C=O.[OH-].[NH4+]>>[NH2:1][C:2]([NH:4][C:5]1[N:14]=[CH:13][C:12]2[CH:11]=[CH:10][C:9]3[C:15]([C:19]([NH2:27])=[O:21])=[N:16][N:17]([CH3:18])[C:8]=3[C:7]=2[N:6]=1)=[O:3]
Reactant: CCOC(=O)c1nn(C)c2c1ccc1cnc(NC(N)=O)nc12
Reactant: CN(C)C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Cn1nc(C(N)=O)c2ccc3cnc(NC(N)=O)nc3c21
Temperature: 65 °C
Reaction time: 48 h
Yield: 50 %

Procedure:
A suspension of 0.20 g (0.63 mmol) of ethyl 8-[(aminocarbonyl)amino]-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate in 15 mL of a mixture methanol/dimethylformamide/ammonium hydroxide 30% 1/1/1 was stirred in a close bottle at 65° C. for 48 hours. The solvent was then evaporated under reduced pressure, the residue redissolved with a mixture dichloromethane/methanol 9/1 and washed with water. The organic layer was dried over anhydrous Na2SO4 and evaporated to dryness. The product was purified by chromatography on a silica gel column (eluant dichloromethane/acetone/methanol) giving 0.09 g (50% yield) of the title compound.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2C=CC(O)=CC=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C1C=C(CC2C([OH:31])=CC=CC=2)C(O)=CC=1.C=O.C1C(C(C2C=CC(O)=CC=2)=C(Cl)Cl)=CC=C(O)C=1.C1(=O)CCCCC1.C1(O)C=CC=CC=1>CC(C)=O>[C:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[OH:31])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: Oc1ccccc1Cc1ccccc1O
Agent: C=O
Agent: Oc1ccc(C(=C(Cl)Cl)c2ccc(O)cc2)cc1
Solvent: CC(C)=O
Solvent: O=C1CCCCC1
Solvent: Oc1ccccc1
Product: CC(C)(C)c1ccccc1O

Procedure:
Bisphenols are exemplified by Bisphenol A, Bisphenol F, Bisphenol C, Bisphenol H and the like. As is well known, Bisphenol A is a dihydric phenol obtained by condensation of phenol and acetone, that is, 2,2-bis(4-hydroxyphenyl)propane; Bisphenol F is the corresponding compound obtained by using formaldehyde instead of the above mentioned acetone; Bisphenol C is the compound obtained by using cyclohexanone instead of the acetone; and Bisphenol H is a dihydric phenol obtained by condensation of o-tert-butyl phenol and acetone. These bisphenols can be used concomitantly.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][C:17]([NH:21]C(OCC3C=CC=CC=3)=O)([CH3:20])[CH2:16][CH2:15]2)=[N:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>C(O)(C)C.CO.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][C:17]([NH2:21])([CH3:20])[CH2:16][CH2:15]2)=[N:12][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(NC(=O)OCc2ccccc2)CCN(c2ccc(C(=O)OC(C)(C)C)cn2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(N)CCN(c2ccc(C(=O)OC(C)(C)C)cn2)CC1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-benzyloxycarbonylamino-4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-5′-carboxylic acid tert-butyl ester (0.29 g, 0.68 mmol) in isopropanol, methanol and ethyl acetate (1:1:1, 5.0 mL) at room temperature was added ammonium formate (0.25 g, 1.07 mmol) and 10% Pd/C (25 mg) under nitrogen. The reaction mixture was stirred at 80° C. for 30 minutes, cooled, filtered through Celite, and concentrated under reduced pressure to provide the titled compound. MS (CT) m/z 292 (M+1)+; 1H NMR (300 MHz, methanol-d4) δ ppm 8.61 (d, 1H), 7.95 (d, d 1H), 6.79 (d, 1H), 4.80 (s, 2H), 3.85-3.79 (m, 2H), 3.66-3.60 (m, 2H), 1.67-1.59 (m, 4H), 1.58 (s, 9H), 1.23 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9](=[O:20])[O:8][C:7]([C:23]([F:26])([F:25])[F:24])([CH:21]=C)[C:6]=2[CH:27]=1.[O:28]=[O+][O-].[BH4-].[Na+].CC(C)=O>ClCCl.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9](=[O:20])[O:8][C:7]([CH2:21][OH:28])([C:23]([F:26])([F:24])[F:25])[C:6]=2[CH:27]=1
Reactant: C=CC1(C(F)(F)F)OC(=O)N(Cc2ccc(OC)cc2)c2ccc(Br)cc21
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1ccc(CN2C(=O)OC(CO)(C(F)(F)F)c3cc(Br)ccc32)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
6-Bromo-1-(4-methoxybenzyl)-4-(trifluoromethyl)-4-vinyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (71.5 g, 0.161 mol) was dissolved in dichloromethane (200 mL) and methanol (200 mL), and the solution was cooled to 0° C. and stirred in an ozone atmospher for 2 hours. After the ozone atmospher was replaced by a nitrogen atmospher, sodium borohydride (12.2 g, 0.323 mol) was slowly added thereto at 0° C. After the reaction solution was stirred at 0° C. for 10 minutes, excess acetone was added thereto. After the solvent was evaporated under reduced pressure, the resulting residue was diluted with ethyl acetate, and 1 N hydrochloric acid was added until the pH of the aqueous layer reached about 6. The organic layer was separated and washed with water and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The resulting residue was crystallized from water and ethanol, whereby the objective compound (62.4 g, 87%) was obtained as a white solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C@H:23]([OH:25])[CH3:24])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[F:27][CH:28]1[CH2:31][NH:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.CN1CCOCC1>C(#N)C>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C@@H:19]([C:20]([N:30]3[CH2:31][CH:28]([F:27])[CH2:29]3)=[O:21])[C@H:23]([OH:25])[CH3:24])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: C[C@@H](O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: FC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1CC(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
A 25 mL round-bottomed flask was charged with (2R,3R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-hydroxybutanoic acid (184 mg, 0.54 mmol), 3-fluoroazetidine hydrochloride (66 mg, 0.59 mmol), and HATU (242 mg, 0.64 mmol). Then added acetonitrile (1.1 mL) followed by N,N-diisopropylethylamine (0.20 mL, 1.1 mmol) and N-methylmorpholine (0.05 mL, 0.45 mmol). The reaction mixture was stirred at room temperature overnight then concentrated. The crude solid was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 10-80% EtOAc) to afford 112 mg (52%) of [(1R,2R)-1-(3-fluoro-azetidine-1-carbonyl)-2-hydroxy-propyl]-carbamic acid 9H-fluoren-9-ylmethyl ester as a white solid. MS: [M+H]+=399.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N+:30]([O-])=O)([O-])=O>Cl>[NH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccccc1NCCCCCCCCCCCCNc1ccccc1[N+](=O)[O-]
Agent: Cl
Product: Nc1ccccc1NCCCCCCCCCCCCNc1ccccc1N
Temperature: 100 °C

Procedure:
20 g (0.045 mol) N,N'-bis(2-nitrophenyl)-1,12-diaminododecane are dissolved in 100 ml concentrated hydrochloric acid, and 43 g (0.19 mol) stannochloride dihydrate dissolved in 50 ml concentrated hydrochloric acid are added. The mixtured is heated to approxiately 100° C. while stirred, and after three hours the product separated off is cooled. The water phase is separated off, and the product is suspended in 200 ml hot water, whereafter it is poured into 500 ml 2M sodium hydroxide. The released tetraamine is extracted twice with 150 ml methylchloride, and the organic phase is dried over magnesium sulphate and evaporated, whereby the product is crystallized. Yield 17.30 g (100%), melting point 85° to 88° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH:17]3[OH:22])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1>C(Cl)Cl>[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][N:19]2[CH2:20][CH2:21][CH:16]([N:13]3[CH2:14][CH2:15][CH:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)[CH:17]([OH:22])[CH2:18]2)=[CH:33][CH:32]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(C2CCNCC2O)CC1
Reactant: Fc1ccc(CBr)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)C1CCN(C2CCN(Cc3ccc(F)cc3)CC2O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.3 %

Procedure:
Into a solution of 13a (132 mg, 0.42 mmol) and triethylamine (17.1 mg, 1.69 mmol) in CH2Cl2 (15 mL), a solution of 4-fluorobenzyl bromide (80 mg, 0.42 mmol) in CH2Cl2(5 mL) was slowly added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water (20 mL×2) and brine solution (20 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatograph using triethylamine/ethyl acetate (1/50, v/v) as mobile phase to afford free base 14a as pale yellow oil (78.9 mg, 45%). 1H NMR (CDCl3): δ 1.53-2.04 (m, 9H), 2.20-2.32 (m, 2H), 2.71-2.76 (m, 2H), 2.91-3.01 (m, 2H), 3.17-3.22 (m, 2H), 3.51-3.63 (m, 3H), 6.96-7.02 (m, 2H), 7.10-7.17 (m, 2H), 7.23-7.27 (m, 2H), 7.93-7.98 (m, 2H). Free base was converted to the oxalate salt by dissolving it in acetone and mixing with 1 equivalent of oxalic acid in acetone. mp: 234° C. (decomposed). Anal. (C24H28F2N2O2.H2C2O4.0.25H2O) C, H, N.
Reaction SMILES: CC(OC([NH:8][CH:9]([CH3:36])[C:10]([NH:12][C:13]1[N:18]=[C:17]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=[O:31])=[CH:15][CH:14]=1)=[O:11])=O)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[NH2:8][CH:9]([CH3:36])[C:10]([NH:12][C:13]1[N:18]=[C:17]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=[O:31])=[CH:15][CH:14]=1)=[O:11]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(-c2cccc(C(=O)O)c2)c(C#Cc2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(N)C(=O)Nc1ccc(-c2cccc(C(=O)O)c2)c(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-[6-[2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoylamino]-2-(2-phenylethynyl)pyridin-3-yl]benzoic acid E2c (16 mg, 0.03 mmol) and DCM:TFA (9:1, 1.7 ml) is stirred at RT for 90 minutes. The mixture is diluted with toluene (10 ml) and concentrated in vacuo. The product is purified by RP HPLC. Yield: 3 mg (24%). HPLC-MS: M+H=386; tR=1.03 min (*Method—1).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.Cl.C[O-].[Na+].C(OCC)C>C(O)/C=C/CCC.C(O)(C)C>[OH:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1
Reactant: O=C1CN2CCC1CC2
Agent: CCC/C=C/CO
Agent: C[O-]
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: OC1CN2CCC1CC2
Temperature: 200 °C
Reaction time: 25 h
Yield: 92.8 %

Procedure:
A 100 ml autoclave ("Magnedrive II", Autoclave Engineers Europe) fitted with a hollow-shaft high-speed stirrer (Dispersimax®) was charged with 5.0 g of quinuclidin-3-one (prepared from the hydrochloride by reaction with sodium methoxide and extraction with diethyl ether), 45 ml of isopropyl alcohol and 0.25 g of catalyst (from Example 1), flushed with nitrogen and placed under a nitrogen pressure of 10 bar at room temperature. While stirring (1500 min-1), the mixture was heated to 200° C. and held at this temperature for 8 hours. The yield was determined as 97.3 percent by means of GC. Repeating the experiment using the same catalyst still gave a yield of 92.8 percent after a reaction time of 13 hours.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]([C:17]3[C:18]([CH3:34])=[C:19]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=[CH:21][CH:22]=3)[CH:12]([N+:14]([O-])=O)[CH3:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.O1CCCC1.C(OCC)(=O)C.[Zn]>[NH2:14][CH:12]([CH3:13])[CH:11]([C:17]1[C:18]([CH3:34])=[C:19]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:20]=[CH:21][CH:22]=1)[C:6]1[C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(c1c[nH]c2cc(Br)ccc12)C(C)[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1C(c1c[nH]c2cc(Br)ccc12)C(C)N
Yield: 94.9 %

Procedure:
A solution of benzyl (3-(1-(6-bromo-1H-indol-3-yl)-2-nitropropyl)-2-methylphenyl)carbamate (4.47 g, 8.56 mmol), ammonium chloride (6.87 g, 128 mmol), and zinc dust (8.40 g, 128 mmol) in methanol (100 mL) and tetrahydrofuran (100 mL) was stirred overnight under nitrogen. The reaction was diluted with ethyl acetate and filtered through a pad of CELITE®. The filtrate was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (150 mL), washed with saturated aqueous sodium bicarbonate (70 mL), and washed with brine (70 mL). The organic layer was collected, and the aqueous layers were sequentially extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give benzyl (3-(2-amino-1-(6-bromo-1H-indol-3-yl)propyl)-2-methylphenyl)carbamate (4.00 g, 8.12 mmol, 95% yield) as a light brown semi-solid and as a ˜1:1 diastereomers. LC/MS M+1=492.1 and 494.1.
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([N:11]1[CH:12]=[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:33][CH2:34][CH2:35][CH3:36])[N:9]=[C:10]1[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: BrCc1ccccc1
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Product: CCCCN(CCCC)C(=O)c1cn(Cc2ccccc2)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Yield: 77.4 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 271F, 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (200 mg, 0.40 mmol) and benzylbromide (83 mg, 0.48 mmol) were converted to the title compound (180 mg, 76%). 1H NMR (CDCl3) 8.68 (d, J=1.6 Hz, 1H), 8.15 (dd, J=8.0, 2.0 Hz, 1H), 7.43 (s, 1H), 7.39-7.34 (m, 4H), 7.28-7.26 (m, 2H), 7.21-7.17 (m, 3H), 6.90-6.88 (m, 2H), 5.15 (s, 2H), 4.64 (s, 2H), 3.96 (s, 3H), 3.90 (br s, 2H), 3.43 (br s, 2H), 1.70-1.59 (m, 4H), 1.37-1.23 (m, 4H), 0.93-0.82 (m, 6H); MS(ESI+) m/z 582.2 (M+H)+.
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)OCCN)(C)(C)C.N1C=CC=CC=1.[N+](C1C=C(CS(Cl)(=O)=O)C=CC=1)([O-])=O.[C:42]([Si:46]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[O:47][CH2:48][CH2:49][NH:50][S:51]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([N+:61]([O-])=O)[CH:56]=1)(=[O:53])=[O:52])([CH3:45])([CH3:44])[CH3:43]>ClCCl.CO.[Pd]>[NH2:61][C:57]1[CH:56]=[C:55]([CH2:54][S:51]([NH:50][CH2:49][CH2:48][O:47][Si:46]([C:42]([CH3:45])([CH3:44])[CH3:43])([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)(=[O:52])=[O:53])[CH:60]=[CH:59][CH:58]=1
Reactant: CC(C)(C)[Si](OCCNS(=O)(=O)Cc1cccc([N+](=O)[O-])c1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[Si](OCCN)(c1ccccc1)c1ccccc1
Agent: O=[N+]([O-])c1cccc(CS(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)(C)[Si](OCCNS(=O)(=O)Cc1cccc(N)c1)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(tert-butyldiphenyl-silanyloxy)-ethylamine (0.76 g, 2.54 mmol) in dichloromethane (15 ml) and pyridine (0.21 ml, 2.54 mmol) at room temperature was added 3-nitro-alpha-toluenesulfonyl chloride (0.50 g, 2.12 mmol) in one portion and the reaction stirred overnight. The reaction was diluted with dichloromethane (35 ml), washed with aqueous copper sulfate and brine, dried over sodium sulfate and concentrated to give a crude product. The crude N-[2-(tert-butyldiphenyl-silanyloxy)-ethyl]-C-(3-nitrophenyl)-methanesulfonamide (theoretical 1.06 g, 2.13 mmol) was dissolved in methanol (30 ml) and placed under an atmosphere of nitrogen prior to the addition of 10% Pd/C (10 Wt %, 100 mg) in one portion. The reaction mixture was evacuated, placed under an atmosphere of hydrogen (1 bar) and stirred vigorously overnight. The reaction was filtered through celite and the filtrate was concentrated in vacuo to afford the crude reduced product. The crude C-(3-aminophenyl)-N-[2-(tert-butyldiphenylsilanyloxy)-ethyl]methanesulfonamide obtained above (theoretical 0.996 g) was dissolved in tetrahydrofuran (20 ml) and a 1M solution of tetrabutlyammonium fluoride in tetrahydrofuran (2.34 ml, 2.34 mmol) was added in one portion. The reaction was stirred at room temperature for 2 h then diluted with ethyl acetate (30 ml) and brine (30 ml), the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by column chromatography using dichloromethane:methanol as eluent to give the named product (0.411 g, 84% over 3 steps); Rf (DCM:MeOH 95:5) 0.06; LCMS Rt=0.83 min, m/z (ES−) 229 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH:11]1[C:23]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:19]2[CH:18]=[CH:17][C:16]3[C:15]4[C:23](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:22][C:21]=3[CH:20]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)Cc1ccccc1-2

Procedure:
p-Chlorobenzoyl chloride (43.8 g.) was added dropwise to a stirred mixture of fluorene (41.5 g.) aluminium chloride (33.4 g.) and carbon disulphide (100 ml.). After the vigorous reaction had subsided the mixture was stirred and boiled under reflux for 6 hours. It was cooled, poured onto ice, the carbon disulphide distilled off on a steam bath, and the solid product filtered off, washed, dried and recrystallised from benzene to give 2 -p-chlorobenzoylfluorene, m.p. 183°C. This was reacted by the method of Example 1 to give trans-1-(2-fluorenyl)-1-p-chlorophenyl3-dimethylaminoprop-1-ene, hydrochloride from ethanol, m.p. 236°-237°C. Isomeric homogeneity was confirmed by n.m.r. spectroscopy.