Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]1[CH2:8][C@@H:7](O)[CH2:6][N:5]1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(S(F)(F)[F:25])CC)C.N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]1[CH2:8][C@H:7]([F:25])[CH2:6][N:5]1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](F)CN1C(=O)c1ccccc1
Temperature: -45 °C
Yield: 64 %

Procedure:
A solution of (trans)-1-benzoyl-4-hydroxy-L-proline methyl ester prepared as described in Example 1 Part A(2) (6 g, 24.1 mmole) was dissolved in dichloromethane and cooled to -45° C. under an argon atmosphere. To the above solution diethylaminosulfur trifluoride (5.2 ml, 42 mmole) was added dropwise. The resulting solution was stirred and warmed to -35° C. To the above solution pyridine was added dropwise (9 ml, 116 mmole). The reaction was allowed to stir overnight while warming to room temperature. The solvent was removed in vacuo and the oily residue treated with ethyl acetate and 1N HCl. The mixture was transferred to a separatory funnel, the aqueous layer removed, and the organic layer washed with additional 1N HCl, then water and saturated sodium bicarbonate solution. The organic solution was dried over sodium sulfate, filtered and concentrated to a yellow oil. The crude product was chromatographed on silica gel using 1:1 ethyl acetate:hexane as eluent. Combination and concentration of product containing fractions produced 3.9 gm (64%) of title compound as an oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O.[O-]CC.[Na+]>C(O)C>[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][O:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:1][C:2]([C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)=[O:3])[CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=Cc1cccc(OCc2ccc3ccccc3n2)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(C=Cc1cccc(OCc2ccc3ccccc3n2)c1)c1ccc(O)cc1

Procedure:
4-Hydroxy acetophenone (0.01 mol) in ethanol (100 ml) is added dropwise to a 0° C. mixture of 3-(2-quinolinylmethyloxy)benzaldehyde (0.01 mol) and sodium ethoxide (0.00 mol) in ethanol (200 ml). The reaction mixture is allowed to thaw to ambient temperature and after several hours it is evaporated and partitioned between ethyl acetate and water. The ethyl acetate fraction is dried and evaporated to give 4-(3-(3-(2-quinolinylmethyloxy)phenyl)-1-oxo-2-propen-1-yl)-phenol.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([O:18]C)=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>>[CH:1]1([CH2:7][CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[CH:1]1([CH2:7][CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([O-:18])=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2CC1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc2c([nH]1)CCC2CC1CCCCC1
Product: O=C([O-])c1cc2c([nH]1)CCC2CC1CCCCC1
Yield: 21 %

Procedure:
The title compound was synthesized from methyl 4-(cyclohexylmethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate and lithium hydroxide monohydrate according to General Procedure 7. The crude product was dried onto silica gel and purified by chromatography (0 to 100% EtOAc/heptane) to give 4-(cyclohexylmethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate as a brown solid (0.018 g, 21%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.87-1.02 (m, 2H) 1.14-1.36 (m, 5H) 1.36-1.54 (m, 2H) 1.63-1.80 (m, 3H) 1.83-2.00 (m, 2H) 2.50-2.77 (m, 3H) 2.97-3.09 (m, 1H) 6.59 (s, 1H). LCMS m/e 248 (M+H). 97.5% pure by HPLC.
Reaction SMILES: [I-:1].[Na+].C(N(C(C)C)CC)(C)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([N:21]2[CH2:26][CH2:25][CH2:24]/[C:23](=[CH:27]\[C:28]3[CH:33]=[CH:32][C:31]([N:34]4[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]4)=[C:30]([O:40][CH3:41])[CH:29]=3)/[C:22]2=[O:42])[CH3:20])=[CH:15][CH:14]=1.[C:43]([O:46][CH2:47]Cl)(=[O:45])[CH3:44]>COCCOC>[I-:1].[C:43]([O:46][CH2:47][N+:36]1[C:37]([CH3:39])=[CH:38][N:34]([C:31]2[CH:32]=[CH:33][C:28](/[CH:27]=[C:23]3/[C:22](=[O:42])[N:21]([C@H:19]([C:16]4[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=4)[CH3:20])[CH2:26][CH2:25][CH2:24]/3)=[CH:29][C:30]=2[O:40][CH3:41])[CH:35]=1)(=[O:45])[CH3:44]
Reactant: COc1cc(/C=C2\CCCN([C@@H](C)c3ccc(F)cc3)C2=O)ccc1-n1cnc(C)c1
Reactant: CC(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: COc1cc(/C=C2\CCCN([C@@H](C)c3ccc(F)cc3)C2=O)ccc1-n1cc(C)[n+](COC(C)=O)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Sodium iodide (54 mg) and IPEA (0.05 mL) were added to a DME solution (2 mL) of (E)-1-[(1S)-1-(4-fluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one (CAS Registry No. 870843-42-8, 100 mg) and chloromethyl acetate (0.03 mL), and the resulting reaction solution was stirred at 80° C. for 1 hr. The reaction solution was allowed to cool to room temperature, and the precipitated solid was collected by filtration. The obtained solid was washed with diethylether and dried in air to give 70 mg of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][CH2:6][C@@:7]1([OH:31])[C:12](=[O:13])[O:11][CH2:10][C:9]2[C:14]([N:16]3[C:28](=[CH:29][C:8]1=2)[C:27]1[N:26]=[C:25]2[C:20]([C:21](N)=[CH:22][CH:23]=[CH:24]2)=[CH:19][C:18]=1[CH2:17]3)=[O:15].[BrH:32]>O>[CH3:5][CH2:6][C@@:7]1([OH:31])[C:12](=[O:13])[O:11][CH2:10][C:9]2[C:14]([N:16]3[C:28](=[CH:29][C:8]1=2)[C:27]1[N:26]=[C:25]2[C:20](=[CH:19][C:18]=1[CH2:17]3)[C:21]([Br:32])=[CH:22][CH:23]=[CH:24]2)=[O:15]
Reactant: Br
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(N)cccc3nc2-1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(Br)cccc3nc2-1
Reaction time: 2 h
Yield: 97.3 %

Procedure:
2.15 g of NaNO2 in 40 mL of H2O were dropped at 5° C. into a solution of 9 g of 9-amino-camptothecin in 850 mL of 16% HBr. After 1 hr at room temperature the solution was dropped in a flask containing 19 g of CuBr in 200 mL of 16% HBr at 70° C. The reaction mixture was kept at 70° C. for 2 hrs, then it was poured into cold water. The precipitate was filtered and the mother liquors were extracted with CH2Cl2; the organic extract, dried and evaporated, was combined with the precipitate and purified by flash chromatography (eluent:CH2Cl2/CH3OH=95/5) to give 8.19 g of the title product (HPLC assay:97.3%).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][NH:23]C(OC(C)(C)C)=O)[C:14]([C:31]3[CH:35]=[CH:34][O:33][CH:32]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C(Cl)[Cl:44]>>[ClH:44].[NH2:23][CH2:22][CH2:21][NH:20][C:15]1[C:14]([C:31]2[CH:35]=[CH:34][O:33][CH:32]=2)=[CH:13][CH:12]=[C:11]([CH2:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:16]=1[C:17]([OH:19])=[O:18]
Reactant: CC(C)(C)OC(=O)NCCNc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NCCNc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O

Procedure:
6-(Benzenesulphonylmethyl)-2-[2-(t-butoxycarbonylamino)ethylamino]-3-(furan-3-yl)benzoic acid (Intermediate 121, 0.1 g) was added to a solution of trifluoroacetic acid (3 ml) in DCM (3 ml) and the resultant mixture was stirred for 45 minutes. The mixture was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of DCM:MeOH:AcOH:water (120:15:3:2). The volume of the product containing fractions was reduced to 5 mL, concentrated HCl (1 ml) was added and the mixture was evaporated to dryness. The solid was triturated with diethyl ether, collected by filteration and dried at 60° C. under vacuum to give 2-(2-aminoethylamino)-6-(benzenesulphonylmethyl)-3-(furan-3-yl)benzoic acid hydrochloride (0.056 g), as a white solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:5].[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.C(C1C=CC=CC=1)(=O)C>O.C(O)C>[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH:3][C:4]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=2)=[O:5])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)c1ccccc1
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1ccc(Br)cc1)c1ccc(Br)cc1
Reaction time: 8 h
Yield: 97 %

Procedure:
Sodium hydroxide (1.8 g, 45 mmol) and 4-bromoacetophenone (7.12 g, 36 mmol) were dissolved in water (18 mL) and ethanol (50 mL). 4-Bromo benzaldehyde (6.62 g, 36 mmol) dissolved in ethanol (20 mL) was added dropwise to the acetophenone solution. A slurry quickly formed, which was allowed to stir overnight. The slurry was filtered, was with water until the filtrate was neutral to pH paper, and dried at 100° C. for 12 hours. A light tan solid was obtained (12.8 g, 97% yield).
Reaction SMILES: C([C:3]1[C:4](Cl)=[N:5][CH:6]=[CH:7][CH:8]=1)#N.CB(O)[OH:12].[C:14]([O-])([O-])=[O:15].[K+].[K+]>O1CCOCC1.C(Cl)Cl.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>[N+:5]1([O-:12])[C:4]([CH:14]=[O:15])=[CH:3][CH:8]=[CH:7][CH:6]=1
Reactant: CB(O)O
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=Cc1cccc[n+]1[O-]
Temperature: 25 °C
Yield: 44.2 %

Procedure:
To a mixture of 3-cyano-2-chloro-pyridine (422 mg, 3.05 mmol), methylboronic acid (209 mg, 3.49 mmol) and K2CO3 (1.22 g, 8.83 mmol) in degassed dioxane (5 mL) under argon was added Pd(PPh3)4 (222 mg, 0.19 mmol) and the mixture stirred at reflux over the weekend. The reaction was cooled to room temperature, diluted with CH2Cl2 (20 mL) and filtered through Celite, washing the cake with CH2Cl2 and MeOH. The filtrate was concentrated in vacuo and purified by column chromatography on silica gel (Hexanes/ethyl acetate, 9:1 then 4:1) to afford the desired product (166 mg, 46%) as a white solid. 1H NMR (CDCl3): δ2.78 (s, 3H), 7.25 (dd, 1H, J=9, 6 Hz), 7.90 (dd, 1H, J=6, 3 Hz), 8.69 (d, 1H, J=3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[NH:25]1[CH2:29][CH:28]=[CH:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:25]1[CH2:29][CH:28]=[CH:27][CH2:26]1)=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: C1=CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CC=CC2)c(Cl)c1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide and 2,5-dihydropyrrole, TBTU, and triethylamine in DMSO.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26]CC=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[CH3:30][NH:31][CH2:32][C:33](O)=O.[C:36]([OH:39])(=[O:38])[CH3:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:33][CH2:32][N:31]([CH3:30])[CH2:37][C:36]([OH:39])=[O:38])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(=O)O
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC=O)c[nH]c34)no2)cc1Cl
Reactant: CNCC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCCN(C)CC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanal (D92) (100 mg), N-methylglycine (43 mg) and acetic acid (0.1 mL) in DCM (15 mL) was added sodium triacetoxyborohydride (103 mg). The reaction was stirred at 40° C. for 3 h. The mixture was cooled to room temperature and partitioned between DCM (25 mL) and water (25 mL). The organic phase was washed with water (25 mL), dried over anhydrous sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford N-{3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propyl}-N-methylglycine (E71) (80 mg, TFA salt). δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 2.08 (2H, m), 2.80 (2H, t), 2.82 (3H, s), 3.18 (2H, t), 4.07 (2H, s), 4.89 (1H, m), 7.23 (1H, t), 7.33 (1H, t), 7.45 (1H, d), 7.84 (1H, d), 7.96 (1H, d), 8.36 (1H, d), 10.87 (1H, s). MS (ES): C26H27ClN4O4 requires 482; found 483.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([NH:14][C:15]3[CH:16]=[C:17]([CH:36]=[CH:37][CH:38]=3)[O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([NH:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][CH2:33]CC4)=[O:26])[CH:20]=3)=[O:13])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.NCCN1CCCCC1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([NH:14][C:15]3[CH:16]=[C:17]([CH:36]=[CH:37][CH:38]=3)[O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([NH:27][C:28]4[CH:29]=[N:30][CH:35]=[CH:34][CH:33]=4)=[O:26])[CH:20]=3)=[O:13])=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: Cn1ncc2cc(NC(=O)Nc3cccc(Oc4ccnc(C(=O)NCCN5CCCCC5)c4)c3)ccc21
Agent: NCCN1CCCCC1
Product: Cn1ncc2cc(NC(=O)Nc3cccc(Oc4ccnc(C(=O)Nc5cccnc5)c4)c3)ccc21

Procedure:
The title compound was prepared in the same manner described for 4-[3-({[(1-methyl-1H-indazol-5-yl)amino]carbonyl}-amino)phenoxy]-N-(2-piperidin-1-ylethyl)pyridine-2-carbox-amide, substituting 3-aminopyridine for 1-(2-aminoethyl)piperidine. 1H-NMR (DMSO-d6) δ 10.39 (s, 1H), 8.93 (s, 1H), 8.72 (s, 1H), 8.63 (d, J=5.4 Hz, 1H), 8.38 to 8.36 (m, 1H), 8.19 (d, J=8.4 Hz, 1H), 7.91 to 7.86 (m, 3H), 7.85 to 7.51 (m, 3H), 7.42 (t, J=2.1 Hz, 1H), 7.52 to 7.17 (m, 4H), 6.85 (dd, J=2.4, 1.5 Hz, 1H), 3.98 (s, 3H); MS LC-MS (M+H)+=480.1, RT=2.81 min.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Mg]Br)=[CH:3][CH:2]=1.Br[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([CH3:34])[CH:15]2[Si:20]([CH:23]1[C:31]2[C:26](=[C:27](Br)[CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1[CH3:33])([CH3:22])[CH3:21]>C1COCC1.[Cl-].[Cl-].[Zn+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[C:14]([CH3:34])[CH:15]3[Si:20]([CH:23]2[C:31]3[C:26](=[C:27]([C:4]4[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=4)[CH:28]=[CH:29][CH:30]=3)[CH:25]=[C:24]2[CH3:33])([CH3:22])[CH3:21])=[CH:3][CH:2]=1
Reactant: CC1=Cc2c(Br)cccc2C1[Si](C)(C)C1C(C)=Cc2c(Br)cccc21
Reactant: Cc1ccc([Mg]Br)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC1=Cc2c(-c3ccc(C)cc3)cccc2C1[Si](C)(C)C1C(C)=Cc2c(-c3ccc(C)cc3)cccc21
Reaction time: 1 h

Procedure:
In an argon atmosphere, to a solution of 15 mL of THF with 34.0 ml of 0.5 M ZnCl2 (17.0 mmol) in THF, 15.2 ml of 1.0 M p-tolylmagnesium bromide (15.2 mmol) in THF was added at ambient temperature. This mixture was stirred for 1 hour, and, then, 11.7 ml of 0.02 M Pd(PtBu3)2 (0.23 mmol, 4 mol. %) in THF and 2.78 g (5.86 mmol) of 1 were added. The resulting mixture was stirred for 5 hours at reflux. The product was isolated by flash chromatography on Silica Gel 60 (40-63 μm, d 30 mm, l 100 mm; eluent: hexanes). Yield 2.79 g (96%) of white solid of ca. 1 to 1 mixture of rac- and meso-compounds.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[C:23]([O:24][CH3:25])=[CH:22][C:21]([CH3:26])=[CH:20][C:19]=3[O:27][CH3:28])[N:17]=2)[C:9]([CH3:12])=[CH:10][CH:11]=1.S(O[CH:37]([CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)[CH3:38])(C(F)(F)F)(=O)=O.O>CCCCCC>[CH:39]1([CH2:37][CH2:38][C:15]2[S:14][C:13]([N:8]3[C:7]([CH3:6])=[CH:11][CH:10]=[C:9]3[CH3:12])=[N:17][C:16]=2[C:18]2[C:23]([O:24][CH3:25])=[CH:22][C:21]([CH3:26])=[CH:20][C:19]=2[O:27][CH3:28])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: COc1cc(C)cc(OC)c1-c1csc(-n2c(C)ccc2C)n1
Reactant: CC(OS(=O)(=O)C(F)(F)F)C1CCCCC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: COc1cc(C)cc(OC)c1-c1nc(-n2c(C)ccc2C)sc1CCC1CCCCC1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 9.1 %

Procedure:
10 ml of 1.6M n-butyllithium in hexane are added, at −30° C., to 4.27 g of 2-(2,5-dimethylpyrrol-1-yl)-4-(2,6-dimethoxy-4-methylphenyl) thiazole and the mixture is left stirring for 30 minutes at −30° C. 4.2 g of cyclohexylethanol triflate are added at −45° C., the mixture is then warmed to 0° C., water is added, this mixture is extracted with Et2O and the extracts are dried and evaporated. The gum formed is chromatographed on silica, eluting with cyclohexane/EtOAc (1/1; v/v). 0.52 g of the expected compound is obtained in the form of a colourless gum.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:15][C@@H:14]2[C@@H:9]([CH2:10][CH2:11][C@H:12]([CH2:16][N:17]3[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:19]=[CH:18]3)[CH2:13]2)[CH2:8][N:7]1C(OC)=O)=[O:5])[CH3:2].I[Si](C)(C)C.ClCCl>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:15][C@@H:14]2[C@@H:9]([CH2:10][CH2:11][C@H:12]([CH2:16][N:17]3[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:19]=[CH:18]3)[CH2:13]2)[CH2:8][NH:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncn(C[C@H]2CC[C@H]3CN(C(=O)OC)[C@H](C(=O)OCC)C[C@H]3C2)c1C(=O)OCC
Agent: C[Si](C)(C)I
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOC(=O)c1ncn(C[C@H]2CC[C@H]3CN[C@H](C(=O)OCC)C[C@H]3C2)c1C(=O)OCC
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
A solution of [3S,4aR,6S,8aR]-ethyl-6-((4,5-bis-ethoxycarbonyl-1H-imidazol-1-yl)methyl)-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate (10.55 g, 0.02138 mol), iodotrimethylsilane (21.39 g, 0.1069 mol), and dichloromethane (428 mL) was stirred for 16 hours at ambient temperature until complete as determined by tic (ethyl acetate/hexane, 2:1). The reaction mixture was concentrated to approximately 200 mL, ethanol (100 mL) was added and the resulting solution concentrated to a yellow foam. The residue was dissolved in methanol (190 mL) and stirred for 30 minutes with Amberlyst 15 resin (50 g). The resin was filtered and washed with methanol (100 mL). The product was eluted from the Amberlyst resin with 2N ammonia in methanol (2×100 mL). The filtrate was concentrated to an oil. The residue was purified by Biotage Flash 40M (dichloromethane/methanol, 19:1) to give 4.72 g of the free base of the final title compound, [3S,4aR,6S,8aR]-ethyl-6-((4,5-bis-ethoxycarbonyl-1H-imidazol-1-yl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][CH2:13][C:12]([C:16]([O-:18])=[O:17])=[CH:11][C:10]=2[CH:19]=1.[OH-].[Na+].Cl>CO.C1COCC1>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][CH2:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=2[CH:19]=1
Reactant: O=C([O-])C1=Cc2cc(OCc3c(F)cccc3F)ccc2CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1=Cc2cc(OCc3c(F)cccc3F)ccc2CCC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 96.5 %

Procedure:
To 2-(2,6-difluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (486 mg, 1.41 mmol) dissolved in a mixed solvent of methanol (7 ml) and THF (7 ml) was added a 1N aqueous solution of sodium hydroxide (4.4 ml), and the resulting mixture was stirred at 50° C. for 6 hours. The reaction mixture was mixed with 1 N hydrochloric acid (4.4 ml) at 0° C., was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was washed with water and was dried under reduced pressure to obtain 2-(2,6-difluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (450 mg, 1.36 mmol, 97%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22](Cl)[C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1)[CH3:11].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([SH:36])=[CH:32][CH:31]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([S:36][C:33]2[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)[C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: COC(=O)C(Cl)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Reactant: COc1ccc(S)cc1
Product: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)Sc1ccc(OC)cc1

Procedure:
The title compound was prepared as a gum from methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-chloropropanoate and 4-methoxythiophenol by a procedure similar to that described in Example 23.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)(=[O:12])=[O:11])[C:8](=[O:21])[N:7]([CH:22]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:23]([NH:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:24])[C:6]=2[CH:40]=1.C=O.[C:43](O[BH-](OC(=O)C)OC(=O)C)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)(=[O:11])=[O:12])[C:8](=[O:21])[N:7]([CH:22]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:23]([NH:25][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][N:31]([CH3:43])[CH2:32][CH2:33]3)=[O:24])[C:6]=2[CH:40]=1
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)NCCN3CCNCC3)c3ccccc3)c3cc(Cl)ccc32)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)NCCN3CCN(C)CC3)c3ccccc3)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 98.0 mg (0.17 mmol) 2-[6-chloro-3-(4-methoxybenzenesulfonyl)-2-oxo-2,3-dihydrobenzimidazol-1-yl]-2-phenyl-N-(2-piperazin-1-yl-ethyl)acetamide (Example 131) in 4 ml of THF was mixed with 5.54 mg (0.19 mmol) of paraformaldehyde and 170 mg of MP-triacetoxyborohydride resin (Argonaut, 2.55 mmol/g, 0.42 mmol) and shaken at room temperature overnight. The solid phase reagent was filtered off and washed with dichloromethane. The filtrate was concentrated under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH2:15][O:16][S:18]([CH3:17])(=[O:20])=[O:19])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(Br)cc(COS(C)(=O)=O)c1
Reaction time: 16 h

Procedure:
To a DCM (20 mL) solution of tert-butyl 3-bromo-5-(hydroxymethyl)benzoate (1.2 g, 4.2 mmol) was added methanesulfonyl chloride (0.62 g, 5.5 mmol) and triethylamine (1.2 mL, 8.4 mmol) at 0° C. The mixture was allowed to stir for 16 hours. TLC showed clean conversion. The reaction was diluted with DCM (100 mL), washed with 0.1 N HCl (100 mL) and brine, dried over sodium sulfate, and concentrated to afford tert-butyl 3-bromo-5-{[(methylsulfonyl)oxy]methyl}benzoate as a light yellow oil, which was used without further purification.