Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1([C:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[Br:1][C:16]1[NH:17][C:18]2[C:23]([C:15]=1[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)=[CH:22][CH:21]=[C:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:19]=2
Reactant: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Reactant: O=C1CCC(=O)N1Br
Product: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Temperature: 25 °C
Yield: 57 %

Procedure:
N-bromosuccinimide (1.1 eq) was added portionwise over 1 h to tert-butyl 3-cyclohexyl-1H-indole-6-carboxylate in CCl4 (from Step 4, 0.07 M) with vigorous stirring. The reaction was stirred at RT for a further hour following complete addition of NBS. The CCl4 was then removed in vacuo and the residue taken up in EtOAc. The organics were washed with a saturated aqueous solution of sodium thiosulfate (twice), brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification was by flash chromatography (5-20% EtOAc/PE gradient) to yield the title compound (57%); MS (ES+) m/z 380 (M+H)+, 378 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:24]([O:23][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:14]#[C:13][CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:16][CH:17]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)c1ccc(C#CC2CCCN2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(C#CC2CCCN2)cc1
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a stirred solution of 1-(tert-butoxycarbonyl)-2-[2-(4-ethoxycarbonylphenyl)ethynyl]pyrrolidine (2.75 g, 8 mmol) in CH2Cl2 (5 ml) was added TFA (5 mL), and the resulting mixture was stirred overnight. The mixture was concentrated in vacuo and made basic with sat. NaHCO3 and extracted with CHCl3. The extract was washed with brine, dried over MgSO4, evaporated to give 1.95 g (q.y.) 2-[2-(4-ethoxycarbonylphenyl)ethynyl]pyrrolidine as a light yellow oil. 1H-NMR (CDCl3) δ1.38 (3 H, t, J=6.8 Hz), 1.82-2.16 (4 H, m), 3.01-3.48 (2 H, m), 4.00-4.11 (1 H, m), 4.37 (2H, q, J=6.8 Hz), 4.54-4.77 (1 H, m), 7.44-7.46 (2 H, m), 7.95-7.97 (2 H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]3[CH:23]=[C:22](I)[N:21]=[CH:20]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]3[CH:23]=[C:22]([C:29]4[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=4)[N:21]=[CH:20]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1F
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 4-(3,4-difluoro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.78) (0.45 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.26 g, 1.2 mmol) according to the general procedure VI. Obtained as a yellow solid (0.036 g, 9%). MS (ISP) 419.1 [(M+H)+]; mp 232° C.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:13][C:14]1[C:18]([CH2:19]Cl)=[CH:17][O:16][CH:15]=1>CN(C)C=O>[C:1]([N:9]1[CH2:13][C:14]2=[CH:15][O:16][CH:17]=[C:18]2[CH2:19]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccccc1
Reactant: ClCc1cocc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1Cc2cocc2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of benzamide (1.38 g) in N,N-dimethylformamide (40 mL) at 0° C., sodium hydride (1.37 g, 60%) was added. The mixture was stirred at ambient temperature for 10 min followed by addition of 3,4-bis(chloromethyl)furan (1.88 g). The resulting mixture was stirred for two days, diluted with ice-water (50 mL) and extracted with ethyl acetate (3×20 mL). The combine organic layers were dried over anhydrous sodium sulfate, filtered and evaporated and purified on a Biotage Horizon® system (silica, ethyl acetate/hexane 40/60) to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C(C)C)=O.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[O:17]
Reactant: Nc1ccccn1
Reactant: CC(C)OC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O

Procedure:
A mixture of 74.3 g (0.25 mol) of isopropyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide and 25.7 g (0.32 mol) of 2-aminopyridine in 2,700 ml of xylene is maintained under reflux for 20 hours. During this time, approximately one third of the solvent is distilled off and is replaced, and finally the mixture is distilled to a final volume of 1,500 ml. The mixture is cooled to 0°-5° C. and filtered and the product washed with xylene. By crystallization with dichloroethane, 63 g (75%) of a crystalline white product, m.p. 198°-200° C. are obtained.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:59])[CH2:24][CH2:25][CH2:26][NH:27][C:28]1[C:40]2[C:39]3[C:34](=[CH:35][C:36]([C:41]([O:43][CH3:44])=[O:42])=[CH:37][CH:38]=3)[NH:33][C:32]=2[N:31]=[C:30]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52](=[N:57][OH:58])[C:53]([F:56])([F:55])[F:54])[CH:47]=2)[N:29]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:59])[CH2:24][CH2:25][CH2:26][NH:27][C:28]1[C:40]2[C:39]3[C:34](=[CH:35][C:36]([C:41]([O:43][CH3:44])=[O:42])=[CH:37][CH:38]=3)[NH:33][C:32]=2[N:31]=[C:30]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52](=[N:57][O:58][S:1]([C:4]3[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=3)(=[O:3])=[O:2])[C:53]([F:54])([F:56])[F:55])[CH:47]=2)[N:29]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=NO)C(F)(F)F)c3)nc(NCCCN(C)CCCNC(=O)OC(C)(C)C)c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=NOS(=O)(=O)c4ccc(C)cc4)C(F)(F)F)c3)nc(NCCCN(C)CCCNC(=O)OC(C)(C)C)c12
Reaction time: 1 h
Yield: 95.9 %

Procedure:
Ts-Cl (0.060 g, 0.315 mmol) was added portion-wise to a mixture of methyl 4-((3-((3-((tert-butoxycarbonyl)amino)propyl)(methyl)amino)propyl)amino)-2-(3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (0.184 g, 0.274 mmol), DMAP (3.35 mg, 0.027 mmol) and triethylamine (0.048 mL, 0.342 mmol) in DCM (12 mL) to give a tan solution. After 1 hour, the reaction mixture was diluted with DCM (12 mL), washed with water (3×12 mL) and the organic layer was dried over anh. MgSO4, filtered and concentrated to dryness to afford methyl 4-((3-((3-((tert-butoxycarbonyl)amino)propyl)(methyl)amino)propyl)amino)-2-(3-(2,2,2-trifluoro-1-((tosyloxy)imino)ethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (217 mg, 96% yield) as a tan foam: MS m/z 826.2 (M+H)+; HPLC 93.2% @ 220 nm and 91.3% @ 254 nm, RT=2.20 minutes.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[N:21]=[C:20]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH3:28])[CH:27]=3)[C:19]3[C:14](=[CH:15][C:16]([O:29]C)=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].B(Br)(Br)Br>ClC(Cl)C.ClCCl>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[N:21]=[C:20]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH3:28])[CH:27]=3)[C:19]3[C:14](=[CH:15][C:16]([OH:29])=[CH:17][CH:18]=3)[N:13]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(Nc3cc(C)n[nH]3)nc(Sc3ccc(NC(C)=O)cc3)nc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)c3ccc(O)cc3n2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A solution of [2-(4-acetamidophenylsulfanyl)-7-methoxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (23 mg, 5.54.10−5 mol) in dichloroethane (3 mL) is treated with 1M BBr3 in dichloromethane (222 μL, 2.21.10−4 mol). The mixture 1s heated at 80° C. for 4 hours before 1M BBr3 in DCM (222 μL, 2.21.10−4 mol) is added. The reaction mixture is heated at 80° C. for a further 3 hours. The solvent is evaporated and methanol is added to the residue to quench residual BBr3. The solvent is evaporated in vacuo and this operation repeated 3 times. 1M HCl (2 mL) is added to the solid residue and the suspension stirred at room temperature for 15 hours. The solid is collected by filtration and suspended in a mixture water/EtOH (3/1, 8 mL). The mixture is neutralized with NaHCO3 and stirred for 2 hours at room temperature. The solid is then collected by filtration, rinsed with water and diethyl ether to give the desired [2-(4-acetamidophenylsulfanyl)-7-hydroxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31]O)[CH3:28]>>[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][O:21][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16](/[CH:15]=[C:14](/[C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=3[CH:7]=2)\[CH3:25])=[CH:17][CH:18]=1)[CH3:28]
Reactant: CCN(CC)CCO
Reactant: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CCN(CC)CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner analogous to that described in Example 11, from p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid and 2-diethylamino-ethanol there can be obtained p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid 2-diethylamino-ethyl ester of melting point 65°-66° C.
Reaction SMILES: C(O)C.[C:4]([O:8][C:9](=[O:39])[CH2:10][C@@:11]1([C:27]([O:29]CC2C=CC(OC)=CC=2)=[O:28])[C@H:15]([CH3:16])[CH2:14][N:13](C(OCC2C=CC=CC=2)=O)[CH2:12]1)([CH3:7])([CH3:6])[CH3:5]>[Pd].O>[C:4]([O:8][C:9](=[O:39])[CH2:10][C@@:11]1([C:27]([OH:29])=[O:28])[C@H:15]([CH3:16])[CH2:14][NH:13][CH2:12]1)([CH3:5])([CH3:6])[CH3:7]
Reactant: COc1ccc(COC(=O)[C@@]2(CC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)C[C@H]2C)cc1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: C[C@@H]1CNC[C@]1(CC(=O)OC(C)(C)C)C(=O)O
Reaction time: 0.08 h
Yield: 95.9 %

Procedure:
Ethanol (50 ml) and 10% Pd/C (500 mg) were added to 1-benzyl 3-(4-methoxyphenyl)methyl (3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-1,3-dicarboxylate obtained in Example 2i (2.92 g, 5.87 mmol), followed by stirring at mom temperature for 38 hours and five minutes under a hydrogen atmosphere. Water (100 ml) was added to the reaction liquid, which was stirred and filtered. The filtrate was concentrated to give the title compound (1.37 g, yield: 95.9%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[OH:11][C:4]1[CH:3]=[C:2]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)[CH:7]=[CH:6][C:5]=1[C:8](=[O:10])[CH3:9]
Reactant: CN1CCNCC1
Reactant: CC(=O)c1ccc(F)cc1O
Product: CC(=O)c1ccc(N2CCN(C)CC2)cc1O

Procedure:
1-(4-Fluoro-2-hydroxy-phenyl)-ethanone (4.5 g, 29.22 mmol) was treated with N-methylpiperazine (5 mL) at 130° C. for 3 h to give 1-[2-hydroxy-4-(4-methyl-piperazin-1-yl)-phenyl]-ethanone in quantitative yield.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C:14]([CH:16]1[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH:17]1[NH:23][C:24](=[O:26])[CH3:25])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:4].O.[Li+].[OH-]>O1CCOCC1>[C:24]([NH:23][CH:17]1[CH2:18][CH:19]([CH3:22])[CH2:20][CH2:21][CH:16]1[C:14]([N:10]([CH:11]([CH3:13])[CH3:12])[C:9]1[CH:8]=[C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])=[O:15])(=[O:26])[CH3:25]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1NC(C)=O)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)NC1CC(C)CCC1C(=O)N(c1cc(-c2ccccc2)sc1C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 89.2 %

Procedure:
3-[(2-Acetylamino-4-methyl-cyclohexanecarbonyl)-isopropyl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (8.5 mg, 0.019 mmol) was dissolved in a 4:1 mixture of dioxane:H2O (250 ul) and then LiOH 1N (22 ul, 0.023 mmol) was added. After 22 hours of stirring at room temperature, solvents were removed and then partitioned between 5 ml of H2O acidified to pH 4 and 5 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×5 mL). The combined ethyl acetate layer was dried (Na2SO4) and concentrated to give 7.5 mg (91%) of 3-[(2-Acetylamino-4-methyl-cyclohexanecarbonyl)-isopropyl-amino]-5-phenyl-thiophene-2-carboxylic acid (Compound 12).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:20])=[O:19])[CH2:14][CH2:13]1)C1C=CC=CC=1.CO.[H][H]>[OH-].[Pd+2].[OH-].O1CCCC1>[C:23]1([CH2:22][CH2:21][S:18]([N:15]2[CH2:14][CH2:13][CH:12]([CH2:11][NH2:10])[CH2:17][CH2:16]2)(=[O:19])=[O:20])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: [H][H]
Reactant: O=C(NCC1CCN(S(=O)(=O)C=Cc2ccccc2)CC1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1

Procedure:
A mixture of [1-(2-phenyl-ethenesulfonyl)-piperidin-4-ylmethyl]-carbamic acid benzyl ester (2.5 g), 20% palladium hydroxide (1 g) on carbon, 200 mL of methanol and 50 mL of tetrahydrofuran were shaken under 50 psi of hydrogen for 2 days at room temperature. The catalyst was filtered off and washed with 250 mL of methanol. Concentration under reduced pressure gave C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine as white solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.Br[CH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18]>C(O)C>[N:7]1([CH2:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[CH:17]=[O:18])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1CCNC1
Reactant: O=Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=Cc1cccc(CN2CCCC2)c1
Temperature: 65 °C
Yield: 88.5 %

Procedure:
A suspension of K2CO3 (2.09 g, 15.2 mmol, 3.00 equiv) in absolute ethanol (20 mL) was treated with pyrrolidine (439 μL, 5.05 mmol, 1.00 equiv). 3-(bromomethyl)-benzaldehyde (1.00 g, 5.05 mmol, 1.00 equiv) was introduced, and the reaction was heated to 65° C. for 1 h. The reaction was cooled and filtered. The cake was washed with more ethanol. The filtrate was concentrated to a cloudy oil and partitioned between DCM (50 mL) and 2% w/v aq NaHCO3 (50 mL). The organic phase was collected, and the aq layer was extracted with DCM (2×50 mL). All organic layers were combined, dried (Na2SO4), filtered, and concentrated, giving 3-(pyrrolidin-1-ylmethyl)-benzaldehyde (846 mg, 88% yield) as a pale yellow oil, which was used without further purification. 1H-NMR: 300 MHz, (CDCl3) δ: 10.00 (s, 1H), 7.84 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.47 (dd, J=7.6 Hz, 7.6 Hz, 1H), 3.69 (s, 2H), 2.52 (m, 4H), 1.79 (m, 4H). LCMS-ESI+: calc'd for C12H16NO: 190.1 (M+H+). Found: 190.1 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH3:18])[CH2:11]2)[CH:7]=[CH:6][C:5]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+].Cl>CO>[CH2:20]([O:19][C:5]1[CH:6]=[CH:7][C:8]([CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH3:18])[CH2:11]2)=[CH:9][C:4]=1[C:3]([OH:27])=[O:2])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCCN1CCOC(c2ccc(OCc3ccccc3)c(C(=O)OC)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCN1CCOC(c2ccc(OCc3ccccc3)c(C(=O)O)c2)C1
Yield: 100 %

Procedure:
To the methyl ester from example 32 (10 mg, 0.28 mmol) in methanol (5 ml) was added 10% sodium hydroxide (aq) (15 ml) and the milky white suspension was refluxed for 2 hours. The now colourless reaction mixture was cooled then neutralised by addition of 2M HCl (aq) (few drops). The reaction mixture was then concentrated in vacuo to give the title compound as an off-white solid (99 mg, 0.28 mmol, 100%). LRMS: m/z 355 (M-H+). This material was taken on crude to example 34.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][CH:9]1[C:10](=[O:12])[NH:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)NCc1ccccc1
Yield: 85.7 %

Procedure:
Using General Procedure I Method A, N-(tert-butoxycarbonyl)-L-proline (1.0 g, 4.6 mmol) is coupled to benzylamine (0.55 g, 5.1 mmol) to give 1.2 g (86%) of 2-benzylcarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester, which is submitted to the following step without further purification.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)CCCCCCCCCCCCCCC(=O)O
Product: COC(=O)CCCCCCCCCCCCCCC(C)C
Temperature: 117 °C
Reaction time: 1.5 h

Procedure:
About 780 grams of isostearic acid (acid number=194.4), 1 gram of p-toluenesulfonic acid were charged to a flask equipped with a heating mantle, stirrer, sub-surface inlet tube with a nitrogen purge and a condenser. The contents of the flask were heated under nitrogen flow to 117° C. About 400 grams of methanol were then added via the sub-surface inlet tube over 3.5 hours (acid number=9.6), 200 grams of additional methanol were added and the reaction continued for another 1.5 hours to obtain a final acid number of 0.6.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH:15]=[C:16]1[C:20]([CH3:22])([CH3:21])[O:19][C:18]([CH3:24])([CH3:23])[C:17]1=[O:25].[OH:26]O.[OH-].[Li+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[CH:15]1[C:16]2([C:17](=[O:25])[C:18]([CH3:24])([CH3:23])[O:19][C:20]2([CH3:21])[CH3:22])[O:26]1
Reactant: OO
Reactant: CC1(C)OC(C)(C)C(=Cc2cc(-c3ccc(Cl)cc3)ccc2Br)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)OC(C)(C)C2(OC2c2cc(-c3ccc(Cl)cc3)ccc2Br)C1=O
Temperature: 35 °C
Reaction time: 0.75 h
Yield: 76.2 %

Procedure:
To a solution of 4-[1-(4-bromo-4′-chlorobiphenyl-3-yl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (3.40 g, 9.03 mmol) in methanol (140 ml) at 35° C. is added 50% aqueous hydrogen peroxide (1.04 ml, 15.60 mmol), immediately followed by 2M aqueous lithium hydroxide (1.15 ml, 2.30 mmol). The reaction mixture is stirred for a further 45 minutes at 35° C., then allowed to cool to room temperature and quenched with saturated sodium metabisulfite. After extracting the product into diethyl ether (×3) the organic phase is separated, washed with additional water, then dried over magnesium sulfate. After filtration the filtrate is concentrated in vacuo to afford 2-(4-bromo-4′-chlorobiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one (3.0 g) as a yellow solid. This material was of sufficient purity to use directly in the next step.
Reaction SMILES: [CH2:1]([C@H:8]([NH:30][C:31]1[CH:36]=[CH:35][NH:34][C:33](=[O:37])[C:32]=1[C:38]1[NH:42][C:41]2[CH:43]=[C:44](Br)[CH:45]=[C:46]([CH3:47])[C:40]=2[N:39]=1)[CH2:9][O:10]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49]1(B(O)O)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.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>[CH2:1]([C@H:8]([NH:30][C:31]1[CH:36]=[CH:35][NH:34][C:33](=[O:37])[C:32]=1[C:38]1[NH:42][C:41]2[CH:43]=[C:44]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:45]=[C:46]([CH3:47])[C:40]=2[N:39]=1)[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Br)cc2[nH]c(-c3c(N[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)Cc4ccccc4)cc[nH]c3=O)nc12
Reactant: OB(O)c1ccccc1
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: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(-c2ccccc2)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Yield: 52.4 %

Procedure:
To a solution of (S)-4-(1-benzyl-2-trityloxy-ethylamino)-3-[6-bromo-4-methyl-1H-benzimidazole-2-yl]-1H-pyridin-2-one (50 mg, 0.072 mmol), phenylboronic acid (13 mg, 0.11 mmol), and 2 M K2CO3 (0.108 mL, 0.22 mmol) in THF (5 mL) was added Pd(PPh3)4 (8.3 mg, 0.007 mmol). The mixture was heated to reflux 14 h. Upon cooling, the reaction mixture was diluted with CH2Cl2, washed with saturated NaHCO3, dried over Na2SO4, and concentrated in vacuo. The residue was used for the next step without purification. LCMS (M+H)+ m/z 693 (t=2.82 min.). The crude product was treated with 4 N HCl dioxane solution (5 mL) at room temperature for 6 h. After concentration in vacuo, the residue was purified by prep. HPLC to yield the title compound (17 mg, 34%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.13–7.67 (13H, m), 6.15 (1H, d, J=7.4 Hz), 3.99–4.11 (1H, m), 3.74–3.77 (2H, m), 3.16 (1H, dd, J=5.4, 13.6 Hz), 2.97 (1H, dd, J=7.8, 13.6 Hz), 2.69 (3H, s). LCMS (M+H)+ m/z 451 (t=2.04 min.).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[CH:19]=O.CC([O-])(C)C.[K+]>CN(C=O)C>[C:2]1([C:8]2[CH:13]=[C:12]([CH:14]=[CH:19][C:18]3[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:17]=3[O:16][CH3:15])[CH:11]=[CH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: Cc1ccnc(-c2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(OC)c(C=Cc2ccnc(-c3ccccc3)c2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
To a mixture of 2-phenyl-4-methylpyridine hydrochloride (1 g, 4.9 mmol) and 2,5-dimethoxybenzaldehyde (1.2 g, 7.3 mmol) in anhydrous DMF (40 ml), solid t-BuOK (2 g, 18 mmol) was added. The resulting mixture was stirred overnight at 80° C. under nitrogen. After evaporating DMF, Et2O was added thereto and the precipitate was filtered and washed with water. The solid was purified by column chromatography (SiO2, CH2Cl2/MeOH, 99/1) to afford 0.6 g (39%) of the desired compound as a yellow solid.