Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N:6]=1)=[N+:2]=[N-:3].[C:12]([O:16][CH3:17])(=[O:15])[C:13]#[CH:14]>C1(C)C=CC=CC=1>[Br:11][C:7]1[N:6]=[C:5]([CH2:4][N:1]2[C:13]([C:12]([O:16][CH3:17])=[O:15])=[CH:14][N:3]=[N:2]2)[CH:10]=[CH:9][CH:8]=1
Reactant: C#CC(=O)OC
Reactant: [N-]=[N+]=NCc1cccc(Br)n1
Solvent: Cc1ccccc1
Product: COC(=O)c1cnnn1Cc1cccc(Br)n1

Procedure:
2-(Azidomethyl)-6-bromopyridine (Example 470 Step 1) (600 mg, 2.82 mmol) and methyl propiolate (355 μL, 4.22 mmol) were combined in toluene (10 mL) and stirred at reflux overnight. The solvent was evaporated, and the residue was purified by flash chromatography (20-100% EtOAc/hexanes), whereby good separation of the two regioisomeric products was achieved. TLC, LC/MS, and 1H NMR analysis confirmed that the first spot (less polar, higher Rf) corresponded to the desired regioisomer. The title compound was isolated as a colorless oil.
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3=[CH:17][CH:18]=[N:19][C:20](=[O:21])[C:14]4=[C:15]3[C:10]([CH2:11][CH2:12][CH:13]4[CH2:22][CH:23]3[CH:28]4[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]4)[CH2:24]3)=[N:9]2)=CC=1>FC(F)(F)C(O)=O.CO>[N:25]12[CH2:30][CH2:29][CH:28]([CH2:27][CH2:26]1)[CH:23]([CH2:22][CH:13]1[CH2:12][CH2:11][C:10]3[C:15]4[C:16](=[CH:17][CH:18]=[N:19][C:20](=[O:21])[C:14]1=4)[NH:8][N:9]=3)[CH2:24]2
Reactant: COc1ccc(Cn2nc3c4c(c(=O)nccc42)C(CC2CN4CCC2CC4)CC3)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=c1nccc2[nH]nc3c2c1C(CC1CN2CCC1CC2)CC3
Yield: 88.4 %

Procedure:
A solution of 2-(4-methoxybenzyl)-7-(quinuclidin-3-ylmethyl)-8,9-dihydro-2H-azepino[5,4,3-cd]indazol-6(7H)-one (219 mg, 0.51 mmol) in trifluoroacetic acid (3 mL) was subjected to microwave irradiation at 130° C. for 18 min. The mixture was diluted with methanol and concentrated in vacuo. The resulting residue was converted to the free base by elution through an SCX-2 cartridge and then purified by column chromatography (silica gel, (12%-100% solvent mixture B in methylene chloride; solvent mixture B=70:27:3 methylene chloride/methanol/concentrated ammonium hydroxide) to afford 7-(quinuclidin-3-ylmethyl)-8,9-dihydro-2H-azepino[5,4,3-cd]indazol-6(7H)-one (140 mg, 88%) as a colorless oil: MS (ESI+) m/z 311 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([NH2:20])=[CH:13][CH:12]=3)=[O:5])[CH3:2].Cl/[CH:22]=[CH:23]\[CH2:24][CH2:25]Cl.C(N(C(C)C)C(C)C)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([N:20]1[CH:25]=[CH:24][CH:23]=[CH:22]1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(N)cc3c2c1C
Reactant: Cl/C=C\CCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1ncc2[nH]c3ccc(-n4cccc4)cc3c2c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.25 g of 6-amino-4-methyl-beta-carboline-3-carboxylic-acid-ethylester in 70 ml of ethanol, together with 1.7 ml of 1,4-dichloro-2-cis-butene and 4.5 g of ethyldiisopropylamine is heated for 10 h at 50° C. After stirring in 250 ml of ice water, the precipitate is filtered, washed and dried in vacuum. The raw product (3.4 g of a mixture of dihydropyrrole derivative and pyrrole derivative) is dissolved in 600 ml of methylene chloride and, after addition of 17 g of pyrolusite, is stirred for 2 h at room temperature. After filtering, and distilling off the solvent, 2.75 g of raw product is obtained crystallizing out of acetone. In this manner, 2.13 g of 4-methyl-6-(1-pyrrolyl)-beta-carboline-3-carboxylic-acid-ethylester with a m.p. of 214°-217° C. is obtained.
Reaction SMILES: [Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH2:22]([N:25]([CH2:37][CH2:38][CH3:39])[CH2:26][CH2:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[CH:31][NH:32]2)[CH2:23][CH3:24].[OH-:40].[Na+]>C(O)(=O)C.O>[CH2:37]([N:25]([CH2:22][CH2:23][CH3:24])[CH2:26][CH2:27][C:28]1[C:29]2[C:33]([CH:34]=[CH:35][CH:36]=1)=[N:32][C:31](=[O:40])[CH:30]=2)[CH2:38][CH3:39]
Reactant: [OH-]
Reactant: CCCN(CCC)CCc1cccc2[nH]ccc12
Agent: [Br-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(=O)O
Product: CCCN(CCC)CCc1cccc2c1=CC(=O)N=2
Temperature: 50 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
A solution of pyridinium tribromide 90% (8.72 g, 24.5 mmol) in acetic acid 50% (50 mL) was added to a solution of 4-[2-(dipropylamino)ethyl]indol (IV) (5 g, 20.5 mmol) in acetic acid 50% (100 mL) and was stirred at 50° C. for 3 h. When the resultant mixture reached room temperature, it was stirred at this temperature for 16 h. The reaction mixture was concentrated to obtain an aqueous residue, which was diluted with water (100 mL), basified with an aqueous solution of NaOH 10% and extracted with AcOEt. The organic layer was dried, filtered and concentrated to obtain 4.3 g (81%) of 4-[2-(dipropylamino)ethyl]indol-2-one (I).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[C:11]([F:16])[C:10]=1[C:17]1[S:21][C:20]([N:22]2[CH2:25][C:24]3([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)[CH2:23]2)=[N:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:46]2[CH:47]=[N:48][NH:49][CH:50]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:46]2[CH:47]=[N:48][NH:49][CH:50]=2)[CH:12]=[C:11]([F:16])[C:10]=1[C:17]1[S:21][C:20]([N:22]2[CH2:25][C:24]3([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)[CH2:23]2)=[N:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3c(F)cc(Br)cc3OCc3ccccc3)s1)C2
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3c(F)cc(-c4cn[nH]c4)cc3OCc3ccccc3)s1)C2
Temperature: 120 °C

Procedure:
A mixture of tert-butyl 2-(5-(2-(benzyloxy)-4-bromo-6-fluorophenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (150 mg, 0.254 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (74 mg, 0.382 mmol) in dioxane (2 mL) was stirred under nitrogen atmosphere. To this suspension was added Pd(PPh3)4 (15 mg, 0.013 mmol) followed by a solution of Na2CO3 (81 mg, 0.763 mmol) in water (0.5 mL). The reaction mixture was sealed and heated at 120° C. for 1 hour under microwave irradiation. A further 1.5 eq of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (74 mg, 0.382 mmol) was added and the reaction was heated for an additional hour at 120° C. under microwave irradiation. A further 1.5 eq of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (74 mg, 0.382 mmol) was added, followed by an additional 0.05 eq of Pd(PPh3)4 (15 mg, 0.013 mmol) and the reaction mixture was heated for 1 hour at 120° C. under microwave irradiation. The reaction mixture was diluted with water (15 mL) and extracted with DCM (20 mL). The organic phase was concentrated in vacuo to afford the crude product as a pale brown oil. The crude material was purified by flash chromatography using a 24 g silica cartridge running a MeOH/DCM gradient to afford a pale brown oil. The oil was purified using a 24 g silica running an EtOAc/heptane gradient to afford the title compound as a clear glass-like solid (86 mg, 58% yield). MS m/z 577.2 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.39 (d, J=1.8 Hz, 1H), 8.09 (d, J=2.0 Hz, 1H), 7.47-7.57 (m, 2H), 7.33-7.44 (m, 4H), 7.28 (dd, J=11.6, 1.5 Hz, 1H), 5.35 (s, 2H), 3.82 (s, 4H), 3.18-3.32 (m, 4H), 1.63-1.77 (m, 4H), 1.40 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][N:13]3[CH3:18])(O)[CH2:3]1.[OH-].[Na+]>Cl>[CH3:18][N:13]1[C:14]2[C:10](=[C:9]([C:4]3[CH2:3][N:2]([CH3:1])[CH2:7][CH2:6][CH:5]=3)[CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1
Reactant: CN1CCCC(O)(c2cccc3c2ccn3C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN1CCC=C(c2cccc3c2ccn3C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
A solution of 15 g of 1-methyl-3-(1-methyl-1H-indol-4-yl)-3-piperidinol in 500 ml of 1 N hydrochloric acid was refluxed for 3 hours and was then cooled to room temperature and stirred for 16 hours. The mixture was cooled in an ice bath while adding sodium hydroxide until the mixture was alkaline and the mixture was extracted with ethyl acetate. The organic phase was washed with aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The 13 g of residue was chromatographed over silica gel and eluted with a 6-3-1 cyclohexanechloroform-triethylamine mixture to obtain 8.7 g of 1-methyl-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole.
Reaction SMILES: [CH2:1](SC1C(NC(=O)C=1)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:15](#N)[CH3:16]>>[C:3]1([C:15]([C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=2)=[CH2:16])[CH:2]=[CH:1][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCCSC1=CC(=O)NC1=O
Reactant: CC#N
Product: C=C(c1ccccc1)c1ccccc1

Procedure:
Hexylsulfanylmaleimide (25 mg, 0.116 mmol) was dissolved in acetonitrile (21 mL) and 1,1-diphenylethyene (203 μL, 1.16 mmol) to provide a 0.005M solution. The resulting solution was degassed for 30 minutes and irradiated in pyrex glassware for 5 minutes with stirring. Solvent was removed in vacuo and purification by flash chromatography (gradient elution in petroleum ether to 30% ethyl acetate in petroleum ether) afforded the desired compound as a colourless oil (30 mg, 0.075 mmol) in 64% yield. δH (600 MHz, CDCl3) 8.15 (s, 1H, NH), 7.42 (m, 2H, 2×H-8), 7.36-7.21 (m, 8H, 8×Ar—H), 3.54 (dd, 1H, J=10.3 and 12.9, HH-6), 3.34 (dd, 1H, J=5.7 and 10.3, H-7), 3.18 (dd, 1H, J=5.8 and 12.9, HH-6), 2.43 (dt, 1H, J=7.3 and 11.0, HH-17), 2.34 (dt, 1H, J=7.4 and 11.0, HH-17), 1.40-1.34 (m, 2H, H2-16), 1.26-1.20 (m, 4H, H2-14 and H2-15), 1.18-1.13 (m, 2H, H2-13), 0.84 (t, 3H, J=7.5, H3-12); δC (150 MHz, CDCl3) 177.16 (C═O), 175.87 (C═O), 142.09 (2×Ar), 141.80 (2×Ar), 128.17 (2×Ar—H), 128.13 (2×Ar—H), 128.10 (2×Ar—H), 128.06 (2×Ar—H), 127.44 (Ar—H), 127.32 (Ar—H), 63.03 (C5), 57.20 (C4), 44.38 (C7), 35.17 (C6), 31.35 (CH2), 30.07 (C17), 28.77 (CH2), 28.71 (CH2) 22.53 (CH2), 14.11 (C12); IR (oil, cm−1) 2927 (m) 1772 (w), 1709 (s); MS (ES−) m/z (relative intensity): 392 ([M], 10), 212 (100); Exact Mass Calcd for [C24H26NO2S] requires m/z 392.1684 Found 392.1674 (ES−).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@H:14]([C:19]([O:21]CC1C=CC=CC=1)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7]>CO.[Pd]>[NH2:1][C@H:2]([C:11]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@@H](N)CC(=O)OC(C)(C)C)C(=O)O
Yield: 89.7 %

Procedure:
The Z-Asp(OtBu)-Leu-OBzl (15.6 g) in methanol (50 mL) was added 10% Pd on carbon (0.17 g) and was hydrogenated on a Paar Shaker. After filtering off the catalyst, the filtrate was concentrated to give a foamy solid. The crude product was triturated with diethyl ether to yield 8.03 g of H-Asp(OtBu)-Leu-OH.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[CH2:12])=[CH:8][CH:7]=[CH:6][CH:5]=2>C(O)C.[Pd]>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: C=C(c1cccnc1)c1c(C)[nH]c2ccccc12
Agent: [Pd]
Solvent: CCO
Product: Cc1[nH]c2ccccc2c1C(C)c1cccnc1
Yield: 60.7 %

Procedure:
A solution of 1-(2-methyl-3-indolyl)-1-(3-pyridyl)ethylene (prepared according to J. Het. Chem., 9, 833, 1972) (9.37 g) in ethanol (200 ml) was hydrogenated at 2.5 atm. pressure in the presence of 10% palladium/charcoal. The solution was filtered and evaporated and the residue was crystallised from ethyl acetate/petrol (b.p. 60°-80°) to give 2-methyl-3[1-(3-pyridyl)ethyl]indole (5.74 g) m.p. 139°-141° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](CC#N)[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:20]([O:23]CC)(=[O:22])[CH3:21]>O.S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:21][C:20]([OH:23])=[O:22])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1ccc2[nH]nc(-c3cccc(F)c3)c2c1

Procedure:
50 mg of 2-[3-(3-fluorophenyl)-1H-5-indazolyl]acetonitrile was suspended in 0.5 ml of water and 0.4 ml of concentrated sulfuric acid, and the suspension was stirred at 95° C. for 2 hours. The reaction mixture was added with 20 ml of ethyl acetate, sequentially washed with water (×2) and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 48 mg of the title compound as pale red crystals.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:11]([Sn:15](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>C1COCC1.CCOCC>[CH2:20]([Sn:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH3:19])/[CH:3]=[CH:2]\[CH2:1][OH:4])[CH2:21][CH2:22][CH3:23]
Reactant: C#CCO
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC[Sn](/C=C\CO)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Propargyl alcohol (5 mL) was added to a solution of lithium aluminium hydride (1M in THF, 43 mL) in THF (70 mL) at −78° C. The resultant mixture was warmed to room temperature and stirred for 18 hours. It was re-cooled to −78° and a solution of tri-n-butyl tin chloride (8.3 mL) in ether (50 mL) was added and the mixture was stirred for 3 hours whilst gradually warming to room temperature. The reaction mixture was cooled to −5° C. and quenched by addition of water and 15% aqueous sodium hydroxide solution then it was allowed to warm to room temperature. Ethyl acetate was added and the mixture was stirred for 1 hour. The mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was purified by chromatography on a silica column which had been pre-washed with 20% triethylamine in acetonitrile. The column was eluted with a mixture of ethyl acetate and pentane with a gradient of 0-10% to give (Z)-3-tributylstannanylprop-2-en-1-ol (5.06 g) as a clear oil.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14].[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC>C1(C)C=CC=CC=1>[CH3:12][O:11][C:9]1[CH:8]=[C:7]2[C:3]([CH:4]=[CH:5][N:6]2[S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[C:2]([CH:22]=[CH2:23])[CH:10]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc(Br)c2ccn(S(=O)(=O)c3ccccc3)c2c1
Solvent: Cc1ccccc1
Product: C=Cc1cc(OC)cc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 106.4 %

Procedure:
4-Bromo-6-methoxy-1-(phenylsulfonyl)-1H-indole (0.33 g, 0.9 mmol; Intermediate 32) was dissolved in dry toluene (4 mL) and tributyl(vinyl)stannane (0.53 mL, 1.8 mmol) and bis(triphenylphosphine)palladium(II)acetate (0.03 g, 0.05 mmol) were added. The mixture was stirred in STEM-block at 110° C. for 16 h. The crude product was combined with an earlier batch of this intermediate, filtrated and the solvent was evaporated. The residue was purified by flash chromatography using isohexane:dichloromethane 1:1 as eluent yielding 0.30 g (89%) of the title compound. MS (ESI+) for C17H15NO3S m/z 314 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][C:48]1[CH:49]=[C:50]2[C:55](=[CH:56][CH:57]=1)[NH:54][CH2:53][CH2:52][CH2:51]2>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:54]4[C:55]5[C:50](=[CH:49][C:48]([CH3:47])=[CH:57][CH:56]=5)[CH2:51][CH2:52][CH2:53]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc2c(c1)CCCN2
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCCc3cc(C)ccc32)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 6-methyl-1,2,3,4-tetrahydroquinoline (Alfa) to give the title product. LC-MS (ES+) 794 [(M+H)+].
Reaction SMILES: [N:1]1C=CC=CC=1N(CCCOC1C(CC(O)=O)CC2C=CC=CC=2CN1)C(OC(C)(C)C)=O.[O:34]=[C:35]1[CH:41]([CH2:42][C:43]([OH:45])=[O:44])[CH2:40][C:39]2[CH:46]=[CH:47][C:48]([O:50][CH2:51][CH2:52][CH2:53][N:54]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=3)C(OC(C)(C)C)=O)=[CH:49][C:38]=2[CH2:37][N:36]1[CH2:68][C:69]1[CH:74]=[CH:73][C:72](C(F)(F)F)=[CH:71][CH:70]=1.C(C(O)=O)(F)(F)F>O>[NH2:1][C:72]1[CH:73]=[CH:74][C:69]([CH2:68][N:36]2[C:35](=[O:34])[CH:41]([CH2:42][C:43]([OH:45])=[O:44])[CH2:40][C:39]3[CH:46]=[CH:47][C:48]([O:50][CH2:51][CH2:52][CH2:53][NH:54][C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=4)=[CH:49][C:38]=3[CH2:37]2)=[CH:70][CH:71]=1
Reactant: CC(C)(C)OC(=O)N(CCCOC1NCc2ccccc2CC1CC(=O)O)c1ccccn1
Reactant: CC(C)(C)OC(=O)N(CCCOc1ccc2c(c1)CN(Cc1ccc(C(F)(F)F)cc1)C(=O)C(CC(=O)O)C2)c1ccccn1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(CN2Cc3cc(OCCCNc4ccccn4)ccc3CC(CC(=O)O)C2=O)cc1
Yield: 44 %

Procedure:
According to the procedure of Example 25(a) except substituting (±)-2-(4-aminobenzyl)-3-oxo-[3-[3-[N-(pyridin-2-yl)-N-(tert-butoxycarbonyl)amino]-1-propyloxy]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid for the (±)-3-oxo-8-[3-[N-(pyridin-2-yl)-N-(tert-butoxycarbonyl)amino]-1-propyloxy]-2-(4-triflouromethylbenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid, the title compound (0.029 g, 44%) was prepared: MS (ES) m/e 475.4 (M+H)+. Anal. Calcd for C27H30N4O4.2 CF3CO2H.1.5 H2O: C, 51.03; H, 4.83; N, 7.68. Found: C, 50.92; H, 4.78; N, 7.64.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[CH3:16][O:17][C:18]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.C(N(CC)CC)C.[BH4-].[Na+]>CO>[CH3:16][O:17][C:18]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH:2][CH2:3][CH:4]([OH:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1
Reactant: COc1cccc(C=O)c1OC
Reactant: COc1ccc(C(O)CN)cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(C(O)CNCc2cccc(OC)c2OC)cc1OC
Temperature: 25 °C
Yield: 75.5 %

Procedure:
α-Aminomethyl-3,4-dimethoxybenzyl alcohol hydrochloride (5.84 g, 25 mmol) was suspended in methanol (30 ml). 2,3-Dimethoxybenzaldehyde (5 g, 30 mmol) was added to the suspension and then triethylamine (3.83 ml, 27.5 mmol) was added dropwise thereto under stirring at room temperature. The resultant solution was heated under reflux for 30 minutes and then sodium borohydride (1.4 g, 37 mmol) was slowly added thereto under stirring under cooling with ice. After the completion of foaming, the solvent was distilled off under reduced pressure. Water was added to the residue, which was made acidic with 3N hydrochloric acid and washed with ether. The cistern was made basic with aqueous ammonia and then subjected to extraction with dichloromethane. The dichloromethane layer was washed with water and then a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resultant crystals were washed with isopropyl ether to obtain 6.56 g of α-[[(2,3-dimethoxybenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11](=[O:13])[CH3:12])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][CH:11]([OH:13])[CH3:12])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: CC(=O)COc1c(Cl)nc(Cl)nc1N1CCOCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CC(O)COc1c(Cl)nc(Cl)nc1N1CCOCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 100.1 %

Procedure:
To a solution of 1-(2,4-dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-propan-2-one (146 mg, 0.48 mmol) in THF (5 mL) at −78° C. was added DIBAL-H (580 μL, 0.58 mmol, 1M solution in toluene) and the resulting mixture warmed to 0° C. and stirred for 1.5 hours. The reaction mixture was cooled to −78° C. before the addition of further DIBAL-H (480 μL, 0.48 mmol) and the mixture warmed to 0° C. and stirred for 2 hours. The reaction mixture was quenched with Rochelle's salt (1M aqueous solution) and the mixture extracted with ethyl acetate. The combined organic extracts were washed with brine, then dried (Na2SO4) and concentrated in vacuo affording 1-(2,4-Dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-propan-2-ol (148 mg, quantitative). LCMS: RT=2.84 min, [M+H]+=308/310/312.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][S:16]([CH2:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](O)=[O:24])(=[O:18])=[O:17]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([CH2:19][S:16]([CH3:15])(=[O:18])=[O:17])[CH:21]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CS(=O)(=O)Cc1cccc(C(=O)O)c1
Product: CS(=O)(=O)Cc1cccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c1

Procedure:
75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 3-(methylsulfonylmethyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-(methylsulfonylmethyl)benzamide. MS (Q1) 401 (M)+.