Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH2:27][CH:28]2[CH2:31][CH2:30][CH2:29]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[F:32][C:33]1[CH:34]=[C:35]([CH2:40][CH2:41][CH2:42][CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:36]=[C:37]([F:39])[CH:38]=1.Cl>>[F:32][C:33]1[CH:34]=[C:35]([CH2:40][CH2:41][CH2:42][CH:43]2[CH2:44][CH2:45][N:46]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@H:14]([CH2:27][CH:28]4[CH2:29][CH2:30][CH2:31]4)[C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[O:16])[CH2:4]3)[CH2:47][CH2:48]2)[CH:36]=[C:37]([F:39])[CH:38]=1
Reactant: COc1ccc(COC(=O)[C@@H](CC2CCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: Fc1cc(F)cc(CCCC2CCNCC2)c1
Agent: Cl
Product: COc1ccc(COC(=O)[C@@H](CC2CCC2)N2C[C@H](CN3CCC(CCCc4cc(F)cc(F)c4)CC3)[C@@H](c3ccccc3)C2)cc1
Yield: 59.7 %

Procedure:
The title compound was prepared from 19 mg (0.04 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-3-(cyclobutyl)propanoic acid, (4-methoxy)benzyl ester (from EXAMPLE 19, Step F) and 12.5 mg (0.04 mmol) of 4-(3-(3,5-difluorophenyl)propyl)piperidine.HCl (from EXAMPLE 95, Step E) using a procedure analogous to that described in EXAMPLE 1, Step J to provide 15.4 mg (53%) of the title compound: RF: 0.40 (1:1 v/v hexanes/EtOAc); 1H NMR (300 MHz) δ 1.04-3.27 (m, 33H), 3.80 (s, 3H), 5.04-5.13 (m, 2H), 6.57-6.69 (m, 21), 6.87 (d, J 8.8, 2H), 7.14-7.33 (m, 8H).
Reaction SMILES: [C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[CH:11][C:10]=1[S:20][CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:24])=[N-]>ClCCl>[C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([O:19][CH3:24])=[O:18])[C:12]2=[CH:11][C:10]=1[S:20][CH3:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1cc2n(c1C(=O)c1ccccc1)CCC2C(=O)O
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)C1CCn2c1cc(SC)c2C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 200 mg of 5-benzoyl-6-methylthio-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 5 ml of dichloromethane is treated with an excess of ethereal diazomethane, and the reaction mixture is maintained at room temperature for 30 minutes. The solvents and excess reagent are eliminated under reduced pressure and the residue crystallized from ethyl acetate-methanol, to yield methyl 5-benzoyl-6-methylthio-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]([O:20][CH3:21])=[C:5]([C:22]([OH:24])=O)[N:4]=1)#[N:2].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.Cl.[CH3:41][O:42][C:43](=[O:46])[CH2:44][NH2:45]>ClCCl>[CH3:41][O:42][C:43](=[O:46])[CH2:44][NH:45][C:22]([C:5]1[N:4]=[C:3]([C:1]#[N:2])[C:12]2[C:7]([C:6]=1[O:20][CH3:21])=[CH:8][CH:9]=[CH:10][C:11]=2[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:24]
Reactant: COC(=O)CN
Reactant: COc1c(C(=O)O)nc(C#N)c2c(Oc3ccccc3)cccc12
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CNC(=O)c1nc(C#N)c2c(Oc3ccccc3)cccc2c1OC
Temperature: 0 °C
Reaction time: 5.5 h
Yield: 58 %

Procedure:
To a mixture of 1-cyano-4-methoxy-8-phenoxy-isoquinoline-3-carboxylic acid (483 mg, 1.51 mmol), triethylamine (466 μL, 3.32 mmol), and dichloromethane (12 mL) was added isobutylchloroformate (211 μL, 1.62 mmol) at 0° C. The mixture was stirred at 0° C. for twenty-five minutes before glycine methyl ester hydrochloride (208 mg, 1.66 mmol) was added. The mixture was stirred at 0° C. for twenty-five minutes and at room temperature for 5.5 hours before it was concentrated. The residue was partitioned between ethyl acetate and 1N HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow solid (343 mg): MS: (+) m/z 391.95 (M+1).
Reaction SMILES: C(OC([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[C:16]([C:17]#[N:18])=[C:15]([Cl:19])[S:14][C:11]=32)[CH2:7]1)=O)C.I[Si](C)(C)C>C(Cl)Cl>[Cl:19][C:15]1[S:14][C:11]2[CH:12]3[CH:8]([CH2:9][C:10]=2[C:16]=1[C:17]#[N:18])[CH2:7][NH:6][CH2:13]3
Reactant: CCOC(=O)N1CC2Cc3c(sc(Cl)c3C#N)C2C1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: N#Cc1c(Cl)sc2c1CC1CNCC21

Procedure:
The product of step b) (13.9 mg, 0.047 mmol) was treated with iodotrimethylsilane (10 μl, 0.07 mmol) in CH2Cl2 (235 μl) at 50° C. for 16 hours. The solvent was concentrated and the residue was dissolved in MeOH and purified by preparative LC/MS providing the title compound as a white solid. 1H NMR (300 MHz, CD3OD, ppm) 2.80-2.90 (m, 1H); 3.10-3.50 (m, 5H); 3.55-3.70 (m, 1H); 4.00-4.21 (m, 1H); MS calculated for C10H9ClN2S+H 225, observed 225.
Reaction SMILES: C(=O)(O)[O-].[Na+:5].[CH3:6][C:7]1[C:8](=[O:27])[C:9]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)=[C:16]([CH2:24][CH2:25][CH3:26])[C:10]=2[O:11][C:12]=1[C:13]([OH:15])=[O:14]>O>[CH3:6][C:7]1[C:8](=[O:27])[C:9]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)=[C:16]([CH2:24][CH2:25][CH3:26])[C:10]=2[O:11][C:12]=1[C:13]([O-:15])=[O:14].[Na+:5]
Reactant: CCCc1c2c(cc3c(=O)c(C)c(C(=O)O)oc13)CCCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCc1c2c(cc3c(=O)c(C)c(C(=O)[O-])oc13)CCCC2

Procedure:
A solution of sodium bicarbonate (0.78 g) in water (30 ml) was added to the product of step (g) (2.8 g). The resulting solution was filtered then evaporated to small volume and diluted with acetone. Crystallisation occurred and the resulting crystals were filtered off and recovered as an off-white solid, which was the desired sodium salt (2.65 g).
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([O:11][CH2:12][C:13](=[O:36])[C@:14]2([OH:35])[C@:31]3([CH3:32])[C@H:17]([C@H:18]4[C@H:28]([C@@H:29]([OH:33])[CH2:30]3)[C@:26]3([CH3:27])[C:21](=[CH:22][C:23](=[O:34])[CH2:24][CH2:25]3)[CH2:20][CH2:19]4)[CH2:16][CH2:15]2)=[O:10])[CH:4]=1.C([O-])(O)=O.[Na+].[O-]S(S([O-])=O)=O.[Na+].[Na+]>CO>[OH:33][C@H:29]1[CH2:30][C@@:31]2([CH3:32])[C@@H:17]([CH2:16][CH2:15][C@:14]2([OH:35])[C:13](=[O:36])[CH2:12][O:11][C:9]([C:5]2[CH2:6][CH:7]=[CH:8][N:3]([CH3:2])[CH:4]=2)=[O:10])[C@H:18]2[C@H:28]1[C@:26]1([CH3:27])[C:21]([CH2:20][CH2:19]2)=[CH:22][C:23](=[O:34])[CH2:24][CH2:25]1
Reactant: C[n+]1cccc(C(=O)OCC(=O)[C@@]2(O)CC[C@H]3[C@@H]4CCC5=CC(=O)CC[C@]5(C)[C@H]4[C@@H](O)C[C@@]32C)c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [I-]
Solvent: CO
Product: CN1C=CCC(C(=O)OCC(=O)[C@@]2(O)CC[C@H]3[C@@H]4CCC5=CC(=O)CC[C@]5(C)[C@H]4[C@@H](O)C[C@@]32C)=C1

Procedure:
The general reduction procedure of Example 11 of U.S. Pat. No. 4,617,298 was followed, using 0.8 mmol of the steroidal quaternary salt prepared in Example 120, 0.34 g of NaHCO3 and 0.42 g of Na2S2O4 in 50% aqueous methanol at 0° C., with a nitrogen purge. The product had the structural formula: ##STR149##
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][P:6]([CH2:11][CH2:12][C:13](=[O:15])[CH3:14])(=[O:10])[O:7][CH2:8][CH3:9])[CH3:4].[Li]CCCC.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>CCCCC.O.C1COCC1>[CH2:8]([O:7][P:6]([CH2:11][CH2:12][C:13](=[O:15])[CH2:14][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:10])[O:5][CH2:3][CH3:4])[CH3:9]
Reactant: BrCc1ccccc1
Reactant: CCOP(=O)(CCC(C)=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(CCC(=O)CCc1ccccc1)OCC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
250 ml of THF are added to a stirred suspension of 300 mmol of sodium hydride, which has been washed with n-pentane, and 280 mmol of 3-oxobutylphosphonic acid diethyl ester (1a) are added dropwise at room temperature. After 2 hours' stirring at constant temperature, the reaction mixture is cooled with an ice/common salt mixture and 1.3 equivalents of n-BuLi are added dropwise. After a further 2 hours' stirring at 0° C., 310 mmol of benzyl bromide (dissolved in 50 ml of THF) are slowly added. The mixture is allowed to rise to room temperature, stirred for a further 3 hours and combined with 20 ml of 1 molar HCl. The reaction solution is poured into iced water, extracted three times with 100 ml portions of chloroform and the combined organic phases are washed with saturated common salt solution. Purification of 1b performed chromatographically on silica gel with methylene chloride and ethyl acetate as mobile solvent. (Reaction conditions, c.f.: B. Resul, J. Stjernschantz, K. No, C. Liljebris, G. Selén, M. Astin, M. Karlsson, L. Z. Bito J. Med. Chem. 1993, 36, 243-248)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][CH:13]([CH2:29][CH2:30][CH3:31])[C:14]([NH:16][C:17]2[N:18]=[CH:19][N:20]([CH2:22][CH2:23]OS(C)(=O)=O)[CH:21]=2)=[O:15])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C(#N)C>[N:38]1([CH2:23][CH2:22][N:20]2[CH:21]=[C:17]([NH:16][C:14](=[O:15])[CH:13]([NH:12][C:10](=[O:11])[CH2:9][C:4]3[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=3)[CH2:29][CH2:30][CH3:31])[N:18]=[CH:19]2)[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(CCOS(C)(=O)=O)cn1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(CCN2CCOCC2)cn1
Temperature: 65 °C

Procedure:
Methanesulfonic acid 2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-ethyl ester (1 equiv) was dissolved in acetonitrile and treated with potassium carbonate (1.5 equic) and morpholine (3 equiv). The reaction was heated to 65° C. for 18 h and quenched with water, extracted with methylene chloride, dried, and concentrated. The residue was purified by column chromatography to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 18.9, 36.0, 43.1, 45.1, 53.1, 53.9, 58.9, 67.1, 102.6, 102.9, 107.9, 112.3, 112.6, 133.5, 137.6, 139.0, 161.0, 162.0, 169.3, 169.4; MS m/z 450.1 (M+1).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[F:24].CN([CH:28]=[O:29])C>C1COCC1.O>[Cl:16][C:17]1[C:18]([F:24])=[C:19]([C:20]([CH3:23])=[CH:21][CH:22]=1)[CH:28]=[O:29]
Reactant: Cc1ccc(Cl)c(F)c1
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(F)c1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 7.2 %

Procedure:
(Reference: E. J. Org. Chem. 2005, 2116-2123) To a solution of 2,2,6,6-tetramethylpiperidine (0.642 mL, 3.80 mmol) in THF (15 mL) at −78° C. was added n-BuLi (2.162 mL, 3.46 mmol) dropwise. The resulting solution was stirred at −78° C. for 1 h and added 1-chloro-2-fluoro-4-methylbenzene (0.5 g, 3.46 mmol) dropwise. The solution was stirred for additional 0.5 h and then added DMF (0.536 mL, 6.92 mmol). The reaction was stirred at −78° C. for 1.5 h and at ambient temperature for 12 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic layer was washed with brine and concentrated. The residue was purified by silica gel chromatography to yield the desired product (43 mg, 7%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:11])[CH:9]=2)[N:4]([CH3:12])[C:3]=1[C:13]([NH:15][C@H:16]([C:20]([NH:22][CH:23]([C:32](=[O:35])[CH2:33][F:34])[CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14].C(O)(C(F)(F)F)=O>C1(OC)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:11])[CH:9]=2)[N:4]([CH3:12])[C:3]=1[C:13]([NH:15][C@H:16]([C:20]([NH:22][CH:23]([C:32](=[O:35])[CH2:33][F:34])[CH2:24][C:25]([OH:27])=[O:26])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14]
Reactant: CC(C)[C@H](NC(=O)c1c(Cl)c2cc(F)ccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(C)[C@H](NC(=O)c1c(Cl)c2cc(F)ccc2n1C)C(=O)NC(CC(=O)O)C(=O)CF
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82.3 %

Procedure:
A solution of N-[(3-chloro-5-fluoro-1-methylindole-2-carbonyl)valinyl]-3-amino-4-oxo-5-fluoropentanoic acid, t-butyl ester (682 mg) in anisole (1 mL) and methylene chloride (10 mL) was treated with TFA (5 mL), and the resultant reaction mixture was stirred for 45 minutes under a nitrogen atmosphere at room temperature. The reaction mixture was concentrated and chased with methylene chloride, then triturated with ether to afford the title product as a white powder (500 mg). MS (EI) for C20H22ClF2N3O5: MH+=458/460; (M−H)−=456/458.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[C:43](Br)[CH:42]=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.[CH3:52][CH2:53]O.CC1(C)C(C)(C)OB(C=C)O1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[C:43]([CH:52]=[CH2:53])[CH:42]=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4cc(Br)ccc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Reactant: CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C=CB1OC(C)(C)C(C)(C)O1
Solvent: O
Product: C=Cc1ccc(-n2ccc(C)n2)c([C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OCC)N(C(=O)OCc3ccccc3)C4)nc(N)n2)C(F)(F)F)c1
Temperature: 80 °C

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(5-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (500 mg, 0.65 mmol) in 4:1 EtOH:H2O (25 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (150 mg, 0.971 mmol), KHCO3 (648 mg, 6.47 mmol), and PdCl2(PPh3)2 (68 mg, 0.097 mmol). The reaction mixture was heated to 80° C. for 1.75 h, then cooled to RT, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification via a 40 g Isco RediSep silica cartridge eluting (EtOAc/hepate) provides (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].CO[CH:7](OC)[CH:8]([N:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[C:11](=[O:13])[CH3:12])Cl.[OH-].[Na+]>ClCCCl>[C:11]([N:10]1[CH:8]=[CH:7][C:20]2[C:15](=[C:16]([Cl:1])[C:17]([Cl:21])=[CH:18][CH:19]=2)[CH2:14]1)(=[O:13])[CH3:12]
Reactant: [Cl-]
Reactant: COC(OC)C(Cl)N(Cc1cccc(Cl)c1)C(C)=O
Agent: [Al+3]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CC(=O)N1C=Cc2ccc(Cl)c(Cl)c2C1
Temperature: 0 °C

Procedure:
To a suspension of 91 g. (0.682 m.) of aluminum chloride in 1400 ml. of 1,2-dichloroethane was added a solution of N-acetyl-2,3-dichlorobenzylaminoacetaldehyde dimethyl acetal (45.5 g., 0.149 m.) in 230 ml. of 1,2-dichloroethane over an hour, the temperature staying below 30° C. The mixture was then cooled to 0° C. and 1000 ml. of 40% NaOH was added. The mixture was stirred and the layers separated. The aqueous fraction was extracted with 500 ml. of 1,2-dichloroethane and the combined organic layers were washed with 300 ml. of water and dried over magnesium sulfate. Evaporation and trituration with ether gave 2-acetyl-7,8-dichloro-1,2-dihydroisoquinoline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH2:6][CH:5]2[CH2:14]Cl.C1(C)C=CC=CC=1.N12CCCN=C1CCCCC2.[N:34]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49])=[N+:35]=[N-:36]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH2:6][CH:5]2[CH2:14][O:50][C:48](=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][N:34]=[N+:35]=[N-:36]
Reactant: O=C1CC(CCl)c2cc(Br)c(O)cc2O1
Reactant: [N-]=[N+]=NCCCCCCCCCCCC(=O)O
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCCCCCCCCCCCC(=O)OCC1CC(=O)Oc2cc(O)c(Br)cc21
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixture of 6-bromo-4-chloromethyl-7-hydroxy-chroman-2-one (0.67 g, 2.3 mmol), dry toluene (3 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (1.4 g, 9.3 mmol) and 12-azido dodecanoic acid (0.84 g, 0.35 mmol) was refluxed for 2 h. The reaction mixture was allowed to cool to room temperature, diluted with chloroform (10 mL), quenched with 1N HCl, and the layers separated. The organic layer was dried over Na2SO4 and evaporated to yield the crude product Purification was done by column chromatography eluting with CH2Cl2 to afford the product (yield 60%). The characterization data were consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH3:21]>CN(C=O)C.C(OCC)C.[I-].[K+]>[CH2:19]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6])[CH2:20][CH3:21]
Reactant: COc1ccc(C=O)cc1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCOc1cc(C=O)ccc1OC
Temperature: 65 °C
Reaction time: 5 h
Yield: 101.4 %

Procedure:
To a suspension of 3-hydroxy-4-methoxybenzaldehyde (2.00 g, 13.2 mmol), potassium carbonate (2.74 g, 19.8 mmol) and potassium iodide (60.0 mg, 0.361 mmol) in DMF (15 mL) was slowly added 1-bromopropane (1.56 mL, 17.2 mmol) via syringe. The reaction mixture was stirred at 65° C. for 5 hours. After cooling to room temperature, the mixture was diluted with diethyl ether (100 mL), and the organic phase was washed with water (2×50 mL). After drying over anhydrous MgSO4, filtration and evaporation of the filtrate in vacuo gave crude 3-(propyloxy)-4-methoxybenzaldehyde (2.60 g) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([N:13]1[CH2:16][CH:15]([OH:17])[CH2:14]1)([CH3:12])([CH3:11])[CH3:10].[OH-].[K+]>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][CH:15]([OH:17])[CH2:14][NH:13][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)N1CC(O)C1
Reactant: Nc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)NCC(O)COc1cccc(N)c1
Temperature: 140 °C
Yield: 42.3 %

Procedure:
A mixture of 21.8 parts of m-aminophenol, 22 parts of 1-(tert.-butyl)-3-azetidinol and 0.7 part of potassium hydroxide was heated under nitrogen gas at 140° C. for 8 hours with agitation. The reaction mixture was cooled and treated in the same manner as in Example 39. Recrystallization from benzene gave 17.2 parts of 1-(3'-aminophenoxy)-3-(tert.-butylamino)-2-propanol in the form of colorless needles melting at 105°-106° C. The yield was 42.3%. The results of infra-red spectrum analysis are as follows:
Reaction SMILES: [NH2:1][C:2]1[C:16]([NH2:17])=[CH:15][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.[N:18]#[C:19]Br.C>>[NH2:18][C:19]1[NH:17][C:16]2[CH:15]=[C:5]3[N:6]=[C:7]([C:9]4[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=4)[NH:8][C:4]3=[CH:3][C:2]=2[N:1]=1
Reactant: N#CBr
Reactant: Nc1cc2nc(-c3ccncc3)[nH]c2cc1N
Product: Nc1nc2cc3[nH]c(-c4ccncc4)nc3cc2[nH]1
Temperature: 25 °C

Procedure:
2.9 g. 5,6-diamino-2-(4-pyridyl)-benzimidazole and 1.3 g. cyanogen bromide are stirred for 2 hours at 85° C. with the exclusion of moisture. After cooling to ambient temperature, the reaction mixture is treated with active charcoal, filtered and the filtrate evaporated to dryness. The residue is suspended in water, the pH value is adjusted to 8.5 with aqueous ammonia solution and filtered off with suction. The 1.47 g. of residue obtained is applied to 15 g. silica gel 60 and eluted with a mixture of methylene chloride and ammoniacal methanol (95:5 v/v to 92:8 v/v). The appropriate fractions are evaporated to dryness and the residue is dissolved in methanol. Isopropanol is added thereto until turbid and then left to crystallise. There is obtained 0.52 g. of the desired compound; m.p. >320° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:16]([N:23]1[CH:27]=[N:26][C:25]([NH2:28])=[N:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[CH:27]=[N:26][C:25]([NH:28][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ncn(Cc2ccccc2)n1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3ncn(Cc4ccccc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-benzyl-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a white solid (Yield=25%). MS ISP (m/e): 356.1 (100) [(M+H)+].
Reaction SMILES: FC1(F)CC1CN1CCN(C2SC(C(OCC)=O)=C(C)N=2)C1=O.[F:24][C:25]1[CH:48]=[CH:47][C:28]([CH2:29][N:30]2[C:34](=[O:35])[N:33]([C:36]3[S:37][C:38]([C:42]([O:44]CC)=[O:43])=[C:39]([CH3:41])[N:40]=3)[CH:32]=[N:31]2)=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:30]2[C:34](=[O:35])[N:33]([C:36]3[S:37][C:38]([C:42]([OH:44])=[O:43])=[C:39]([CH3:41])[N:40]=3)[CH:32]=[N:31]2)=[CH:47][CH:48]=1
Reactant: CCOC(=O)c1sc(-n2cnn(Cc3ccc(F)cc3)c2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(CC3CC3(F)F)C2=O)nc1C
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Yield: 99 %

Procedure:
Following the procedure as described in Preparation 14, making variations as required to replace ethyl 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate with ethyl 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a white solid in 99% yield: 1H NMR (300 MHz, DMSO-d6) δ 13.40 (br s, 1H), 8.74 (s, 1H), 7.37-7.31 (m, 2H), 7.19-7.11 (m, 2H), 4.96 (s, 2H), 2.57 (s, 3H); MS (ES−) m/z 333.0 (M−1).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[C@@H:6]([C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:38][CH3:39])([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:25]([CH3:37])[CH:24]=3)[CH2:21][CH3:22])=[CH:16][C:15]=2[CH3:40])[CH:11]=[CH:12][CH:13]=1)[OH:7].Cl>CO>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C@@H:6]([OH:7])[C:5]([OH:41])=[O:4])[CH:9]=2)=[C:15]([CH3:40])[CH:16]=1)([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:34])([CH3:35])[CH3:33])=[C:25]([CH3:37])[CH:24]=1)[CH2:38][CH3:39])[CH3:22]
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cccc([C@@H](O)C(=O)OC)c2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cccc([C@@H](O)C(=O)O)c2)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.9 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.095 mL) was added to a solution of (R)-(4′-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-3-yl)hydroxy-acetic acid methyl ester (Example 157-(2); 24.2 mg, 0.0456 mmol) in methanol (0.65 mL) at room temperature, and the mixture was stirred at room temperature for four hours. The mixture was acidified with dilute hydrochloric acid aqueous solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (24 mg, 100%).