Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH3:14])[CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:10][CH2:9]2)=[C:4]([CH3:14])[CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: Cc1cc(Cl)ccc1N1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: Cc1cc(Cl)ccc1N1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 54.6 %

Procedure:
To a solution of 1-(4-chloro-2-methyl-phenyl)-piperazine (0.13 g, 0.6 mmol) in isopropanol (6.0 mL) was added 2,6-lutidine (95 uL, 0.802 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol), added in portions over 2 h. The solution was then stirred at 80° C. for an additional 12 h. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate/5% methanol to 90% ethyl acetate/10% methanol) to yield the title compound (0.11 g, 54%). 1H-NMR (DMSO) δ: 1.45 (6H, s), 2.30-2.65 (8H, m), 2.75-2.85 (4H, m), 3.30 (3H, d), 5.30 (2H, br s), 6.20 (1H, t), 6.75 (1H, d), 7.00-7.47 (6H, m), 7.80 (1H, dd), 8.50 (1H, dd). ESI-MS m/z: 504 (M+1), UV retention time: 1.65 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]=[C:10]=[S:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][NH2:13]>C1C=CC=CC=1.C(O)C>[Cl:1][C:2]1[C:3]([NH:9][C:10]([NH:13][CH3:12])=[S:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: S=C=Nc1ncc(Cl)cc1Cl
Reactant: CN
Solvent: c1ccccc1
Solvent: CCO
Product: CNC(=S)Nc1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3,5 dichloro-2-pyridylisothiocyanate (5.13 g.) in benzene (20 ml.) was added to a solution of methylamine in ethanol (5 ml., 33%) and the mixture was stirred for 18 hours at ambient temperature. Petroleum ether (60°-80° C., 30 ml.) was added and the resulting precipitate was filtered off and recrystallised from benzene-light petroleum to give colourless microcrystals of 1-(3,5-dichloro-2-pyridyl)-3-methyl-2-thiourea (4.18 g.) m.pt. 105°-109° C.
Reaction SMILES: [CH:1]1([C:10]([OH:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N+:13]([O-])([OH:15])=[O:14]>ClCCl.OS(O)(=O)=O>[N+:13]([C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][CH2:2][CH:1]2[C:10]([OH:12])=[O:11])=[CH:5][CH:6]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)C1CCc2ccccc21
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=C(O)C1CCc2ccc([N+](=O)[O-])cc21
Yield: 112.1 %

Procedure:
A solution of 1-indancarboxylic acid (30 g), prepared according to the method of Hansen et al. Helv.Chim.Acta 1982, 33, 325-343, in dichloromethane (50 ml) was mixed with concentrated sulphuric acid (300 ml) at −10° C. A mixture of 100% HNO3 (11.4 g) in concentrated H2SO4 (96 ml) was added dropwise under vigorous stirring below −10° C. After stirring for one hour at 10° C., the mixture was poured onto ice. Extraction with ethyl acetate (2×300 ml), drying (anh. MgSO4) and finally evaporation of the organic solvent afforded 42 g of the title compound. Mp: 126-130° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[N:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][C:16](OCC)=[O:17])=[CH:10][CH:9]=1.[OH-].[Na+]>O>[N:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:7]=[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]3[C:16](=[O:17])[CH:15]=2)=[CH:10][CH:9]=1
Reactant: Nc1ccccn1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1cc(-c2ccncc2)nc2ccccn12
Temperature: 140 °C
Yield: 16 %

Procedure:
0.406 g (4.31 mmol) of pyridin-2-amine and 1.00 g (5.17 mmol) of ethyl 3-(4-pyridinyl)-3-oxopropionate were added to 3 g of polyphosphoric acid (84% min.). The reaction mixture was heated at 140° C. for 12 hours. After cooling, water was added and the mixture was neutralized with an aqueous solution of sodium hydroxide (30%) and extracted with chloroform. The extracts were washed with a saturated aqueous solution of sodium chloride, dried and evaporated. The residue obtained was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 99/1/0.1 to 85/15/1.5 to give 0.154 g (16%) of the desired compound which was transformed into the oxalate salt in the usual manner to give the pure product as a solid.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([CH3:13])[C:10]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[O:15])[CH2:9]1)C1C=CC=CC=1.Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>ClCCl>[C:30]([O:29][C:27](=[O:28])[CH2:26][C:10]1([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[O:15])[CH:11]([CH3:13])[CH2:12][N:8]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH2:9]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc(COC(=O)C2(CC(=O)OC(C)(C)C)CN(Cc3ccccc3)CC2C)cc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2(CC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)CC2C)cc1
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
A solution of (4-methoxyphenyl)methyl (3RS,4SR)-1-benzyl-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-3-carboxylate obtained in Example 2g (18 g, 39.7 mmol) in dichloromethane (85.7 ml) was adjusted to an internal temperature of 10 to 20° C., and benzyl chloroformate (11.9 ml, 79.4 mmol) was added thereto. After returning to mom temperature and stirring for 0.5 hour, the reaction mixture was concentrated directly. The resulting crude product was purified by column chromatography (silica gel, elution solvent: ethyl acetate/heptane) to give the title compound (12.89 g, yield: 65.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:26]=[CH:25][C:16]([O:17][CH2:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:15]([CH3:27])[CH:14]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:28].C(N(CC)CC)C.C(Cl)Cl.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl.ClCCl>[CH3:21][C:20]([CH3:22])([CH3:23])[C:19](=[O:24])[CH2:18][O:17][C:16]1[CH:25]=[CH:26][C:13]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:40]([CH3:39])(=[O:42])=[O:41])=[C:3]([CH3:28])[CH:4]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:14][C:15]=1[CH3:27]
Reactant: CCC(CC)(c1ccc(N)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)(c1ccc(NS(C)(=O)=O)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a 0° C. mixture of 1-{4-[1-(4-amino-3-methyl-phenyl)-1-ethyl-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (763 mg, 2 mmol), triethylamine (0.42 mL, 3 mmol) and CH2Cl2 (7 mL) is added methanesulfonyl chloride (0.155 mL, 2 mmol). The reaction is warmed to RT and stirred for 3 h. The reaction is diluted with CH2Cl2 dichloromethane and washed with 0.2 N HCl. The organic phase is Na2SO4 dried, concentrated, and chromatogrpahed (0% to 25% EtOAc/Hex) to give the title compound (800 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[C:33]([NH:32][C:28]1[CH:27]=[C:26]([CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][NH:16][C:13]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:15])[CH2:21][CH2:22]2)[CH:31]=[CH:30][CH:29]=1)(=[O:35])[CH3:34]
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCC3)CC2)c1

Procedure:
Example 78 was prepared from 1-(4-chlorophenyl) cyclopentanecarboxylic acid and N-{3-[1-(3-amino propyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.34–7.26 (m, 7H), 6.97 (d, 1H, J=7.6 Hz), 6.54 (br s, 1H), 3.28 (dd, 2H, J=5.6, 12.0 Hz), 2.95 (d, 2H, J=12.0 Hz), 2.54–2.48 (m, 3H), 2.33 (t, 2H, J=6.8 Hz), 2.20 (s, 3H), 2.00–1.95 (m, 4H), 1.84–1.60 (m, 10H); ESMS m/e: 482.2 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([O-:11])=[O:10])[CH2:3][CH2:4][CH2:5][CH3:6].[Na].[K]>>[OH:1][CH:2]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(O)c1ccccc1C(=O)[O-]
Agent: [K]
Agent: [Na]
Product: CCCCC(O)c1ccccc1C(=O)O

Procedure:
2-(α-hydroxypentyl)benzoate of general formula (I) wherein M is a monovalent metal ion (e.g., sodium or potassium) is solved in a solvent, then a inorganic acid is added to the solution to adjust pH value to 6.0-2.0 at the temperature of −20-20° C., preferably −20-0° C., to acidify the 2-(α-hydroxypentyl)benzoate and 2-(α-hydroxypentyl)benzoic acid is obtained.
Reaction SMILES: [N:1]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:8])=[CH:3][C:2]=1[CH3:9].[Br:10][CH:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].N>O1CCCC1>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:8][C:4]1[CH:5]=[C:6]([CH3:7])[N:1]=[C:2]([CH3:9])[CH:3]=1
Reactant: CCCCCC(Br)Br
Reactant: Cc1cc(C)nc(C)c1
Agent: N
Solvent: C1CCOC1
Product: Cc1cc(CCCCCCCBr)cc(C)n1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Sodium amide was formed from sodium (1.0 g, 43.5 mmol) in liquid ammonia (100 ml) according to Example 1. Collidine (1) (5.0 g, 41.3 mmol) dissolved in tetrahydrofuran (5 ml) was added dropwise and after 45 min a well-cooled solution of dibromohexane (51.2 g, 210 mmol) in THF (100 ml) was added quickly. The reaction mixture was stirred for 1 h at -40° C. and then left stirring overnight during which times ammonia evaporated.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[NH:16][N:15]=1>>[F:24][C:13]([F:12])([F:23])[C:14]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[N:16]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=2)[N:15]=1
Reactant: CCC(=O)c1ccc(Br)cc1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Product: CCC(=O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from 1-(4-bromophenyl)-1-propanone and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similar procedure to that described for Example 1.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[C:15]([OH:21])([C:17]([F:20])([F:19])[F:18])=[O:16]>C(Cl)Cl>[CH3:1][C:2]1[S:6][C:5]([NH2:7])=[CH:4][CH:3]=1.[F:18][C:17]([F:20])([F:19])[C:15]([OH:21])=[O:16]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(N)s1

Procedure:
A solution of tert-butyl 5-methylthiophen-2-ylcarbamate (0.825 g, 3.87 mmol) in CH2Cl2 (10 mL) and TFA (6 mL) wad stirred at room temperature for 20 h. Solvents was removed in vacuo to give 5-methylthiophen-2-amine as trifluoroacetic acid salt (0.870 g).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:30][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:36])C.[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH:31]1([CH2:30][O:29][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:37])=[O:3])=[C:8]([CH3:36])[CH:9]=3)[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:17]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCC3CCCC3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(Sc2cc(C#CCN3CCOCC3)cc(OCC3CCCC3)c2)ccc1OCC(=O)O
Reaction time: 0.5 h

Procedure:
{4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (80 mg; 0.15 mmol) was dissolved in THF (2 mL) and ethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 30 min. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 43 mg (57%). HPLC-MS: m/z: 495.8 (M)+; Rt: 1.92 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:15](=[O:16])[CH:14]2[CH:9]1[CH:10]1[CH2:17][CH:13]2[CH:12]=[CH:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:18]1CCCC1.[OH-].[Li+].Cl>O.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH:10]2[CH2:17][CH:13]([CH:12]=[CH:11]2)[CH:14]1[C:15]([OH:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C3C=CC(C3)C21
Reactant: C1CCOC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1C2C=CC(C2)C1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine 4-Oxo-3-aza-tricyclo[4.2.1.0(2,5)]non-7-ene-3-carboxylic acid tert-butyl ester (60.94 g, 0.2590 mol) and Tetrahydrofuran (800 mL, 10 mol) in 2 L Erlenmeyer flask. Addition of 1.00 M of Lithium hydroxide in Water (780 mL) gave a slight exotherm and the flask was cooled during addition of LiOH solution with an ice water bath. The mixture was then warmed to rt following addition and stirred at room temperature overnight. Cooled 0° C. in ice/water bath. Added conc HCl to pH 2. A milky white liquid ensued. The THF was mostly removed by rotovap to give a precipitated solid in the water. This aqueous/solid mixture was diluted with 700 mL of CH2Cl2 and stirred for two hours during which the solid completely dissolved in the organic layer. The aqueous was further extracted with 400 mL of CH2Cl2 and the combined organics were dried (MgSO4), filtered and concentrated to give 3-tert-Butoxycarbonylamino-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid as an off-white solid, put on high vac at 40° C. to remove excess dichloromethane present in the solid sample. (60.40 g, 92%). 1H-NMR (CDCL3, 400 MHz): δ 12.0 (broad absorption, 1H) 6.97 (d, J=10.6 Hz, 1H), 6.20 (s, 1H); 3.96 (t, J=9.6 Hz, 1H), 2.99 (s, 1H), 2.74 (s, 1H), 2.60 (d, J=8.4 Hz, 1H), 2.09 (d, J=9.3 Hz, 1H), 1.66 (d, J=9.4 Hz, 1H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1C=CC=CC=1>[CH2:14]([O:13][C:11]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([CH3:1])[CH:3]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(N)cc1C
Solvent: c1ccccc1
Product: CCOC(=O)Nc1ccc(C)c(C)c1
Reaction time: 8 h

Procedure:
The above-named compound is prepared by first dissolving 51.5 grams of 3,4-dimethylaniline in 250 ml. of benzene. Then, while maintaining the solution at a temperature in the range of between 20° C. and 30° C., a benzene solution containing 23.9 grams of ethyl chloroformate is slowly added. The mixture is permitted to stand overnight at room temperature and then filtered. The filtrate is stripped by evaporation under vacuum, leaving the desired product, in the form of a dark purple liquid weighing 30 grams.
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][C:5]([OH:7])=[O:6].[CH:8](=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11].Cl>O>[CH:8]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[O:11][CH2:4][C:5]([OH:7])=[O:6])=[O:16]
Reactant: O=Cc1ccccc1O
Reactant: O=C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1ccccc1OCC(=O)O
Temperature: 75 °C
Yield: 37 %

Procedure:
A solution of NaOH (13.3 g; 0.33 mole) in water (34.4 ml) was carefully added, with cooling, to a mixture of chloroacetic acid (15.8 g; 0.17 mole) and salicylaldehyde (20.3 g; 0.17 mole) in water (134 ml). The mixture was heated to 75° C. with magnetic stirring to facilitate dissolution. The warm solution was pumped through the CMR (15 ml/minute; 170°-2° C.; 700 kPa) and carefully acidified with conc. HCl (32 ml). After steam distillation to recover unreacted salicylaldehyde (6.0 g), the residue was cooled and the product, m.p. 130°-1° C., crystallised, filtered off and dried (7.9 g; 37% yield based on consumed salicylaldehyde). For a conventional preparation see ref.12.
Reaction SMILES: Cl.[NH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)([CH2:6]3)[CH2:4]1)[CH2:10]2.[H][H]>C(O)(=O)C.[Pt]=O>[NH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([CH:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)([CH2:6]3)[CH2:4]1)[CH2:10]2
Reactant: [H][H]
Reactant: NC12CC3CC(C1)CC(c1ccccc1)(C3)C2
Agent: O=[Pt]
Agent: Cl
Solvent: CC(=O)O
Product: NC12CC3CC(C1)CC(C1CCCCC1)(C3)C2
Yield: 70 %

Procedure:
Dissolve 0.011 mol of 1-amino-3-phenyl adamantane (V) in 150 ml glacial acetic acid, mix with 0.3 g of platinum oxide (1% on activated carbon) and hydrate in a Parr apparatus at 35° C. at a hydrogen pressure of 3 bar. Subsequently, remove the catalyst by filtration and evaporate the filtrate to dryness. Take up the residue in methanol and precipitate the product with ether. Suck off and dry. (Yield: 70%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13].[C:17]1([CH2:23][O:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][CH:29]=[CH:28]3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([CH2:23][O:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=2/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:28]3)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CCOC(=O)/C=C/c1cc(F)ccc1CBr
Product: CCOC(=O)/C=C/c1cc(F)ccc1Cc1cc2cc(OCc3ccccc3)ccc2[nH]1

Procedure:
The benzylic bromide of Step 2 (3.16 g; 11.0 mmol) was coupled with 5-(phenylmethoxy)indole according to the same procedure described in step 1 of example 2 to yield 2.27 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:46])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37][CH2:38][C:39]([OH:41])=O)=[O:36])=[CH:33][C:32]=2[O:44][CH3:45])=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:80][CH2:81][CH2:82][O:83][CH2:84][CH2:85][O:86][CH2:87][CH2:88][O:89][CH2:90][CH2:91][OH:92]>O1CCCC1>[OH:92][CH2:91][CH2:90][O:89][CH2:88][CH2:87][O:86][CH2:85][CH2:84][O:83][CH2:82][CH2:81][NH:80][C:39]([CH2:38][O:37][C:35](=[O:36])[C:34]1[CH:42]=[CH:43][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:46])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:29])=[C:32]([O:44][CH3:45])[CH:33]=1)=[O:41]
Reactant: COc1cc(C(=O)OCC(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: NCCOCCOCCOCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)OCC(=O)NCCOCCOCCOCCO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reaction time: 0.5 h
Yield: 10.6 %

Procedure:
In a 20 mL round-bottomed flask, 2-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)-acetic acid (Example 69, 150 mg, 152 μL, 222 μmol), HATU (84.6 mg, 222 μmol) and Hunig's base (86.2 mg, 117 μL, 667 μmol) were combined with dry tetrahydrofuran (2 mL) to give an off-white suspension at room temperature. It was stirred for 30 min and the solution became clear. 2-(2-(2-(2-Aminoethoxy)ethoxy)ethoxy)ethanol (43.0 mg, 222 μmol) was added. After stirring at room temperature overnight, the reaction mixture was concentrated. The residue was reconstituted with ethyl acetate. It was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was absorbed on small amount of silica gel and loaded on a 24 g pre-packed silica gel column. Eluting the column with 0-10% methanol in ethyl acetate over 20 min gave 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid (2-{2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy}-ethylcarbamoyl)-methyl ester as an off-white solid (20 mg, 10% yield). LCMS (ES+) m/z calcd. for C41H48Cl2F2N4O9 [(M+H)+]: 849. found: 849.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C@H:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([I:17])[CH:12]=1)[CH2:8][OH:9].CCN(CC)CC>C1COCC1>[Cl:1][CH2:2][C:3]([NH:6][C@@H:7]([CH2:8][OH:9])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([I:17])[CH:12]=1)=[O:4]
Reactant: N[C@@H](CO)Cc1cccc(I)c1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)N[C@@H](CO)Cc1cccc(I)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Chloroacetylchloride (1.05 mL, 13.1 mmol) was added dropwise to a 0° C. solution of (R)-2-amino-3-(3-iodo-phenyl)-propan-1-ol A-8 (3.03 g, 10.9 mmol) and Et3N (1.98 mL, 14.2 mmol) in THF (50 mL) under argon and the resulting suspension was warmed to RT and stirred for 30 min. The reaction mixture was cooled back to 0° C. before being quenched with water and concentrated in vacuo. The remaining aq. phase was extracted with EtOAc (2×) and the combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give the title compound as a cream solid that was used further without purification. LC-MS B: tR=0.71 min; [M(35Cl)+H]+=353.75.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:19]=[CH:18][C:17](O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(Cl)Cl>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:19]=[CH:18][C:17]([O:1][C@@H:2]3[CH2:6][CH2:5][NH:4][C:3]3=[O:7])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1
Reactant: Oc1ccc(OCCC2CC2)nc1
Reactant: O=C1NCC[C@@H]1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1NCC[C@H]1Oc1ccc(OCCC2CC2)nc1

Procedure:
A mixture of (S)-3-hydroxy-pyrrolidin-2-one (0.79 g), 6-(2-cyclopropyl-ethoxy)-pyridin-3-ol (1.4 g), triphenylphosphine (2.25 g), DCM (30 mL) and THF (20 mL) was added DIAD (1.74 g). After 2 days the mixture was filtered and the filtrate was evaporated. The residue was purified by SGC (eluent: EA/MeOH 9:1) to provide the title compound. MS ESI+: m/z=263 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([O:13]C)=[O:12])=[N:3]1.[OH-].[Na+].Cl>CO.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=[O:12])=[N:3]1
Reactant: COC(=O)c1nn(C)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1nc(C(=O)O)c2ccccc21
Yield: 92.1 %

Procedure:
A solution of 1-methylindazole-3-carboxylic acid, methyl ester (1.00 g, 0.0053 mol) was stirred in a mixture of methanol (10 mL)/2N NaOH solution (120 mL) at reflux temperature for 2 hours. After cooling, the mixture was diluted with water (100 mL) and acidified with 6N HCl solution. The white solid that formed was collected by filtration and dried under ambient conditions for 6 days to give 0.86 g (92% yield) of the product; mp 215°-216° C.