Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[C:14]([C:18]#[N:19])=[C:15]([NH2:17])[S:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>>[C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[C:14]([C:18]#[N:19])=[C:15]([NH:17][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([O:21][CH3:20])[CH:23]=3)[S:16][C:10]=2[CH2:9]1)=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc(N)c2C#N)C1
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)Nc2sc3c(c2C#N)CCN(C(=O)OC(C)(C)C)C3)c1

Procedure:
Prepared according to general procedure A starting from 2-amino-3-cyano-4,7-dihydro-thieno[2,3-c]pyridine-6(5H)-carboxylic acid 1,1-dimethylethyl ester (compound A2) and 3-methoxybenzoyl chloride.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([NH2:12])[CH2:9][CH2:10][NH2:11]>N1C=CC=CC=1>[NH2:11][CH2:10][CH2:9][CH2:8][NH:12][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1ccccn1
Reactant: NCCCN
Solvent: c1ccncc1
Product: NCCCNc1ccccn1

Procedure:
To a stirring solution of 2-fluoropyridine in pyridine (0.5 M) was added 1,3-propanediamine (5 eq), and the solution was refluxed overnight. The solution was then concentrated in vacuo and the residue was partitioned between ethyl acetate and 10% sodium carbonate. The phases were separated, and the organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (silica; 10:1:1 EtOH/NH4OH/H2O) to afford a viscous pale yellow oil. EI-MS m/z 152 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].O1CCCC1.C([Li])CCC.C([O:22][B:23](OCCC)[O:24]CCC)CC>CCCCCC>[F:1][C:2]1[C:3]([F:8])=[CH:4][CH:5]=[CH:6][C:7]=1[B:23]([OH:24])[OH:22]
Reactant: CCCOB(OCCC)OCCC
Reactant: Fc1ccccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1cccc(F)c1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
1,2-Difluorobenzene (40 g, 0.35 mol) and dry tetrahydrofurane (400 ml) were placed in 1 L flask equipped with mechanical stirrer, nitrogen inlet and outlet, pressure-equilibrated dropping funnel and thermometer. The reaction flask was flushed with nitrogen and minor flow was held during whole reaction time. The mixture was cooled down to −78° C. with dry ice/acetone bath and 2.5 mol/L hexane solution of n-butyllithium (140 ml; 0.35 mol) was added dropwise, keeping the reaction temperature below −70° C. After addition of all butyllithium solution the mixture was stirred at −78° C. for 2 h and then tripropylborate (66 g, 0.35 mol) was added dropwise keeping the reaction temperature below −70° C. After addition of tripropyl borate the cooling bath was removed and the reaction mixture continuously stirred to reach the room temperature then the solvents were evaporated. The thick liquid residue was acidified and then propanol was evaporated and the remaining solid was filtered off, washed out with hexane and recrystalized from water. The white crystalline product 47 g was obtained, with 85% of theor. yield.
Reaction SMILES: CN([SiH3])[Si:3]([CH3:6])(C)[CH3:4].[F:8][C:9]([F:20])([F:19])[C:10]([O:12]C(=O)C(F)(F)F)=[O:11]>>[F:8][C:9]([F:20])([F:19])[C:10]([O:12][SiH:3]([CH3:6])[CH3:4])=[O:11]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CN([SiH3])[Si](C)(C)C
Product: C[SiH](C)OC(=O)C(F)(F)F

Procedure:
Additionally, for example when mixing tetramethyldisilazane as the silicon compound B and trifluoroacetic anhydride as the acid B, the trifluoroacetic anhydride is rapidly reacted to form dimethylsilyl trifluoroacetate as the acid A.
Reaction SMILES: [CH:1](=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8].N1CCCCC1>C(O)(=O)C>[C:7](/[C:9](=[CH:1]\[CH2:2][CH:3]([CH3:5])[CH3:4])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8]
Reactant: CC(C)CC=O
Reactant: CCOC(=O)CC#N
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)/C(C#N)=C/CC(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
To a mixture of 3.00 mL (28.0 mmoles) of isovaleraldehyde and 3.00 mL (28.1 mmoles) of ethyl cyanoacetate in 4.0 mL of glacial acetic acid was added a solution of 0.10 mL of piperidine in 1.0 mL of glacial acetic acid. This mixture was subsequently stirred at room temperature for 18 hours, after which the product was isolated by diluting the mixture with 50 mL of 10% aqueous sodium chloride and extraction with ether. The combined extracts were washed thoroughly with 50 mL portions of 10% aqueous NaCl, followed by washes with 50 mL of 1:1 (v/v) 1M aqueous NaOH:saturated brine and saturated brine. The organic extracts were then dried over anhydrous magnesium sulfate and subsequently filtered. Removal of the ether by evaporation at reduced pressure, followed by distillation, afforded 3.91 g (77% yield) of cyanoester 5: bp 78°-90° C. (bath temperature, 0.07 mm).
Reaction SMILES: C(O[CH:4](OCC)[N:5]([CH3:7])[CH3:6])C.[N:11]1([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=[CH:14][N:13]=[N:12]1>>[CH3:4][N:5]([CH3:7])[CH:6]=[C:16]([N:11]1[CH:15]=[CH:14][N:13]=[N:12]1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)Cn1ccnn1
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)C(=CN(C)C)n1ccnn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
44.2 ml (38.0 g, 257.8 mmol) of N,N-dimethylformamide diethyl acetal are added to 20.0 g (128.9 mmol) of the compound from Example 2A, and the mixture is stirred at 100° C. for 16 h. After cooling to RT, the reaction mixture is concentrated under reduced pressure. The residue is triturated with diethyl ether, filtered off and washed with diethyl ether. Yield: 18.0 g (67% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[F:18][C:19]1[CH:47]=[CH:46][C:22]([CH:23]([N:31]2[C:39]3[C:34](=[CH:35][C:36](/[C:40](/[CH3:45])=[CH:41]/[C:42](O)=[O:43])=[CH:37][CH:38]=3)[CH:33]=[CH:32]2)[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:21][CH:20]=1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH:23]([N:31]2[C:39]3[C:34](=[CH:35][C:36](/[C:40](/[CH3:45])=[CH:41]/[C:42]([NH:1][C:2]4[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=4[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:43])=[CH:37][CH:38]=3)[CH:33]=[CH:32]2)[C:22]2[CH:46]=[CH:47][C:19]([F:18])=[CH:20][CH:21]=2)=[CH:25][CH:26]=1
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2ccc(F)cc2)c2ccc(F)cc2)c1
Reactant: CCOC(=O)CCCOc1cc(F)ccc1N
Product: C/C(=C\C(=O)Nc1ccc(F)cc1OCCCC(=O)O)c1ccc2c(ccn2C(c2ccc(F)cc2)c2ccc(F)cc2)c1

Procedure:
169 mg of compound 62 was obtained in a similar manner to those described in the Examples 1 and 2 using 359 mg of ethyl 4-(2-amino-5-fluorophenoxy)butyrate and 300 mg of 3-[1-(4,4'-difluorobenzhydryl)indol-5-yl] isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:13][C:14]3[N:18]([CH3:19])[N:17]=[CH:16][N:15]=3)=[N:7][NH:8][C:9]2=[O:12])=[C:4](/[N:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[NH:20][CH:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:13]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][N:15]=3)[C:6]3=[N:7][NH:8][C:9](=[O:12])[C:10]([CH:11]=1)=[C:5]23
Reactant: Cn1ncnc1Cc1n[nH]c(=O)c2cc(F)cc(/N=C/c3ccc(F)cc3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncnc1C1c2n[nH]c(=O)c3cc(F)cc(c23)NC1c1ccc(F)cc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 79.4 %

Procedure:
To a suspension of (E)-7-fluoro-5-(4-fluorobenzylideneamino)-4-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)phthalazin-1(2H)-one (8) (2.0 g, 5.3 mmol) in THF (80 mL) was added cesium carbonate (3.4 g, 10.6 mmol). The reaction mixture was stirred at 55° C. for 4 hours and cooled down to room temperature. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated to dryness to afford the title compound as a white solid (1.6 g, yield 80%). LC-MS (ESI) m/z: 381 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.66 (s, 3H), 4.97-5.04 (m, 2H), 6.91-6.94 (dd, J1=2.4, J2=11.2 Hz, 1H), 7.06-7.09 (dd, J1=2.4, J2=8.8 Hz, 1H), 7.14-7.18 (m, 3H), 7.47-7.51 (m, 2H), 7.72 (s, 1H), 7.80 (s, 1H), 12.35 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][P:4]([NH:9][NH2:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[C:18]([NH:10][NH:9][P:4]([O:5][CH2:6][CH3:7])([O:3][CH2:1][CH3:2])=[O:8])(=[O:20])[CH3:19]
Reactant: CCOP(=O)(NN)OCC
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(NNC(C)=O)OCC

Procedure:
Diethylphosphorohydrazidate (5.3 g) and triethylamine (13 ml) were dissolved in dichloromethane (15 ml). To this solution was added dropwise with stirring and cooling a solution of acetyl chloride (7.4 g) in dichloromethane (15 ml). The mixture was then stirred at ambient temperature and then filtered to remove the triethylamine hydrochloride after the addition of 50 ml of anhydrous diethylether. The filtrates were stripped on a rotary evaporator to yield a red-brown oil which was distilled under high vacuum to give a pale yellow liquid, b.p. 180° C./1 mm, identified as the product.
Reaction SMILES: [CH3:1][SH:2].C([O:6][C@H:7]1[CH2:24][C@@:22]2([CH3:23])[C@@H:18]([CH2:19][CH2:20][C@@H:21]2OS(C)(=O)=O)[C@H:17]2[C@@:8]1([F:32])[C@:9]1([CH3:31])[C:14]([CH2:15][CH2:16]2)=[CH:13][C:12](=[O:30])[CH:11]=[CH:10]1)(=O)C.O>CN(C)C=O>[F:32][C@:8]12[C@@H:7]([OH:6])[CH2:24][C@@:22]3([CH3:23])[C@@H:18]([CH2:19][CH2:20][C@H:21]3[S:2][CH3:1])[C@@H:17]1[CH2:16][CH2:15][C:14]1[C@:9]2([CH3:31])[CH:10]=[CH:11][C:12](=[O:30])[CH:13]=1
Reactant: CS
Reactant: CC(=O)O[C@H]1C[C@]2(C)[C@@H](OS(C)(=O)=O)CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Solvent: CN(C)C=O
Solvent: O
Product: CS[C@@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Temperature: 25 °C

Procedure:
To a suspension of 50% sodium hydride/paraffin (100 mg) in dry dimethylformamide (10 ml), cooled and stirred in an ice bath, a stream of methanethiol was passed until a homogeneous solution resulted. (11β,17β)-11-(Acetyloxy)-9-fluoro-17-(methanesulfonyloxy)androsta-1,4-dien-3-one (280 mg, 0.64 mmole) was added and the solution was heated in an atmosphere of nitrogen in a bath at 100°-120° C. for 5.0 hours. The mixture was then cooled to room temperature and water (1.0 ml) was added. After stirring for 20 minutes, the mixture was poured into water and was extracted with chloroform. The chloroform solution was washed with water, dried (anhydrous magnesium sulfate) and evaporated in vacuo. The residue was dissolved in chloroform-hexane (7:3; 15 ml) and absorbed on a column of silica gel (5.0 g). The column was first eluted with chloroform to remove the paraffin. Further elution of the column with chloroform: hexane (9:1) gave the title compound (179 mg) which had a small amount of a slightly less polar impurity (tlc). One crystallization of this from ethyl acetate followed by drying (110° C., 0.3 mm of Hg, 20 hours) gave the analytical specimen (157 mg), melting point 235°-236° C. with consistent spectral data.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH3:8])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CC(Cl)OC(=O)Cl
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCOCCOCCOCCOCCOCCOCCOCCOC(=O)OC(C)Cl

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (Aldrich) was reacted with octaethylene glycol monomethyl ether (TCI) and pyridine in methylene chloride at −78° C. for 3 h to give 1-chloroethyl 2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl carbonate. This was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid in the presence of cesium carbonate in dimethylformamide overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 27-oxo-2,5,8,11,14,17,20,23,26,28-decaoxatriacontan-29-yl-4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid. MS (ES+) m/z calcd. for C51H68Cl2F2N3O15: [(M+H)+]: 1071, found: 1070.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:4]2[C:9]([C:10]=1[C:11]([O:13]CC)=[O:12])=[CH:8][C:7]([CH3:16])=[CH:6][CH:5]=2.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[N:3]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:4]2[C:9]([C:10]=1[C:11]([OH:13])=[O:12])=[CH:8][C:7]([CH3:16])=[CH:6][CH:5]=2
Reactant: CCOC(=O)c1c(C)n(CCc2ccccc2)c2ccc(C)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2c(c1)c(C(=O)O)c(C)n2CCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of ethyl 2,5-dimethyl-1-phenethyl-1H-indole-3-carboxylate (500 mg) and NaOH (500 mg) in ethanol (15 mL) was heated at 100° C. for 3 h at which point the reaction was found complete by TLC and LC-MS. The reaction mixture was acidified to pH 4-5 by adding ethanolic HCl and evaporated under reduced pressure. The residue (1 g), that also contained NaCl generated during NaOH neutralization, was carried forward to next reaction without any purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][C:25]([CH3:32])=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=2)=[CH:19][C:18]=1[CH3:33]>N1C=CC=CC=1>[CH3:31][O:30][C:28]([C:26]1[N:27]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:9]([C:4]3[NH:5][C:6]([CH2:7][CH3:8])=[C:2]([Cl:1])[N:3]=3)=[O:11])=[C:18]([CH3:33])[CH:19]=2)[O:24][C:25]=1[CH3:32])=[O:29]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1nc(-c2ccc(N)c(C)c2)oc1C
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)c(C)o3)cc2C)nc1Cl
Yield: 77.1 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.18 g, 1.03 mmol), thionyl chloride (4 mL), methyl 4-amino-3-methylphenyl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (108e) (0.28 g, 1.14 mmol) and pyridine (5 mL), to obtain 0.32 g of the title compound as a colorless solid (77%).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:3]1[OH:28].[C:29]1([CH2:35][CH2:36][C:37](Cl)=[O:38])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:20]([NH:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH:1][C:37](=[O:38])[CH2:36][CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@H:3]1[OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Reactant: O=C(Cl)CCc1ccccc1
Product: O=C(CCc1ccccc1)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Yield: 145.8 %

Procedure:
1-(6-Benzoylamino-9H-purin-9-yl)-3-(3-phenylpropionylamino)-1,3-dideoxy-β-D-ribofuranuronic acid (490 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid (250 mg) prepared in Example 1 with 3-phenylpropionyl chloride (132 mg) according to a similar manner to that of Example 17.
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][C:10]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>CO>[C:15]([C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][C:11]=1[OH:14])[CH:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]2)(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)C1CCc2cc(C(=O)c3ccccc3)c(O)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(c1ccccc1)c1cc2c(cc1O)C(C(=O)O)CC2
Reaction time: 3 h

Procedure:
A solution of 8.2 g of 5-benzoyl-6-hydroxy-indane-1-carboxylic acid methyl ester in 150 ml of methanol is mixed with 20 ml of 2 N sodium hydroxide solution and the mixture is boiled for 3 hours under reflux. It is then evaporated to dryness in vacuo and the evaporation residue is partitioned between 100 ml of 2 N hydrochloric acid and 3 times 100 ml of methylene chloride. The organic phases are washed until neutral, dried over sodium sulphate, treated with active charcoal and evaporated in vacuo. The evaporation residue, when crystallized from ethanol-petroleum ether, gives 5-benzoyl-6-hydroxy-indane-1-carboxylic acid in the form of yellow platelets of melting point 185-7° C.
Reaction SMILES: C([N:8]([CH:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])C1C=CC=CC=1>[Pd].C(O)C>[CH2:14]([O:13][C:11]([CH2:10][CH2:9][NH:8][CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:12])[CH3:15]
Reactant: CCOC(=O)CCN(Cc1ccccc1)C(C(=O)OCC)C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCNC(C(=O)OCC)C(=O)OCC
Reaction time: 5.5 h
Yield: 89 %

Procedure:
55 g. (0.15 moles) of diethyl N-benzyl-N-(2-ethoxycarbonylethyl)-amino-malonate prepared according to Example 1 (a) are dissolved in 400 ml. of ethanol and subjected to hydrogenation in the presence of 22 g. of palladium-on-charcoal. Hydrogenation is carried out at 40° to 50° C. for 3 hours and at room temperature for 5 to 6 hours. After filtering off the catalyst the solution is evaporated in vacuo. 37 g. (89%) of diethyl N-(2-ethoxycarbonylethyl)-amino-malonate are obtained. By crystallization from ethanol saturated with hydogen chloride gas upon addition of ether the corresponding hydrochloride is obtained. Yield. 38.3 g. (82%) of diethyl N-(2-ethoxycarbonylethyl)-amino-malonate hydrochloride, melting at 156° to 157° C. (Ethanol/ether).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[O:22]=[C:23]1[C:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:26][CH2:25][N:24]1[CH2:41][C:42](O)=[O:43].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][CH2:11][N:12]([C:42](=[O:43])[CH2:41][N:24]3[CH2:25][CH2:26][CH2:27][C:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]3=[O:22])[CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(bis(4-fluorophenyl)methyl)piperazine (0.14 g, 0.5 mmol) in dichloromethane (10 mL) under nitrogen was added 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.16 g, 0.50 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.19 g, 1.00 mmol) and N,N-dimethylpyridin-4-amine (6 mg, 0.05 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:3) gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.18-7.36 (m, 14H), 6.95-7.01 (m, 4H), 4.22 (s, 1H), 4.19 (s, 2H), 3.63 (t, J=4.7 Hz, 2H), 3.48 (t, J=6.4 Hz, 2H), 3.41-3.46 (m, 2H), 2.60-2.65 (m, 2H), 2.31-2.39 (m, 4H), 1.78-1.87 (m, 2H)); MS (DCI+) m/z 580 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Cl[CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(=O)CC>[C:18]1([CH3:21])[CH:17]=[CH:16][C:15]([S:12]([N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]2[C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:31])[CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:33][CH2:34][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:28][CH:29]=2)=[O:22])(=[O:13])=[O:14])=[CH:20][CH:19]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1
Reactant: ClCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccc(OCCN3CCCC3)cc2)C(=O)O)cc1

Procedure:
The methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)-L-prolyl-L-tyrosine methyl ester with 1-(2-chloroethyl)pyrrolidine in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide. The title compound was prepared using the procedure described in Method 7 as a solid, mp=127-130° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:19]=2)[C:14]([O:16]CC)=[O:15])=[CH:3][CH:2]=1.O[Li].O>C1COCC1.O>[N:1]1[CH:2]=[CH:3][C:4](/[CH:7]=[CH:8]/[C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:19]=2)[C:14]([OH:16])=[O:15])=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cncc(/C=C/c2ccncc2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cncc(/C=C/c2ccncc2)c1

Procedure:
A mixture of Example 18A (1.60 g, 6.3 mmol) and LiOH.H2O (2.64 g) in THF/water (50 mL/50 mL) was stirred at room temperature for 2 hours. The THF was removed under vacuum and the aqueous layer was acidified with 1N HCl (aq.). The solid was collected by filtration and dried to provide the desired product. MS (DCI/NH3) m/e 227 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH:23]=[CH:24][C:25]3[C:30]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)=[CH:29][CH:28]=[C:27]([C:41]#[N:42])[CH:26]=3)=[CH:17][C:16]=2[C:43]([F:46])([F:45])[F:44])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:48](=[O:56])[CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([C:48]([CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[O:56])[CH2:22][CH:23]=[CH:24][C:25]3[C:30]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)=[CH:29][CH:28]=[C:27]([C:41]#[N:42])[CH:26]=3)=[CH:17][C:16]=2[C:43]([F:46])([F:44])[F:45])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(COc2ccc(C#N)cc2C=CCNc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)c(C(F)(F)F)c2)cc1
Reactant: CCOC(=O)CCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CCC(=O)N(CC=Cc1cc(C#N)ccc1OCc1ccc(OC)cc1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To 4-(N′-(t-butoxycarbonyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-((4-methoxybenzyl)oxy)-3-cyanophenyl)prop-2-en-1-yl)benzenamine (1.39 g) in 20 mL of CH2Cl2 was added ethyl 4-chloro-4-oxobutyrate (0.43 g) and pyridine (1 mL) at 0° C. The resulting solution was allowed to warm to ambient temperature for 30 minutes and then diluted with 100 mL CH2Cl2. The organic layer was washed with saturated copper sulfate, dried and concentrated to afford 4-(N′-(t-butoxycarbonyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(ethoxycarbonyl)ethylcarbonyl)-N-(3-(6-((4-methoxybenzyl)oxy)-3-cyanophenyi)prop-2-en-1-yl)benzenamine as a blue solid.