Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1>CC#N.C(Cl)(Cl)Cl>[Br-:23].[F:34][C:30]1[CH:29]=[C:28]([CH2:27][O:26][CH2:25][CH2:24][N+:1]23[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)([CH2:3][CH2:2]2)[CH2:7][CH2:8]3)[CH:33]=[CH:32][CH:31]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: Fc1cccc(COCCBr)c1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCOCc3cccc(F)c3)(CC1)CC2
Product: [Br-]
Temperature: 60 °C
Yield: 29.6 %

Procedure:
1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (94 mg, 0.321 mmol) was added to a solution of 1-{[(2-bromoethyl)oxy]methyl}-3-fluorobenzene (75 mg, 0.321 mmol) in 2:3 CH3CN/CHCl3 (4 mL), and the reaction was heated at 60° C. for 3 days. The reaction was concentrated under reduced pressure, and the crude product was washed with EtOAc (3×2 mL). The product was dried under high vacuum to give the title compound (50 mg, 30%). LC/MS ESI RT 1.95 min M+446
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[O:13][CH3:14].[CH2:15]1[CH2:19]O[CH2:17][CH2:16]1.C(Br)(Br)(Br)[Br:21]>>[Br:21][CH2:17][CH2:16][CH2:15][CH2:19][O:11][C:10](=[O:12])[CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:13][CH3:14])[CH:4]=1
Reactant: C1CCOC1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(C=CC(=O)O)ccc1O
Product: COc1cc(C=CC(=O)OCCCCBr)ccc1O
Reaction time: 48 h
Yield: 265.4 %

Procedure:
To a solution of 3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid (10 g, 51.5 mmoles) in THF (400 ml) triphenylphosphine (2.7 g, 10.3 mmoles) and carbon tetrabromide (34.16 g, 10.3 mmoles) are added and the solution is left at room temperature, under magnetic stirring, for 48 hours. The solid is filtered and then evaporated at reduced pressure. The obtained crude product is purified by chromatogrphy on silica gel eluting with n-hexane/ethyl acetate 7/3. 9 g of 3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid 4-bromobutyl ester are obtained. M.p.=86–89° C.
Reaction SMILES: COC1C=CC(C[CH:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20](=[O:36])[C@H:21]([CH:33]([CH3:35])[CH3:34])[NH:22][C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:15]([O:37][C:38](=[O:54])[C@H:39]([CH:51]([CH3:53])[CH3:52])[NH:40][C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])[CH:14]=2)[C:9]([O-:11])=[O:10])=CC=1.C(O)(C(F)(F)F)=O>ClCCl>[C:41]([NH:40][C@H:39]([C:38]([O:37][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[O:19][C:20](=[O:36])[C@H:21]([CH:33]([CH3:35])[CH3:34])[NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH2:12][CH2:8][C:9]([OH:11])=[O:10])=[O:54])[CH:51]([CH3:52])[CH3:53])([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42]
Reactant: COc1ccc(CC(Cc2ccc(OC(=O)[C@@H](NC(=O)OCc3ccccc3)C(C)C)c(OC(=O)[C@@H](NC(=O)OCc3ccccc3)C(C)C)c2)C(=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc(CCC(=O)O)cc1OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Yield: 79.4 %

Procedure:
4-Methoxybenzyl-3,4-di-(N-CBZ-L-valyloxy)hydrocinnamate (10 g, 13 mmol) was dissolved in dichloromethane and 1,1,1 trifluoroacetic acid (30 ml) and left at ambient temperature for 3.5 h. Evaporation under reduced pressure and purification by chromatography (chloroform-methanol, 10:1) yielded 6.7 g (80%) pure title product. The compound can be activated and esterified to a drug or further modified as described below.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([CH2:13][S:14]([CH2:17][S:18]([CH2:21][C:22](O)=O)(=[O:20])=[O:19])(=[O:16])=[O:15])(O)=O>C(O)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:13]/[S:14]([CH2:17][S:18](/[CH:21]=[CH:22]/[C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:20])=[O:19])(=[O:16])=[O:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Solvent: CC(=O)O
Product: O=S(=O)(/C=C/c1ccc(Br)cc1)CS(=O)(=O)/C=C/c1ccc(Br)cc1
Yield: 82 %

Procedure:
A solution of 4-bromobenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 82% yield. m.p. 213-215° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][C:4]=1[NH2:5].[F:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22]C)C(O)=O>>[F:12][C:13]1[CH:14]=[C:15]([C:1]2[O:2][C:3]3[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:4]=3[N:5]=2)[CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: COc1ccc(C(=O)O)cc1F
Reactant: COc1ccc(OC)c(N)c1
Product: Oc1ccc2oc(-c3ccc(O)c(F)c3)nc2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,5-dimethoxyaniline, and 3-fluoro-4-methoxybenzoic acid and was obtained as a white solid, m.p. 262-268° C.; MS m/e 244 (M−H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:12])([F:11])[F:10].[Mg].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[O:25]>CCOCC.C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2([OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: FC(F)(F)Oc1ccccc1Br
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C1(O)c1ccccc1OC(F)(F)F
Temperature: 25 °C
Yield: 45.8 %

Procedure:
A solution of 25 g of 1-bromo-2-trifluoromethoxybenzene in 130 ml of ether is added dropwise to a mixture of 2.8 g of magnesium in 20 ml of ether, the reflux being maintained once it has started. At the end of the addition, the mixture is refluxed for one hour. A mixture of 7.5 g of 5-chloro-1H-indole-2,3-dione in 100 ml of THF is then added, at a temperature below 40° C., followed by refluxing for one hour. After cooling to RT, the reaction mixture is poured into an ice/concentrated HCl mixture and extracted with EtOAc, the organic phase is washed with water and with 1N NaOH solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. 6.5 g of the expected product are obtained after crystallization from a DCM/iso ether mixture (20/80; v/v); m.p.=214° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:30])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:15][CH2:14]2)=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].C(O)C.[H][H]>[C].[Pd].O>[NH2:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:14][CH2:15][N:16]([C:19](=[O:30])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:17][CH2:18]2)=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: COc1ccc(C(=O)N2CCN(c3ccc(N)c(C=CC(=O)O)c3)CC2)cc1OC
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)N2CCN(c3ccc(N)c(CCC(=O)O)c3)CC2)cc1OC
Yield: 29.9 %

Procedure:
2-Amino-5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]cinnamic acid (5 g) was dissolved in a mixed solvent consisting of ethanol and water. After adding 5% palladium-carbon (0.5 g), the mixture was reduced at atmospheric pressure of hydrogen gas. After absorption of theoretical amount of hydrogen gas, the catalyst was removed by filtration and the ethanol-water phase was concentrated to dryness. The residue was dissolved in chloroform and separated through silica gel column chromatography to give 1.5 g of 3-{2-amino- 5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]phenyl}-propionic acid, m.p. 98°-101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([O:13]C)=[O:12])=[C:4]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])(=[O:18])=[O:17])[CH:3]=1.O[Li].O.Cl>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:4]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])(=[O:18])=[O:17])[CH:3]=1
Reactant: COC(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
To a solution of methyl 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]propanoate (545 mg, 1.24 mmol) in THF (10 ml) was added a solution of LiOH.H2O (104 mg, 2.48 mmol) in H2O (2 ml). The reaction was stirred at room temperature for 1.5 hours, acidified with 1M HCl, and was extracted with EtOAc (×2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated. The crude product was triturated with CH2Cl2, filtered, rinsed with H2O, and dried to yield the title compound as beige solid (500 mg, 95%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7](O)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=2)[CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:17].CC(=O)OCC>CC#N>[Cl:17][C:7]1[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:11][N:10]=[C:9]([S:12][CH3:13])[N:8]=1
Reactant: CSc1ncc(OCC2CC2)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CSc1ncc(OCC2CC2)c(Cl)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To the title compound of step 2 (29.00 g, 136.79 mmol) and N(CH3)4C1 (22.47 g, 205.19 mmol) in anhydrous MeCN (300 mL), was added POCl3 (123.93 g, 820.74 mmol). The mixture was stirred at r.t. for 30 min and at 70° C. for 1 h. After concentration under vacuum, EA extractive work up and silica gel chromatography (PE:EA=50:1-5:1) gave the title compound (20 g, 63.6% yield) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.16 (s, 1H), 3.95 (d, J=6.8 Hz, 2H), 2.56 (s, 3H), 1.33-1.28 (m, 1H), 0.72-0.70 (m, 2H), 0.41-0.37 (m, 2H). LCMS: 230.9 (M+1)+
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].N1CCCCC1.[OH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:34]=[CH:33][C:30](C=O)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>C(O)C>[OH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:34]=[CH:33][C:30]([CH:11]=[CH:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=Cc1ccc(N2CCC(O)CC2)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(N3CCC(O)CC3)cc2)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A one liter three necked flask fitted with a dropping funnel, mechanical stirrer and condenser is charged with 34.35 g of 4-nitrophenylacetic acid. Piperidine (16.2 g) is added dropwise over a period of 30 minutes. At the end of the addition, 38.4 g of 4-(4-hydroxypiperidyl)benzaldehyde is added. The reaction mixture is heated at 100° C. for three hours, and at 130° C. for three hours. After cooling, the semi-solid product mass is ground in ethanol in a blender, then filtered, washed, and vacuum dried. The crude product is recrystallized from chlorobenzene, m.p. 248°-250° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:7]Cl)[S:5][CH:6]=1.[NH:9]1[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[N:10]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[N:3]=[C:4]([CH2:7][N:9]2[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[N:10]2)[S:5][CH:6]=1
Reactant: ClCc1nc(Br)cs1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(Cc2nc(Br)cs2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
To a solution (4 mL) of the compound (1.57 g, 7.39 mmol) obtained in Example 30b in N,N-dimethylformamide were added ethyl 1H-pyrazole-4-carboxylate (1.3 g, 9.28 mmol) and potassium carbonate (1.5 g, 10.9 mmol), and the mixture was stirred at 80° C. overnight. The reaction mixture was allowed to cool to room temperature, water was added and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane-hexane/ethyl acetate=70/30) to give the title compound (1.51 g, 66%) as a pale-brown oil.
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:24][C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[C:13]([NH:15][C@H:16]([C:21]([OH:23])=O)[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:34][C@@H:35]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH:36]([OH:41])[C:37]([O:39][CH3:40])=[O:38].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:1]1([CH2:11][CH:12]([CH2:24][C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[C:13]([NH:15][C@H:16]([C:21]([NH:34][C@@H:35]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH:36]([OH:41])[C:37]([O:39][CH3:40])=[O:38])=[O:23])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[C:10]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(O)[C@@H](N)CC(C)C
Reactant: CC(C)C[C@H](NC(=O)C(CC(=O)N1CCOCC1)Cc1cccc2ccccc12)C(=O)O
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)C(CC(=O)N1CCOCC1)Cc1cccc2ccccc12
Reaction time: 8 h
Yield: 38.2 %

Procedure:
To a solution of 83 mg of N-[2-(1-naphthylmethyl)-3-(morpholinocarbonyl)propionyl]-L-leucine and 40 mg of methyl (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoate hydrochloride in 3 ml of N,N-dimethylformamide were added 0.049 ml of diphenylphosphoryl azide and 0.058 ml of triethylamine under ice-cooling, and the mixture was stirred overnight. The reaction mixture was evaporated under reduced pressure, and to the residue was added a 5% aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: chloroform/methanol = 10/1 by volume: Rf = 0.43) to obtain 43 mg of methyl (2RS, 3S)-3-{N-[2-(1-naphthylmethyl)-3-(morpholinocarbonyl)propionyl]-L-leucyl}amino-2-hydroxy-5-methylhexanoate as a white powder.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([N:18]2[CH2:22][CH:21]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]3([C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:37])[CH:19]2[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=2[F:45])=[O:17])[CH2:10][CH2:9]1.C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>ClCCl>[CH3:53][S:54]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([N:18]2[CH2:22][CH:21]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]3([C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:37])[CH:19]2[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=2[F:45])=[O:17])[CH2:10][CH2:9]1)(=[O:56])=[O:55]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)CC1CN(C(=O)NCC2CCNCC2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1CN(C(=O)NCC2CCN(S(C)(=O)=O)CC2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 27, rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid (piperidin-4-ylmethyl)-amide trifluoroacetic acid prepared in Example 44 (35 mg, 0.05 mmol) was reacted with triethylamine and methanesulfonyl chloride (6.5 mg, 0.06 mmol) in dichloromethane to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid (1-methanesulfonyl-piperidin-4-ylmethyl)-amide as a white solid (Yield, 13 mg, 39%).
Reaction SMILES: O=[C:2]([CH:8]([CH3:10])[CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C([O-])(=O)C.[NH4+:15]>CO>[C:4]([OH:6])(=[O:5])[CH3:3].[NH2:15][CH:2]([CH:8]([CH3:10])[CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(=O)C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: CC(=O)O
Product: COC(=O)CC(N)C(C)C
Temperature: 80 °C
Reaction time: 67 h

Procedure:
Ru(OAc)2((R)-dm-binap) (0.221 g, 0.231 mmol), methyl 3-oxo-4-methylpentanoate (10.00 g, 69.4 mmol), ammonium acetate (5.52 g, 69.4 mmol) and methanol (50 mL) were placed in a 100 mL stainless steel autoclave under nitrogen atmosphere, and then the mixture was stirred under a hydrogen pressure of 3 MPa at 80° C. for 67 hours. After completion of the reaction, the solvent was removed by evaporation to give methyl (−)-3-amino-4-methylpentanoate acetate as a crude material (11.42 g). The crude product was treated with 7N ammonia/methanol and analyzed by GLC using a capillary column TC-5HT, indicating that the yield of methyl (−)-3-amino-4-methylpentanoate was 85.7%. The enantiomeric excess of methyl (−)-3-amino-4-methylpentanoate in the crude product was determined to be 97.8% ee by HPLC analysis using a SUMICHIRAL OA-4100R column after conversion into methyl 3-(4-nitrobenzoylamino)-4-methylpentanoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C.C1COCC1>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: BrCc1ccccn1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccn3)c3cc(Cl)ccc23)c1
Temperature: 0 °C

Procedure:
3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.050 g, 0.15 mmol) and 2-(bromomethyl)pyridine hydrobromide (0.049 g, 0.175 mmol) were dissolved in DMF:THF (1:1, 4 mL) and the mixture was cooled to 0° C. Cesium carbonate (0.122 g, 0.373 mmol) was added and the reaction was warmed to 90° C. for 30 minutes. The reaction as submitted to aqueous workup and silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=1.[OH-].[Li+]>O1CCCC1.O>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc(-n2ccccc2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-n2ccccc2=O)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A mixture of ethyl 4-(2-oxopyridin-1(2H)-yl)benzoate (0.40 g, 1.64 mmol) and lithium hydroxide (0.28 g, 6.60 mmol) in tetrahydrofuran/water mixture was stirred at 70° C. for 1 h. The organic solvent was removed in vacuo. The water layer was washed with ethyl acetate (25 mL) and then acidified by addition of 15% hydrochloric acid solution. The solid obtained was collected by filtration, washed with water and dried in air to afford the title compound in 85% yield (0.30 g); 1H NMR (300 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.65 (dd, J=1.9, 6.9 Hz, 1H), 7.51 (d, J=8.5 Hz, 2H), 7.48 (dd, J=1.9, 6.9 Hz, 1H), 6.47 (d, J=9.2 Hz, 1H), 6.31 (dt, J=1.0, 6.9 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.C(N(CC)CC)C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][S:37]([C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The operation is carried out as in Stage 1 of Example 10 starting from 280 mg of the product obtained in Stage 1 of Example 7, 3 ml of methylene chloride, 0.17 ml of triethylamine and 0.128 ml of 4-fluorobenzenesulphonic acid chloride in place of the 4-methyl-benzenesulphonic acid chloride then the reaction medium is agitated at ambient temperature for approximately 30 min. Then 2 ml of water is added, followed by extracting with 3×5 ml of methylene chloride, washing with 5 ml of saturated sodium chloride, drying, evaporating, impasting in 5 ml of ether then in 5 ml of pentane, separating and drying. In this way 360 mg of expected product is obtained.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][CH2:14][CH2:15][OH:16]>N1C=CC=CC=1>[CH3:12][O:13][CH2:14][CH2:15][O:16][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCO
Solvent: c1ccncc1
Product: COCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A slurry of p-toluenesulfonyl chloride (205 g, 1.08 mol) and pyridine (150 mL) is stirred under an argon atmosphere. The temperature is maintained below 5° C. (ice-water bath), while ethylene glycol monomethyl ether (80 ml, 1 mol) is added slowly from a dropping funnel. After the addition is complete, the mixture is stirred for 1 h below 5° C. The mixture is poured into ice-water (1 L) and is extracted with dichloromethane (1.2 l). The organic layer is washed with ice-cold 6 M HCl (3×350 ml), and is reduced to a minimum volume by evaporation in vacuo.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:7][N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]1=[O:14].C(N(CC)CC)C>O1CCCC1>[C:1]([OH:5])(=[O:7])[C:2]([CH3:4])=[CH2:3].[OH:7][N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]1=[O:14]
Reactant: C=C(C)C(=O)Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)O

Procedure:
Methacryloyl chloride (0.1 mol) in 25 ml of tetrahydrofuran was added dropwise with stirring and ice cooling to the solution of N-hydroxysuccinimide (0.1 mol) and triethylamine (0.1 mol) in 100 ml of tetrahydrofuran. After 1 hour of stirring at room temperature the precipitate is removed and filtrate is evaporated in vacuum. The residue was crystallized from methanol to give the product with 75% yield. M.P. 102-104° C.; M.p. lit. 103° C. (H.-G. Batz et al. Angew. Chem. Intern. Edit., 1972, v.11, N12, 1103-1104).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([NH:15][CH2:16][CH2:17][CH3:18])[CH2:10]2)(=[O:3])[CH3:2].[CH:19](O)=O.C=O.N>C(Cl)Cl.O>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH2:10]2)(=[O:3])[CH3:2]
Reactant: O=CO
Reactant: CCCNC1CCc2c(cccc2NC(C)=O)C1
Agent: C=O
Agent: N
Solvent: O
Solvent: ClCCl
Product: CCCN(C)C1CCc2c(cccc2NC(C)=O)C1

Procedure:
2.46 g (0.010 mol) of 5-acetylamino-2-n-propylamino-tetraline (Example 4.1.1) are heated with 2.34 g (0.050 mol) of formic acid and 2.2 ml of 30% formalin solution (0.022 mol of formaldehyde) for 30 minutes over a boiling water bath. The reaction mixture is shaken with 50 ml of water, 50 ml of methylene chloride and 2 ml of conc. ammonia. The aqueous phase separated off is extracted twice more with 15 ml of methylene chloride. The combined methylene chloride extract are washed with 20 ml of water, dried with sodium sulphate and concentrated by evaporation, after removal of the drying agent, in a rotary evaporator, finally at 80° C. under a total water jet vacuum. The residue is crystallised from 5 ml of acetone and 20 ml of petroleum ether. The title compound is obtained in a yield of 1.80 g (69.2% of theory) and with a melting point of 78° C.