Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].Br[CH2:11][CH2:12][CH2:13][CH3:14].[OH-].[Na+]>C(O)C.O>[CH2:11]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][OH:1])[CH2:12][CH2:13][CH3:14]
Reactant: OCc1ccccc1O
Reactant: CCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCOc1ccccc1CO
Temperature: 50 °C
Yield: 77.7 %

Procedure:
A solution of 2-(hydroxymethyl)phenol (Aldrich; 1.24 g, 10 mmol) and 1-bromobutane (Acros; 1.18 ml, 11 mmol) in ethanol (5 ml) (total volume approximately 7 ml) was mixed in a flow reactor (Vapourtec R4, 30 ml PFA tubing, 110° C.) with a solution of aqueous NaOH (2 N, 5 ml, 10 mmol) in water (2 ml). The reagents were each pumped at 0.5 ml/min), giving a reaction time of 30 minutes. After the 30 ml reactor, the solution passed through a second “cooling” reactor (5 ml) at 50° C. At the reactor output, a 250 psi back pressure regulator was used. After all starting solutions had been consumed, the system was purged with an additional 70 ml solvent (1:1, ethanol:water). The collected material was concentrated in vacuo. The residue was partitioned between water and EtOAc, and treated with saturated aqueous sodium bicarbonate solution. The aqueous phase was further extracted with EtOAc, and the combined organic extracts were dried (hydrophobic frit) and concentrated in vacuo. The residue was purified on silica (100 g) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and concentrated in vacuo to give the title compound (1.4 g); LCMS (System 4): MNH4+=198, tRET=2.51 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:44])=[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:32]=[CH:33][C:34]3[O:38][C:37]([C:39]([O:41]C)=[O:40])=[N:36][C:35]=3[CH:43]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:1][C:2]1[C:3]([F:44])=[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])([CH3:25])[CH3:26])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:32]=[CH:33][C:34]3[O:38][C:37]([C:39]([OH:41])=[O:40])=[N:36][C:35]=3[CH:43]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)ccc2o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc3oc(C(=O)O)nc3c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 12.4 %

Procedure:
A solution of chiral methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)benzo[d]oxazole-2-carboxylate (64.5 mg, 0.101 mμmol) in THF (5 ml) was reacted with LITHIUM HYDROXIDE MONOHYDRATE (17.1 mg, 0.407 mmol) in water (2.5 ml) and stirred at rt for 4.5 hrs. The reaction mixture was treated with 1 N HCl (pH 5-6) and extracted with ethyl acetate. The organic extracts were washed with water, brine, dried with sodium sulfate, filtered and purified by silica gel chromatography with methylene chloride and methanol to give chiral-5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)benzo[d]oxazole-2-carboxylic acid (7.8 mg., 12.4%) a white lyophilized solid. MS (ES+) m/z Calcd: [(M+H)+]: 627.13. found: 627.2. and chiral (2R,3S,4R,5S)—N-(benzo[d]oxazol-5-yl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamide (38.3 mg., 65.3%) as a white lyophilized solid. MS (ES+) m/z Calcd: [(M+H)+]: 583.14. found: 583.2.
Reaction SMILES: [CH2:1]([OH:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(C1C(=O)C(Cl)=C(Cl)[C:15](=[O:16])C=1C#N)#N>CO>[C:1]([O:16][CH3:15])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: OCC=Cc1ccccc1
Solvent: CO
Product: COC(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
A homogeneous mixture containing cinnamyl alcohol (7.5 mmol), DDQ (22.5 mmol), MeOH (20 mL) is taken in a round bottom flask and catalytic amount of AMBERLYST® 15 (0.1 g) is added to it. The mixture is stirred for 20 hrs at room temperature. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with MeOH (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. Methyl cinnamate is isolated in 86% yield whose NMR values are found matching with reported values as in example 1.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:54])[C@@H:6]([NH:23][C:24]([C@@H:26]1[CH2:35][C:34]2[CH:33]=[C:32]3[O:36][CH2:37][C@H:38]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH:48]5[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]5)=[CH:42][CH:41]=4)[O:39][C:31]3=[CH:30][C:29]=2[CH2:28][NH:27]1)=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])=[CH:10][CH:9]=1.[CH:55](=O)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[CH3:3][O:4][C:5](=[O:54])[C@@H:6]([NH:23][C:24]([C@@H:26]1[CH2:35][C:34]2[CH:33]=[C:32]3[O:36][CH2:37][C@H:38]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH:48]5[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]5)=[CH:42][CH:41]=4)[O:39][C:31]3=[CH:30][C:29]=2[CH2:28][N:27]1[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1Cc1ccccc1)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3

Procedure:
(S)-2-{[(3S,8S)-3-(4-Cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester di-hydrochloride (19 mg) was reacted with benzaldehyde according to General Procedure D. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH up to 1:1 hexanes EtOAc+5% MeOH) to give (S)-2-{[(3S,8S)-7-benzyl-3-(4-cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester. This ester was hydrolyzed according to General Procedure B to give the title compound (14 mg). LCMS (m/z): 783.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.N1([CH2:26][OH:27])C2C=CC=CC=2N=N1.[Li+].CC([N-]C(C)C)C>>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([N:9]2[CH2:10][CH2:11][S:12](=[O:15])(=[O:16])[CH2:13][CH2:14]2)[CH2:26][OH:27])[CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCN(Cc2cccc(Br)n2)CC1
Reactant: OCn1nnc2ccccc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=S1(=O)CCN(C(CO)c2cccc(Br)n2)CC1

Procedure:
The title compound was prepared as described in Example 3, Step 1 using 4-[(6-bromopyridin-2-yl)methyl]thiomorpholine 1,1-dioxide (2.94 g, 9.63 mmol), 1H-1,2,3-benzotriazol-1-ylmethanol (2.87, 19.17 mmol), and LDA (16 mL of 1.8 M in tetrahydrofuran/heptane/ethylbenzene) as starting materials. LRMS (APCI) calcd for C11H16BrN2O3S [M+H]+: 335.0, Found: 334.9.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[N:10]([CH2:12][CH2:13][CH2:14][C:15](=O)[NH:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:18]=1[NH2:27])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:1]([O:8][C:9](=[O:29])[N:10]([CH2:12][CH2:13][CH2:14][C:15]1[NH:27][C:18]2[CH:19]=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:17]=2[N:16]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(N)c(NC(=O)CCCN(C)C(=O)OCc2ccccc2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2nc(CCCN(C)C(=O)OCc3ccccc3)[nH]c2cc1OC
Temperature: 150 °C

Procedure:
To a mixture of crude [3-(2-amino-4,5-dimethoxy-phenylcarbamoyl)-propyl]-methyl-carbamic acid benzyl ester acid (obtained from 4-(methylamino)butyric acid and benzylchloroformate) in 6 mL toluene were added a few drops of DMF and 358 mg of TsOH and the reaction mixture was heated at 150° C. for 2 h in the microwave. Saturated aq. NaHCO3 solution was added, the phases were separated and the organic phase was washed with brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. Purification by CC EtOAc-MeOH (95:5) yielded 0.65 g of [3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-carbamic acid benzyl ester as brown oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[S:22](Cl)([CH3:25])(=[O:24])=[O:23].C(N(CC)CC)C.C(OCC)(=O)C>O1CCCC1>[C:15]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:22]([CH3:25])(=[O:24])=[O:23])([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCCCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCCCCCCCCCOS(C)(=O)=O
Reaction time: 1 h

Procedure:
To a solution of 8.96 g of tert-butyl N-(12-hydroxydodecyl)carbamate in 60 ml of tetrahydrofuran were successively added dropwise under ice-cooling 2.1 ml of mesyl chloride and 3.8 ml of triethylamine and the mixture was stirred for one hour. To the reaction solution was added ethyl acetate and the mixture was washed successively with water, a saturated aqueous solution of sodium hydrogen carbonate, water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to afford 8.06 g of the title compound.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[Br:13][C:14]1[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=1.[C:22]([N:29]1[CH2:36][CH2:35][CH2:34][C@H:30]1[C:31](O)=O)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O.C(O)(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]2[N:20]=[C:31]([C@@H:30]3[CH2:34][CH2:35][CH2:36][N:29]3[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[NH:21][C:16]=2[CH:15]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(Br)cc2[nH]1
Temperature: 85 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
EDCI.HCl (16.9 g, 88.0 mmol) was added to a mixture of 4-bromobenzene-1,2-diamine (15.0 g, 80.0 mmol), N-Boc-L-proline (18.13 g, 84.0 mmol) and 1-hydroxybenzotriazole (12.28 g, 80.0 mmol) in CH2Cl2 (500 mL) and stirred at ambient conditions for 16 h. The mixture was then diluted with water. The resulting white precipitate was filtered away and the layers were separated. The organic layer was washed with water, dried (brine; Na2SO4), filtered and concentrated in vacuo to provide a brown foam. Acetic acid (300 mL) was added to the foam and the mixture was heated at 85° C. (bath temperature) for 5 h. The volatile component was removed in vacuo and the residue was dissolved in EtOAc, washed with water and the organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The resultant crude material was submitted to flash chromatography (silica gel; 0-37% EtOAc/CH2Cl2). The partially pure material was re-submitted to flash chromatography (silica gel; 20-35% EtOAc/CH2Cl2) to provide (S)-tert-butyl 2-(6-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (17.98 g, 61.2% yield) as yellow foam. LC-MS retention time 1.23 min; Calcd. for C16H20BrN3O2: 365.07 Found m/z 368.07 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min and an analysis time of 4 min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 7.59-7.75 (m., 1H), 7.38-7.53 (m, 1H), 7.31-7.38 (m, 1H), 5.04-5.09 (m, 0.3H), 4.94-5.00 (m, 0.7H), 3.68-3.76 (m, 1H), 3.50-3.59 (m, 1H), 2.34-2.51 (m., 1H), 1.95-2.12 (m., 3H), 1.47 (br s, 3H), 1.15 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:25])[CH:11]=[CH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=[CH:5][C:4]=1[N+:26]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].O.C(OCC)(=O)C>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:25])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=[CH:5][C:4]=1[NH2:26]
Reactant: COc1ccc(NC(=O)C=Cc2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(NC(=O)/C=C/c2cc(OC)c(OC)c(OC)c2)cc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
A solution of N-(4-methoxy-3-nitrophenyl)-3-(3,4,5-trimethoxyphenyl) -2-propenamide (Example 3) (1.3 mmol) in acetone/water (10:5) was heated to 50° C. After 30 minutes, sodium hydrosulfite (Na2S2O4) (26.3 mmol) was added slowly. The resulting mixture was heated at reflux for one hour and then cooled to room temperature. Water was added to the cooled reaction mixture. The product was isolated by extraction with ethyl acetate. The organic layer washed with 10% aqueous NaHCO3 and then dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude product thereby obtained was recrystallized from 2-propanol to yield the title compound, melting point 202-204° C., in 32% yield.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])[CH2:3][CH2:2]1.[Br:15]N1C(=O)CCC1=O>CN(C=O)C>[Br:15][C:11]1[CH:12]=[CH:13][C:8]([NH:7][CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[C:9]([OH:14])[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1ccccc1NC1CCOCC1
Solvent: CN(C)C=O
Product: Oc1cc(Br)ccc1NC1CCOCC1
Yield: 46.6 %

Procedure:
A solution of intermediate D7 (0.66 g, 3.415 mmol) and N-bromosuccinimide (0.669 g, 3.757 mmol) in DMF (10 ml) was stirred at r.t. for 1 h. Subsequently, the r.m. was washed with an aqueous saturated NaHCO3 solution. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/EtOAc 8:2 as eluent). The desired fractions were collected and evaporated in vacuo to yield D9 (0.433 g, 46.6%) as a reddish solid.
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]([OH:21])([C:17]([F:20])([F:19])[F:18])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)([CH3:9])[CH3:8])C.C([Sn](CCCC)(CCCC)[C:28]([O:30]CC)=[CH2:29])CCC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O>[C:28]([C:13]1[CH:12]=[CH:11][C:10]([C:7]([CH3:9])([CH3:8])[CH2:6][C:5]([OH:21])([C:17]([F:20])([F:18])[F:19])[C:4]([OH:3])=[O:22])=[CH:15][CH:14]=1)(=[O:30])[CH3:29]
Reactant: CCOC(=O)C(O)(CC(C)(C)c1ccc(Br)cc1)C(F)(F)F
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(C(C)(C)CC(O)(C(=O)O)C(F)(F)F)cc1

Procedure:
Analogously to the compound above of 4-(4-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, tributyl-1-ethoxyvinyltin, tri-o-tolylphosphine and bis-tri-o-tolylphosphine-palladium(II) chloride in dimethylformamide to 120° C. and subsequent acidic hydrolysis of the enol ether and alkaline saponification, melting point 158-162° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[C:33]1([NH:43]N)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:43][C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=32)=[CH:4][CH:3]=1
Reactant: NNc1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(F)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(F)cc4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 548.2 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].[Cl:15][CH2:16][C:17](Cl)=[O:18].O>C1(C)C=CC=CC=1>[Cl:15][CH2:16][C:17]([NH:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:18]
Reactant: NCCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(CCl)NCCc1ccccc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
β-phenylethylamine (0.68 kg) was taken in dry toluene (4.42 L) and sodium bicarbonate (0.612 kg) was added at 30° C. and cooled to 0-5° C. Chloroacetyl chloride was slowly added under nitrogen blanket at 0-10° C., stirred and maintained for 2 hr. After completion of the reaction, water was added slowly and reaction mass was allowed to attain 33±2° C. and the layers were separated. To the aqueous layer toluene was added, stirred and two layers were separated. To the organic layer dil HCl solution (0.653 L DM water+0.272 L con HCl) was added, stirred and two layers were separated. To the organic layer again sodium bicarbonate solution (0.653 L DM water+0.068 kg sodium bicarbonate) was added, stirred and two layers were separated. Water was added to the organic layer, stirred and two layers were separated. From the organic layer toluene was distilled out, methanol was added, heated to 58° C., stirred. To the reaction mass water was added, temperature was maintained at 58° C., stirred for 1-1.5 hr, cool to 30±2° C. for 3 hrs under stirring. Stirring was continued for 3 hrs at 0-5° C. The reaction mass was filtered, washed with water and dried.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:11]2[N:7]([CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:18][CH:17]=3)[C:10]=2[CH2:14][CH3:15])[CH:6]=1)(=[O:3])[CH3:2].[C:30]([O:34][CH3:35])(=[O:33])[C:31]#[CH:32].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:11]2[N:7]3[C:6]=1[C:31]([C:30]([O:34][CH3:35])=[O:33])=[CH:32][C:8]3=[C:9]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:18][CH:17]=1)[C:10]=2[CH2:14][CH3:15])(=[O:3])[CH3:2]
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2cc(NC(C)=O)ccc12
Reactant: C#CC(=O)OC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(C(=O)OC)c3c(NC(C)=O)ccc1n23
Temperature: 90 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A solution of 6-acetylamino-2-(4-benzyloxyphenyl)-1-ethylindolizine (38.5 g, 0.1 mol) in 3000 ml of toluene was stirred in a nitrogen atmosphere at 50° C. while methyl propiolate (10.2 ml, 0.115 mol) was added dropwise. The mixture was heated to 90° C. and stirring was continued for 3 hours. The mixture was cooled to 4° C. and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (22.6 g, 0.1 mol) was added in portions. The cooling source was removed and stirring was continued for 16 hours. The mixture was filtered through celite and the celite pad was washed several times with toluene. The combined filtrates were evaporated to app. 500 ml and 1000 ml of petroleum ether was added. The precipitate was filtered off and dried to yield 38.7 g (83%) of the title compound. M.p. 210-13° C. 1H-NMR (DMSO-d6, 200 Hz) δ: 1.38 (t, 3H), 2.27 (s, 3H), 3.15 (q, 2H), 3.96 (s, 3H), 5.18 (s, 2H), 7.20 (d, 2H), 7.35-7.55 (m, 5H), 7.75 (d, 2H), 7.90 (s, 1H), 8.13 (d, 1H), 8.95 (d, 1H), 11.78 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([C:5](=[O:8])[CH2:6][Cl:7])[CH:3]=[O:4].[CH2:10](O)[CH2:11][OH:12].O>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:7][CH2:6][C:5](=[O:8])[C:2]([CH:3]1[O:12][CH2:11][CH2:10][O:4]1)([CH3:9])[CH3:1]
Reactant: OCCO
Reactant: CC(C)(C=O)C(=O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C(=O)CCl)C1OCCO1
Yield: 79.4 %

Procedure:
204 g (1.38 mol) of 2,2-dimethyl-4-chloro-3-keto-butanal are heated with 93 g (1.5 mols) of ethylene glycol and 0.7 g of p-toluenesulphonic acid in 400 ml of methylene chloride for 3 hours in a water separator. The organic phase is extracted with 150 ml of 5% strength sodium hydroxide solution, and thereafter with 400 ml of water. The solvent is distilled off and the residue is distilled under the vacuum from a water jet. 211 g (79.8% of theory) of 1-chloro-3-(dioxolan-2-yl)-3-methylbutan-2-one of boiling point 127°-28° C./14 mbar are obtained. ##STR24##
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][NH:27]2>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][NH:27]2)(=[O:3])[CH3:2]
Reactant: Nc1cccc2[nH]ccc12
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cccc3[nH]ccc23)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 55 mg (0.417 mmol) of 4-aminoindole was added. The resulting mixture was stirred at room temperature for one hour and the final product was collected by filtration and washed with diethylether to yield the title compound (83 mg, 79.8% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][C:11]([OH:13])=[O:12])=[C:4]([F:14])[CH:3]=1>C(OCC)(=O)C.[Pd]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:4]([F:14])[CH:3]=1
Reactant: O=C(O)C/C=C/c1ccc(Br)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)CCCc1ccc(Br)cc1F
Reaction time: 16 h

Procedure:
To a solution of (E)-4-(4-bromo-2-fluoro-phenyl)-but-3-enoic acid (0.730 g, 2.536 mmol) in ethyl acetate (12 mL) is added palladium on carbon (10% wt., 0.270 g, 0.254 mmol) and the flask is flushed with hydrogen. After 16 hours under a H2 atmosphere (balloon pressure), the mixture is filtered, concentrated and then resubmitted to the same conditions. After 6 hours, the mixture is filtered and concentrated to give 4-(4-bromo-2-fluoro-phenyl)-butyric acid, which is used in the next step without purification.