Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)C1C=CC=C(CNC(=O)C2C=CC(OC)=C(OC)C=2)C=1.IC.[H-].[Na+].[OH-].[Na+].Cl.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:51]=[CH:52][C:53]=1[O:54][CH3:55])[C:37]([N:39]([CH2:41][C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](O)=[O:46])[CH3:40])=[O:38].[C:56]([O:60][C:61]([N:63]1[CH2:72][CH2:71][C:70]2[C:65](=[CH:66][CH:67]=[C:68]([NH2:73])[CH:69]=2)[CH2:64]1)=[O:62])([CH3:59])([CH3:58])[CH3:57].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:56]([O:60][C:61]([N:63]1[CH2:72][CH2:71][C:70]2[C:65](=[CH:66][CH:67]=[C:68]([NH:73][C:45](=[O:46])[C:44]3[CH:48]=[CH:49][CH:50]=[C:42]([CH2:41][N:39]([C:37](=[O:38])[C:36]4[CH:51]=[CH:52][C:53]([O:54][CH3:55])=[C:34]([O:33][CH3:32])[CH:35]=4)[CH3:40])[CH:43]=3)[CH:69]=2)[CH2:64]1)=[O:62])([CH3:59])([CH3:57])[CH3:58]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Reactant: COc1ccc(C(=O)N(C)Cc2cccc(C(=O)O)c2)cc1OC
Agent: COC(=O)c1cccc(CNC(=O)c2ccc(OC)c(OC)c2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(C(=O)N(C)Cc2cccc(C(=O)Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)C4)c2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-[(3,4-Dimethoxy-benzoylamino)-methyl]-benzoic acid methyl ester (100 mg, 0.32 mmol), was dissolved in 5 mL DMF. Iodomethane (20 mL, 0.32 mmol) and NaH (15 mg, 0.62 mmol) were added. The mixture was stirred at room temperature for 2 hours, then diluted with 15 mL water and extracted with 3×10 mL ethyl acetate. The combined organic solvent was dried with Na2SO4 and evaporated to give 80 mg of crude product which was used without purification. The intermediate, 3-{[(3,4-dimethoxy-benzoyl)-methyl-amino]-methyl}-benzoic acid methyl ester, was dissolved in methanol (20 mL). NaOH (2 mL, 4M, 8 mmol) was added and the mixture was stirred at room temperature overnight, then diluted with 20 mL water. The resulting solution was neutralized with 1N HCl and extracted with dichloromethane (3×15 mL). Evaporation of the solvent afforded 80 mg of crude product as yellow oil which was used without further purification. The intermediate, 3-{[(3,4-dimethoxy-benzoyl)-methyl-amino]-methyl}-benzoic acid (80 mg, 0.24 mmol) was combined with 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (70 mg, 0.28 mmol), EDC (80 mg, 0.51 mmol) and HOBt (80 mg, 0.59 mmol) in a reaction vial. DMF (2 mL) was added followed by Hunig's base (0.1 mL, 0.57 mmol). The mixture was stirred at room temperature for 16 h. The product was purified by preparative HPLC using an acetonitrile/water/formic acid gradient providing the intermediate, 6-(3-{[(3,4-dimethoxy-benzoyl)-methyl-amino]-methyl}-benzoylamino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester, as a yellow oil. This intermediate was dissolved in dichloromethane (4 mL), and trifluoroacetic (1 mL) was added thereafter. The mixture was stirred at room temperature for 2 h. The mixture was concentrated to give the title product as a TFA salt (119 mg, 65% yield, 4 steps); MS, electrospray, 460 (M+H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[C:29]([O:37][CH2:38][C:39]([F:42])([F:41])[F:40])[CH:28]=4)[CH:24]=[C:23]([C:43]([F:46])([F:45])[F:44])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:42][C:39]([F:40])([F:41])[CH2:38][O:37][C:29]1[CH:28]=[C:27]([C:25]2[CH:24]=[C:23]([C:43]([F:45])([F:46])[F:44])[N:22]=[C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)[N:26]=2)[CH:32]=[CH:31][C:30]=1[C:33]([F:34])([F:35])[F:36]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.6 %

Procedure:
To a cooled and stirred solution of 3′-{4-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidin-2-yl}-biphenyl-3-sulfonic acid tert-butylamide (0.45 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into saturated NaHCO3 solution (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. Further purification by crystallization (dischloromethane/MeOH/hexane) yielded the title compound as a white solid (0.25 g, 59%). MS (ISP) 622.2 [(M+H)+]; mp 188° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]=[C:10]2[CH2:13][C:14]#[N:15])=[CH:5][CH:4]=1.C(OCC=C)(=O)C(C)=C>C1(C)C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]#[N:15])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(CC#N)=CCC2
Agent: [Pd]
Agent: C=CCOC(=O)C(=C)C
Solvent: Cc1ccccc1
Product: COc1ccc2cccc(CC#N)c2c1
Temperature: 25 °C
Yield: 91 %

Procedure:
There are introduced into a 670 litre reactor 12.6 kg of 5% palladium-on-carbon in toluene, which is heated at reflux; then 96.1 kg of (7-methoxy-3,4-dihydro-1-naphthalenyl)-acetonitrile dissolved in toluene are added as well as 63.7 kg of allyl methacrylate. The reaction is continued at reflux and is followed by vapour phase chromatography. When all the starting substrate has disappeared, the reaction mixture is cooled to ambient temperature and then filtered. After removal of the toluene by evaporation, the resulting solid residue is recrystallised from an ethanol/water (80/20) mixture to give the title product in a yield of 91% and with a chemical purity exceeding 99%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[CH:10](O)=O>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[NH:8][CH:10]=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1cnc(Cl)cc1N
Reactant: O=CO
Product: Clc1cc2nc[nH]c2cn1
Yield: 82 %

Procedure:
A mixture of 6-chloropyridine-3,4-diamine (4.00 g, 27.86 mmol) in formic acid (20.0 mL) was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure to give a brown oil, which was partitioned between EtOAc (300 mL) and a sat'd aq NaHCO3 (100 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (6% to 9% MeOH) to afford 3.5 g (82%) of 6-chloro-3H-imidazo[4,5-c]pyridine as white solid, MS (ESI): m/z=154.1 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:13]([C:21]([O-:23])=[O:22])=[N:14][C:15]([N:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=2)[N:4]=1.[K+].[CH2:25]([O:27][C:28]([O:30][CH:31](Cl)[CH3:32])=[O:29])[CH3:26].O>CN(C)C=O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:13]([C:21]([O:23][CH:25]([O:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:26])=[O:22])=[N:14][C:15]([N:18]([CH3:19])[CH3:20])=[CH:16][CH:17]=2)[N:6]=1
Reactant: CCOC(=O)OC(C)Cl
Reactant: COc1cc(OC)nc(Oc2ccc(N(C)C)nc2C(=O)[O-])n1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)OC(C)OC(=O)c1nc(N(C)C)ccc1Oc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2.0 g (5.6 mmol) of potassium 3-(4,6-dimethoxypyrimidin-2-yl)oxy-6-dimethylaminopicolinate and 0.8 g (5.7 mmol) of 1-(ethoxycarbonyloxy) ethylchloride were suspended in 5 ml of dimethylformamide, and were stirred at room temperature for 6 hours. The reaction mixture was poured into water, and was extracted with ethyl acetate twice. The organic layer was then washed with water and dried, and the solvent was distilled off to obtain a viscous product which was then column-purified to obtain an aimed compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@H:35]([C:37](O)=[O:38])[CH3:36])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH2:73]([O:80][CH2:81][C@@H:82]([NH2:90])[CH2:83][C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1)[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@@H:35]([CH3:36])[C:37]([NH:90][C@@H:82]([CH2:83][C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1)[CH2:81][O:80][CH2:73][C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)=[O:38])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: N[C@H](COCc1ccccc1)Cc1ccccc1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](COCc1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Reaction time: 8 h

Procedure:
To a solution of 20 mg (29 μmol) of N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-2-carboxy-1-methoxypropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide in 1 ml of DMF were added, at RT, 15.3 μl (88 μmol) of N,N-diisopropylethylamine, 6.7 mg (44 μmol) of HOBt and 6.7 mg (35 mmol) of EDC, and the mixture was stirred for 30 min. Subsequently, 7.8 mg (32 μmol) of (2S)-1-(benzyloxy)-3-phenylpropan-2-amine hydrochloride were added. After stirring overnight, the reaction mixture was separated directly into its components via preparative HPLC. 26 mg (98% of theory) of the title compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[C:9]3[CH:19]=[C:20]([CH:23]([CH3:25])[CH3:24])[CH:21]=[CH:22][C:8]=3[S:7][C:6]=2[CH:26]=1.[OH:27][CH2:28][CH2:29]CN1CCNCC1.C(Cl)(Cl)Cl>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([N:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:29][CH2:28][OH:27])[CH2:16][CH2:17]3)[C:9]3[CH:19]=[C:20]([CH:23]([CH3:24])[CH3:25])[CH:21]=[CH:22][C:8]=3[S:7][C:6]=2[CH:26]=1
Reactant: CC(C)c1ccc2c(c1)C(N1CCN(C)CC1)Cc1ccc(F)cc1S2
Reactant: OCCCN1CCNCC1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccc2c(c1)C(N1CCN(CCCO)CC1)Cc1ccc(F)cc1S2

Procedure:
A mixture of 4.0 g 10-chloro-3-fluoro-8-isopropyl-10,11-dihydrodibenzo (b,f) thiepin (Example 1), 4.0 g 1-(3-hydroxypropyl) piperazine (T. Zawisa et al., Acta Polon. Pharm. 22, 477, 1965) and 7 ml of chloroform was refluxed for 5 hours and then processed in the manner described in Example 2. 4.4 g (76%) of an oily base which was converted to a crystalline dimaleate, m.p. 106°-108° C. (ethanol) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br:18]N1C(=O)CCC1=O.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:18])=[CH:6][C:5]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(C)cc1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1-c1ccccc1
Yield: 84.2 %

Procedure:
A mixture of 4-methyl-2-phenylbenzoic acid methyl ester (2.26 g, 10 mmol), prepared as in Example 227B, N-bromosuccinimide (1.87 g, 10.5 mmol) and 2,2′-azobisisobutyronitrile (25 mg) in carbon tetrachloride (40 mL) was stirred at reflux for 7 hours. The reaction mixture was poured into ethyl acetate and extracted with water (2×), aqueous sodium hydrogen sulfite and brine, dried, filtered, and concentrated in vacuo. Chromatography on silica gel (10% ethyl acetate-hexane) gave 4-bromomethyl-2-phenylbenzoic acid methyl ester (2.57 g, 84%).
Reaction SMILES: [H-].[Na+].[Cl-].[CH:4]1([C:7]([C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)=[CH:8][CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5]1.[F:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][C:42]=1[O:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.Cl>CCCCCCC.CS(C)=O>[CH:4]1([C:7]([C:29]2[CH:30]=[CH:31][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:33][CH:34]=2)=[CH:8][CH:9]=[CH:45][C:44]2[CH:47]=[CH:48][C:41]([F:40])=[C:42]([O:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH:43]=2)[CH2:5][CH2:6]1
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: FC(F)(F)Oc1ccc(C(=CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)C2CC2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CCCCCCC
Solvent: CS(C)=O
Product: Fc1ccc(C=CC=C(c2ccc(OC(F)(F)F)cc2)C2CC2)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
Under a nitrogen atmosphere, 14.6 grams (0.36 mole) of sodium hydride (60% in mineral oil) was washed with two 100 mL portions of heptane. The washed sodium hydride was stirred with 350 mL of dimethyl sulfoxide, and the mixture was heated at 50°-55° C. for 3.5 hours until a clear solution formed. The reaction mixture was cooled to 25° C., and a solution of 176.0 grams (0.327 mole) of [3-cyclopropyl-3-(4-trifluoromethoxyphenyl)-2-propen-1-yl]triphenylphosphonium chloride in 300 mL of dimethyl sulfoxide was added in a steady stream. The reaction mixture temperature was maintained at 30° C. or less throughout the addition. Upon completion of addition the reaction mixture was stirred for 30 minutes, and then 69.5 grams (0.323 mole) of 4-fluoro-3-phenoxybenzaldehyde was added in a steady stream during a 15 minute period. The reaction mixture temperature was maintained at 35° during the addition. Upon completion of addition the reaction mixture was stirred for 1 hour and then was poured into a mixture of 2500 mL of aqueous 1N hydrochloric acid in 500 mL of ice. The mixture was stirred until the ice melted and then was extracted with three 1000 mL portions of diethyl ether. The combined extracts were in turn washed with one 1000 mL portion and two 500 mL portions of aqueous 0.5N hydrochloric acid, one 1500 mL portion of an aqueous solution saturated with sodium bicarbonate, two 1000 ml portions of water, and two 500 ml portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 20% methylene chloride in heptane. The appropriate fractions were combined and concentrated under reduced pressure yielding 112.6 grams of 1-cyclopropyl-1-(4-trifluoromethoxyphenyl)-4-(4-fluoro-3-phenoxyphenyl)-1,3-butadiene.
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH:12]([C:13](OCC2C=CC=CC=2)=[O:14])[CH2:11][C:10]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[BH4-].[Na+]>C(O)(=O)C.O.C(OCC)(=O)C>[CH2:1]([O:8][N:9]1[CH:12]([CH2:13][OH:14])[CH2:11][C:10]1=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)C1CC(=O)N1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1CC(CO)N1OCc1ccccc1
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 311 mg. (1 mmole) of 1-benzyloxy-4-benzyloxycarbonylazetidin-2-one in 10 ml. of tetrahydrofuran, cooled in an ice bath, was added a solution of 37 mg. of sodium borohydride in 3 ml. of water. The solution was stirred at ice bath temperature for one hour and was then poured into a separatory funnel containing 25 ml. of ethyl acetate, 25 ml. of water and 2 ml. of acetic acid. After shaking, the layers were separated and the aqueous layer was extracted twice with 25 ml. portions of ethyl acetate. These two extracts were combined with the organic layer. The organic layer was washed twice with 15 ml. portions of 5% aqueous sodium bicarbonate and 15 ml. of brine and was dried over sodium sulfate, filtered and evaporated to give the product as a crude oil. The oil was chromatographed on silica gel with gradient elution (30% ethyl acetate -70% hexanes to 100% ethyl acetate) The fraction containing the purified product (Rf=0.15, silica gel thin layer in 1:1 ethyl acetate-hexanes) was evaporated to yield 121 mg. (61% yield) of the product as an oil.
Reaction SMILES: C[Si](C)(C)Cl.[NH:6]1[C@@H:14]2[C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16].Cl.[C:19]([C@@H:24]([NH:28][C@H:29]([C:31](Cl)=[O:32])[CH3:30])[CH2:25][CH2:26][CH3:27])([O:21][CH2:22][CH3:23])=[O:20].[OH-].[Na+]>ClCCl.[Cl-].[Na+].O.C(N(CC)CC)C>[CH3:27][CH2:26][CH2:25][C@H:24]([NH:28][C@H:29]([C:31]([N:6]1[C@H:7]([C:15]([OH:17])=[O:16])[CH2:8][C@H:9]2[C@@H:14]1[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:32])[CH3:30])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCC[C@H](N[C@@H](C)C(=O)Cl)C(=O)OCC
Reactant: O=C(O)[C@@H]1C[C@@H]2CCCC[C@@H]2N1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC[C@H](N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@@H]21)C(=O)OCC
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
Trimethylchlorosilane (2.86 ml) and triethyl amine (3.08 ml) were added to (2S,3aS,7aS)-octahydroindole-2-carboxylic acid (3.72 g) in dichloromethane (60 ml) at 20-25° C. and stirred at 20-25° C. for two hours. After two hours triethyl amine (2.8 ml) was added, the suspension was cooled to −15° C., a suspension of N-((S)-1-carbethoxybutyl)-L-alanyl chloride hydrochloride (5.5 g) in dichloromethane (60 ml), which has been cooled to −15° C., was poured thereto and the stirring was continued at −15° C. for two hours. The reaction solution was heated to 0° C., brine (25 ml) with dissolved NaOH (0.8 g) was added, and the pH was adjusted to 4.2 with a 20% NaOH solution. The organic phase was separated and the aqueous layer was once more washed with dichloromethane (20 ml). The combined dichloromethane layers were evaporated, the residue was dissolved in ethyl acetate (100 ml), the undissolved part was filtered off and t-butylamine (2.2 ml) was added to the filtrate. The precipitated crystals were dissolved at the boiling point of the solution, the clear solution was cooled to 10-20° C. and the stirring was continued for two hours. After two hours the precipitated crystals were filtered off, washed with ethyl acetate (12 ml) and dried at 35-40° C. in an air drier.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:32])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][C:23]=2[CH:22]=[CH:21][CH:20]=1)C1C=CC=CC=1>[Pd]>[OH:8][NH:9][C:10](=[O:32])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(CCCCCCCOc1cccc2[nH]c3ccccc3c12)NOCc1ccccc1
Agent: [Pd]
Product: O=C(CCCCCCCOc1cccc2[nH]c3ccccc3c12)NO
Yield: 46.2 %

Procedure:
In a manner anologous to that of example 1(c), 8-(9H-Carbazol-4-yloxy)-octanoic acid benzyloxyamide (300 mg, 0.7 mmol) was hydrogenated in the presence of palladium on barium sulfate to give the title compound (110 mg) in 46% yield as an amorphous solid. MS (M−H+)=339.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[O:16])[CH:12]=[C:11]([Cl:24])[C:10]=1[F:25])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[O:16])[CH:12]=[C:11]([Cl:24])[C:10]=1[F:25]
Reactant: CN1CCN(C(=O)c2cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(C(=O)c2cc(Cl)c(F)c(CN)c2)CC1

Procedure:
was prepared according to Scheme C3 (step B) from [3-chloro-2-fluoro-5-(4-methyl-piperazine-1-carbonyl)-benzyl]-carbamic acid tert-butyl ester (165 mg, 0.43 mmol) and TFA (2 mL) in CH2Cl2. MS (LC-MS): 286.0 [M]+; tR (HPLC conditions c): 1.47 min.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)O1.[CH:16]([N:20]1[CH:24]=[C:23](I)[C:22]([C:26]2[S:27][CH:28]=[C:29]([Cl:31])[CH:30]=2)=[N:21]1)([CH2:18][CH3:19])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH:16]([N:20]1[CH:24]=[C:23]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[C:22]([C:26]2[S:27][CH:28]=[C:29]([Cl:31])[CH:30]=2)=[N:21]1)([CH2:18][CH3:19])[CH3:17]
Reactant: CCC(C)n1cc(I)c(-c2cc(Cl)cs2)n1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCC(C)n1cc(-c2ccncc2)c(-c2cc(Cl)cs2)n1
Temperature: 25 °C
Yield: 26.7 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.48 mmol) and bis(tricyclohexylphosphine)palladium(II) chloride (0.04 mmol) were weighed into a microwave vial (reaction volume 2-5 mL). A solution of 1-sec-butyl-3-(4-chloro-2-thienyl)-4-iodo-1H-pyrazole (0.40 mmol) in 3.0 mL degassed dioxane and 1.0 mL of a degassed 2 M aqueous sodium carbonate solution were added. The reaction mixture was purged with argon, the microwave vial was capped with a septum and transferred to a laboratory microwave oven. The reaction mixture was irradiated to a reaction temperature of 120° C. for 12 min. After cooling to room temperature, the reaction mixture was diluted with dioxane and filtered through a short pad of silica. The filtered solid was washed thoroughly with dioxane, ethyl acetate and dichloromethane. The combined filtrates were concentrated in vacuum. The residue was purified by chromatography on silica gel (cyclohexane:ethyl acetate 97:3 to 0:100) to afford 34 mg 4-[1-sec-butyl-3-(4-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (27% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:21]2[CH2:22][CH2:23][NH:24][CH2:25][C:20]=2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1>[Pd].C1(C)C(C)=CC=CC=1>[CH3:26][C:2]1([CH3:1])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
A mixture of 4.20 g. of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine, 0.8 g. of 10% palladium on carbon and 80 ml. of xylene was stirred and refluxed for 25 hours. After cooling, the catalyst was removed by filtration. The filtrate was evaporated in vacuo and the product was recrystallized from autonitrile; m.p. 155°-157°.