Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH:24](=O)[CH3:25]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][CH2:24][CH3:25])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: CC=O
Product: CCNc1c[nH]nc1-c1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)N3CC

Procedure:
5-Ethyl-2-(4-ethylamino-1H-pyrazol-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (100 mg, 0.32 mmol) and acetaldehyde (30 μl, 0.53 mmol). The title compound was obtained as light grey powder (23 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([O:13][C:14]([C:16]1[NH:17][C:18]([CH:27]=O)=[C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[C:20]=1[CH3:21])=[O:15])[CH3:12]>>[CH2:11]([O:13][C:14]([C:16]1[NH:17][C:18]([CH:27]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[C:20]=1[CH3:21])=[O:15])[CH3:12]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCOC(=O)c1[nH]c(C=O)c(CCC(=O)O)c1C
Product: CCOC(=O)c1[nH]c(C=C2C(=O)Nc3ccccc32)c(CCC(=O)O)c1C
Yield: 65 %

Procedure:
Oxindole (0.25 g, 1.88 mmol) was condensed with 4-(2-carboxyethyl)-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.5 g, 1.97 mmol) to give 0.45 g (65%) of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]2[S:9](=[O:19])[C:10]([C:16](O)=[O:17])=[C:11]([O:12][CH:13]([CH3:15])[CH3:14])[C:7]=2[CH:6]=1.S(Cl)(Cl)=O.[NH3:26].Cl>[Cl-].[Na+].O.C1COCC1.CN(C=O)C>[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]2[S:9](=[O:19])[C:10]([C:16]([NH2:26])=[O:17])=[C:11]([O:12][CH:13]([CH3:15])[CH3:14])[C:7]=2[CH:6]=1
Reactant: COc1ccc2c(c1)C(OC(C)C)=C(C(=O)O)S2=O
Reactant: N
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)C(OC(C)C)=C(C(N)=O)S2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
Sodium hydride (326 mg, 8.15 mmol) is washed free of oil and added to a room temperature solution of 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxylic acid-1-oxide (2.30 g, 8.1 mmol) in a solvent system consisting of 25 mL of DMF and 75 mL of THF. After stirring at room temperature for 1.5 hours, the thick precipitate is cooled to -10° C. and thionyl chloride (713 μL, 9.78 mmol) is added. After 2 hours the solution is cooled to -78° C. resulting in the formation of a suspension. Ammonia gas is introduced under the surface for about 1 minute. After 10 minutes the reaction mixture is poured into a mixture of 6N HCl and brine. The organic phase is washed with additional acidic brine followed by saturated NaHCO3, then brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The resulting solid is recrystallized from EtOAc:hexane to provide 1.44 g (63%) of 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide-1-oxide; mp 168.5°-169.5° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[C:6]([O:13][CH3:14])[CH:5]=1.[CH2:15](I)[CH3:16]>CN(C=O)C>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:15][CH3:16])=[C:6]([O:13][CH3:14])[CH:5]=1
Reactant: COc1cc(Br)cc2[nH]ccc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc2c(OC)cc(Br)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.6 %

Procedure:
NaH (96 mg, 4 mmol) was suspended in 7 mL DMF in a round bottom flask and cooled to 0° C. 6-bromo-4-methoxy-1H-indole (0.75 g, 3.3 mmol) was added dropwise as a solution in DMF (1 mL). Ethyl iodide (0.28 mL, 3.5 mmol) was added dropwise and the reaction mixture was stirred for 10 min. Volatiles were removed under reduced pressure and the residue partitioned between DCM and water. The aqueous layer was extracted with DCM and the combined organics layers were dried over MgSO4, filtered, and evaporated to give a red oil. The resulting residue was purified on silica gel column chromatography eluting with hexanes/ethyl acetate (0-10%) to afford pure 36-2 (584 mg, 70%) as a white solid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19].Cl>C1COCC1>[CH2:15]([C:2]([CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:16][CH2:17][CH:18]=[CH2:19]
Reactant: C=CCCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCCC(CCCC=C)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diethyl malonate (25 g, 156 mmol) was dissolved in 150 mL dry THF in a 3 necked round bottom flask, and NaH (18.74 g of 60% dispersion in mineral oil, 469 mmol, 3.0 eq.) was added portionwise. The suspension was magnetically stirred for 30 minutes. Subsequently, 58.1 g 5-bromo-1-pentene (390 mmol, 2.5 eq.) was added in one portion via syringe. The yellow suspension was heated at reflux overnight and cooled to room temperature. Aqueous 1 M HCl was added until the pH of the mixture was ≦7. The THF was removed via rotary evaporation and diethyl ether (300 mL) was added. The mixture was extracted with 2×150 mL aqueous 1 M HCl and 2×150 mL brine. The organic layer was then dried over MgSO4, filtered, and concentrated to give a yellow-brown oil, diethyl di-(4-pentenyl)malonate. This oil was placed in a 500 mL round-bottomed flask and 100 mL ethanol was added, followed by a large excess (30 g, ˜5 eq.) of NaOH, some of which did not dissolve. H2O (5 mL) was added and the resulting mixture was stirred at reflux overnight. Subsequently, the entire mixture was poured into a large beaker, cooled to 0° C. using an ice water bath, and stirred (additional H2O may be added to dissolve any residual solids interfering with stirring). Concentrated aqueous HCl was added portionwise until the pH of the mixture was ≦7; solids were formed upon acidification. Diethyl ether (300 mL) was added to the mixture at room temperature, and the aqueous layer was extracted with 2×150 mL diethyl ether. The combined organic layers were extracted with 4×150 mL 1 M aqueous NaOH. The combined aqueous fractions from the extractions were then transferred to a beaker and acidified with concentrated aqueous HCl until the pH of the mixture was ≦7. Diethyl ether (200 mL) was added. The aqueous layer was extracted with 3×100 mL diethyl ether, and all of the combined organic layers were dried over MgSO4 and filtered. Volatiles were removed to give 2,2-di-(4-pentenyl)malonic acid as a yellow-brown oil. Subsequently, 2,2-di-(4-pentenyl)malonic acid (60 g, 250 mmol) was placed in a large round-bottomed flask equipped with a reflux condenser and heated with vigorous magnetic stirring to 200° C.–210° C. using an oil bath. Gas evolution was observed upon reflux. After a 1 hour period, decarboxylation (evidenced by vigorous frothing) was complete and the mixture was cooled to room temperature and purified by flash chromatography on silica using 15% ethyl acetate:hexanes as mobile phase to give 2-(4-pentenyl)-6-heptenoic acid (23 g, 79%). 1H NMR (CDCl3): δ 11.2–12.2 (br, 1H), 5.6–6.0 (m, 2H), 4.8–5.0 (m, 4H), 2.2–2.4 (m, 1H), 1.9–2.1 (m, 4H), 1.8–1.9 (m, 2H), 1.2–1.8 (m, 6H) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][N:14]([C:18]4[CH:23]=[C:22]([N:24]5[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]5)[N:21]=[C:20]([NH2:31])[N:19]=4)[CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[F:32].[CH3:33][N:34](C)CCN(C)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN1CCCC1=O>[NH2:31][C:20]1[N:19]=[C:18]([N:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][C:8]([C:5]4[CH:4]=[C:3]([F:32])[C:2]([C:33]#[N:34])=[N:7][CH:6]=4)=[CH:9][CH:10]=3)[CH2:15]2)[CH:23]=[C:22]([N:24]2[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]2)[N:21]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(-c5cnc(Cl)c(F)c5)cc4C3)nc(N)n2)CC1
Reactant: CN(C)CCN(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Product: CN1CCN(c2cc(N3CCc4ccc(-c5cnc(C#N)c(F)c5)cc4C3)nc(N)n2)CC1
Temperature: 160 °C

Procedure:
4-[7-(6-chloro-5-fluoropyridin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (186 mg, 0.410 mmol, Example 6), Zinc cyanide (57 mg, 0.48 mmol), N,N,N′,N′-tetramethylethylenediamine (86 μL, 0.57 mmol), tris(dibenzylideneacetone)dipalladium(0) (16 mg, 0.018 mmol, Alfa Aesar Cat. No. 12760) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (30 mg, 0.053 mmol) (Aldrich, Cat. No. 526460) were added successively to N-Methylpyrrolidinone (5 mL) in a microwave tube. The tube was sealed and degassed with nitrogen and heated at 160° C. overnight. The reaction mixture was cooled to r.t. and filtered. The filtration was diluted with MeOH and purified by RP-HPLC (pH=10) to afford the desired compound. LCMS (M+H)+: m/z=445.3.
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:32][C:33]([C:35]3[N:36]=[C:37]([C:48]4[C:53]([F:54])=[CH:52][CH:51]=[CH:50][C:49]=4[F:55])[S:38][C:39]=3[NH:40]C(OC(C)(C)C)=O)=[O:34])[C:13]([N:14]3[CH2:19][C@H:18]([C:20]([F:23])([F:22])[F:21])[CH2:17][C@H:16]([NH:24]C(OC(C)(C)C)=O)[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.[OH-].[Na+].O.CO>C1COCC1>[NH2:40][C:39]1[S:38][C:37]([C:48]2[C:49]([F:55])=[CH:50][CH:51]=[CH:52][C:53]=2[F:54])=[N:36][C:35]=1[C:33]([NH:32][C:12]1[C:13]([N:14]2[CH2:19][C@H:18]([C:20]([F:22])([F:23])[F:21])[CH2:17][C@H:16]([NH2:24])[CH2:15]2)=[C:8]2[CH2:7][CH2:6][CH:5]([OH:4])[C:9]2=[N:10][CH:11]=1)=[O:34]
Reactant: CC(=O)OC1CCc2c1ncc(NC(=O)c1nc(-c3c(F)cccc3F)sc1NC(=O)OC(C)(C)C)c2N1C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1C[C@@H](N)C[C@@H](C(F)(F)F)C1)CCC2O
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
To a solution of 3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (110.3 mg, 0.1384 mmol) in THF (1.0 mL) was added a 1.0 M NaOH solution in water (1.00 mL, 1.00 mmol) followed by MeOH (2.0 mL). The reaction mixture was stirred at room temperature for 1 h, and then concentrated under reduced pressure. To the resulting residue was added DCM (2.0 mL), followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford both diastereoisomers of the title compound as white solids (9.3 mg for each, total yield 24%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:12]1[C:20]2[C:15](=[CH:16][C:17]([CH:21]3[C:26](=[O:27])[NH:25][C:24](=[O:28])[NH:23][C:22]3=[O:29])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>>[CH2:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3([C:2]4[C:3]5[CH:11]=[CH:10][CH:9]=[N:8][C:4]=5[N:5]=[CH:6][N:7]=4)[C:22](=[O:29])[NH:23][C:24](=[O:28])[NH:25][C:26]3=[O:27])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: O=C1NC(=O)C(c2ccc3c(c2)CCC3)C(=O)N1
Reactant: Clc1ncnc2ncccc12
Product: O=C1NC(=O)C(c2ccc3c(c2)CCC3)(c2ncnc3ncccc23)C(=O)N1
Temperature: 130 °C

Procedure:
A slurry of 4-chloro-pyrido[2,3-d]pyrimidine (1.656 g, 10 mM) and 5-(5-indanyl) barbituric acid (2.443 g, 10 mM) is stirred in an oil bath. The temperature is raised to 130° C. in a period of 15 min. Then the temperature is further increased from 130° C. to 170° C. During this period apparently a reaction occurs since the slurry solidifies. The resulting solid is maintained for further 10 min at about 170° C. Then the reaction mixture is cooled, triturated with sodium bicarbonate solution and hexane. The solid is filtered off, washed with water and dried under vacuum. The raw product is submitted to the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.[CH2:16]1[O:27][C:26]2[C:18](=[C:19]([CH:23]=[CH:24][CH:25]=2)[C:20](O)=[O:21])[O:17]1.NCC1OCCN(CC2C=CC(C#N)=CC=2)C1.NC1C(Cl)=CC(C(O)=O)=C(OC)C=1>>[CH2:16]1[O:27][C:26]2[C:18](=[C:19]([CH:23]=[CH:24][CH:25]=2)[C:20]([NH:1][CH2:2][CH:3]2[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:4]2)=[O:21])[O:17]1
Reactant: NCC1CN(Cc2ccccc2)CCO1
Reactant: O=C(O)c1cccc2c1OCO2
Agent: COc1cc(N)c(Cl)cc1C(=O)O
Agent: N#Cc1ccc(CN2CCOC(CN)C2)cc1
Product: O=C(NCC1CN(Cc2ccccc2)CCO1)c1cccc2c1OCO2

Procedure:
The title compound is prepared in substantially the same manner as in Example 6(1), using 2-aminomethyl-4-benzylmorpholine and 2,3-methylenedioxybenzoic acid, respectively, in place of 2-aminomethyl-4-(4-cyanobenzyl)morpholine and 4-amino-5-chloro-2-methoxybenzoic acid in Example 6(1). The free base thus obtained is treated in substantially the same manner as in Example 6(2) to give the fumarate 1/4 hydrate of the title compound, mp 144°-146° C. (recrystallized from ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[NH:22][C:21]([C:23]3[CH:28]=CC=CN=3)=[N:20][N:19]=2)=[CH:4][CH:3]=1.Cl[C:30]1C=CC(C2N=C3C=CC=CN3C=2CC(NN)=O)=CC=1.Cl.C(=N)(N)C(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[NH:22][C:21]([CH:23]([CH3:30])[CH3:28])=[N:20][N:19]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2nc3ccccn3c2Cc2nnc(-c3ccccn3)[nH]2)cc1
Reactant: NNC(=O)Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: CC(C)C(=N)N
Agent: Cl
Product: CC(C)c1nnc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)[nH]1

Procedure:
The title compound was prepared according to the experimental described for compound 230 from 2-(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetohydrazide and isobutyrimidamide hydrochloride. M/e+ 352 for C19H19ClN5 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.05 (m, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.27 (m, 4H), 7.04 (t, J=7.3 Hz, 1H), 6.75 (t, J=6.6 Hz, 1H), 4.42 (s, 2H), 3.12 (m, 1H), 1.39 (s, 3H), 1.37 (s, 3H) ppm.
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[Br:14][C:15]1[CH:16]=[C:17]([Mg]Br)[CH:18]=[CH:19][CH:20]=1>>[Br:14][C:15]1[CH:20]=[C:19]([CH:2]2[C:9]3[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=3[CH2:4][CH2:3]2)[CH:18]=[CH:17][CH:16]=1
Reactant: Br[Mg]c1cccc(Br)c1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Product: COC(=O)c1cc2c([nH]1)CCC2c1cccc(Br)c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.502 g, 2.80 mmol) and (3-bromophenyl)magnesium bromide (synthesized in situ) were reacted according to General Procedure 3 to give the endo olefin-containing compound methyl 4-(3-bromophenyl)-1,6-dihydrocyclopenta[b]pyrrole-2-carboxylate. (Note: (3-Bromophenyl)magnesium bromide was synthesized as follows: Activated magnesium (0.306 g, 12.6 mmol) was placed in a flask and anhydrous THF (50 mL) was added. 1,3-dibromobenzene (1.6 mL, 13.2 mmol) and a catalytic amount of 12 was added. The solution was stirred gently at ambient temperature for 30 min. Additional anhydrous THF (25 mL) was added and the solution refluxed for 3 h, and then allowed to cool to ambient temperature). Methyl 4-(3-bromophenyl)-1,6-dihydrocyclopenta[b]pyrrole-2-carboxylate was hydrogenated according to General Procedure 6 (with Pt2O), and was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-30% EtOAc/heptane affording a 1:1 mixture of the title compound and dehalogenated product as a slightly yellow solid: 0.315 g (67% yield). LCMS (ESI−) 318.0 (M−H).
Reaction SMILES: [Cl:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][CH:3]=1.[Li]CCCC.[CH2:16]([CH:18]([C:21]1[C:22]2[N:23]([C:28](I)=[C:29]([CH3:31])[N:30]=2)[N:24]=[C:25]([CH3:27])[CH:26]=1)[CH2:19][CH3:20])[CH3:17]>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:28]1[N:23]2[N:24]=[C:25]([CH3:27])[CH:26]=[C:21]([CH:18]([CH2:16][CH3:17])[CH2:19][CH3:20])[C:22]2=[N:30][C:29]=1[CH3:31]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Clc1csc2cccnc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc4cccnc4c3Cl)c(C)nc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 46.4 %

Procedure:
80 mg of 3-Chloro-thieno[3,2-b]pyridine (0.47 mmol) is dissolved in 3.0 ml of dry THF and cooled to −78° C. 0.19 ml of n-BuLi (0.47 mmol) is added slowly and stirred at −78° C. for 10 min. 0.94 ml of 0.5M ZnCl2 in THF (0.47 mmol) is added at −78° C. and stirred at room temperature for 10 min. 161 mg of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.47 mmol) and 22 mg of PdCl2(dppf) (0.03 mmol) are added and the vial is capped with a Teflon cap and heated at 80° C. overnight. The reaction mixture is concentrated and applied onto a silica-gel chromatography column (Hexane:AcOEt:2M NH3 in MeOH=20:4:1) to give 84 mg of the title compound (47%). mass spectrum (m/e): 385; 1H-NMR (CDCl3): 8.84 (d, 1H, J=4.7 Hz), 8.20 (d, 1H, J=8.3 Hz), 7.38 (dd, 1H, J=4.7 Hz, 8.3 Hz), 6.76 (s, 1H), 3.34 (m, 1H), 2.56 (s, 3H), 2.52 (s, 3H), 1.85 (m, 4H), 0.89 (t, 6H, J=7.4 Hz) ppm.
Reaction SMILES: Cl[CH:2]([O:4][C:5]([N:7]1[CH2:12][CH2:11][S:10](=[O:14])(=[O:13])[CH2:9][CH2:8]1)=[O:6])[CH3:3].[Cl:15][C:16]1[C:17]([F:56])=[C:18]([C@@H:22]2[C@:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])([C:27]#[N:28])[C@H:25]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:24][C@H:23]2[C:42]([NH:44][C:45]2[CH:53]=[CH:52][C:48]([C:49]([OH:51])=[O:50])=[CH:47][C:46]=2[O:54][CH3:55])=[O:43])[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C@@:26]2([C:27]#[N:28])[C@H:25]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:24][C@@H:23]([C:42]([NH:44][C:45]3[CH:53]=[CH:52][C:48]([C:49]([O:51][CH:2]([O:4][C:5]([N:7]4[CH2:12][CH2:11][S:10](=[O:14])(=[O:13])[CH2:9][CH2:8]4)=[O:6])[CH3:3])=[O:50])=[CH:47][C:46]=3[O:54][CH3:55])=[O:43])[C@@H:22]2[C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[C:17]=2[F:56])=[C:30]([F:36])[CH:31]=1
Reactant: CC(Cl)OC(=O)N1CCS(=O)(=O)CC1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OC(C)OC(=O)N2CCS(=O)(=O)CC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 87.4 %

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (Oakwood, 1.32 g, 1 mL, 9.27 mmol) was reacted with thiomorpholine 1,1-dioxide (1.1638 g, 8.61 mmol) and pyridine (783 mg, 801 μl, 9.9 mmol) in methylene chloride (15 mL) at room temperature for 3 h to give 1,1-dioxo-thiomorpholine-4-carboxylic acid 1-chloro-ethyl ester. A portion of 1,1-dioxo-thiomorpholine-4-carboxylic acid 1-chloro-ethyl ester (577 mg, 1.614 mmol) 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 (150.5 mg, 0.244 mmol) in the presence of cesium carbonate (598.4 mg, 1.84 mmol) in dimethylformamide (7 mL) overnight to give 1,1-dioxo-thiomorpholine-4-carboxylic acid 1-(4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoyloxy)-ethyl ester as an off-white solid (175.3 mg, 87% yield). MS (ES+) m/z calcd. for C38H41Cl2F2N4O8S: [(M+H)+]: 821, found: 821
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]2[N:23](CC3C=CC=CC=3)[CH:24]=[CH:25][N:26]=2)=[C:9]1[C:34]([O:36][CH2:37][CH3:38])=[O:35].Cl.CC(C)=O>C(O)C.[Pd]>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]2[NH:26][CH:25]=[CH:24][N:23]=2)=[C:9]1[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)C1=C(COCc2nccn2Cc2ccccc2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: [Pd]
Agent: Cl
Solvent: CC(C)=O
Solvent: CCO
Product: CCOC(=O)C1=C(COCc2ncc[nH]2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 47.8 %

Procedure:
4-(2-Chlorophenyl)-2-[(1-benzyl-2-imidazolyl)methoxymethyl]-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (Example 10) (2 g) was dissolved in ethanol (70 ml) and acidified with hydrogen chloride gas. Then 10% palladium on charcoal catalyst (0.25 g) was added and the suspension was stirred under hydrogen at 50 p.s.i. and room temperature overnight. Examination of the reaction mixture by t.l.c. showed that about one third of the starting material had been converted to a more polar product. The catalyst was removed by filtration, the ethanol was evaporated and the residue partitioned between chloroform (50 ml) and dilute aqueous ammonia (30 ml). The chloroform solution was dried (Na2CO3), filtered and evaporated. The residue was dissolved in a little toluene and chromatographed on silica (t.l.c. grade, 6 g). Elution with toluene removed unreacted starting material; elution with chloroform and then chloroform plus 2-4% v/v methanol gave the product, which was converted to the hydrochloride salt by addition of ethereal hydrogen chloride to an acetone solution of the free base. Recrystallisation of the hydrochloride salt from methanol-ethyl acetate (1:4) gave the title compound (430 mg), m.p. 190° C.
Reaction SMILES: NCC1C=CC=C(C)C=1N.[NH2:11][C:12]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:13]=1[C:14]([NH2:16])=O>>[NH2:16][CH2:14][C:13]1[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:12]=1[NH2:11]
Reactant: COc1ccc(C(N)=O)c(N)c1
Agent: Cc1cccc(CN)c1N
Product: COc1ccc(CN)c(N)c1

Procedure:
The title compound was prepared in analogy to a) (2-aminomethyl-6-methyl-phenylamine) from 2-amino-4-methoxybenzamide. 2-Amino-4-methoxybenzamide can be prepared by the method of Koko, M. C.; Santilli, A. A. U.S. Pat. No. 5,948,775, 1999.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=O)=O)=CC=1.[C-:19]#[N:20].[Na+]>CS(C)=O>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:12][CH2:11][C:19]#[N:20]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCCc2cccs2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCc1cccs1
Temperature: 90 °C

Procedure:
A mixture was prepared from 20.8 g of 2-[2-(4-toluenesulfonyloxy)ethyl]thiophene, 5.4 g of sodium cyanide and 175 ml of dimethylsulfoxide and this mixture was heated to 90° C. The mixture was quenched by pouring it into saturated aqueous ammonium chloride solution and the resulting solution was extracted into ethyl acetate. The ethyl acetate solution was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give crude 2-thiophenepropionitrile. This product was mixed with 175 ml of 1M diborane in tetrahydrofuran and allowed to stir at room temperature. The reaction was quenched in ethanol and methanolic hydrogen chloride was added. The white solid which formed was separated by filtration, washed with ether and dried in a vacuum oven to give 3-(2-thienyl)propylamine hydrochloride melting at about 197-°198° C.