Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)CC1C(=CC=CC=1)C(O)=O.NC(N)=O.N.[C:19]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]2[CH2:20]1.[H-].[Na+].Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:43]=[CH2:44]>CS(C)=O.O.CO>[CH2:44]([N:24]1[C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]2[CH2:20][C:19]1=[O:30])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH:35]=[CH2:34]
Reactant: O=C1Cc2ccccc2C(=O)N1
Reactant: C=CCCCCCCCCCBr
Agent: N
Agent: NC(N)=O
Agent: O=C(O)Cc1ccccc1C(=O)O
Solvent: O
Solvent: CS(C)=O
Solvent: CO
Product: C=CCCCCCCCCCN1C(=O)Cc2ccccc2C1=O
Reaction time: 0.33 h
Yield: 35.5 %

Procedure:
This example illustrates a synthesis of N-(10,11-Oxidoundecyl)homophthalimide (inventive compound no. 1114). A mixture of homophthalic acid (54.0 g; 0.3 mole) and finely powdered urea (19.82 g; 0.33 mole) were heated to 175-185° C. until no more ammonia evolves, evidenced by pH paper. The crude product was refluxed with methanol (500 mL) and homophthalimide isolated by filteration (29 g; 60%). Sodium hydride(95%) (576 mg, 24 mmol) was added to a solution of homophthalimide (3.2 g, 20 mmol) in anhydrous dimethylsulfoxide (75 mL). After 20 minutes of stirring, 1-bromoundec-10-ene (5.6 g, 24 mmol) was added. After 16 hours of stirring at room temperature, the reaction mixture was poured into a separatory funnel containing 500 mL of water and extracted with ethyl acetate (3×100 mL). The organic extracts were combined, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using petroleum ether/5% ethyl acetate eluant to yield 2.2 g (35.5% yield) N-(10-Undecenyl)homophthalimide.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH2:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:23]([C:24](O)=[O:25])=[C:22]([F:27])[C:21]([CH2:28][NH:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])=[CH:20][CH:19]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH:16][C:24](=[O:25])[C:23]3[C:18]([Cl:17])=[CH:19][CH:20]=[C:21]([CH2:28][NH:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])[C:22]=3[F:27])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1ncnc2c(N)cccc12
Reactant: CC(C)(CO)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Nc1ncnc2c(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)CO)c3F)cccc12
Yield: 10.8 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(tert-butyl)quinazoline-4,8-diamine (Intermediate-55, 100 mg, 0.46 mmol), 6-chloro-2-fluoro-3-((3-hydroxy-2,2-dimethylpropanamido)methyl)benzoic acid (Intermediate-59, 168 mg, 0.56 mmol), oxalyl chloride (116 mg, 0.92 mmol), DMF (1 drop) and DIPEA (178 mg, 1.37 mmol) in CH2Cl2 (2 mL) to afford 25 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.41 (s, 1H), 8.68 (d, J=7.8 Hz, 1H), 8.51 (s, 1H), 8.17 (d, J=8.1 Hz, 1H), 8.11 (t, 1H), 7.52-7.38 (m, 4H), 4.91 (t, 1H), 4.33 (d, J=6.3 Hz, 2H), 3.42 (d, 2H), 1.55 (s, 9H), 1.08 (s, 6H); MS [M+H]+: 502.46.
Reaction SMILES: Cl[CH2:2][CH:3]1[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[CH2:6][CH2:5][O:4]1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[Na+].[I-].Cl>CN(C=O)C.O>[S:11]1[C:7]2[CH2:6][CH2:5][O:4][CH:3]([CH2:2][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:8]=2[CH:9]=[CH:10]1
Reactant: C1CCNC1
Reactant: ClCC1OCCc2sccc21
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1cc2c(s1)CCOC2CN1CCCC1
Temperature: 130 °C
Reaction time: 6 h

Procedure:
A mixture of 4-(chloromethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran (1 g, 5.305 mmol, 1 eq), pyrrolidine (11.3 g, 159.1 mmol, 30 eq) and NaI (50 mg) in DMF (50 mL) in a sealed tube was stirred at 130° C. for 6 hr. The reaction mixture was cooled and poured into H2O and the pH was adjusted to ˜2 with 2N HCl. The resulting solution was washed with EtOAc. The aqueous layer was then adjusted to pH 9-10 and extracted with EtOAc. The EtOAc layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting crude product was purified by preparative HPLC. After removal of organic volatiles of the collected HPLC fractions, the pH of remaining aqueous phase was adjusted to ˜8 with saturated Na2CO3 solution. The aqueous solution was extracted with EtOAc (3 times). The combined EtOAc extract was washed with brine, dried with Na2SO4, and concentrated to give the desired product.
Reaction SMILES: C[O-].[Na+].[Na].[CH3:5][SH:6].[CH2:7]1[O:16][C:10]([CH2:12][CH2:13][CH2:14]Cl)([CH3:11])[O:9][CH2:8]1>C1(C)C=CC=CC=1.CO>[CH2:7]1[O:16][C:10]([CH2:12][CH2:13][CH2:14][S:6][CH3:5])([CH3:11])[O:9][CH2:8]1
Reactant: CS
Reactant: CC1(CCCCl)OCCO1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: CSCCCC1(C)OCCO1
Yield: 100.7 %

Procedure:
To a solution of sodium methoxide prepared by slowly adding 2.4 g (54 mmol) of sodium to 40 mL of methanol was added 4.8 g (48 mmol) of methylmercaptan followed by 6.6 g (40 mmol) of 5-chloro-2-pentanone ethylene ketal. The mixture was refluxed for 4 h and an additional 50 mmol each of sodium and methylmercaptan was added and then refluxed an additional 4 hours to complete the reaction. 50 mL of toluene was added and the mixture washed twice with 10 mL of 1N sodium hydroxide. The toluene layer was dried over magnesium sulfate and evaporated to give 7.1 g of 5-methylthio-2-pentanone ethylene ketal. This was stirred in 60 mL of 70% trifluoroacetic acid for 24 h at room temperature. The mixture was neutralized with sodium carbonate and extracted with 200 mL of ether. The ether extract was dried and evaporated to yield 3.5 g of the desired ketone as an oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][O:28][C:29]([C:31]1[S:32][C:33]([CH3:36])=[CH:34][CH:35]=1)=[O:30]>C(Cl)(Cl)Cl>[CH3:27][O:28][C:29]([C:31]1[S:32][C:33]([CH2:36][Br:1])=[CH:34][CH:35]=1)=[O:30]
Reactant: COC(=O)c1ccc(C)s1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(CBr)s1
Temperature: 60 °C
Yield: 94.5 %

Procedure:
N-Bromosuccinimide (Aldrich; 1.70 g, 9.6 mmol) and a catalytic amount of benzoyl peroxide were added to a solution of 5-methyl-thiophene-2-carboxylic acid methyl ester (1.40 g, 9.0 mmol) in chloroform (15 mL). The reaction mixture was stirred under argon at reflux (˜60° C.) for 3 h, then filtered through Celite™ and evaporated under reduced pressure to give 5-bromomethyl-thiophene-2-carboxylic acid methyl ester (2 g) as a yellow oil which was used directly in the next step without further purification.
Reaction SMILES: C(OP([C:9]([O:25][CH3:26])([O:23][CH3:24])[CH2:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1)(OCC)=O)C.[Li]CCCC.[CH3:32][C:33]1[S:37][C:36]([C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([CH:48]=O)[CH:46]=3)[C:41]([CH3:51])([CH3:50])[CH2:40][CH:39]=2)=[CH:35][CH:34]=1.CC1SC(C2C3C(=CC=C(C=O)C=3)C(CC)(CC)CC=2)=CC=1>C1COCC1.CCOCC>[CH3:26][O:25][CH:9]([O:23][CH3:24])[CH2:10]/[C:11](/[C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=1)=[CH:48]\[C:45]1[CH:46]=[C:47]2[C:42]([C:41]([CH3:51])([CH3:50])[CH2:40][CH:39]=[C:38]2[C:36]2[S:37][C:33]([CH3:32])=[CH:34][CH:35]=2)=[CH:43][CH:44]=1
Reactant: Cc1ccc(C2=CCC(C)(C)c3ccc(C=O)cc32)s1
Reactant: CCOC(=O)c1ccc(CCC(OC)(OC)P(=O)(OCC)OCC)cc1
Agent: CCC1(CC)CC=C(c2ccc(C)s2)c2cc(C=O)ccc21
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(/C(=C/c2ccc3c(c2)C(c2ccc(C)s2)=CCC3(C)C)CC(OC)OC)cc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To a cold (−78° C.) solution of ethyl 4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D, 1.4 g, 3.6 mmol), in THF (20 mL) was added n-BuLi (1.6 M solution in hexane, 2.5 ml, 4 mmol). The mixture was stirred for 20 minutes at −78° C. and 10 min. at −10° C. The reaction mixture was recooled to −78° C. and 1(5-methyl-thien-2-yl)3,4-dihydro-4,4-dimethyl-7-naphthaldehyde (Compound G, 650 mg, 2.3 mmol) in THF (4 mL) was added to it. The mixture was stirred for 2 hours at −10° C. and diluted with ether (100 mL), washed with brine (10 mL) dried with MgSO4 and the solvent was removed by distillation to to afford a cis and trans (E and Z) isomeric mixture. Purification by chromatography on silica gel of the crude material afforded the title compound as an oil (˜90% purity).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1.[C:24]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])(=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.CCCCCC.O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:24](/[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)\[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:22][CH:23]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CON)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CCOC(=O)C/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (1.00 g), ethyl benzoylacetate (0.612 ml), acetic acid (0.554 ml), sodium acetate (528 mg) and ethanol (20 ml) was heated to reflux for 12 hours and cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl E-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-3-phenylpropionate (1.29 g, yield 83%) as a colorless oil from an ethyl acetate-hexane (1:3, v/v).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:13][C:14]([F:32])([F:31])[C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=2)=[N:19][CH:20]=1.C(N(CC)CC)C>C(O)C>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][N:3]=[C:2]2[NH:30][CH2:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:32])([F:13])[F:31])=[CH:20][N:19]=2)=[CH:27][CH:26]=1
Reactant: Fc1cccc2c(Cl)ncnc12
Reactant: NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Fc1cccc2c(NCCc3ccc(Oc4ccc(C(F)(F)F)cn4)cc3)ncnc12
Yield: 58.4 %

Procedure:
A mixture of 4-chloro-8-fluoroquinazoline (1.82 g, 0.01 mol), 2-(4-(5-trifluoromethyl-2-pyridinyloxy)-phenyl)ethylamine (2.82 g, 0.01 mol), triethylamine (1.1 g, 0.011 mol) and ethanol (50 mL) was heated under reflux for three hours and allowed to cool. Solvent was evaporated under reduced pressure, and the residue dissolved in dichloromethane. This was washed with 0.5M sodium hydroxide solution and water, and dried over anhydrous sodium sulphate. Evaporation of the solvent under reduced pressure and recrystallization from ethyl acetate:hexane gave 2.5 g of product. MP 152° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:16]([C:17]([NH2:19])=[O:18])[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:8](=[O:9])[CH2:7][C:5]=2[CH:6]=1.C(OCC)(=O)C.[OH-].C[N+](C)(C)C>CN(C)C=O.C(O)=O.O>[OH:9][C@@H:8]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[N:16]([C:17]([NH2:19])=[O:18])[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[CH2:7]1
Reactant: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=CO
Product: NC(=O)N1c2ccccc2C[C@H](O)c2ccccc21
Reaction time: 0.75 h

Procedure:
In a 250 ml flask with thermometer, reflux condenser, stirrer and under nitrogen was added 8 g oxcarbazepine, 60 ml of ethyl acetate, 18 ml tetramethylammonium hydroxide (25% solution in water), 2 ml formic acid and 5 ml water. 21 mg RuCl [(S,S)-Ts-DPEN](p-cymene) (SigmaAldrich 703915) was dissolved in 5 ml dimethylformamide and added to the reaction. The reaction was heated in an oil bath to reflux. The pH was checked approximately every 30 to 60 minutes and formic acid added as required to about pH 5. In this way the pH was maintained between 5 and 9. After 7 hours the conversion was 80% and after overnight reaction without further formic acid addition a conversion (HPLC area % at 210 nm) of 96% was obtained with a product ee of 97.1% of (S)-(+)-10-hydroxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (pH 8.5). The reaction was cooled on ice for 4 hours with stirring, filtered and washed 2 times with 20 ml methyl tert-butyl ether (MTBE) to yield 7.5 g alcohol after drying with a purity of 99,3% (HPLC ala %).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[O:22][CH3:21])=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1ccccc1CN
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: COc1ccccc1CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (0.1 mg, 0.28 mmol) and 2-methoxy-benzylamine (46 mg, 0.33 mmol). The title compound was obtained as a yellow solid (25.0 mg, 19.0% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.20 (1H, m), 8.98 (2H, s), 8.58 (1H, s), 7.25 (1H, m), 7.18 (1H, m), 7.00 (1H, m), 6.90 (1H, m), 4.36 (2H, m), 3.79 (3H, s). MS m/z: 468.05, 470.05 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH:3]1[CH3:26].[F:27][C:28]([Mg]Br)([F:30])[F:29]>O1CCCC1>[F:27][C:28]([F:30])([F:29])[C:2]1([OH:1])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH:3]1[CH3:26]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)C(C)C3)c(F)c2)C(=O)O1
Reactant: FC(F)(F)[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(C(F)(F)F)C(C)C3)c(F)c2)C(=O)O1
Yield: 78 %

Procedure:
By reacting (S)—N-{3-[4-(4-oxo-3-methyl-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (2.40 mmol) and trifluoromethyl magnesium bromide (2.6 mmol) in tetrahydrofuran (20 ml) followed by silica gel chromatographic separation of diastereomer the compound was obtained in 78% yield. M.P. 144-146° C. and MS (M+1)=434 (MH+, 100%) for M.F.=C19H23F4N3O4.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:31])[CH2:29][CH3:30]>C(Cl)(Cl)Cl>[CH2:28]([NH:31][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])[CH2:29][CH3:30]
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: CCCN
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)c1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 85.6 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroform ate in 40 ml of chloroform is added dropwise to the above mixture at -10° C. during 20 minutes. After stirring for 5 minutes, a solution containing 5.2 g (0.088 mol) of propylamine in 80 ml of chloroform is added dropwise at -15° C. during 30 minutes, then the mixture is stirred for 1 hour below -10° C. Then the mixture is allowed to stand overnight under cooling by ice. For working up, the chloroform mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The chloroform phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 16.8 g (85.6%) of the named product in the form of yellow crystals after recrystallization from ethanol, m.p.: 158°-160° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]2[CH2:7][CH:6]([CH:17]([CH3:19])[CH3:18])[C:5](=[O:20])[C:4]=2[C:3]=1[CH3:21].[H-].[Na+].[CH3:24]I.[OH-].[Na+].Cl>CN(C)C=O.O>[CH3:1][C:2]1[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]2[CH2:7][C:6]([CH3:24])([CH:17]([CH3:18])[CH3:19])[C:5](=[O:20])[C:4]=2[C:3]=1[CH3:21]
Reactant: Cc1c(C)c2c(c3c1OC(C(=O)O)C3)CC(C(C)C)C2=O
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c3c1OC(C(=O)O)C3)CC(C)(C(C)C)C2=O
Temperature: 50 °C

Procedure:
A solution of 4,5-dimethyl-6-oxo-7-isopropyl1,2,7,8-tetrahydro-6H-indeno[5,4-b]furan-2-carboxylic acid (0.01 mole) in dimethylformamide (50 ml.) at 15°C. is treated with sodium hydride (50% dispersion in mineral oil, (0.-25 mole). The solution is warmed to 50°C., cooled to 25°C., treated with methyl iodide (0.025 mole) then warmed to 50°C. Thereafter, water (50 ml.) and 10 N sodium hydroxide (2 ml.) are added; the reaction is heated at 95°C. for 0.5 hours then poured into cold 1.0N hydrochloric acid to afford 4,5,7-trimethyl-6-oxo-7-isopropyl-1,2,7,8-tetrahydro-6H-indeno[5,4-b]furan-2-carboxylic acid.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[N:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>C(Cl)Cl>[C:1]([NH:5][S:13]([C:10]1[CH:11]=[N:12][C:7]([Cl:6])=[CH:8][CH:9]=1)(=[O:15])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a mixture of 17.3 mL (165 mmol) of tert-butylamine and 69 mL (495 mmol) of TEA in 330 mL of DCM are added portionwise, at 0° C., 35 g (165 mmol) of 6-chloropyridine-3-sulfonyl chloride. After stirring for 2 hours at 0° C., the reaction medium is taken up in 600 mL of DCM, washed with water (1 L), saturated NaHCO3 solution (1 L) and brine (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure. 32.4 g of N-tertbutyl-6-chloropyridine-3-sulfonamide are obtained in the form of a white solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41](O)=[O:42].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:16]=[C:11]([C:10]([NH:9][C@H:6]2[CH2:7][CH2:8][C@H:3]([NH:2][C:41]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=3)=[O:42])[CH2:4][CH2:5]2)=[O:27])[C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[N:13][CH:14]=1
Reactant: O=C(O)c1ccccn1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](NC(=O)c3ccccn3)CC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N-(trans-4-amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (250 mg, 0.666 mmol) in dimethylformamide (5 ml) and triethylamine (278 μl, 2.0 mmol) was treated with 2-pyridine carboxylic acid (90 mg, 0.73 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (141 mg, 0.73 mmol) and 1-hydroxybenzotriazole (99 mg, 0.73 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium hydrogen carbonate solution (10 ml) and ethyl acetate (15 ml) and the aqueous phase was extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with water (2×10 ml), brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure to give the title compound (175 mg) as a white solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][O:29][CH2:30][CH2:31][C:32]([CH2:45][CH2:46][O:47][CH3:48])([NH2:44])[C:33]([N:35]([CH3:43])[C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)=[O:34]>>[CH3:28][O:29][CH2:30][CH2:31][C:32]([CH2:45][CH2:46][O:47][CH3:48])([NH2:44])[C:33]([N:35]([C:36]1[CH:37]=[CH:38][C:39]([NH:42]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:40][CH:41]=1)[CH3:43])=[O:34]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: COCCC(N)(CCOC)C(=O)N(C)c1ccc(N)cc1
Product: COCCC(N)(CCOC)C(=O)N(C)c1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(di-(2-methoxyethyl)-amino-methylcarbonyl)-N-methyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C32H36N4O6
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([C:12]1[C:16](I)=[C:15]([CH:18]=[O:19])[NH:14][C:13]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:11].[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)#[CH:28]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.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].[Cu]I>[CH2:10]([C:12]1[C:16]([C:28]#[C:27][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[C:15]([CH:18]=[O:19])[NH:14][C:13]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:11]
Reactant: CCc1c(C(=O)OC(C)(C)C)[nH]c(C=O)c1I
Reactant: C#Cc1ccccn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cu]I
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCc1c(C(=O)OC(C)(C)C)[nH]c(C=O)c1C#Cc1ccccn1
Temperature: 80 °C

Procedure:
Tert-butyl 3-ethyl-5-formyl-4-iodo-1H-pyrrole-2-carboxylate was obtained following the procedures described in Example 1. Pd(Pt-Bu3)2 (7.0 mg, 0.010 mmol), Pd2(dba)3 (6.0 mg, 0.010 mmol), and CuI (2.0 mg, 0.010 mmol) were combined in a dry flask under N2 prior to evacuating the flask and refilling with argon. After the flask was charged with dioxane (2.0 mL) it was sparged with argon prior to the sequential addition of i-Pr2NEt (0.0259 mL, 0.19 mmol), a solution of tert-butyl 3-ethyl-5-formyl-4-iodo-1H-pyrrole-2-carboxylate (56.0 mg, 0.16 mmol) in dioxane (1.0 mL), and 2-ethynylpyridine (0.0194 mL, 0.19 mmol). The reaction was heated to 80° C. until complete consumption of the starting material. After the reaction was cooled to ambient temperature, it was filtered through a plug of silica gel and concentrated in vacuo. The resultant residue was dissolved in acetonitrile and purified by reverse phase HPLC. Proton NMR for the product was consistent with the title compound. 1H NMR (500 MHz, CDCl3) δ 10.23 (s, 1H); 3.10 (q, J=7.3 Hz, 2H); 1.61 (s, 9H); 1.16 (t, J=7.3 Hz, 3H). HRMS (ES) exact mass calculated for C21H21F3N2O5 (M+H+): 325.1547. Found 325.1549.