Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:13][C:14](=[O:20])[NH:15][S:16](Cl)(=[O:18])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[OH:33])([CH3:23])[CH3:22].C(N(CC)CC)C>C1COCC1>[CH2:1]([O:13][C:14](=[O:20])[NH:15][S:16]([O:33][C:25]1[C:26]([CH:30]([CH3:31])[CH3:32])=[CH:27][CH:28]=[CH:29][C:24]=1[CH:21]([CH3:23])[CH3:22])(=[O:18])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOC(=O)NS(=O)(=O)Cl
Reactant: CC(C)c1cccc(C(C)C)c1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOC(=O)NS(=O)(=O)Oc1c(C(C)C)cccc1C(C)C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
A solution of n-dodecyl(chlorosulfonyl)carbamate (5.0 g, 15.2 mmoles) in 80 mL THF was added dropwise to a solution of 2,6-diisopropyl phenol(2.72 g, 15.2 mmoles) and excess triethylamine in 100 mL THF at room temperature under an atmosphere of N2. The mixture was stirred for 16 hours and then concentrated in vacuo. The residue was partitioned between 1N HCl and EtOAc. The organic layer was dried with MgSO4, filtered, and evaporated to give a clear oil. Chromatography (SiO2, 5% EtOAc/hexanes) gave 4.26 g of the title compound as a waxy solid, mp 32°-35° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[C:25]([O:27][CH3:28])=[O:26])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c(C(=O)OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
A mixture of dimethyl (S)-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinylmethoxy]isophthalate (2.01 g, 5.11 mmol), TFA (20 mL), and CH2Cl2 (25 mL) was stirred for 1.5 hr at room temp. The resulting mixture was concentrated in vacuo and made basic with sat. NaHCO3. The mixture was extracted with CH2Cl2, washed with brine, dried over Na2CO3, and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3-MeOH (9:1, v/v) as eluent to give 0.80 g (53%) dimethyl (S)-4-(2-pyrrolidinylmethoxy)isophthalate as a yellow oil. 1H-NMR (CDCl3) δ 1.71 (m, 1 H), 1.89 (m, 2 H), 2.00 (m, 1 H), 3.05–3.13 (m, 2 H), 3.67 (m, 1 H), 3.90 (s, 3 H), 3.91 (s, 3 H), 4.05–4.18 (m, 2 H), 7.00 (d, 1 H, J=8.8 Hz), 8.14 (dd, 1 H, J=2.4, 8.8 Hz), 8.50 (d, 1 H, J=2.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].O>CN(C)C=O>[Si:22]([O:11][CH2:10][C@@H:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:12])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23]
Reactant: C[C@@H](CO)Nc1cccc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1cccc(Cl)c1
Temperature: 50 °C
Reaction time: 14 h
Yield: 65.4 %

Procedure:
To a solution of (2S)-2-[(3-chlorophenyl)amino]propane-1-ol (7.00 g) in N,N-dimethylformamide (19 mL) were added imidazole (2.82 g) and tert-butyl(chloro)dimethylsilane (6.38 g), and the mixture was stirred at 50° C. for 14 hr. Water (200 mL) was added to the reaction solution, and the mixture was extracted with diethyl ether. The obtained organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→40%) to give the title compound as a colorless oil (yield: 7.40 g, 65%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH:18]([N:31]1[C:39]2[C:34](=[CH:35][C:36](/[C:40](/[CH3:45])=[CH:41]/[C:42](O)=[O:43])=[CH:37][CH:38]=2)[CH:33]=[CH:32]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:18]([N:31]1[C:39]2[C:34](=[CH:35][C:36](/[C:40](/[CH3:45])=[CH:41]/[C:42]([NH:1][C:2]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:43])=[CH:37][CH:38]=2)[CH:33]=[CH:32]1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)CCCOc1ccc(Cl)cc1N
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2ccccc2)c2ccccc2)c1
Product: C/C(=C\C(=O)Nc1cc(Cl)ccc1OCCCC(=O)O)c1ccc2c(ccn2C(c2ccccc2)c2ccccc2)c1

Procedure:
268 mg of compound 47 was obtained in a similar manner to those described in the Examples 1 and 2 using 773 mg of ethyl 4-(2-amino-4-chlorophenoxy)butyrate and 551 mg of 3-(1-benzhydrylindol-5-yl)isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [CH:1]1[C:18]2[CH:17]=[CH:16][C:15]3[C:6](=[CH:7][C:8]([CH2:19][NH:20][C:21]([CH3:26])([CH2:24][OH:25])[CH2:22][OH:23])=[C:9]4[C:14]=3[CH:13]=[CH:12][CH:11]=[CH:10]4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:27](O)(=[O:31])[CH:28]([CH3:30])[OH:29]>CO>[C:27]([O:25][CH2:24][C:21]([NH:20][CH2:19][C:8]1[CH:7]=[C:6]2[C:15](=[C:14]3[C:9]=1[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:16]=[CH:17][C:18]1[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=1)([CH3:26])[CH2:22][OH:23])(=[O:31])[CH:28]([CH3:30])[OH:29]
Reactant: CC(O)C(=O)O
Reactant: CC(CO)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12
Solvent: CO
Product: CC(O)C(=O)OCC(C)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12
Yield: 44.1 %

Procedure:
A mixture of 2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol free base (1D) (3.45 g, 10 mmol) and lactic acid (Fisher Scientific Co., 711 Forbes Ave., Pittsburgh, PA, 15219, 85% liquid, 1.04 g, 10 mmol) in CH3OH (500 mL) was brought to reflux and filtered through a glass fritted funnel. The solvent was removed by rotary evaporation to give a crude white solid. This was crystallized (CH3OH/Et2OH) 3× to give 1.84 g (42.2%) of 2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol lactate mp 163°-164°. (C,H,N).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N:10]3[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH:37]1[CH2:40][CH2:39][CH2:38]1>CN(C=O)C.C(OCC)(=O)C>[CH:37]1([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([N:10]4[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH3:19])[CH2:12][CH2:11]4)=[N:7][C:6]=3[CH:28]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: BrCC1CCC1
Reactant: C[C@@H](COC1CCN(c2nc3cc(O)ccc3o2)CC1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](COC1CCN(c2nc3cc(OCC4CCC4)ccc3o2)CC1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 83.2 %

Procedure:
To a solution of tert-butyl [(1S)-2-{[1-(5-hydroxy-1,3-benzoxazol-2-yl)piperidin-4-yl]oxy}-1-methylethyl]carbamate (389 mg) in DMF (5 mL) were added potassium carbonate (413 mg) and (bromomethyl)cyclobutane (297 mg), and the mixture was stirred with heating at 60° C. for 6 hr under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (380 mg).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[CH3:8][CH:9]([CH2:12][CH2:13][CH3:14])C=O.N1CCCCC1.Cl>N1C=CC=CC=1>[CH3:8][CH:9]([CH2:12][CH2:13][CH3:14])/[CH:1]=[CH:2]/[C:3]([OH:5])=[O:4]
Reactant: O=C(O)CC(=O)O
Reactant: CCCC(C)C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCCC(C)/C=C/C(=O)O
Reaction time: 2 h
Yield: 46.4 %

Procedure:
Malonic acid (44 g, 0.42 mol), 2-methylpentan-1-al (14 g, 0.14 mol) and piperidine (1.7 ml) were suspended in 85 ml pyridine and heated under reflux. Gas formation was observed which ceased after two hours. Heating was continued for 1 hour. The cooled reaction mixture was poured into 2M hydrochloric acid (200 ml) after which two phases were obtained which were separated in a separating funnel. The aqueous phase was extracted once with dichloromethane (60 ml). The organic phases were combined and the solvent removed under reduced pressure. The residue was purified by column chromatography (pre-packed silica column, gradient of pentane/ethyl acetate). 9.3 g (0.065 mol, 47% yield) of (E)-4-methyl-hept-2-enoic acid were obtained as a solid. NMR (1H, CDCl3, 300 MHz): 11.86 (s, 1H), 7.00 (dd, 1H), 5.79 (d, 1H), 2.35 (m, 1H), 1.35 (m, 4H), 1.06 (d, 3H), 0.89 (m, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:15](=[O:24])[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:11]N(C)C)=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl.[OH-:26].[K+]>>[OH:17][C:16]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](=[O:24])[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=2)=[CH:11][O:26]1
Reactant: [OH-]
Reactant: CN(C)C=C(C(=O)C(=O)c1ccccc1)c1ccc(C(=O)O)cc1
Agent: Cl
Agent: [K+]
Product: O=C(O)c1ccc(C2=COC(O)(c3ccccc3)C2=O)cc1
Temperature: 0 °C
Yield: 71 %

Procedure:
A solution of 3.23 g of 2-(4-carboxyphenyl)-1-dimethylamino-4-phenyl-1-butene-3,4-dione in 100 ml of 2% potassium hydroxide solution was stirred at room temperature for 5 hrs. The reaction mixture was poured onto 300 ml of ice-water and acidified with 100 ml of 1N hydrochloric acid. The precipitate was collected, washed with water and then dissolved in 300 ml of ether. The solution was dried over anhydrous sodium sulfate. The drying agent was collected and the filtrate was evaporated. Recrystallization from ether gave 2.12 g (71%) of 2-hydroxy-2-phenyl-4-(4-carboxyphenyl)-3(2H)-furanone, m.p. 294°-299° C. dec.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[CH:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>>[CH:3]1[C:4]2[NH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][C:2]=1[C:20]1[CH:21]=[CH:22][C:17]([CH:15]=[O:16])=[CH:18][CH:19]=1
Reactant: Brc1ccc2c(c1)[nH]c1ccccc12
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1ccc(-c2ccc3c(c2)[nH]c2ccccc23)cc1
Yield: 53 %

Procedure:
10.0 g of 2-bromo-9H-carbazole (4.06 10−2 mol), 9.22 g of 4-formylphenylboronic acid (6.15 10−2 mol), 0.63 g of tetrakistriphenylpalladium (5.5 10−4 mol), 42.0 g of potassium carbonate (3 10−1 mol) are initially introduced. After flushing through 300 ml of water with argon, 400 ml of THF is added. The reaction mixture is stirred under reflux for 2 days. After filtration through Celite, the organic phase is separated, dried over Na2CO4, and the aqueous phase is washed 2× with CH2Cl2 and dried over Na2SO4. Column chromatography with toluene as eluent give 2.0 g (53%) of clean product.
Reaction SMILES: [NH2:1][C:2]1[C:28]([Cl:29])=[CH:27][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:11][C@H:10]2[OH:26])=[O:7])=[C:4]([O:30][CH3:31])[CH:3]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40]>O1CCCC1>[C:39]([O:26][C@H:10]1[C@@H:9]([NH:8][C:6](=[O:7])[C:5]2[CH:27]=[C:28]([Cl:29])[C:2]([NH2:1])=[CH:3][C:4]=2[O:30][CH3:31])[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:11]1)(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7.5 parts of cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-hydroxy-4-piperidinyl]-2-methoxybenzamide in 68 parts of tetrahydrofuran were added dropwise 2.02 parts of N,N-diethylethanamine. After cooling to 0° C., there was added dropwise a solution of 1.4 parts of acetyl chloride in 9 parts of tetrahydrofuran at a temperature below 0° C. Upon completion, stirring was continued for a while while cooling in an ice-bath. The reaction mixture was allowed to reach slowly room temperature and stirring was continued overnight at room temperature. The reaction mixture was evaporated and the residue was taken up in a sodium carbonate solution in water. The product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further separated by HPLC using a mixture of trichloromethane, hexane and methanol (48:48:4 by volume) as eluent. The second fraction (B-isomer) was collected and the eluent was evaporated. The residue was suspended in petroleum ether. The product was filtered off and dried, yielding 1.7 parts of cis-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-[3-(4-fluorophenoxy)propyl]-3-piperidinol acetate (ester); mp. 58.8° C. (compound 232).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][N:10]([CH2:20][C:19]4[CH:22]=[CH:23][CH:24]=[C:17]([O:16][CH3:15])[CH:18]=4)[CH2:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: COc1cccc(CBr)c1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(CN2CCc3[nH]c4ncc(Cl)cc4c3C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.8 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg; 0.24 mmol), 3-methoxybenzyl bromide (0.04 ml; 0.29 mmol), and K2CO3 (0.04 ml; 0.72 mmol) were dissolved in DMF (2 ml) and stirred overnight at room temperature. Prep-LC-MS purification provided 17 as an off-white powder (14 mg, 18% yield). LC-MS (M+H=328, obsd.=328).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].C([O-])([O-])=O.[K+].[K+].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[F:22]>CN(C=O)C.O>[F:22][C:14]1[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=1[O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCO
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc([N+](=O)[O-])cc1F
Temperature: 70 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
To a stirred suspension of methyl glycol (2.2 mL, 28.28 mmol, 1.5 eq.) and K2CO3 (7.8 g, 56.60 mmol, 3.0 eq.) in DMF (20 mL) was added 1,2-difluoro-4-nitrobenzene (3.0 g, 18.85 mmol, 1.0 eq.) and the mixture was stirred for 16 h at 70° C. The reaction mixture was cooled and diluted with water (30 mL) and extracted with ethyl acetate (40 mL). The organic layer was separated and washed with water (50 mL), brine (50 mL), and dried over sodium sulfate and the solvent evaporated under vacuum. The crude product was washed with n-pentane (30 mL) to obtain 2-fluoro-1-(2-methoxyethoxy)-4-nitrobenzene (3 g, 74%, as solid; TLC system: EtOAc/PE (1:9), Rf: 0.2).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[N:21][CH:22]=[C:23]([CH:26]=2)[CH:24]=[O:25])O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:10][C:4]1[CH:3]=[C:2]([C:19]2[CH:20]=[N:21][CH:22]=[C:23]([CH:24]=[O:25])[CH:26]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cncc(C=O)c2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 0.4-bromo-2-chlorobenzonitrile (1.082 g, 5 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinaldehyde (1.165 g, 5.00 mmol), Pd(PPh3)4 (0.144 g, 0.125 mmol), sodium carbonate (2.5 mL, 5.00 mmol) in 1,4-dioxane (20 mL) was heated to reflux for 6 h. After cooling to room temperature, the solid was filtered and washed by ethyl acetate and water. After drying under vacuum, yellow powder was collected (1 g). 1H NMR (400 MHz, CDCl3): δ 7.63 (dd, J=1.68, 8 Hz, 1H), 7.79 (d, J=1.68 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 8.35 (dd, J=2.24 Hz, 2.04 Hz, 1H), 9.07 (d, J=2.36 Hz, 1H), 9.15 (d, J=1.88 Hz, 1H), 10.22 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.[F:10][C:11]1[CH:20]=[CH:19][C:18](I)=[CH:17][C:12]=1[C:13]([NH:15][CH3:16])=[O:14].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:18]2[CH:19]=[CH:20][C:11]([F:10])=[C:12]([CH:17]=2)[C:13]([NH:15][CH3:16])=[O:14])[CH:5]=[N:4][CH:3]=1
Reactant: CNC(=O)c1cc(I)ccc1F
Reactant: C#Cc1cncc(Cl)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CNC(=O)c1cc(C#Cc2cncc(Cl)c2)ccc1F
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (45 mg, 0.06 mmol), copper (I) iodide (26 mg, 0.14 mmol), and 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (200 mg, 1.45 mmol) to a solution of 2-fluoro-5-iodo-N-methylbenzamide, (prepared as described in PREPARATION 39), (0.39 g, 1.39 mmol) in triethylamine (6 mL, 43 mmol) and heat at 70° C. After 10 min, add toluene (10 mL) to the solidified reaction mixture and heat at 70° C. for 1 h. Concentrate and purify using silica gel chromatography, eluting with 40:60 ethyl acetate:hexanes, to give the title compound as a white solid (300 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[C:9]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:17](I)[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:17]([O:11][C:10]1[C:2]([Cl:1])=[C:3]([CH:7]=[CH:8][C:9]=1[S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[C:4]([OH:6])=[O:5])[CH3:18]
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1c(S(=O)(=O)CC)ccc(C(=O)O)c1Cl
Temperature: 90 °C

Procedure:
A mixture of the 2-chloro-4-ethylsulfonyl-3-hydroxybenzoic acid prepared in Example 4 (0.075 mole), ethyl iodide (0.5 mole), and potassium carbonate (0.1 mole) in dimethylformamide (150 ml) was heated at 90° C. for 7 hours. After cooling, the reaction mixture was partitioned between ethyl acetate and 5% potassium carbonate. The ethyl acetate layer was then washed with brine, dried over magnesium sulfate, and concentrated in vacuo to afford the crude ethyl ester of the desired benzoic acid. Hydrolysis of the ester to the acid was accomplished by stirring the ester (0.075 mole) with a base such as sodium hydroxide (0.1 mole) in ethanol (100 ml) at room temperature for 16 hours. The reaction mixture was acidified with 2N HCl, and then partitioned between methylene chloride and water. The methylene chloride layer was dried over magnesium sulfate and concentrated in vacuo to afford the acid as an oil.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([S:14]([C:17]3[CH:18]=[C:19]([OH:25])[C:20]([OH:24])=[CH:21][C:22]=3[CH3:23])(=[O:16])=[O:15])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:33](Br)[C:34]([OH:36])=[O:35].Cl>CN(C)C=O>[CH3:23][C:22]1[C:17]([S:14]([C:12]2[CH:11]=[CH:10][C:8]3[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[S:6][C:7]=3[CH:13]=2)(=[O:16])=[O:15])=[CH:18][C:19]2[O:25][CH:33]([C:34]([OH:36])=[O:35])[O:24][C:20]=2[CH:21]=1
Reactant: O=C(O)C(Br)Br
Reactant: Cc1cc(O)c(O)cc1S(=O)(=O)c1ccc2nc(C(C)(C)C)sc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1S(=O)(=O)c1ccc3nc(C(C)(C)C)sc3c1)OC(C(=O)O)O2
Reaction time: 21 h

Procedure:
39.6 g (approximately 0.105 mol) of 4-[(2-tert.butyl-6-benzothiazolyl)-sulphonyl]-5-methyl-1,2-benzenediol and 72.3 g (0.523 mol) of potassium carbonate are stirred in 300 ml of dimethylformamide at room temperature under inert gas protection. In the course of 20 minutes there is added dropwise thereto half of a solution of 45.6 g (0.209 mol) of dibromoacetic acid in 100 ml of dimethylformamide. The reaction mixture is subsequently stirred for 21 hours at 100° and, during this time, the remainder of the dibromoacetic acid solution is added in small portions. For working up, the dimethylformamide is distilled off in a rotary evaporator under a water jet vacuum. The residue is dissoled in water and adjusted to pH 1-2 with concentated hydrochloric acid. The precipitated acid is extracted three times with ethyl acetate. The combined ethyl acetate solutions are washed once with water, dried over sodium sulphate, filtered and concentrated by evaporation. The residue is dissolved in 500 ml of ethanol, and after the addition of 0.5 ml of concentrated hydrochloric acid the solution is left to stand at room temperature for 10 days. During this time, the ethyl ester of 5-methyl-6-[(2 -tert.-butyl-6-benzothiazolyl)-sulphonyl]-1,3-benzodioxole-2-carboxylic acid is precipitated in the form of colourless crystals. The crystal suspension is cooled to 0° and the crystals are filtered off. 90 ml of 2N sodium hydroxide solution are added to the crystals, still moist with ethanol, and the mixture is stirred for 2 hours at room temperature, a solution being formed. This is acidified with concentrated hydrochloric acid and the precipitated acid is extracted three times with ethyl acetate. The ethyl acetate solutions are washed with water, dried over sodium sulphate, filtered and concentrated by evaporation in vacuo to dryness. The residue is recrystallised from ethyl acetate, yielding 5-methyl-6-[(2-tert.-butyl-6-benzothiazolyl)-sulphonyl]-1,3-benzodioxole-2-carboxylic acid in the form of colourless crystals having a melting point of 247° (decomposition), after sintering from 203°.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:29][CH2:30][CH3:31])[CH:28]=1)[CH:24]=O)[CH3:19].O>CO>[CH2:30]([O:29][C:27]1[CH:26]=[C:23]([CH:22]=[C:21]([O:20][CH2:18][CH3:19])[CH:28]=1)[CH2:24][NH:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4])[CH3:31]
Reactant: CCOc1cc(C=O)cc(OCC)c1
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Solvent: CO
Solvent: O
Product: CCOc1cc(CN[C@@H](C)[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)cc(OCC)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 53.5 %

Procedure:
To a solution of the amine (4) (127 mg, 0.486 mmol) and 3,5-diethoxybenzaldehyde (123 mg, 0.632 mmol) in methanol (3.3 mL) was added borane-pyridine complex (155 μL, 1.46 mmol) at 40° C. and the resulting mixture was stirred for 2.5 hours. The reaction mixture was cooled to room temperature and water was added thereto, followed by extraction with a mixed solvent (ethyl acetate:methanol=10:1) and subsequent washing of the organic layer with saturated brine. The organic layer was dried and concentrated and the obtained crude product was purified by amine silica gel column chromatography (eluent; chloroform:methanol=7:1) to obtain the desired amine (10) as a yellow solid (114 mg, Yield: 54%).