Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39](=[O:47])[C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[N:42][CH:41]=1>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([C:39]([C:40]2[CH:41]=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=2)=[O:47])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1ccc(C)nc1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Product: Cc1ccc(C(=O)c2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(N3C[C@@H](C)O[C@@H](C)C3)c(Cl)c2F)cn1

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42) and N-methoxy-6,N-dimethyl-nicotinamide.
Reaction SMILES: Br[C:2]1[C:3]([CH:11]=[O:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CO.CCOCC.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:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:3]([CH:11]=[O:12])=[CH:4][C:5]3[O:9][CH2:8][O:7][C:6]=3[CH:10]=2)=[CH:16][CH:15]=1
Reactant: O=Cc1cc2c(cc1Br)OCO2
Reactant: OB(O)c1ccc(Cl)cc1
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: Cc1ccccc1
Solvent: CO
Solvent: CCOCC
Product: O=Cc1cc2c(cc1-c1ccc(Cl)cc1)OCO2

Procedure:
To a solution of 6-bromobenzo[d][1,3]dioxole-5-carbaldehyde (4.6 g), 4-chlorophenylboronic acid (3.78 g) and tetrakis(triphenylphosphine)palladium(0) (0.232 g) in toluene (80 mL) and methanol (30 mL) was added 2N aqueous Na2CO3 (30 mL). The mixture was stirred at reflux overnight. The mixture was diluted with ether (400 mL) and washed with water, brine and dried over Na2SO4. After filtration and concentration of the solvent, the residue was loaded on a column and eluted with 3% ethyl acetate in hexane to give the product.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH3:12][N:13]([CH3:17])[C:14](N)=[O:15].ClC1C=CC(Cl)=CC=1Cl.CNC.ClC(Cl)(Cl)C1C=C(NC(N(C)C)=O)C=CC=1>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([NH:6][C:14]([N:13]([CH3:17])[CH3:12])=[O:15])[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)C(N)=O
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN(C)C(=O)Nc1cccc(C(Cl)(Cl)Cl)c1
Agent: CNC
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: CN(C)C(=O)Nc1cccc(C(F)(F)F)c1

Procedure:
Using the amount of 3-trifluoromethylaniline and N,N-dimethylurea indicated in Example 4, but using the mother liquor from Example 4 instead of pure 1,2,4-trichlorobenzene as the diluent and using 11.4 g (0.25 mol) of dimethylamine, 4.8 g of N-(3-trichloromethylphenyl)-N',N'-dimethylurea, i.e. 83% of theory, having a melting point of 160° to 161° C. and a purity of 99.7% were obtained in the manner described in Example 2.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:13]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:21]([O:20][C:18]([N:14]1[CH2:15][CH2:16][CH2:17][C:12](=[O:11])[CH2:13]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(OCc1ccccc1)N1CCCC(O)C1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 111.8 %

Procedure:
800 ml of a solution of 52.4 ml of oxalyl chloride in methylene chloride was cooled to −78° C., 53.2 ml of DMSO was added dropwise to the solution, and the mixture was stirred at −78° C. for 0.5 hour. A solution of 75.5 g of benzyl 3-hydroxypiperidine-1-carboxylate dissolved in 200 ml of methylene chloride was added dropwise to the mixture, and further 293 ml of triethylamine was added dropwise to the same, and the mixture was stirred for 16 hours while a temperature thereof was gradually raised to room temperature. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated to obtain 83.7 g of 1-benzyloxycarbonyl-3-piperidone. MS•APCI (m/z): 234 [M+H]+ (3) To a solution of 83.7 g of 1-benzyloxycarbonyl-3-piperidone dissolved in 1.2 liters of methylene chloride was added 55.0 g of (R)-(+)-1-(1-naphthyl)ethylamine, and after the mixture was stirred at room temperature for 2 hours, 69 ml of acetic acid and 160 g of sodium triacetoxy borohydride were added to the mixture, and the mixture was stirred at room temperature for 15 hours. To the reaction mixture was added an aqueous sodium hydroxide to make the mixture basic, and then, chloroform was added to the mixture, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→0:1) to obtain 98.7 g of benzyl 3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate. MS•APCI (m/z): 389 [M+H]+ (4) To a solution of 40.95 g of triphosgene dissolved in 800 ml of methylene chloride was added dropwise a mixed solution containing 80.6 g of benzyl 3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate and 86.6 ml of triethylamine dissolved in 200 ml of methylene chloride at 0° C., and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added water, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was washed with 200 ml of diethyl ether, and the crystal collected by filtration was recrystallized from chloroform and diethyl ether to obtain 48.9 g of benzyl (R)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][O:6][CH2:5][C@:4]2([C:20]3[CH:19]=[C:18]([OH:21])[N:17]=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][C:10]([Br:22])=[CH:11][CH:12]=3)[N:3]=1.[F-].[Cs+].C(#N)C.[F:28][C:29]([F:41])(S(F)(=O)=O)C(O[Si](C)(C)C)=O>CCOC(C)=O>[Br:22][C:10]1[CH:9]=[C:8]2[C@:4]3([N:3]=[C:2]([NH2:1])[CH2:7][O:6][CH2:5]3)[C:20]3[CH:19]=[C:18]([O:21][CH:29]([F:41])[F:28])[N:17]=[CH:16][C:15]=3[O:14][C:13]2=[CH:12][CH:11]=1
Reactant: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(O)cc12
Reactant: C[Si](C)(C)OC(=O)C(F)(F)S(=O)(=O)F
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(OC(F)F)cc12
Reaction time: 0.25 h
Yield: 19.7 %

Procedure:
A flask was charged with (S)-5′-amino-7-bromo-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-3-ol (0.250 g, 0.690 mmol), cesium fluoride (9.17 mg, 0.069 mmol), and acetonitrile (6.90 mL). Trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.272 mL, 1.381 mmol) was added slowly and the reaction was stirred for 15 minutes. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (0-10% MeOH/DCM), to afford (S)-7-bromo-3-(difluoromethoxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.056 g, 0.136 mmol, 19.68% yield) as a light yellow solid. [M+H]+=411.9
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:18]([CH3:22])=[C:19]([CH3:21])[N:20]=2)[CH:9]=[C:10]([C:12](OC(C)C)=[O:13])[CH:11]=1.[CH2:28]([CH2:30][NH2:31])[OH:29].N12CCCN=C1CCCCC2>CO>[CH3:21][C:19]1[N:20]=[C:7]2[C:6]([NH:5][CH2:4][C:3]3[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:2]=3[CH3:1])=[CH:11][C:10]([C:12]([NH:31][CH2:30][CH2:28][OH:29])=[O:13])=[CH:9][N:8]2[C:18]=1[CH3:22]
Reactant: NCCO
Reactant: Cc1cccc(C)c1CNc1cc(C(=O)OC(C)C)cn2c(C)c(C)nc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: Cc1cccc(C)c1CNc1cc(C(=O)NCCO)cn2c(C)c(C)nc12
Temperature: 5 °C
Yield: 81.9 %

Procedure:
Isopropyl 8-[(2,6-dimethylbenzyl)amino]-2.3-dimethylimidazo[1,2-a]pyridine-6-carboxylate (obtained as described in WO2/20523) (5 g, 14 mmol), ethanolamine (2.0 g 33 mmol) and 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) 1.5 g, 10 mmol) were dissolved in methanol (25 ml). The mixture was refluxed over night. The reaction mixture was cooled to 5° C. The solid product was filtered off and washed with methanol (15 ml). 4.2 g (84%) of the title compound was obtained as a white solid. The structure of the compound was confirmed with 1H-NMR spectrum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:33]1([NH:43]N)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:43][C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=32)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1
Reactant: NNc1cccc2ccccc12
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(F)c4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 548.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]#[CH:6])([CH3:4])([CH3:3])[CH3:2].Br[CH2:8][CH2:9][CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.C(OCC)C>O1CCCC1>[CH3:2][C:1]([CH3:4])([CH3:3])[C:5]#[C:6][CH2:8][CH2:9][CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: BrCCCOC1CCCCO1
Reactant: C#CC(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)C#CCCCOC1CCCCO1
Temperature: -78 °C
Yield: 40.7 %

Procedure:
0.81 g of tert-butylacetylene was dissolved in 19 ml of tetrahydrofuran, and 6.1 ml of a 0.55M n-butyllithium-hexane solution was added dropwise with stirring at -78° C. After the mixture was stirred at this temperature for 1 hour, 2.2 g of 3-bromo-1-(2-tetrahydropyranyloxy)propane was added. The solution was warmed to the room temperature, and then heated at 80° C. with stirring for 8 hours. The reaction mixture was poured into the ice water, and ethyl ether was added. The organic layer separated was worked up in a customary manner, and the product was purified by silica gel column chromatography [hexane/ethyl acetate=20/1] to give 0.90 g of 6,6-dimethyl-1-(2-tetrahydropyranyloxy)- 4-heptyne.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[CH2:5]=[C:6]1[O:10][C:8](=[O:9])[CH2:7]1>ClCCl.CN(C)C1C=CN=CC=1.CC(C)=O>[C:8]([O:4][CH2:3][CH2:2][Br:1])(=[O:9])[CH2:7][C:6]([CH3:5])=[O:10]
Reactant: C=C1CC(=O)O1
Reactant: OCCBr
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(=O)CC(=O)OCCBr
Reaction time: 1 h

Procedure:
250 g of 2-bromoethanol are dissolved in 1.3 l of dichloromethane, and 1.2 g of 4-dimethylaminopyridine are added. 400 ml of a 50% strength diketene solution in acetone are added dropwise with vigorous stirring, so that the solvent boils moderately. After the dropwise addition, stirring is continued for a further 1 h at the boiling point and the mixture is then left to stand overnight. After the solvent has been evaporated off in a rotary evaportor in vacuo, the residue is distilled. 402 g of the title compound of b.p. 80°-83° C./0.04 mbar are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][C:16]([CH3:18])=[CH2:17])[C:10]([O:12]CC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][C:16]([CH3:18])=[CH2:17])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)CC(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=C(C)CC(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of ethyl (2RS)-2-tert-butoxycarbonylamino-4-methyl-4-pentenoate EXAMPLE 1.C, above (6.9 g, 26.9 mmol) in acetone (50 mL was added LiOH (108 mL of 1 N aqueous solution, 108 mmol). The clear solution was stirred at room temperature for 0.5 hour. Acetone was evaporated under reduced pressure, the pH of the resulting aqueous solution was then adjusted to 3 by addition of 1 N HCl and the aqueous layer was extracted with EA (3×50 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the desired acid as a pale yellow oil in quantitative yield.
Reaction SMILES: [C:1]1([CH3:31])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[OH:22])[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[OH:30])[N:10]=1.[CH2:32]([O:36][CH2:37][CH:38]([CH2:43][CH3:44])[CH2:39][CH2:40][CH2:41][CH3:42])[CH:33]1[O:35][CH2:34]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1(C)C=C(C)C=C(C)C=1.C(OCC)(=O)C>[C:1]1([CH3:31])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[N:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:34][CH:33]([OH:35])[CH2:32][O:36][CH2:37][CH:38]([CH2:43][CH3:44])[CH2:39][CH2:40][CH2:41][CH3:42])=[CH:25][C:24]=2[OH:30])[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:34][CH:33]([OH:35])[CH2:32][O:36][CH2:37][CH:38]([CH2:43][CH3:44])[CH2:39][CH2:40][CH2:41][CH3:42])=[CH:17][C:16]=2[OH:22])[N:14]=1
Reactant: Cc1cc(C)c(-c2nc(-c3ccc(O)cc3O)nc(-c3ccc(O)cc3O)n2)c(C)c1
Reactant: CCCCC(CC)COCC1CO1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: Cc1cc(C)cc(C)c1
Solvent: CCOC(C)=O
Product: CCCCC(CC)COCC(O)COc1ccc(-c2nc(-c3ccc(OCC(O)COCC(CC)CCCC)cc3O)nc(-c3c(C)cc(C)cc3C)n2)c(O)c1
Temperature: 140 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
A mixture of 39.5 g (0.095 mol) of 2-mesityl-4,6-bis(2,4-dihydroxyphenyl)-1,3,5-triazine (compound 1b), 40.7 g (0.2185 mol) of 2-ethylhexyl glycidyl ether (purity 98%) and 3.5 g (9.5 mmol) of ethyltriphenylphosphonium bromide (purity 97%) in 250 ml of mesitylene (purity 99%) is stirred at 140° C. under nitrogen for 16 hours. The clear solution is freed from solvent under reduced pressure. The crude product is dissolved in 200 ml of ethyl acetate and filtered through a 6.0 cm layer of silica gel 60 (230-400 mesh) of diameter 8.0 cm, with elution with 1000 ml of ethyl acetate. Removal of the solvent and drying for 2 hours at 100° C. and a pressure of 0.6 mmHg (80 Pa) give 61.3 g (yield 81.8%) of the title product (compound 7; Tg 54.4° C.) of the formula ##STR106## where R=CH2 --CH(OH)--CH2O--CH2 --CH(C2 H5)--CH2CH2CH2CH3.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[C:7]2[C:3]=1[C:4]1[CH:23]=[C:22]([CH3:24])[CH:21]=[N:20][C:5]=1[NH:6]2.[CH2:25]([S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28])[CH3:26].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>CCOC(C)=O.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].O1CCOCC1>[CH2:25]([S:27]([C:30]1[CH:35]=[C:34]([C:2]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[C:7]3[C:3]=2[C:4]2[CH:23]=[C:22]([CH3:24])[CH:21]=[N:20][C:5]=2[NH:6]3)[CH:33]=[CH:32][CH:31]=1)(=[O:28])=[O:29])[CH3:26]
Reactant: Cc1cnc2[nH]c3c(OCC4CCN(C)CC4)ccc(Cl)c3c2c1
Reactant: CCS(=O)(=O)c1cccc(B(O)O)c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCC3CCN(C)CC3)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 125 °C
Reaction time: 6 h
Yield: 75.2 %

Procedure:
To a stirred solution of Compound 175 (170 mg, 0.49 mmol) and 3-(ethylsulfonyl)phenylboronic acid (265 mg, 1.24 mmol) in anhydrous and degassed dioxane (5 mL), were added Pd(dba)2 (70 mg, 0.12 mmol), PCy3 (0.34 mL, 20% wt solution in toluene, 0.24 mmol) and Cs2CO3 (479 mg, 1.47 mmol), under nitrogen. After being stirred for 6 h. under reflux (oil bath temperature 125° C.) the reaction was diluted with EtOAc and filtered through a small pad of celite. The residue was washed thoroughly with EtOAc and 10% MeOH in CH2Cl2. All the washings and filtrate were concentrated in vacuum and the crude residue was triturated with ether and then with MeOH and then purified through preparative HPLC to give Compound 176 (176 mg, 75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (t, J=7.34 Hz, 3H) 1.50-1.61 (m, 2H) 2.18 (br. s., 1H) 2.13-2.20 (m, 1H) 2.23-2.31 (m, 5H) 2.82 (s, 3H) 2.98-3.09 (m, 2H) 3.39 (q, J=7.34 Hz, 2H) 3.54 (d, J=10.60 Hz, 2H) 4.12 (d, J=6.52 Hz, 2H) 7.06-7.17 (m, 2H) 7.53 (s, 1H) 7.85 (t, J=7.74 Hz, 1H) 7.96 (d, J=7.66 Hz, 1H) 8.00 (d, J=7.66 Hz, 1H) 8.06 (s, 1H) 8.28 (d, J=1.47 Hz, 1H) 11.83 (br. s., 1H), [M+H] calc'd for C27H32N3O3S, 478.2; found, 478.4; [M+H+TFA] calc'd for C29H33N3O5F3S, 592.2; found, 592.4.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1.[Li]C(C)(C)C.[C:13](=[O:15])=[O:14]>CCOCC.CCCCC>[Br:7][C:6]1[C:2]([C:13]([OH:15])=[O:14])=[CH:3][S:4][CH:5]=1
Reactant: Brc1cscc1Br
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: O=C(O)c1cscc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
To a solution of 3,4-dibromothiophene (15 g, 62 mmol) in 80 mL ether under a positive nitrogen atmosphere was added dropwise 75 mL 1.7M t-BuLi in pentane at below -73° C. and the resulting reaction solution was stirred at -78° C. for 0.5 h. After that, the ether solution was poured into dry ice and extracted with water. The aq solution was washed with ether and then acidified with concentrated HCl. The solid was filtered and air-dried to give 9 g of 4-bromo-3-thiophenecarboxylic acid, yield 70.3%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)CCC>>[S:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Reactant: Brc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Product: c1ccc2sc(-c3cnc4c(c3)C[C@@]3(CN5CCC3CC5)O4)nc2c1

Procedure:
Prepared by a method analogous to that described for the preparation of Example 1 from (2′R)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] and 2-tri-n-butylstannylbenzothiazole. The title compound was obtained as a colourless solid; m/e 350 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[CH:14][C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)([OH:3])=[O:2].[CH3:24]O.OS(O)(=O)=O>C1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[CH:14][C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)([O:3][CH3:24])=[O:2]
Reactant: O=C1Nc2ccc(C(=O)O)cc2C1=Cc1c[nH]c2ncccc12
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: COC(=O)c1ccc2c(c1)C(=Cc1c[nH]c3ncccc13)C(=O)N2
Yield: 90 %

Procedure:
A solution of 5-carboxy-3-[(7-azaindol-3-yl)methylene]-2-oxindole (3.053 g, 10 mmol), methanol (3.2 g, 0.1 mol) and H2SO4 95% (1 g) in benzene (100 ml) was heated in a Soxhlet apparatus for 10 h. To dry the distillate continuously, the cap of the Soxhlet contained anhydrous MgSO4. After cooling, water was added, the organic phase repeatedly washed with water and then evaporated under vacuum. Thus almost pure title compound was obtained in about 90% yield.
Reaction SMILES: O.O.Cl[Sn]Cl.[N+:6]([C:9]1[CH:10]=[C:11]([Br:18])[C:12]2[S:16][CH:15]=[N:14][C:13]=2[CH:17]=1)([O-])=O.[OH-].[Na+]>Cl>[NH2:6][C:9]1[CH:10]=[C:11]([Br:18])[C:12]2[S:16][CH:15]=[N:14][C:13]=2[CH:17]=1
Reactant: O=[N+]([O-])c1cc(Br)c2scnc2c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Nc1cc(Br)c2scnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9687.5 %

Procedure:
To a solution of SnCl2.2H2O (0.5 g, 2.2 mmol) in 5 mL of HCl was added 5-nitro-7-bromobenzothiazole (82 mg, 0.32 mmol) in a portion and the resulting reaction mixture was stirred for 1 h at 25° C. The reaction mixture was basified with aq. NaOH and extracted with EtOAc. Organic extracts were dried over Na2SO4 and concentrated in vacuo to yield 70 mg (31 mmol, 96%) of the desired product.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH2:24]([N:26]([CH2:29][C:30]([N:32]([C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)[CH3:33])=[O:31])[CH2:27][CH3:28])[CH3:25].[OH-].[Na+]>CN(C=O)C.CO>[CH2:24]([N:26]([CH2:29][C:30]([N:32]([C:34]1[CH:40]=[CH:39][C:37]([NH:38]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:36][CH:35]=1)[CH3:33])=[O:31])[CH2:27][CH3:28])[CH3:25]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: CCN(CC)CC(=O)N(C)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CCN(CC)CC(=O)N(C)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 43 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-(N-diethylaminomethylcarbonyl-N-methyl-amino)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]1([N:22]=[C:23]=[O:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:23]([NH:22][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)=[O:24]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1cccc2ccccc12
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1cccc2ccccc12

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(1-naphthyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 1-naphthyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product precipitated from methylene chloride and filtered. The resulting solid was titruated with 1:3 triethyl amine:methylene chloride. The fiterate was concentrated in vacuo. The resulting residue was dissolved in methylene chloride and treated with 1N HCl in water. The desired product precipitated from solution and was collected by filtration(0.11 g, 10%). EI-MS m/z 324(M+H)+
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[C:10]([C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1)#[CH:11]>>[C:10]([C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)#[CH:11]
Reactant: C#Cc1cccc(O)c1
Reactant: ClCCN1CCCC1
Agent: Cl
Product: C#Cc1cccc(OCCN2CCCC2)c1

Procedure:
Prepared analogously to Example 18a from 1-(2-chloro-ethyl)-pyrrolidine-hydrochloride and 3-ethynyl-phenol.