Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][C@@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:9]=[C:8]([CH3:18])[C:7]=1Br)(=[O:3])[CH3:2].[OH:20][CH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.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]>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][C@@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:9]=[C:8]([CH3:18])[C:7]=1[C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:21][OH:20])[CH:27]=1)(=[O:3])[CH3:2]
Reactant: OCc1cccc(B(O)O)c1
Reactant: CC(=O)OCc1cc(O[C@@H]2CCOC2)cc(C)c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)OCc1cc(O[C@@H]2CCOC2)cc(C)c1-c1cccc(CO)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 66.8 %

Procedure:
The crude (R)-2-bromo-3-methyl-5-((tetrahydrofuran-3-yl)oxy)benzyl acetate 35c (658 mg, 2 mmol) was dissolved in 50 mL of dioxane, followed by addition of 3-hydroxymethyl phenylboronic acid (608 mg, 4 mmol) and 6 mL of aqueous potassium carbonate solution (636 mg, 4 mmol), and then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (74 mg, 0.10 mmol). The reaction solution was heated to 70° C. and stirred for 4 hours. The resulting solution was cooled, poured into 100 mL 1M aqueous hydrochloric acid solution, and extracted with ethyl acetate (30 mL×3). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound (R)-(3′-(hydroxymethyl)-6-methyl-4-((tetrahydrofuran-3-yl)oxy)biphenyl-2-yl)methyl acetate 35d (476 mg, yield 66.8%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[CH:5]=[C:4]([C@@H:13]([NH:15][C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH3:14])[N:3]=1.[C:34]([Zn]C#N)#[N:35].O>CN(C=O)C.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:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([C:34]#[N:35])=[N:3][C:4]([C@@H:13]([NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]3[C:17]=1[N:18]=[CH:19][N:20]3[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH3:14])=[CH:5]2
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(Cl)n4)ncnc32)cc1
Reactant: N#C[Zn]C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C#N)n4)ncnc32)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ((S)—N-(1-(1,8-dichloroisoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 1 (1.5 g, 3.1 mmol, 1.0 eq) and tetrakis(triphenylphosphine)palladium (181 mg, 0.16 mmol, 0.05 eq) in DMF (50 mL) at RT, dicyanozinc (476 mg, 4.06 mmol, 1.3 eq) was added and the resulting mixture was stirred at 100° C. overnight. The reaction mixture was poured into water (100 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-10% MeOH-DCM) to afford the product (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carbonitrile 29.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:10]([N+:12]([O-:14])=[O:13])=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1c(Cl)cccc1Cl
Agent: O=S(=O)(O)O
Product: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,6-Dichloro-benzoic acid (10 g, 52 mmol) was treated with a previously stirred mixture of nitric acid (15 mL) and sulfuric acid (30 mL) at 55° C. for 30 minutes followed by stirring at room temperature for 30 minutes. The reaction mixture was poured in ice cold water (1 L) and the solid obtained was filtered and dried to afford the product (9 gm). The filtrate was extracted with ethyl acetate (2×200 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated to dryness to yield more product (2 gm). (11 g, 88%).
Reaction SMILES: C(O[C:9]1C=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:18](=[O:21])[NH:19][N:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl.Cl.[NH2:29]N>C(O)C>[N:29]1[CH:9]=[CH:10][CH:11]=[C:12]([C:15]2[CH:16]=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:18](=[O:21])[NH:19][N:20]=2)[CH:13]=1
Reactant: NN
Reactant: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)n[nH]c1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cccnc2)n[nH]c1=O

Procedure:
Working as in example 19 for the preparation of ethyl 6-[4-(benzyloxy)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylate, but starting with 8.85 g of diethyl hydroxy(pyridin-3-oxoethyl)malonate, 3.67 g of hydrazine dihydrochloride and 250 cm3 of ethanol, and after recrystallization from ethanol, 3.6 g of ethyl 6-pyridin-3-yl-3-oxo-2,3-dihydropyridazine-4-carboxylate were obtained in the form of a green solid melting at a temperature in the region of 150° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Mg].[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>O1CCCC1>[CH3:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:3][CH:4]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C

Procedure:
1-Bromo-4-(1,1-dimethylethyl)benzene (10.656 g) in dry tetrahydrofuran (40 ml) was added dropwise with stirring to magnesium metal (1.264 g) in dry tetrahydrofuran (10 ml). After the reaction had been initiated by warming the 1-bromo-4-(1,1-dimethylethyl)benzene was added dropwise at such a rate to maintain boiling of the solvent. After the addition the mixture was heated under reflux for 1 hour then cooled to room temperature and tri-n-butyltin chloride (14.12 ml) in dry tetrahydrofuran (20 ml) was added dropwise. The mixture was heated under reflux for 1 hour poured into ice water (300 ml), extracted with diethyl ether (2×100 ml), washed with sodium hydrogen carbonate (50 ml), dried (MgSO4) and the solvent removed in vacuo to give a yellow liquid which was poured on to flash silica gel (25 g) on a sinter. The product was washed through with hexane and the hexane was removed in vacuo to give a colourless liquid which was used directly in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:41])=[C:6]([CH2:8][CH:9]([NH:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=2[C:19]2[NH:40][C:22]3=[CH:23][C:24]4[C:25](=[O:39])[N:26]([CH:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)[C:27](=O)[C:28]=4[C:29]([CH3:30])=[C:21]3[N:20]=2)[CH3:10])[CH:7]=1>[Zn].C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:41])=[C:6]([CH2:8][CH:9]([NH:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=2[C:19]2[NH:40][C:22]3[C:21]([N:20]=2)=[C:29]([CH3:30])[C:28]2[CH2:27][N:26]([CH:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[C:25](=[O:39])[C:24]=2[CH:23]=3)[CH3:10])[CH:7]=1
Reactant: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2c(C)c3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2c(C)c3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3
Yield: 3.8 %

Procedure:
A mixture of 2-(4-(1-(5-fluoro-2-methylphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-4-methyl-6-(1-methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.81 g, 1.46 mmol), zinc dust (0.95 g, 14.55 mmol), and 25 mL of acetic acid was heated at reflux for 13-14 h under an argon atmosphere. Product was separated by a silica gel column using methylene chloride and methanol (85:15 v/v) as eluent to afford 30 mg of the designed compound as yellowish solid. 1H NMR (500 MHz, DMSO-d6) δ; Mass (ESI, positive) m/z 543.2 [M+H]+, 565.2 [M+Na]+.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][C:9]#[CH:10])SC)#[N:2].[S:11]1[CH:15]=[CH:14][N:13]=[C:12]1[CH2:16][S:17][CH2:18][CH2:19][NH2:20]>>[C:1]([NH:3][C:4]([NH:7][CH2:8][C:9]#[CH:10])=[N:20][CH2:19][CH2:18][S:17][CH2:16][C:12]1[S:11][CH:15]=[CH:14][N:13]=1)#[N:2]
Reactant: NCCSCc1nccs1
Reactant: C#CCN=C(NC#N)SC
Product: C#CCNC(=NCCSCc1nccs1)NC#N

Procedure:
The product of Step A is reacted with about an equimolar amount of 2-[(thiazol-2-yl)methylthio]ethylamine to give, after workup, the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].[C:17]([N:25]=[C:26]=[S:27])(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[CH2:17]([NH:25][C:26]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])=[S:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ccccc1C(=O)Nc1ccccc1
Solvent: CCOCC
Product: O=C(Nc1ccccc1)c1ccccc1NC(=S)NCc1ccccc1
Yield: 1015.8 %

Procedure:
To a stirred mixture of 1.0 g of 2-amino-N-phenylbenzamide and 500 ml of ether was added dropwise, a solution of 7.7 g of benzoyl isothiocyanate in 100 ml of ether over 20 minutes. After standing several hours, the solid was collected, giving 17.3 g of the desired product as cream- colored crystals mp 197°-200° C. (dec.).
Reaction SMILES: [OH:1][B:2]1[C@@H:7]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][N:10]=2)[CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:4]=2[O:3]1.[C:22](=[O:30])([O:26][CH:27]([CH3:29])[CH3:28])[O:23][CH2:24]Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:1][B:2]1[C@@H:7]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][N:10]=2)[CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([O:21][CH2:24][O:23][C:22]([O:26][CH:27]([CH3:29])[CH3:28])=[O:30])=[O:20])[C:4]=2[O:3]1
Reactant: Cn1cnnc1S[C@H]1Cc2cccc(C(=O)O)c2OB1O
Reactant: CC(C)OC(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)OCOC(=O)c1cccc2c1OB(O)[C@@H](Sc1nncn1C)C2
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To the solution of acid 15 (0.5 mmol) in DMF (5 mL) was added chloromethyl isopropyl carbonate (1 mmol), followed by K2CO3 (0.75 mmol). The resulting mixture was stirred at 50° C. for 18 hours and brought to room temperature and concentrated. The residue was purified by purified by prep-HPLC (C18, acetonitrile and water as mobile phases, 0.1% formic acid) to obtain the titled compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([NH2:15])=[O:14])=[N:11][CH:12]=2)[CH2:3]1.[C:16](Cl)(=[O:27])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>N1C=CC=CC=1>[C:16](=[O:27])([O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)[O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[N:11][C:10]([C:13](=[O:14])[NH2:15])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: NC(=O)c1ccc(N2CCC(O)C2)cn1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: NC(=O)c1ccc(N2CCC(OC(=O)Oc3ccc([N+](=O)[O-])cc3)C2)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.6 %

Procedure:
To a solution of 5-(3-hydroxypyrrolidin-1-yl)picolinamide (1 g, 4.83 mmol) and 4-nitrophenyl carbonochloridate (1.46 g, 8.3 mmol) in pyridine (30 mL) was added DIPEA (1.25 g, 11 mmol) and the resulting mixture was stirred at rt for 3 days. The precipitate was collected by filtration and the cake was washed with DCM (20 mL) to give the desired compound (1.0 g, 56%) as a pale yellow solid. [LCMS: RtA=1.48 min, m/z 373.2 [M+H]+].
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[C:24](OCC)[C:25]=1[F:26])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)[CH3:2].C(OC1C=C(C=CC=1F)C=O)C.OC1C=C(C=CC=1F)C(O)=O.ClC1C=CC(C=O)=CC=1OCC.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:22]=[N:21][CH:20]=[N:19][CH:18]=2)=[O:16])[CH2:10][CH2:9]1)[CH3:2]
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cncnc3)CC2)cc(OCC)c1F
Agent: CCOc1cc(C=O)ccc1Cl
Agent: CCOc1cc(C=O)ccc1F
Agent: O=C(O)c1ccc(F)c(O)c1
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC(NC(=O)c3cncnc3)CC2)ccc1F

Procedure:
In analogy to the procedure described in example 50k), pyrimidine-5-carboxylic acid piperidin-4-ylamide (example 56) was reacted with 3-ethoxy-4-fluoro-benzaldehyde [prepared from 3-hydroxy-4-fluoro-benzoic acid in analogy to the procedure described for the synthesis of 4-chloro-3-ethoxy-benzaldehyde in example 1a)], sodium cyano-borohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as light yellow solid. MS: 359.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[S:15][C:16](Br)=[C:17]([Br:20])[C:18]=2[CH3:19])[N:11]([CH3:22])[N:10]=1.C(O)(=O)C.O>[Zn].CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[S:15][CH:16]=[C:17]([Br:20])[C:18]=2[CH3:19])[N:11]([CH3:22])[N:10]=1
Reactant: Cc1c(-c2nc(-c3c(F)cccc3Cl)nn2C)sc(Br)c1Br
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: Cc1c(Br)csc1-c1nc(-c2c(F)cccc2Cl)nn1C
Temperature: 100 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
Into 250-mL three-necked round bottom flask equipped with a mechanical stirrer and condenser under an atmosphere of nitrogen was added 19.26 g of 3-(2-chloro-6-fluorophenyl)-1-methyl-5-(4,5-dibromo-3-methyl-2-thienyl)-1H-1,2,4-triazole, 72 mL of acetic acid, 16 mL of water, and 3.25 g of zinc dust. The temperature of the reaction mixture was heated to 100° C. and was maintained at that temperature. After three hours the mixture was allowed to cool to room temperature and was poured into ether (500 mL) and washed with water (2×150 mL), saturated sodium bicarbonate (3×150 mL), brine, dried (Na2SO4) and the solvent removed in vacuo to give 15.4 g (96.4% yield) of the title compound as a white solid: mp 120-121° C; 1H NMR (CDCl3) δ 7.5 (s, b, 1H), 7.3-7.4 (m, 2H), 7.1 (m, 1H), 4.0 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.[NH2:37][CH:38]1[CH:43]2[CH2:44][CH2:45][N:40]([CH2:41][CH2:42]2)[CH2:39]1>C(#N)C>[N:40]12[CH2:45][CH2:44][CH:43]([CH2:42][CH2:41]1)[CH:38]([NH:37][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=1)[CH2:39]2
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: NC1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC1CN2CCC1CC2)c1cccc(Cl)c1
Reaction time: 20 h
Yield: 99.6 %

Procedure:
In 400 ml of acetonitrile was suspended 25 g of m-chlorobenzoic acid and while the suspension was stirred with ice-cooling, 39.5 g of N,N'-dicyclohexylcarbodiimide and 27.0 g of 1-hydroxybenzotriazole monohydrate were added. The mixture was stirred for 2 hours. Then, 20.2 g of 3-aminoquinuclidine was added and the mixture was further stirred with ice-cooling for 2 hours and, then, at room temperature for 20 hours. The reaction mixture was filtered to remove insolubles and the solvent was evaporated off. The residue was dissolved by addition of diluted hydrochloric acid and washed twice with ethyl acetate. The aqueous layer was neutralized with aqueous solution of sodium hydroxide and extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate and the chloroform was evaporated off to give 42.1 g of the desired compound as white crystals.
Reaction SMILES: S(Cl)(Cl)=O.C([O:7][C:8](=[O:27])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([OH:26])=O)=[CH:12][CH:11]=1)C>>[O:26]=[C:24]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][S:16][C:13]2[CH:14]=[CH:15][C:10]([CH2:9][C:8]([OH:7])=[O:27])=[CH:11][C:12]1=2
Reactant: CCOC(=O)Cc1ccc(SCc2ccccc2C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CS2
Reaction time: 1.5 h

Procedure:
66 cc of thionyl chloride are added at room temperature to 13.2 g of 4-(2-carboxy-benzyl-thio)phenyl-acetic acid ethyl ester and the mixture is stirred for 90 minutes until gas evolution stops. The mixture is completely concentrated by evaporation at reduced pressure and the resulting light yellow oil is dissolved in ether, whereby 4-(2-chloro-carbonyl-benzyl-thio)phenyl-acetic acid ethyl ester precipitates in the form of light yellow crystals. M.P. 78°-79°.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9]2[C:4](=[C:5]([F:22])[C:6]([F:21])=[C:7]([F:20])[CH:8]=2)[N:3]=1.CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]([C:12]([C:13](=[CH:25][N:26]([CH3:28])[CH3:27])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19])=[CH:10][C:9]2[C:4](=[C:5]([F:22])[C:6]([F:21])=[C:7]([F:20])[CH:8]=2)[N:3]=1
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A suspension of ethyl 3-(2-chloro-6,7,8-trifluoro-3-quinolyl)-3-oxopropionate (26.7 g) in ethyl acetate (270 cc) and N,N-dimethylformamide dimethyl acetal (32 cc) is heated to a temperature in the region of 75° C. with stirring for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C. The dry extract is taken up with isopropyl ether (175 cc), drained and washed with the same solvent (2×85 cc). Ethyl 2-(2-chloro-6,7,8-trifluoro-3-quinolinecarbonyl)-3-(dimethylamino)acrylate (19.32 g) is obtained in the form of an orange-colored solid, m.p. 118° C., which is used without further purification for the subsequent steps.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:14])=O)=[CH:8]2)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCCC1>[CH2:1]([C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:35])[NH2:14])=[CH:8]2)[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=O)[nH]c12
Solvent: C1CCOC1
Product: CCc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Yield: 131.1 %

Procedure:
A mixture of 7-ethyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide (3.4 g), a Lawesson's reagent (2.3 g), and dry tetrahydrofuran (70 mL) was stirred at 55° C. for 3 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=25:75 to 60:40, volume ratio), and the obtained yellow crystals were washed with ethyl acetate-hexane to give the title compound (2.8 g, yield 79%) as pale-yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[NH3:15]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: N
Solvent: O
Product: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 4-nitrobenzenesulfonyl chloride (6.7 g) was added ammonia water (10 ml) while ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with ethyl acetate (100 ml), and the extract was washed with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, followed by evaporation of the solvent under a reduced pressure, to obtain 4-nitrobenzenesulfonamide (5.9 g).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].C1C[O:10]CC1.[CH2:12]([NH:16][C:17]([C:19]1[S:23][C:22]2[S:24][C:25]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:26][C:21]=2[CH:20]=1)=[O:18])[CH2:13][S:14][CH3:15]>O>[O:10]=[S:14]([CH3:15])[CH2:13][CH2:12][NH:16][C:17]([C:19]1[S:23][C:22]2[S:24][C:25]([S:27]([NH2:30])(=[O:28])=[O:29])=[CH:26][C:21]=2[CH:20]=1)=[O:18]
Reactant: CSCCNC(=O)c1cc2cc(S(N)(=O)=O)sc2s1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CS(=O)CCNC(=O)c1cc2cc(S(N)(=O)=O)sc2s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium periodate (1.40 g., 6.54 mmoles) was dissolved in water (20 mL). THF (20 mL) was added followed by 5-[N-(3-thia-n-butyl)carbamoyl]thieno[2,3-b]thiophene-2-sulfonamide (1.10 g., 3.27 mmoles) were stirred at room temperature under Argon for 24 hours. The solution was filtered and then stripped of the THF and all but 2-2 mL of water. The product was then crystallized, collected and dried. Recrystallization from nitromethane gave 1.0 g. of 5-[N-(3-oxo-3-thia-n-butyl)carbamoyl]thieno[2,3-b]thiophene-5-sulfonamide, mp 242°-243° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.[CH:54]([N:57]([CH:60]([CH3:62])[CH3:61])CC)([CH3:56])[CH3:55].CC1C=CC(C)N1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:57]1[CH:60]([CH3:61])[CH:62]=[CH:56][CH:54]1[CH3:55])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CC1C=CC(C)N1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3C(C)C=CC3C)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2,5-dimethyl-2,5-dihydro-1H-pyrrole in DMSO at ambient temperature.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>C(Cl)Cl.C(OCC)(=O)C.O1CCCC1>[Br:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]1[O:9][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][N:6]=1
Reactant: O=C(NNC(=O)c1ccccc1Br)Nc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Brc1ccccc1-c1nnc(Nc2ccccc2)o1
Temperature: 25 °C
Yield: 83.9 %

Procedure:
To a solution of 1-(2-bromobenzoyl)-4-phenylsemicarbazide (330 mg, 0.98 mmol; Reference Compound 5-(1)), triphenylphosphine (390 mg, 1.5 mmol) and triethylamine (0.20 mL, 9.7 mmol) in methylene chloride (30 mL) were added carbon tetrachloride (2.5 mL, 1.4 mmol) and tetrahydrofuran (5 mL) under ice-cooling. The mixture was refluxed for 2 hours and then cooled to room temperature. Ethyl acetate (20 mL) was added thereto and the ethyl acetate solution was washed with a saturated brine solution (20 mL) twice, dried over anhydrous sodium sulfate, and concentrated under a reduced pressure to dryness. The residue was purified with a silica gel column chromatography (hexane/ethyl acetate) to give 260 mg (82%) of the titled compound as a colorless solid.