Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][C:5]=2[CH2:4][CH2:3]1)[N:12]=[C:11]([CH3:15])[N:10]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]3=[O:24].CC([NH3+])(C)CO.[NH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([O-:38])=[O:37])=[C:34]([F:41])[CH:33]=1.C(=O)([O-])[O-].[Ca+2].CS(C)=O>O>[F:41][C:34]1[CH:33]=[C:32]([NH:31][CH:2]2[C:6]3[CH:7]=[C:8]4[C:13](=[CH:14][C:5]=3[CH2:4][CH2:3]2)[N:12]=[C:11]([CH3:15])[N:10]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]4=[O:24])[CH:40]=[CH:39][C:35]=1[C:36]([OH:38])=[O:37]
Reactant: Nc1ccc(C(=O)[O-])c(F)c1
Reactant: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(Br)CC3
Agent: CC(C)([NH3+])CO
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(Nc1ccc(C(=O)O)c(F)c1)CC3
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 6-bromo-2-methyl-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (26 g), p-amino-o-fluorobenzoic acid 1,1-dimethyl-2-hydroxyethylammonium salt (42 g), calcium carbonate (21.4 g) and DMSO (200 ml) was stirred at ambient temperature for 72 hours. The mixture was poured onto a mixture of ice and water (1 liter). The precipitate was isolated, washed with water and dried under vacuum. The product was purified by column chromatography using initially a 9:1 mixture of methylene chloride and methanol and then a 9:1:0.1 mixture of methylene chloride, methanol and acetic acid as eluant. There was thus obtained o-fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]benzoic acid as a gum (20 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:4]=2[S:5][CH:6]=1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.O>CN1CCCC1=O>[ClH:11].[Cl:11][C:8]1[CH:9]=[CH:10][C:3]2[C:2]([NH:1][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:6][S:5][C:4]=2[CH:7]=1
Reactant: Clc1ccncc1
Reactant: Nc1csc2cc(Cl)ccc12
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1ccc2c(Nc3ccncc3)csc2c1
Yield: 174.5 %

Procedure:
A solution of 3-amino-6-chlorobenzo[b]thiophene (5 g, 27 mmol) and 4-chloropyridine hydrochloride (6 g, 40 mmol) in 75 mL of 1-methyl-2-pyrrolidinone was stirred at 80° for 1.5 h, and then was cooled, stirred with water and extracted with ether. The aqueous layer was basified with sodium carbonate and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution and then was dried (anhydrous magnesium sulfate), filtered and concentrated to a dark oil. Elution through silica with ethyl acetate via flash column chromatography yielded 7 g of an amber oil. Conversion to the hydrochloride salt in 20% methanol in ether yielded 4.2 g of yellow crystals, mp 264-266° (dec.).
Reaction SMILES: [OH:1][C@@H:2]([C@H:7]([OH:15])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>ClCCl>[F:14][C:11]1[CH:10]=[CH:9][C:8]([C@@H:7]([OH:15])[C@H:2]([O:1][S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H](O)[C@H](O)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](OS(=O)(=O)c1ccc(C)cc1)[C@H](O)c1ccc(F)cc1
Reaction time: 44 h
Yield: 83.2 %

Procedure:
Under argon atmosphere, a solution of methyl (2S,3R)-2,3-dihydroxy-3-(4-fluorophenyl)propionate (3.95 g, 18.4 mmol) dissolved in dichloromethane (100 ml) was cooled to -3° to -5° C., and triethylamine (3.86 ml, 27.7 mmol) and p-toluenesulfonyl chloride (3.62 g, 19.0 mmol) were added to the solution. After the mixture was stirred at -3° to -5° C. for 44 hours, the reaction mixture was washed with water and brine. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed, and the residue obtained was purified by silica gel flash column chromatography (ethyl acetate/hexane=1/2) to obtain methyl (2S,3R)-3-(4-fluorophenyl)-3-hydroxy-2-p-toluenesulfonyloxypropionate (5.64 g, yield: 83%).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].C([O:16][CH2:17][N:18]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1)[C:19](=[O:24])[CH2:20]S(C)=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.O>[OH:4][CH:20]1[O:16][CH2:17][N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=2)[C:19]1=[O:24]
Reactant: CCOCN(C(=O)CS(C)=O)c1cccc(C(F)(F)F)c1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1C(O)OCN1c1cccc(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic anhydride (17.6 g) was added dropwise to a stirred solution of crude product of Step 3 in tetrahydrofuran (220 ml) with water bath cooling to 20° C. After 2 hours the mixture was left to stand for 20 hours. A solution of sodium hydrogen carbonate (14.1 g) in water (220 ml) was added during 5 minutes with stirring and cooling to 20° C. After 30 minutes the mixture was refluxed for 41/2 hours, cooled to 25° C., extracted with dichloromethane (3×300 ml), the extract dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a brown oil (21.4 g). The brown oil (20.09 g) was dissolved in 1,4-dioxane (500mi) and hydrogen chloride gas bubbled in for 31/4 hours, with stirring, at 23° C. The mixture was left in a stoppered flask for 20 hours, concentrated under reduced pressure, dissolved in dichloromethane (400 ml), neutralised with a minimum of saturated aqueous sodium hydrogen carbonate, dried over magnesium sulphate, filtered and concentrated under reduced pressure to a brown oil (21.9 g). The oil was subjected to column chromatography on silica gel, gradient eluting with dichloromethanet-butyl methylether mixtures to give the crude product as a yellow gum (4.7 g). The gum was crystallised from hexane solution to give a yellow solid. 1H NMR (CDCl3): δ 4.43(1 H,bs); 5.49(1 H,s); 5.68(2 H,m); 7.49-7.8(4 H,m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: O=C(CCCCl)c1ccc(Br)cc1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 1-(4-bromophenyl)-4-chloro-1-butanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 457.1 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5]Cl.[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.[K]>>[Cl:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:11]1[C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]2[C:7]1=[O:17]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClC/C=C/CCl
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1C/C=C/CCl
Temperature: 20 °C
Yield: 61 %

Procedure:
Ex-7a) Under argon, to 65.8 g of trans-1,4-dichloro-2-butene was added in portions 47 g of potassium phthalimide with mechanical stirring maintaining the temperature between 100° C. and 110° C. The reaction mixture was then stirred for 2 h keeping the temperature between 145° C. to 150° C. It was then cooled to 20° C. and extracted with 3×400 mL of ether. The ether layer was separated and stripped to give a solid. This solid was recrystallized from ethanol to yield yellow crystals of N-(trans-4-Chloro-2-butenyl)phthalimide, wt. 36 g, 61% yield. Analysis calcd. for C12H10ClNO2 (MW 237.25): C, 61.26; H, 4.29; N, 6.02; Cl, 14.94; Found C, 61.18; H, 4.30; N, 5.98; Cl, 14.62.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[C:11](=[O:23])[C:10]([O:24][CH3:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.Br[C:27]1[S:28][CH:29]=[CH:30][N:31]=1.Cl>C(O)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[C:11](=[O:23])[C:10]([O:24][CH3:25])=[N:9][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:27]4[S:28][CH:29]=[CH:30][N:31]=4)[CH:3]=3)[C:13]2=[O:14])=[CH:17][CH:18]=1
Reactant: COc1nn(-c2cccc(N)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Reactant: Brc1nccs1
Agent: Cl
Solvent: CCO
Product: COc1nn(-c2cccc(Nc3nccs3)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 100 °C
Yield: 6.5 %

Procedure:
According to Scheme 9 Step 2: To a Solution of 2-(3-Aminophenyl)-4-(4-chlorobenzyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione (125 mg, 0.34 mmol) in ethanol (10 ml) was added bromothiazole (124 μL, 1.4 mmol) and 5 mL of concentrated hydrochloric acid. The reaction mixture was heated to 100° C. for 48 hours. The reaction mixture was quenched and neutralised with sat NaHCO3 and extracted in ethyl acetate (×3). The organic layers were combined and successively washed with water, brine, dried over MgSO4, filtered and concentrated. The crude oily solid was purified by flash chromatography, 10 g prepacked column, cyclohexane/ethyl acetate 70/30 to afford 4-(4-chlorobenzyl)-6-methoxy-2-(3-(thiazol-2-ylamino)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 4.144 (10 mg (Yield=6.5%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][C:24]([O:27][C:28]([NH:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](O)=[O:35])=[O:29])([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:34]([C:33]3[CH:32]=[C:31]([NH:30][C:28](=[O:29])[O:27][C:24]([CH3:25])([CH3:23])[CH3:26])[CH:39]=[CH:38][CH:37]=3)=[O:35])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.5 %

Procedure:
A mixture of Intermediate 7 (250 mg, 0,83 mmol) and 3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)benzoic acid (196 mg, 0.83 mmol, e.g. available from Fluka) in N,N-dimethylformamide (4 ml) was treated with N,N-diisopropylethylamine (0.569 ml, 3.3 mmol) and (1H-1,2,3-benzotriazol-1-yloxy)(tri-1-pyrrolidinyl)phosphonium hexafluorophosphate (472 mg, 0.91 mmol) and allowed to stir at room temperature for 4 hours. An additional portion of (1H-1,2,3-benzotriazol-1-yloxy)(tri-1-pyrrolidinyl)phosphonium hexafluorophosphate (0.5 equivalents, 0.41 mmol) was added and the mixture stirred for an additional hour. The solvent was evaporated and the residue partitioned between ethyl acetate (50 ml) and aqueous sodium bicarbonate solution (50 ml); saturated sodium chloride solution was added and the layers allowed to separate overnight. The aqueous layer was further extracted with ethyl acetate (50 ml), and the organic fractions collected, dried (Na2SO4) and evaporated; however the residue contained very little product. A white solid was filtered off from the aqueous layer and dried to give the title compound (193 mg). LCMS showed MH+=523; TRET=2.99 min.
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].[CH3:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=[S:21]>>[CH3:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]1[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:21]1
Reactant: CC(C)C[C@H](N)CO
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Product: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[N:7]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[N:14][CH:15]=1)=[C:8]=[S:9]>>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:8](=[S:9])[NH:7][C:10]2[CH:15]=[N:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:3]1
Reactant: O[C@H]1CCNC1
Reactant: COc1ccc(N=C=S)cn1
Product: COc1ccc(NC(=S)N2CC[C@H](O)C2)cn1
Yield: 99 %

Procedure:
The title compound was prepared from (S)-3-hydroxypyrrolidine and 5-isothiocyanato-2-methoxypyridine (J. Org. Chem. (1980), 45, 4219), using the same method as that described for preparation 35, in 99% yield. 1H NMR (400 MHz, CD3OD) δ: 1.91-2.22 (m, 2H), 3.69-3.81 (m, 4H), 3.88 (s, 3H), 4.40-4.52 (m, 1H), 6.78 (d, 1H), 7.69 (dd, 1H), 8.00 (m, 1H); LCMS m/z 254 [M+H]+
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[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][N:29]([CH2:31][C:32]([N:34]([CH3:42])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)=[O:33])[CH3:30]>>[CH3:30][N:29]([CH2:31][C:32]([N:34]([C:35]1[CH:36]=[CH:37][C:38]([NH:41]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:39][CH:40]=1)[CH3:42])=[O:33])[CH3:28]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Reactant: CN(C)CC(=O)N(C)c1ccc(N)cc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(N(C)C(=O)CN(C)C)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenylenediamine
Reaction SMILES: [CH2:1]([S:8][C:9]([CH3:35])([CH:33]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:32])[S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:37][OH:38].C(=O)([O-])[O-].[K+].[K+].CO>O>[CH2:1]([S:8][C:9]([CH3:35])([CH:33]=[N:37][OH:38])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:32])[S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1cccc2cc(C(=O)NCC(C)(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(c1cccc2cc(C(=O)NCC(C)(C=NO)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.3 %

Procedure:
A mixture of N-[2-(benzylthio)-2-methyl-3-oxopropyl]-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.00 g), hydroxylamine hydrochloride (0.26 g), potassium carbonate (0.52 g) and methanol (8 ml) was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated to give the title compound (0.25 g, yield 55%) as colorless amorphous crystals. MS: 543 (MH+).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[C:12]=3[CH2:14]O)[C:7](=[O:23])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.S(Cl)([Cl:31])=O>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[C:12]=3[CH2:14][Cl:31])[C:7](=[O:23])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(CO)c(N3CCOCC3)c(F)cc2c1=O
Reactant: O=S(Cl)Cl
Product: CCOC(=O)c1cn(C2CC2)c2c(CCl)c(N3CCOCC3)c(F)cc2c1=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To ethyl 1-cyclopropyl-7-morpholino-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (80 mg) is added thionyl chloride (1 ml), and the mixture is stirred at room temperature for 4 hours and further at 50° C. for one hour. The solvent is concentrated under reduced pressure to give crude ethyl 1-cyclopropyl-7-morpholino-6-fluoro-8-chloromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (84 mg).
Reaction SMILES: [C:1]([C:9]1[O:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[O:13][C:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(C(=O)c3ccccc3)o2)c1

Procedure:
Acid (9) (48 mg, 0.22 mmol) was coupled to aniline (2) (43 mg, 0.22 mmol) using Method B, except that DIPEA (57 mg, 0.44 mmol) and DMF (0.5 mL) were used. The crude product was purified by preparative HPLC to give the title compound. Yield: 28 mg; LC-MS tr 41.54 min; MS (ES+) m/z 389 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]=[C:10]2[N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][N:13]3[C:12](=[O:19])[S:11]2)=[CH:4][C:3]=1[N:20]1[C:25](=[O:26])[NH:24][C:23](=[O:27])[N:22]([CH2:28][C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[C:21]1=[O:35].C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][C:44]([O:46][CH:47]([CH3:49])[CH3:48])=[O:45].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]=[C:10]2[N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][N:13]3[C:12](=[O:19])[S:11]2)=[CH:4][C:3]=1[N:20]1[C:25](=[O:26])[N:24]([CH2:43][C:44]([O:46][CH:47]([CH3:49])[CH3:48])=[O:45])[C:23](=[O:27])[N:22]([CH2:28][C:29]([O:31][CH:32]([CH3:33])[CH3:34])=[O:30])[C:21]1=[O:35]
Reactant: CC(C)OC(=O)Cn1c(=O)[nH]c(=O)n(-c2cc(N=c3sc(=O)n4n3CCCC4)c(F)cc2Cl)c1=O
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OC(=O)Cn1c(=O)n(CC(=O)OC(C)C)c(=O)n(-c2cc(N=c3sc(=O)n4n3CCCC4)c(F)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
A mixture of isopropyl 3-{2-chloro-4-fluoro-5-[(tetrahydro-3-oxo-1H,3H-[1,3,4]thiadiazolo[3,4-a]-pyridazin-1-ylidene)amino]phenyl}tetrahydro-2,4,6-trioxo-s-triazine-1(2H)-acetate (0.85 g, 1.62 mmol), potassium carbonate (0.27 g, 1.95 mmol) and isopropyl bromoacetate (0,353 g, 1.95 mmol)in N,N-dimethylformamide is stirred overnight at room temperature and poured into water. The aqueous mixture is extracted with ethyl acetate. The organic extract is washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an orange gel. Flash column chromatography of the gel using silica gel and an ethyl acetate/hexanes solution (2:3) gives the title product as a yellow gel (0.3 g) which is identified by NMR spectral analysis.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18]C(O)=[C:16]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[O:22])[CH:15]=1.Cl>O1CCCC1.N1C=CC=CC=1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][C:5]2[O:4][C:2](=[O:3])[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=3)[C:21](=[O:22])[C:16]=2[CH:15]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=c1oc2ccc(-c3ccc(F)cc3F)cc2c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 13 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 6 (1.56 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 18.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C@@H:8]1[C:12]2[NH:13][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:11]=2[C:10](=[O:25])[NH:9]1.Br[C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[C:34]([NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])[N:33]([CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C:32]2=[O:53]>O1CCOCC1.O.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[C:38]([NH:37][C:34]1[N:33]([CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:47])[CH3:48])[C:32](=[O:53])[C:31]2[C:36](=[C:27]([C:14]3[NH:13][C:12]4[C@@H:8]([CH3:7])[NH:9][C:10](=[O:25])[C:11]=4[CH:15]=3)[CH:28]=[CH:29][CH:30]=2)[N:35]=1)([CH3:39])([CH3:41])[CH3:40]
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)n1CCCO[Si](C)(C)C(C)(C)C
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(NC(C)(C)C)nc34)[nH]c21
Temperature: 80 °C
Yield: 54.9 %

Procedure:
Potassium carbonate (Mallinkrodt; 0.091 g, 0.657 mmol), 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (Aldrich; 5.82 mg, 8.22 μmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705; 0.086 g, 0.329 mmol), 8-bromo-2-(tert-butylamino)-3-(3-((tert-butyldimethylsilyl)oxy)propyl)quinazolin-4(3H)-one (500b; 0.077 g, 0.164 mmol) were combined in 2 mL dioxane and 0.4 mL water. Argon was bubbled into the reaction for 1 min. The reaction was sealed and heated to 80° C. for 1 h. The reaction was adsorbed onto 1 g silica gel and The material was and purified by silica gel chromatography (12 g column) using 0-100% EtOAc/hexanes. The product-containing fractions were concentrated to afford (R)-2-(tert-butylamino)-3-(3-((tert-butyldimethylsilyl)oxy)propyl)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (0.047 g, 0.090 mmol, 54.6% yield) as a light-yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 12.52 (1H, br. s.), 7.88-8.23 (2H, m), 7.22 (1H, t, J=7.7 Hz), 6.84 (1H, d, J=1.2 Hz), 5.89 (1H, br. s.), 5.31 (1H, s), 4.68 (1H, q, J=6.7 Hz), 4.18 (2H, t, J=7.1 Hz), 3.79 (2H, t, J=5.3 Hz), 1.92-2.02 (2H, m), 1.65 (9H, s), 1.54 (3H, d, J=6.8 Hz), 0.96 (9H, s), 0.15 (6H, s). m/z (ESI, +ve ion) 524.2 (M+H)+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)([OH:11])=[O:10].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1](=[N:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([C:9]([OH:11])=[O:10])=[CH:13][CH:14]=1)(=[O:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(S(=O)(=O)N=Cc2ccccc2)cc1

Procedure:
In the same manner as Example 2, 4.00 g (38 mmol) of benzaldehyde, 7.58 g (38 mmol) of 4-carboxybenzenesulfonamide and 20 mg of TsOH in 150 mL of toluene were heated for 36 hours to afford 7.40 g (71%) of SULF-4 as a light tan powder: IR (Nujol) 3800-2600 (br), 1685, 1600, 1283, 1155 cm-1 ; 1H NMR (DMSO-d6, TMS ext std) δ 9.05 (s, 1), 8.2-7.2 (m, 9).