Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][SH:6].[H-].[Na+].Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1>CN(C=O)C.CCOCC>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1
Reactant: OCCCCS
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)c1ccc(SCCCCO)cc1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 4-hydroxybutanethiol (5.0 g, 47 mmol) in DMF (100 mL) was added NaH (60% dispersion in mineral oil, 2.1 g). After the effervescence had ceased, p-chloroacetophenone (4.3 mL, 33 mmol) was added. The solution was then stirred at 110° C. for 3 h. The mixture was cooled to RT and then diluted with ether (200 mL). The ethereal suspension was washed with 5% HCl (aq, 2×100 mL), water (100 mL), and then brine (50 mL). The ether extract was dried (MgSO4), filtered and concentrated to afford crude 1-[4-(4-hydroxybutylsulfanyl)phenyl]ethanone, which was used without purification. 1-[4-(4-hydroxybutylsulfanyl)phenyl]ethanone was taken up in dimethylformamide dimethylacetal (100 mL) and stirred at reflux for 12 h. The mixture was cooled and then concentrated to about one half of the original volume. Hexane was added to precipitate 3-Dimethylamino-1-[4-(4-hydroxybutylsulfanyl)phenyl]propenone. The mixture was filtered, washed with hexanes (50 mL), and dried to afford 3-Dimethylamino-1-[4-(4-hydroxy-butylsulfanyl)phenyl]propenone (6.4 g, 23 mmol). HPLC Retention Time; 5.58 min. (Method B) M+1; 279.8.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:18])[CH2:6]1)C.Cl.[C:20]([NH2:25])(=[NH:24])[CH:21]([CH3:23])[CH3:22]>>[F:17][C:14]1[CH:15]=[CH:16][C:9]2[NH:8][C:7](=[O:18])[CH2:6][C:5]3[CH:4]=[N:24][C:20]([CH:21]([CH3:23])[CH3:22])=[N:25][C:11]=3[C:10]=2[CH:13]=1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(F)cc2C1=O
Reactant: CC(C)C(=N)N
Agent: Cl
Product: CC(C)c1ncc2c(n1)-c1cc(F)ccc1NC(=O)C2
Yield: 60 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepine-2,5-dione and isobutyramidine hydrochloride. Yield: 60%.
Reaction SMILES: Cl.[CH2:2]([O:4][N:5]=[C:6]([C:32]1[N:33]=[C:34]([NH:37]C=O)[S:35][CH:36]=1)[C:7]([NH:9][CH:10]1[C:30](=[O:31])[N:12]2[C:13]([C:27]([OH:29])=[O:28])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][CH:25]=[CH2:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH3:3]>CO.O1CCCC1>[CH2:2]([O:4][N:5]=[C:6]([C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1)[C:7]([NH:9][CH:10]1[C:30](=[O:31])[N:12]2[C:13]([C:27]([OH:29])=[O:28])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][CH:25]=[CH2:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH3:3]
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC)c3csc(N)n3)[C@H]2SC1
Temperature: 30 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
Conc. hydrochloric acid (0.9 g) was added at ambient temperature to a solution of 7-[2-ethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(2.4 g) in a mixture of methanol (16.8 ml) and tetrahydrofuran (4.8 ml) and the mixture was stirred for 3 hours at 30° C. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate. The aqueous solution was washed with ethyl acetate and adjusted to pH 2.8 with conc.hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.72 g).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[CH:7][C:6]=2[CH:5]=[C:4]([O:20][CH3:21])[CH:3]=1.[C:22]1(=[O:28])[NH:26][C:25](=[O:27])[CH:24]=[CH:23]1.[Sn](Cl)Cl>>[Br:1][C:2]1[C:10]2[O:9][C:8]3[CH2:11][CH:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[Cl:19])[CH:23]4[CH:24]([C:25](=[O:27])[NH:26][C:22]4=[O:28])[C:7]=3[C:6]=2[CH:5]=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: O=C1C=CC(=O)N1
Reactant: COc1cc(Br)c2oc(/C=C/c3ccccc3Cl)cc2c1
Agent: Cl[Sn]Cl
Product: COc1cc(Br)c2oc3c(c2c1)C1C(=O)NC(=O)C1C(c1ccccc1Cl)C3
Temperature: 150 °C

Procedure:
A solution of (859) (4.89 g, 0.0185 mol) prepared as described in example 441, maleimide (1.44 g, 0.02 mol) and tin(II) chloride (2.8 g, 0.02 mol) in xylenes (40 mL) was heated to 150° C. overnight. After the addition of more maleimide (1.44 g, 0.02 mol) and tin(II) chloride (1.44 g, 0.01 mol) the reaction was again heated to 150° C. overnight. The solid which formed was collected and washed with xylenes (20 mL) before dissolving in ethyl acetate (200 mL). Water (50 mL) was added and the mixture was filtered through a pad of Celite. The resulting layers were separated, the organic phase was washed with brine (50 mL) dried over magnesium sulphate, filtered and concentrated to dryness. The product (860) (6.1 g, 71%) was used without further purification. 1H NMR δ (CDCl3) 7.60 (d, J=6.5 Hz, 1H), 7.40 (m, 2H), 7.25 (m, 1H), 7.1 (m, 2H), 4.36 (dd, J=7.3, 1 Hz, 1H), 4.0 (m, 1H), 3.86 (s, 3H), 3.81 (m, 1H), 3.45 (m, 1H), 3.10 (dd, J=4.7, 17 Hz, 1H); MH+:462,460.
Reaction SMILES: [C:1]1([C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:8][CH2:9][P:10]([CH2:15][N:16]=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:14])[O:11][CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:36][C:37]([CH2:39]Br)=[CH2:38]>>[C:24]1([C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:16][CH:15]([P:10]([CH:9]([N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:39][C:37]([Br:36])=[CH2:38])(=[O:14])[O:11][CH2:12][CH3:13])[CH2:39][C:37]([Br:36])=[CH2:38])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C=C(Br)CBr
Reactant: CCOP(=O)(CN=C(c1ccccc1)c1ccccc1)CN=C(c1ccccc1)c1ccccc1
Product: C=C(Br)CC(N=C(c1ccccc1)c1ccccc1)P(=O)(OCC)C(CC(=C)Br)N=C(c1ccccc1)c1ccccc1
Yield: 71 %

Procedure:
Analogously to Example 6, the bis-alkylated phosphinates 9 were prepared in a yield of 71% from the protected phosphinate 3 and 2,3-dibromopropene.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH:2]=1.[H-].[Na+].C([O:16][C:17]1[C:22]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:21][C:20]([CH2:27][CH2:28][CH2:29]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:19][C:18]=1[C:41]([CH3:44])([CH3:43])[CH3:42])(=O)C>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:41]([C:18]1[CH:19]=[C:20]([CH2:27][CH2:28][CH2:29][O:10][CH2:9][CH2:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:21]=[C:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[OH:16])([CH3:43])([CH3:44])[CH3:42]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(CCCOS(=O)(=O)c2ccc(C)cc2)cc1C(C)(C)C
Reactant: OCCCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CCCOCCCc2cccnc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution of 3.66 g (26.68 mmol) of 3-(3-pyridyl)propanol in 30 ml anhydrous THF and 3.5 ml dry HMPA is added via syringe to a stirred suspension of 2.56 g (60% oil dispersion, 53.33 mmol) of NaH in 35 ml of anhydrous THF under an inert atmosphere at O° C., followed by a 2 h period at reflux. The sodium alcoholate solution is then recooled to 0° C. and 10.68 g (23.19 mmol) of 3-(4-acetoxy-3,5-di-tert-butylphenyl)-1-(tosyloxy)propane, dissolved in 35 ml of anhydrous THF, is added, fo-Wowed by refluxing for 2 h and stirring overnight at room temperature. After usual workup, the crude product (9.88 g; brown oil) is purified by flash-chromatography over silica gel, eluting with n-hexane/ethyl acetate 3:1, yielding 2.88 g (62% of 2,6-ditert-butyl-4-[7-(3-pyridyl)-4-oxaheptyl]phenol as amber oil. (C25H37NO2 ; F.W. 383.6).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.Br[C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=1>>[OH:1][C:2]1([C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=2)[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: Cc1ccnc(Br)c1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Product: Cc1ccnc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)c1
Yield: 56 %

Procedure:
Obtained in 56% yield by an analogous method to Example 321, preparation of starting materials, starting from benzyl 4-oxo-1-piperidinecarboxylate and 2-bromo-4-methylpyridine.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][NH+:6]=[CH:5][CH:4]=1.[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[N:10]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:6]1[CH:7]=[CH:8][C:3]([N:10]2[N:11]=[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]3=[N:9]2)=[CH:4][CH:5]=1
Reactant: c1ccc2[nH]nnc2c1
Reactant: Clc1cc[nH+]cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2nn(-c3ccncc3)nc2c1
Temperature: 130 °C

Procedure:
A mixture of 4-chloropyridinium hydrochloride (25.0 g, 166 mmol), benzotriazole (29.6 g, 249 mmol), potassium carbonate (69.1 g, 500 mmol), and dimethylformamide (DMF) (500 mL) was stirred and heated under argon at 130° C. for 3 days. After cooling, the solid was filtered off, and the solvent was evaporated under reduced pressure. The residue was treated with dichloromethane (200 mL), filtered and chromatographed using a column filled with silica gel (500 mL) and hexane/ethyl acetate (1:1) as an eluent. Fractions containing the desired product were combined, and the solvent was distilled off. The residue was triturated with ethanol, the solid was filtered off and dried in a vacuum oven to give 2-(pyridin-4-yl)-2H-benzo[d][1,2,3]triazole, 6.45 g, 20%). 1H NMR (400 MHz, CDCl3): δ 8.80 (m, 2H, pyridine), 8.26 (m, 2H, pyridine), 7.93 (m, 2H, benzotriazole), 7.46 (m, 2H, benzotriazole).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=O)=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[NH2:16][C@@H:17]([CH2:21][CH:22]1[CH2:24][CH2:23]1)[C:18]([NH2:20])=[O:19]>>[C:18]([C@@H:17]([NH:16][C:13]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12]2)[N:6]=1)=[O:15])[CH2:21][CH:22]1[CH2:24][CH2:23]1)(=[O:19])[NH2:20]
Reactant: NC(=O)[C@@H](N)CC1CC1
Reactant: O=C(O)c1ccc(Br)c(OCC2CC2)n1
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1ccc(Br)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 9 d) and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=382.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)=[C:4]([F:9])[C:5](F)=[N:6][CH:7]=1.C[N:16]1C(=O)CCC1.N>O>[Cl:1][C:2]1[C:3]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)=[C:4]([F:9])[C:5]([NH2:16])=[N:6][CH:7]=1
Reactant: Fc1ncc(Cl)c(-n2cccn2)c1F
Reactant: CN1CCCC1=O
Agent: N
Solvent: O
Product: Nc1ncc(Cl)c(-n2cccn2)c1F

Procedure:
A mixture of 5-chloro-2,3-difluoro-4-(1H-pyrazol-1-yl)pyridine (37 g, 0.17 mol, 1.0 equiv) and NMP (200 mL) in a pressure vessel was stirred at 50° C. under 20 psi of ammonia gas overnight. The mixture was diluted with water (400 mL) and extracted with EtOAc (2×300 mL). The organic fractions were combined, dried over Na2SO4, and concentrated under vacuum. To the residue was added water (300 mL) with stirring. The resulting solid was collected by filtration, and the cake was washed with isopropanol (100 mL) and dried under vacuum to give the desired product (24 g) as a yellow solid. The solid was recrystallized from isopropanol (40 mL) and EtOAc (20 mL) to give 19 g of pure product as an off white solid. The mother liquors were concentrated under vacuum and recrystallized from isopropanol (30 mL) to give another 5.1 g for a combined total of 24 g (67%) of desired product as an off white solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:10][CH:9]=2)[C:5](=[O:23])[CH2:4]1.C(N(C(C)C)C(C)C)C.[F:33][CH:34]([F:38])[C:35](O)=[O:36].N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[B-](F)(F)F>CN(C)C=O>[F:33][CH:34]([F:38])[C:35]([NH:2][C@H:3]1[CH2:4][C:5](=[O:23])[N:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:12][CH:13]=2)[CH2:7]1)=[O:36]
Reactant: N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reactant: O=C(O)C(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1)C(F)F
Reaction time: 6 h
Yield: 18.5 %

Procedure:
A solution of 103 mg (0.3 mmol) of (S)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride [Example 2g)] in 0.5 ml of N,N-dimethylformamide is treated successively with 180 μl (1.0 mmol) of N-ethyl-diisopropylamine, 20 μl (0.3 mmol) of difluoroacetic acid, and 102 mg (0.3 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate (TBTU) at RT, and thereafter, stirred for 6 hours. For the working-up, the reaction mixture is evaporated under reduced pressure. The resulting residue is dissolved in 3 ml of dichloromethane and the solution is washed with 1.5 ml of a saturated solution of sodium hydrogenate and with 1.5 ml of hydrochloric acid (0.1 N). The organic phase is dried over sodium sulfate and evaporated. For purification, the crude material is chromatographed on silica gel using a 98:2-mixture of dichloromethane and methanol as the eluent. There are obtained 21 mg (18% of theory) of (S)-2,2-difluoro-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide as a white solid. MS: m/e=396 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.C(O[K])(C)(C)C.[N+:11]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])([O-:13])=[O:12]>CS(C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[NH:17][C:16]2[C:15]([CH:4]=1)=[C:14]([N+:11]([O-:13])=[O:12])[CH:20]=[CH:19][CH:18]=2
Reactant: CC(C)=O
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)(C)O[K]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc2c([N+](=O)[O-])cccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Acetone (1.0 mL) and tert-butoxy potassium (2.7 g) were added to a solution of 3-nitroaniline (1.38 g) in dimethylsulfoxide (20 ml), and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, and washed successively with an aqueous ammonium chloride solution and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The residue was purified by column chromatography on silica gel (developing solvent:hexane-ethyl acetate) to obtain 2-methyl-4-nitro-1H-indole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH2:5].[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH:5][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][Cl:10]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(Cl)CCCCCl
Product: COC(=O)[C@@H](NC(=O)CCCCCl)C(C)C

Procedure:
Using the method of Example 1, Step A, valine methyl ester and 5-chloropentanoyl chloride were coupled to provide N-(5-chloropentanoyl)valine methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[C:20]1([CH2:26][CH2:27][CH2:28][C:29]([NH2:31])=[S:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:31]=[C:29]([CH2:28][CH2:27][CH2:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:30][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: NC(=S)CCCc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2sc(CCCc3ccccc3)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylthiophenyl)ethanone (Example 1, step 3) (0.100 g, 0.295 mmol) in ethanol (3 mL) in a 10 mL round bottom flask was added 4-phenylthiobutyramide from step 1 (0.055 g, 0.310 mmol) and the mixture heated to reflux overnight. The reaction was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with Na2CO3 (10% solution), brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude thiazole was flash chromatographed (9:1, hexane:ethyl acetate) yielding 4-(4-fluorophenyl)-5-(4-methylthiophenyl)-2-(3-phenylpropyl)thiazole (0.118 g, 95%) as crystalline solid: mp 62°-63° C.; 1HNMR (CDCl3) 300 mHz 7.49 (d of d, J=5.52 and 8.85, 2H), 7.33-7.14 (m, 9H), 6.98 (t, J=8.85, 2H), 3.05 (t, J=7.74, 2 H), 2.82 (t, J=7.74 Hz, 2H), 2.49 (s, 3H), 2.18 (m, 2 H); MS (FAB) m/z 420 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1(CCC)[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[C:22]([OH:33])[C:21]=3[CH2:34][CH:35]=[CH2:36])=[CH:14][C:7]=2[O:6]1)=[O:4].S(OC)(O[CH3:44])(=O)=O.[OH-].[K+]>C1COCC1>[CH3:44][O:33][C:22]1[C:21]([CH2:34][CH:35]=[CH2:36])=[C:20]([CH:25]=[CH:24][C:23]=1[C:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27])[O:19][CH2:18][CH2:17][CH2:16][O:15][C:13]1[CH:12]=[CH:11][C:8]2[CH2:9][CH2:10][CH:5]([C:3]([O:2][CH3:1])=[O:4])[O:6][C:7]=2[CH:14]=1
Reactant: C=CCc1c(OCCCOc2ccc3c(c2)OC(CCC)(C(=O)OC)CC3)ccc(C(=O)N2CCCC2)c1O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCc1c(OCCCOc2ccc3c(c2)OC(C(=O)OC)CC3)ccc(C(=O)N2CCCC2)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 27 (280 mg, 0.51 mmol) dimethyl sulfate (192 mg, 153 mmol) and potassium hydroxide (57 mg, 1 mmol) was added to about 20 ml of THF, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was washed with water and thoroughly extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Chromatography of the crude material on silica gel using 75% ethyl acetate/hexane as eluant gave the product.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:32])([F:31])[C:14]1[N:19]=[CH:18][C:17]([CH:20]([N:23]2[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25][CH2:24]2)[CH2:21][NH2:22])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([N:23]1[CH2:24][CH2:25][C:26]([F:30])([F:29])[CH2:27][CH2:28]1)[C:17]1[CH:18]=[N:19][C:14]([C:13]([F:12])([F:31])[F:32])=[CH:15][CH:16]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1ccc(C(F)(F)F)nc1)N1CCC(F)(F)CC1
Product: O=C(NCC(c1ccc(C(F)(F)F)nc1)N1CCC(F)(F)CC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(6-(trifluoromethyl)-3-pyridyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][NH:30][CH2:29]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[NH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][N:30]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:29]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: Nc1ccc2c(c1)CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c1F)C2
Yield: 34.3 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 81 mg of 5-aminoisoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 78 mg of the target compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C@H:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([NH2:19])[CH2:14]1)[C:8]([CH3:20])=[N:7]2.[CH3:21][C@@H:22]1[C:26]2[NH:27][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:29][C:25]=2[C:24](=[O:39])[NH:23]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1>[NH2:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][C@H:13]([NH:12][C:9]2[C:8]([CH3:20])=[N:7][C:6]3[C:11]([N:10]=2)=[C:2]([C:28]2[NH:27][C:26]4[C@@H:22]([CH3:21])[NH:23][C:24](=[O:39])[C:25]=4[CH:29]=2)[CH:3]=[CH:4][CH:5]=3)[CH2:14]1
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: Cc1nc2cccc(Br)c2nc1N[C@H]1CCC[C@@H](N)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3cc4c([nH]3)[C@@H](C)NC4=O)c2nc1N[C@H]1CCC[C@@H](N)C1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 84.3 %

Procedure:
A mixture of (1S,3R)—N1-(8-bromo-3-methylquinoxalin-2-yl)cyclohexane-1,3-diamine (483b, 1.62 g, 4.83 mmol), (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, 2.53 g, 9.65 mmol), dichlorobis(p-dimethylaminophenylditbutylphosphine)palladium (II) (0.171 g, 0.24 mmol), and potassium phosphate (3.07 g, 14.48 mmol) in 1,4-dioxane (38.6 mL)/water (9.65 mL) was sparged with nitrogen for 3 min and was stirred at 80° C. for 45 min. The reaction mixture was diluted with water (200 mL), added to a separatory funnel, and extracted with 3:2 chloroform/IPA (5×100 mL); the combined organic layers were separated, dried over Na2SO4, and concentrated. The crude product in 10% MeOH/DCM was loaded onto the column and was purified via automated flash chromatography (silica gel) with 100% DCM to 50% 2 M ammonia in MeOH/DCM to give (R)-2-(3-4(1S,3R)-3-aminocyclohexyl)amino)-2-methylquinoxalin-5-yl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (483, 1.59 g, 4.07 mmol, 84% yield) as a brown amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.16 (m, 1H) 1.29-1.42 (m, 3H) 1.43 (d, J=6.65 Hz, 3H) 1.82 (d, J=11.15 Hz, 2H) 1.99-2.18 (m, 3H) 2.55 (s, 3H) 2.82 (t, J=10.27 Hz, 1H) 3.33 (br. s., 1H) 4.04-4.14 (m, 1H) 4.56 (q, J=6.52 Hz, 1H) 7.03 (s, 1H) 7.13 (br. s., 1H) 7.34 (t, J=7.82 Hz, 1H) 7.60 (dd, J=7.92, 1.08 Hz, 1H) 7.64 (s, 1H) 7.86-7.91 (m, 1H) 12.08 (br. s., 1H). MS (ESI, pos. ion) m/z: 391.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[S:21]([NH2:24])(=[O:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CS(C)=O>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[S:21]([NH:24][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)(=[O:22])=[O:23]
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: NS(=O)(=O)c1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1cccc(Cl)c1Cl
Temperature: 150 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
2,3-Dichloroquinoxaline (1.00 g, 5.02 mmol), 2,3-dichlorobenzenesulfonamide (1.41 g, 5.02 mmol) and potassium carbonate (694 mg, 5.02 mmol) were suspended in dimethyl sulfoxide (30 mL) and the mixture was stirred at 150° C. for 3 hours. The reaction mixture was slowly added to a mixture (300 ml) of a 1% aqueous acetic acid solution and ice, and the mixture was stirred for 3 hours. The resulting solid was collected by filtration and washed with water. Then, slurry purification was performed using diisopropyl ether, to give 2,3-dichloro-N-{3-chloroquinoxalin-2-yl}benzenesulfonamide (Compound AA) (1.53 g, yield: 78%).