Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[O:6][CH:7]=[CH:8][CH:9]=1)=O.[NH2:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1>>[BrH:1].[O:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3]1[N:10]=[C:11]2[N:15]([CH:2]=1)[C:14]1[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=1[S:12]2
Reactant: Nc1nc2ccccc2s1
Reactant: O=C(CBr)c1ccco1
Product: Br
Product: c1coc(-c2cn3c(n2)sc2ccccc23)c1
Yield: 30 %

Procedure:
The title compound is prepared from 2-Bromo-1-furan-2-yl-ethanone and 2-aminobenzothiazole using method B in 30% yield: mp>250° C. (dec); 1H-NMR (DMSO-d6) 6.63 (s, 1H), 6.78 (s, 1H), 7.48 (t, 1H), 7.60 (t, 1H), 7.77 (s, 1H), 8.09 (d, 1H), 8.13 (d, 1H), 8.68 (s, 1H); Anal. (C13H9BrN2OS ⅔ H2O) C, H, N.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][N:21](S(C4C=CC(C)=CC=4)(=O)=O)[C:18]3=[N:19][CH:20]=2)=[CH:11][C:5]=1[C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[C:2]=[O:3].C(N(CC)C(C)C)(C)C.[CH:51]([NH:54][CH2:55][CH:56]1[CH2:60][CH2:59][CH2:58][O:57]1)([CH3:53])[CH3:52]>C(Cl)Cl>[CH:51]([N:54]([CH2:55][CH:56]1[CH2:60][CH2:59][CH2:58][O:57]1)[C:2](=[O:3])[NH:1][C:4]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][NH:21][C:18]3=[N:19][CH:20]=2)=[CH:11][C:5]=1[C:6]([N:8]([CH3:10])[CH3:9])=[O:7])([CH3:53])[CH3:52]
Reactant: CC(C)NCC1CCCO1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N=C=O)c(C(=O)N(C)C)c3)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(NC(=O)N(CC4CCCO4)C(C)C)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.3 %

Procedure:
2-Isocyanato-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (125 mg, 0.22 mmol), N,N-diisopropylethylamine (0.06 mL, 0.34 mmol), isopropyl-(tetrahydro-furan-2-ylmethyl)-amine (315 mg, 2.2 mmol), and methylene chloride (3 ml) were combined and stirred at room temperature for 18 hours. The reaction was concentrated to dryness in vacuo. The crude material was dissolved in a solution of tetrahydrofuran (4 mL) and methanol (1 mL). To the mixture was added 0.2 mL 50% w/v aqueous potassium hydroxide and the combined mixture stirred for 30 minutes. The reaction was quenched with saturated sodium bicarbonate, and the mixture was extracted with methylene chloride. The organic layer was dried over sodium sulfate and concentrated to dryness in vacuo. The crude material was purified by preparative HPLC to give 15 mg (27 μmol, 12%) of 2-[3-isopropyl-3-(tetrahydro-furan-2-ylmethyl)-ureido]-5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide. 1H-NMR (250 MHz, CDCl3) δ 11.90 (s, 1H), 8.52 (d, J=2.1 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.72-7.52 (m, 4H), 7.30 (t, J=7.1 Hz, 1H), 7.13 (d, J=7.9 Hz, 1H), 7.05 (t, J=7.4 Hz, 1H); MS: m/z 556.4 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7]([SH:9])=[N:8][C:4]=2[CH:3]=1.Cl.[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH2:24]Cl)[CH:19]=2)[CH2:15][CH2:14]1.[OH-].[Na+]>O.CO>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7]([S:9][CH2:24][C:20]3[CH:19]=[C:18]([O:17][CH2:16][CH:13]4[CH2:15][CH2:14]4)[CH:23]=[CH:22][N:21]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2[nH]c(S)nc2c1
Reactant: ClCc1cc(OCC2CC2)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Fc1ccc2[nH]c(SCc3cc(OCC4CC4)ccn3)nc2c1
Yield: 82.5 %

Procedure:
To 5-fluoro-2-mercapto-1H-benzimidazole (0.88 g, 0.0051 mol) in methanol (25 ml) NaOH (0.2 g, 0.0051 mol) dissolved in H2O (1 ml) and 4-cyclopropylmethoxy-2-chloromethylpyridine hydrochloride (0.91 g, 0.0046 mol) dissolved in methanol (10 ml) were added in the given order. The mixture was heated to boiling and NaOH (0.2 g, 0.005 mol) dissolved in H2O (1 ml) was added and the mixture was refluxed for 1 hour. After evaporation of methanol, CH2Cl2 (75 ml) and H2O (50 ml) were added and pH adjusted to 10. The mixture was vigorously stirred, the phases were separated, the organic phase was dried over Na2SO4 and evaporated giving the desired product (1.25 g, 72%). NMR data for the product is given below.
Reaction SMILES: C(O)(=O)C.[CH3:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[O:15])=[CH:9][CH:8]=1.[CH3:17][C:18]([CH3:36])([C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:27]=1[O:28][CH2:29][O:30][CH3:31])[CH2:23]N)[CH3:19]>C1(C)C=CC=CC=1>[CH3:35][C:32]([C:26]1[CH:25]=[C:22]([CH2:23][NH:16][C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([S:6][CH3:5])=[CH:12][CH:11]=2)=[O:15])[CH:21]=[C:20]([C:18]([CH3:36])([CH3:19])[CH3:17])[C:27]=1[O:28][CH2:29][O:30][CH3:31])([CH3:33])[CH3:34]
Reactant: COCOc1c(C(C)(C)C)cc(CN)cc1C(C)(C)C
Reactant: CSc1ccc(NC(N)=O)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COCOc1c(C(C)(C)C)cc(CNC(=O)Nc2ccc(SC)cc2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.2 %

Procedure:
Acetic acid (1.08 g; 18 mmol), 4.5 g (24.7 mmol) of the compound of Example 5 and 5.0 g (18 mmol) of the compound of Example 1 were dissolved in 180 ml of toluene. The resulting solution was heated to reflux, stirred at that temperature for 4 hours and then cooled to room temperature. The cooled solution was washed with a IN hydrochloric acid solution, a saturated sodium bicarbonate solution, water and a saturated brine solution. The washed solution was then filtered to remove any solid particulates which had formed and the liltrate was concentrated to dryness to provide a residue. This residue was purified by column chromatography using a 20-40% ethyl acetate in hexane gradient as eluent. Fractions containing the above titled compound were combined and then concentrated to dryness to provide 3.14 g of title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(CNc2ncccc2C(F)(F)F)cc1
Temperature: 140 °C
Yield: 83.1 %

Procedure:
A mixture of 2-chloro-3-trifluoromethylpyridine (64.83 g, 357 mmol), 4-methoxybenzylamine (56 mL, 429 mmol) and DIPEA (73.4 mL, 429 mmol) in n-butanol (100 mL) was refluxed (oil bath temp. 140° C.) for 3.5 days. Concentrated in vacuum, partitioned between 25% HCl and TBME, reextracted the organic layer twice with 25% HCl, the aqueous layer was made alkaline with 32% NaOH, extracted with TBME, washed with brine and dried over Na2SO4. Removal of the solvent in vacuum left a brown oil (105.21 g, 104%). Vacuum distillation gave the title compound as a colorless liquid (83.766 g, 83%, 4877-2/2; by 139-141° C. at 1.4 mbar). MS (ISP) 283.3 [(M+H)+].
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.CCN(C(C)C)C(C)C.[F:24][C:25]([F:38])([F:37])[O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:37])[F:38])=[CH:32][CH:31]=2)(=[O:35])=[O:34])[CH2:7]1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CCN1
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethylethyl(2S)-2-methyl-1-piperazinecarboxylate (2.50 g, 12.5 mmol), DIPEA (4.58 ml, 26.2 mmol) and 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (3.25 g, 12.5 mmol) in DCM (200 ml) was stirred at room temperature overnight. The mixture was washed with saturated aqueous NaHCO3, then brine and concentrated under vacuum. The residue was redissolved in 1,4-dioxane (200 ml), then 4M HCl in dioxane (20 ml) and water (0.5 ml) were added and the mixture stirred overnight. The mixture was concentrated under vacuum and applied to an SCX-2 cartridge (20 g) washing with MeOH. The product was eluted with 0.5M NH3 in MeOH; concentration left the title compound as a white solid (2.56 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:32])[CH2:14][S:15][C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]=[CH:28][N:29](C)C)[CH:22]=3)[N:20]=2)[CH2:8][CH2:7]1.Cl.[OH:38]N>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:32])[CH2:14][S:15][C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][CH:28]=[N:29][OH:38])[CH:22]=3)[N:20]=2)[CH2:8][CH2:7]1
Reactant: CN(C)C=Nc1cccc(-c2csc(SCC(=O)NC3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)n2)c1
Reactant: NO
Agent: Cl
Solvent: CO
Product: O=C(CSc1nc(-c2cccc(NC=NO)c2)cs1)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 30 h
Yield: 92 %

Procedure:
The product (100 mg) of Example 173 was dissolved in methanol (10 mL), and hydroxyamine hydrochloride (15 mg) was added to the solution. The mixture was stirred for 30 hrs. The solvent was evaporated under reduced pressure, and the obtained residue was extracted with chloroform, then washed with saturated brine, and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:1–20:1) to give the title compound (90 mg) as a white amorphous solid.
Reaction SMILES: [N:1]1([C:7]2[CH:25]=[C:24]3[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]4[S:23][CH2:22][C:16]5([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]5)[O:15][C:14]=43)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:28]([C:32]1[CH:42]=[CH:41][C:35]([O:36][CH2:37][C@@H:38]2[CH2:40][O:39]2)=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([C:32]1[CH:42]=[CH:41][C:35]([O:36][CH2:37][C@@H:38]([OH:39])[CH2:40][N:19]2[CH2:18][CH2:17][C:16]3([O:15][C:14]4[C:24]5[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]=4[S:23][CH2:22]3)=[CH:9][CH:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:25]=5)[CH2:21][CH2:20]2)=[CH:34][CH:33]=1)([CH3:29])([CH3:30])[CH3:31]
Reactant: O=C1C(=O)c2ccc(N3CCOCC3)cc2C2=C1SCC1(CCNCC1)O2
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1
Product: CC(C)(C)c1ccc(OC[C@@H](O)CN2CCC3(CC2)CSC2=C(O3)c3cc(N4CCOCC4)ccc3C(=O)C2=O)cc1

Procedure:
Compound 214 was synthesized using 9-morpholin-4-ylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=107-109° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.74 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.8 Hz, 2H), 7.18 (brs, 1H), 7.0 (d, J=8.8 Hz, 1H), 6.83 (d, J=8.4 Hz, 2H), 4.85 (brs, 1H), 3.91 (m, 2H), 3.82 (m, 1H), 3.74 (m, 4H), 3.43 (m, 4H), 3.05 (s, 2H), 2.76 (m, 2H), 2.43 (m, 4H), 1.97 (m, 2H), 1.78 (m, 2H), 1.22 (s, 9H); LCMS: 593 [M+H].
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[I:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.N1C=CC=CC=1.C(Cl)Cl>>[I:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: Nc1nccs1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nccs1)c1ccc(I)cc1
Reaction time: 96 h
Yield: 54.8 %

Procedure:
2-Aminothiazole (1.32 g, 0.0132 mol) was added to a solution of 4-iodobenzenesulfonyl chloride (4.00 g, 0.0132 mol) in Pyridine (10 mL, 0.1 mol) and methylene chloride (36 mL, 0.56 mol). After stirring 4 d, the reaction mixture was concentrated in vacuo. The resulting oil was taken up in 1:1 methylene chloride-methanol and stirred. A white precipitate formed. The solid was collected by filtration. 2.65 g (49%) of the product was obtained as an off-white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13].[C:17](#[N:19])[CH3:18]>>[OH:13][CH:12]([C:11]1[CH:14]=[CH:15][CH:16]=[C:9]([O:8][CH2:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:10]=1)[CH2:18][C:17]#[N:19]
Reactant: CC#N
Reactant: O=Cc1cccc(OCC2CCCCO2)c1
Product: N#CCC(O)c1cccc(OCC2CCCCO2)c1

Procedure:
Addition of acetonitrile to 3-((tetrahydro-2H-pyran-2-yl) methoxy)benzaldehyde gave 3-hydroxy-3-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propanenitrile as a yellow oil. Yield (1.1 g, 66%): 1H NMR (400 MHz, CDCl3) δ 7.26-7.31 (m, 1H), 6.93-6.99 (m, 2H), 6.87-6.92 (m, 1H), 4.97-5.03 (m, 1H), 3.68-4.01 (m, 4H), 3.47-3.55 (m, 1H), 2.75 (d, J=6.4, 2H), 1.90-1.93 (m, 1H), 1.43-1.71 (m, 5H).
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:18]([C@H:21]([C@H:29]1[CH2:33]OS(=O)(=O)[O:30]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[N+:19]=[N-:20].S(=O)(=O)(O)O.[OH-].[Na+]>O1CCCC1.CO>[N:18]([C@@H:21]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:29]([OH:30])[CH2:33][N:9]1[C@H:8]([C:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10]1)=[N+:19]=[N-:20]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Reactant: [N-]=[N+]=N[C@@H](Cc1ccccc1)[C@H]1COS(=O)(=O)O1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)N=[N+]=[N-]
Temperature: 25 °C
Yield: 13.3 %

Procedure:
A solution of 237 mg (1 mmol) of N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide and 300 mg (1.1 mmol) of 4(S)-[1(S)-azido-2-phenylethyl]-1,3,2-dioxathiolane 2.2-dioxide in 10 ml of tetrahydrofuran was stirred at room temperature under an argon atmosphere for 2 days, during which time some white solid deposits formed. The mixture was evaporated to give a white powder which was taken up in a 10% solution of sulphuric acid in 70% aqueous methanol and heated under reflux for 30 minutes. After cooling to room temperature the solution was adjusted to pH 10 with 10% aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The ethyl acetate extracts were combined, washed with sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated. Purification of the crude product by flash chromatography on silica gel using n-hexane/ethyl acetate (4:1) for the elution gave 57 mg of 2-[3(S)-azido-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide; MS: m/e 428 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1O>>[ClH:14].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: Oc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Product: Cl
Product: Clc1ccccc1O[C@H]1CCNC1
Yield: 54 %

Procedure:
The title compound was prepared from tert-butyl(3R)-3-hydroxypyrrolidine-1-carboxylate and 2-chlorophenol, using the same method as that described for preparation 84, as a pale pink solid in 54% yield. LCMS APCI m/z 198 [M+H]+
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([NH2:12])[CH2:10][CH3:11])=[CH:5][C:4]=1[F:13].C(Cl)Cl.C1N=CN([C:22](N2C=NC=C2)=[O:23])C=1.Cl.[N:30]1[C:35]2[CH2:36][NH:37][CH2:38][CH2:39][C:34]=2[CH:33]=[N:32][C:31]=1[NH:40][C@@H:41]([CH2:44][CH3:45])[CH2:42][OH:43]>O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([NH:12][C:22]([N:37]2[CH2:38][CH2:39][C:34]3[CH:33]=[N:32][C:31]([NH:40][C@@H:41]([CH2:44][CH3:45])[CH2:42][OH:43])=[N:30][C:35]=3[CH2:36]2)=[O:23])[CH2:10][CH3:11])=[CH:5][C:4]=1[F:13]
Reactant: CC[C@@H](N)c1ccc(Cl)c(F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC[C@@H](CO)Nc1ncc2c(n1)CNCC2
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC[C@@H](CO)Nc1ncc2c(n1)CN(C(=O)N[C@H](CC)c1ccc(Cl)c(F)c1)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 139 (0.173 g, 0.773 mmol) and DCM (5 mL) at RT was added TEA (0.235 g, 2.32 mmol) and CDI (0.125 g, 0.773 mmol) and the reaction was stirred at RT for 30 min. To this solution was added dropwise a solution of 216 (0.200 g, 0.773 mmol), TEA (0.235 g, 2.32 mmol) and DCM (5 mL) and the resulting solution stirred for 4 h then poured into water and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:40) to afford 0.050 g (14.8%) of I-57: MS m/z (APCI-pos) M+1=436.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].CCN(CC)CC.Br[CH2:17][C:18](OCC)=[O:19]>CN(C=O)C>[NH:7]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:8][CH2:17][C:18]1=[O:19]
Reactant: CCOC(=O)CBr
Reactant: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CNc2ccccc2N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.8 %

Procedure:
To a solution of o-phenylenediamine (1.08 g, 10 mmol) in DMF (50 mL) was added Et3N (2.9 mL, 21 mmol), and ethyl 2-bromoacetate (1.2 mL, 11 mmol). The reaction mixture was stirred at room temperature for 16 h, then at 80° C. for 3 h. The DMF was evaporated under reduced pressure and the reaction mixture partitioned between H2O and EtOAc. The EtOAc layer was washed with sat. NaHCO3, brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude residue purified by flash chromatography eluting with petroleum ether/EtOAc (4/1) to give 3,4-dihydroquinoxalin-2(1H)-one (560 mg, 38%) as yellow solid. LC-MS (ES-API); rt 7.40 min; m/z calculated for C8H8N2O [M+H]+ 149.0, found 149.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]1[C:12](=[O:26])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH:15]([C:16](O)=[O:17])[C:5]2=1.[C:27](N1C=CN=C1)([N:29]1C=CN=[CH:30]1)=O.CNC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]1[C:12](=[O:26])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH:15]([C:16]([N:29]([CH3:30])[CH3:27])=[O:17])[C:5]2=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1c2c(c3cc(F)ccc31)C(C(=O)O)CN(Cc1ccccc1)C2=O
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)C1CN(Cc2ccccc2)C(=O)c2c1c1cc(F)ccc1n2C

Procedure:
A solution of 4 g (11 mmol) of (±)-6-fluoro-9-methyl-1-oxo-2-(phenylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylic acid and 2.2 g (30 mmol) of 1,1'-carbonyldiimidazole in 200 ml of tetrahydrofuran is heated at 40° C. for 2 h. The reaction mixture is cooled and a large excess of liquefied dimethylamine is added and the mixture is allowed to stir for a few hours.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH3:14])=[O:5].Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Br:13][C:9]1[C:8]([CH3:14])=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:18][CH:17]=[C:16]([F:19])[CH:15]=3)[NH:1][C:21]2=[O:23])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1c(Br)cccc1NC(=O)c1cc(F)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1-n1c(=O)[nH]c2ccc(F)cc2c1=O
Yield: 87.7 %

Procedure:
A solution of 2-amino-N-(3-bromo-2-methylphenyl)-5-fluorobenzamide (0.893 g, 2.76 mmol) and triphosgene (0.984 g, 3.32 mmol) in THF (30 mL) was stirred at room temperature for 2 h. The mixture was carefully treated with saturated aqueous NaHCO3 and stirred until gas evolution ceased. The mixture was extracted twice with DCM. The combined organic phases were washed with water, dried and concentrated. The residue was triturated with DCM to give a white solid, isolated by filtration. The filtrate was concentrated and subjected to column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (gradient from 0-80%), to provide additional solid. The two solids were combined to provide 3-(3-bromo-2-methylphenyl)-6-fluoroquinazoline-2,4(1H,3H)-dione as a white solid (845 mg, 87% yield). Mass spectrum m/z 349, 351 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1S(N)(=O)=O.[Cl:15]C1C=CC(O)=CC=1.C1(=O)OCCO1.OCCOC1C=CC(Cl)=CC=1.C(Cl)(Cl)=O.S(Cl)(Cl)=O>>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:15])=[CH:7][CH:6]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccccc1OCCCl
Agent: O=C(Cl)Cl
Agent: OCCOc1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Solvent: O=C1OCCO1
Product: ClCCOc1ccc(Cl)cc1

Procedure:
A process for the preparation of 2-(2-chloroethoxy)-benzenesulfonamide of formula I ##STR15## which process comprises the etherification of 4-chlorophenol of formula II ##STR16## with ethylene carbonate at a temperature between +130° C. and +150° C. and chlorination of the resulting 4-(2-hydroxyethoxy)-chlorobenzene of formula III ##STR17## with phosgene or thionyl chloride at a temperature between +70° C. and +90° C. to give 4-(2-chloroethoxy)-chlorobenzene of formula IV ##STR18## which is converted with chlorosulfonic acid, at a temperature between -20° C. and +60° C. and subsequent neutralizaion with sodium hydroxide to the sulfonic acid sodium salt of formula V ##STR19## which is hydrogenated at a temperature between +20° C. and +70° C. to the compound of formula VI ##STR20## which is subsequently reacted with phosgene at a temperature between +60° C. and +120° C. to the sulfonic acid chloride of formula VII ##STR21## which is reacted with ammonia at a temperature between 0° C. and +100° C. to the sulfonamide of formula I.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([C:15]([O:17]CC)=O)[C:10]([O:12]CC)=O.Cl.[NH2:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.[CH2:27]1[CH2:35][N:34]2[C:29](=[N:30][CH2:31][CH2:32][CH2:33]2)[CH2:28]1>CN(C)C=O>[OH:17][C:15]1[N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[N:21]=[C:10]([OH:12])[C:9]=1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1].[CH2:27]1[CH2:35][N:34]2[C:29](=[N:30][CH2:31][CH2:32][CH2:33]2)[CH2:28]1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cccc1Cl
Reactant: Nc1ncc[nH]1
Agent: C1CN=C2CCCN2C1
Agent: Cl
Solvent: CN(C)C=O
Product: Oc1nc2nccn2c(O)c1-c1c(F)cccc1Cl
Temperature: 100 °C
Yield: 44.5 %

Procedure:
A mixture of 2.89 g of diethyl (2-chloro-6-fluorophenyl)malonate, 1.20 g of aminoimidazole hydrochloride, 2.48 g of 1,5-diazabicyclo[4.3.0]-5-nonene (DBN) and 10 ml of N,N-dimethylformamide (DMF) was heated at 100° C. for 4 hours. The reaction mixture was allowed to cool, filtered the precipitate and dried to give 1.80 g of 5,7-dihydroxy-6-(2-chloro-6-fluorophenyl)imidazo[1,2-a]pyrimidine DBN salt.