Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH2:11][Cl:12])=[O:9].[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])(=[O:16])[CH:14]=[CH2:15]>ClCCl>[C:8](=[O:9])([O:22][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:13](=[O:16])[CH:14]=[CH2:15])[O:10][CH2:11][Cl:12]
Reactant: O=C(Cl)OCCl
Reactant: C=CC(=O)OCCCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC(=O)OCCCCOC(=O)OCCl
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution of chloromethyl chloroformate (0.98 ml, 11.00 mmol) and 4-hydroxybutyl acrylate (1.38 ml, 10.00 mmol) in dichloromethane (12 ml) at 3° C. under a dry N2 atmosphere. After 15 min. at 3° C. and 17 hours at 20° C. the reaction mixture is transferred to a separating funnel with the aid of dichloromethane (10 ml). The reaction mixture is washed with hydrochloric acid (1.00M, 10 ml), saturated aqueous sodium hydrogen carbonate (10 ml) and water (2×10 ml). The organic phase is dried (MgSO4) and the solvent evaporated under reduced pressure to give 1.76 g (74%) of the title product. 1H NMR (60 MHz, CDCl3): δ 1.82 (4H, m, CH2 --CH2), 4.27 (4H, m, 2×CH2 --O), 5.77 (2H, s, Cl--CH2 --O), 5.8-6.7 (3H, m, CH=CH2)
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[C:3]=1[CH2:10][CH3:11].[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:14])[CH3:13])=[C:4]([CH3:9])[C:3]=1[CH2:10][CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1c(Br)ccc(N)c1C
Solvent: c1ccncc1
Product: CCc1c(Br)ccc(NC(C)=O)c1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3.86 g of the bromide prepared in Example 212a in 48 ml pyridine, 2.04 ml of acetic anhydride was added dropwise at 0° C. and stirred for 20 hours at 25° C. The reaction mixture was concentrated in vacuo and the crude product thus obtained was purified by column chromatography on silica gel with hexane/0-100% ethyl acetate. In this manner, 3.73 g of the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:26]3[CH:25]=[C:24]([Cl:27])[CH:23]=[CH:22][C:21]=3[O:20][CH3:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cc(Cl)ccc3OC)cccc2c1N
Yield: 76.2 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 2-methoxy-5-chloro-phenylboronic acid (186 mg, 1.000 mmol) were reacted to afford the title compound (137 mg, 77% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.54 (br, 1H), 7.89 (m, 1H), 7.71 (m, 2H), 7.40-7.29 (m, 2H), 6.95 (m, 1H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 1.65 (apparent sextet, J=7.0 Hz, 3H). MS APCI, m/z=371 (M+H). HPLC 2.00 min.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[N:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][S:33]([C:36]2[S:37][C:38](Br)=[CH:39][CH:40]=2)(=[O:35])=[O:34])=[CH:27][CH:26]=1>>[N:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][S:33]([C:36]2[S:37][C:38]([C:13]#[C:12][C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]5[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=5)=[N:6][C:7]=34)=[CH:39][CH:40]=2)(=[O:35])=[O:34])=[CH:27][CH:26]=1
Reactant: O=S(=O)(NCc1ccncc1)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=S(=O)(NCc1ccncc1)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid (pyridin-4-ylmethyl)-amide (example B.55) (167 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (96 mg, 33%). MS (ISN) 588.2 [(M−H)−]; mp 141° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][N:25]([CH2:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH3:26].[OH-].[Na+]>CN(C=O)C.CO>[CH3:26][N:25]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([NH:32]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:11]\2=[CH:10][CH:9]=[CH:8][CH:7]=3)/[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:33][CH:34]=1)[CH3:24]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: COc1ccc(C(Cl)=C2C(=O)N(C(C)=O)c3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(/C(Nc2ccc(CN(C)C)cc2)=C2/C(=O)Nc3ccccc32)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(4-methoxyphenyl)-methylidene)-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:10]1([S:16]([NH:19][C:20]([C:22]2[N:27]=[C:26]3[N:28]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([CH2:39]OS(C)(=O)=O)=[CH:35][C:34]=4[Cl:45])[C:29]([CH3:31])=[N:30][C:25]3=[CH:24][CH:23]=2)=[O:21])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>CN(C)C=O.O>[C:10]1([S:16]([NH:19][C:20]([C:22]2[N:27]=[C:26]3[N:28]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([CH2:39][O:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[CH:35][C:34]=4[Cl:45])[C:29]([CH3:31])=[N:30][C:25]3=[CH:24][CH:23]=2)=[O:21])(=[O:17])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccccc1
Reactant: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)nc2n1Cc1ccc(COS(C)(=O)=O)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)nc2n1Cc1ccc(COc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.7 %

Procedure:
To a solution of phenol (12 mg, 0.13 mmol) in N,N-dimethylformamide (0.5 ml) was added sodium hydride (60% in mineral oil, 5.2 mg) under ice-cooling. Thirty minutes later, a solution of 5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-((methanesulfonyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (68 mg, 0.12 mmol) in N,N-dimethylformamide (1 ml) was dropwise added, which was followed by stirring at room temperature for 3 hr. The reaction mixture was cooled with ice and water was added. Its pH was adjusted to 4 by dropwise addition of 1N hydrochloric acid. The resulting product was extracted with ethyl acetate, washed three times with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel thin layer chromatography (eluent: chloroform/methanol=20/1) and crystallized from ethyl acetate to give 5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-((phenyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (30 mg) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([NH2:10])=[O:9])[N:5]([CH3:7])[CH:6]=1.[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([C:26]1[CH:36]=[CH:35][CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[C:27]=1[CH2:28][O:29]C(=O)C)[N:19]=[CH:18]2)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([C:26]1[C:27]([CH2:28][OH:29])=[C:33]([C:2]3[CH:3]=[C:4]([C:8]([NH2:10])=[O:9])[N:5]([CH3:7])[CH:6]=3)[CH:34]=[CH:35][CH:36]=1)[N:19]=[CH:18]2)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)ccc2c1=O
Reactant: Cn1cc(Br)cc1C(N)=O
Product: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)ccc4c3=O)c2CO)cc1C(N)=O
Yield: 20 %

Procedure:
This compound was prepared with the same method as described in Example 1 by using 4-bromo-1-methyl-1H-pyrrole-2-carboxylic acid amide (intermediate-3) and acetic acid 2-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (intermediate 4). The desired compound was prepared in two steps (20% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.04 (d, J=1.5 Hz, 1H), 8.01 (dd, J=1.8, 8.4 Hz, 1H), 7.48-7.45 (m, 2H), 7.28-7.23 (m, 2H), 7.08 (d, J=1.8 Hz, 1H), 4.35 (s, 2H), 3.89 (s, 3H), 1.41 (s, 9H). LC-MS calcd for C25H26N4O3 (m/e) 430.20, obsd 431 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[O:17][C:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[N:19][N:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:15])[C:16]4[O:17][C:18]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=5)=[N:19][N:20]=4)=[CH:4][CH:3]=3)=[CH:42][CH:41]=2)[CH2:38][CH2:39]1)=[O:36])[CH3:33]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1nnc(Cc2cccc(C(F)(F)F)c2)o1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4nnc(Cc5cccc(C(F)(F)F)c5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[5-(3-trifluoromethyl-benzyl)-[1,3,4]oxadiazol-2-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1([CH2:19][O:20][C:21]([NH:23][C@@H:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][C:26](O)=[O:27])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.[NH2:44][C:45]1[S:49][C:48]([SH:50])=[N:47][N:46]=1>C1COCC1>[C:13]1([CH2:19][O:20][C:21](=[O:22])[NH:23][C@@H:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][C:26]([NH:44][C:45]2[S:49][C:48](=[S:50])[NH:47][N:46]=2)=[O:27])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)C[C@@H](NC(=O)OCc1ccccc1)c1ccccc1
Reactant: Nc1nnc(S)s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C[C@@H](NC(=O)OCc1ccccc1)c1ccccc1)Nc1n[nH]c(=S)s1
Reaction time: 0.5 h
Yield: 14.5 %

Procedure:
Carbonyldiimidazole (0.879 g, 5.42 mmol) is added to a solution of (R)-β-[[(phenylmethoxy)carbonyl]amino]benzenepropanoic acid (1.08 g, 3.62 mmol) in 25 mL THF under N2 at room temperature and allowed to stir for 0.5 hours. Diisopropylethylamine (0.63 mL, 3.6 mmol) and 5-amino-1,3,4-thiadiazole-2-thiol (0.482 g, 3.62 mmol) are added and the reaction is stirred at ambient temperature for 18 hours. The reaction is concentrated in vacuo, diluted with 50 mL CH2Cl2, and washed with (3×25 mL) 1 M citric acid. The organic phase is dried (Na2SO4), combined with the precipitate that formed in the aqueous phase, absorbed onto silica gel and chromatographed (2-5% MeOH/CH2 Cl2). The precipitate which formed in the fractions containing product is collected and dried to afford 0.217 g product as white needles.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:3].[CH:11]1[C:17]([NH2:18])=[N:16][C:14](=[O:15])[N:13]([C@@H:19]2[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[C:20]2([F:28])[F:27])[CH:12]=1.Cl>>[F:28][C:20]1([F:27])[C@H:21]([OH:26])[C@@H:22]([CH2:24][OH:25])[O:23][C@H:19]1[N:13]1[CH:12]=[CH:11][C:17]([NH:18][C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:3])=[N:16][C:14]1=[O:15]
Reactant: CCCCCCOC(=O)Cl
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Agent: Cl
Product: CCCCCCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Yield: 99 %

Procedure:
Using Method A and hexyl chloroformate, gemcitabine hydrochloride was converted to 36 (white solid, 99% yield): 1H NMR (200 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.23-8.28 (d, 1H), 7.11-7.15 (d, 1H), 6.34-6.37 (d, 1H), 6.16-6.24 (t, 1H), 5.34 (s, 1H), 4.21-4.26 (m, 1H), 4.10-4.18 (t, 2H), 3.65-3.94 (m, 3H), 1.60-1.67 (t, 2H), 1.31-1.33 (t, 6H), 0.87-0.94 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:48]1[C:43](=[CH:44][C:45]([Cl:58])=[C:46]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[CH:47]=1)[O:42][CH:41]([OH:59])[CH2:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:60]1(C)C=CC(S(O)(=O)=O)=CC=1>CO.COC(OC)OC>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:48]1[C:43](=[CH:44][C:45]([Cl:58])=[C:46]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[CH:47]=1)[O:42][CH:41]([O:59][CH3:60])[CH2:40]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)OC(O)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: CO
Product: CCc1ccc(Cc2cc3c(cc2Cl)OC(OC)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: 65 °C
Yield: 104.3 %

Procedure:
To a solution of 41 (85 mg, 105 μmol) in anhydrous MeOH (1 mL) and trimethylorthoformate (0.5 mL) was added 4-toluenesulfonic acid (15 mg). The mixture was heated in a closed vial at 65° C. for 2 h, cooled to rt, evaporated, loaded onto a preparatory TLC plate, and developed using 15% EtOAc in petroleum ether to yield 42 (75 mg, 91% yield) as two diastereomers. LCMS m/z 847 (M+Na).
Reaction SMILES: N#N.[CH2:3]([O:5][C:6](=[O:10])[C:7]([NH2:9])=[S:8])[CH3:4].[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O.CC(=O)OCC>C1(C)C=CC=CC=1>[CH2:3]([O:5][C:6]([C:7]1[S:8][CH:15]=[C:13]([CH2:12][Cl:11])[N:9]=1)=[O:10])[CH3:4]
Reactant: CCOC(=O)C(N)=S
Reactant: O=C(CCl)CCl
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(CCl)cs1

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of amino-thioxo-acetic acid ethyl ester (7.29 g. 54.74 mmol) in toluene (58 mL) was treated with 1,3-dichloroacetone (8.41 g, 62.95 mmol). The resulting mixture was stirred at reflux for 2 h. EA (60 mL) was added and the org. layer was washed with sat. aq. NaHCO3, brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (70:30 hept-EA) gave the title compound as an orange oil. TLC:rf (4:1 hept-EA)=0.26. LC-MS-conditions 02: tR=0.89 min; [M+H]+=206.45.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)(=[O:40])=[O:39])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccccc4)cc3)cc2C1=O
Reaction time: 0.08 h

Procedure:
To a solution of compound of example 6 (0.250 g, 0.0073 mol) in dichloromethane (5 mL), pyridine (0.174 g, 0.00219 mol) was added and stirred for 5 min. To this reaction mixture, benzene sulfonyl chloride was added and stirred for about 16 h. After completion of the reaction, solvent was evaporated and the crude title compound obtained was directly used for the preparation of compound of example 78.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[O:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: c1ccc(OCc2ccccn2)cc1
Yield: 102.6 %

Procedure:
To a mixture of phenol (5.25 g, 55.8 mmol) and 2-chloromethylpyridine hydrochloride (10 g, 61.0 mmol) in 80 mL of toluene was added sodium hydroxide (5.35 g, 134 mmol. The mixture was refluxed for 16 hours. The mixture was washed twice with 60 mL of water. The organic layer was then extracted three times with 25 mL of 6 N HCl. The aqueous layer was made basic with 250 mL of 10% NaOH and extracted three times with 150 mL of CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a yellow oil (10.6 g, 94%). ES (+) MS m/e=186 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH2:27])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH:27][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(C)c(C(=O)NCc3ccccc3)s2)cc1
Yield: 43 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 4-methylbenzenesulfonyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 43% yield; m.p. 242-245° C.; 1H NMR (DMSO-d6, 300 MHz) δ 12.89 (s, br, 1H), 8.58 (s, br, 1H), 7.66 (d, J=8.2 Hz, 2H), 7.33-7.17 (m, 7H), 4.32 (d, J=5.8 Hz, 2H), 2.32 (s, 3H), 2.31 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 166.2, 160.6, 143.0, 139.7, 139.6, 139.5, 129.9, 128.7, 127.8, 127.3, 126.2, 111.7, 43.1, 21.4, 13.6; MS (ES+) m/z 402.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(C)(C)C)=[C:4]([C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH:3]=1.[OH-].[Na+]>OS(O)(=O)=O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:16]
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C(=O)c1cccnc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(Cl)cc1C(=O)c1cccnc1
Temperature: 95 °C
Yield: 77.5 %

Procedure:
N-[4-chloro-2-(pyridine-3-carbonyl )-phenyl]-2,2-dimethyl-propionamide (0.65 g) was suspended in 5 mL of 70% H2SO4 and heated at 95° C. in oil bath overnight. After cooling to room temperature the solution was added drop wise with stirring to 20 mL of 40% NaOH solution placed in an ice-water bath. The fine yellow precipitate formed was collected by vacuum filtration, washed well with water and dried under vacuum to give 370 mg of product. 1H NMR (CDCl3) δ 8.84 (dd, J=2.4 Hz, 0.8 Hz, 1H) 8.77 (dd, J=4.8 Hz, 2.0 Hz, 1H) 7.93 (dt, J=8.4 Hz, 2.0 Hz, 1H) 7.43 (m, 1H) 7.35 (d, J=2.0 Hz, 1H) 7.25 (d, J=0.8 Hz, 1H) 6.71 (d, J=8.8 Hz, 1H) 6.21 (s, 2H) MS (ES) m/z=233.0 (MH)+
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][SH:5].[Cl:6][CH2:7][C:8]1[N:9]=[C:10]([NH:13][C:14]([NH:17][CH3:18])=[N:15][CH3:16])[S:11][CH:12]=1>Cl>[ClH:6].[ClH:1].[CH3:16][N:15]=[C:14]([NH:17][CH3:18])[NH:13][C:10]1[S:11][CH:12]=[C:8]([CH2:7][S:5][CH2:4][CH2:3][NH2:2])[N:9]=1
Reactant: NCCS
Reactant: CN=C(NC)Nc1nc(CCl)cs1
Agent: Cl
Product: CN=C(NC)Nc1nc(CSCCN)cs1

Procedure:
Cysteamine hydrochloride (2.25 g; 19.6 mmoles) and 4-chloromethyl-2-(2,3-dimethylguanidino)thiazole (5 g; 19.6 mmoles) [prepared from 1,3-dichloro-2-propanone and (N,N'-dimethylamidino)thiourea which is itself prepared from dimethyl cyanodithioiminocarbonate and methylamine] were dissolved in 17.5 ml of concentrated hydrochloric acid and heated at an oil bath temperature of 100°. After 24 hours the reaction mixture was evaporated under reduced pressure and the residue crystallized from absolute ethanol to yield the title compound, mp 243°-245°.
Reaction SMILES: C[O:2][CH:3](OC)[CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1.FC(F)(F)C(O)=O.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>O>[CH:3]([CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1)=[O:2]
Reactant: COC(OC)C1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(c1cccc2cc(C3=NCC(C=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 2 h
Yield: 103.8 %

Procedure:
A mixture of N-{2-[5-(dimethoxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (1.18 g), trifluoroacetic acid (3 mL), concentrated sulfuric acid (3 mL) and water (10 mL) was stirred at 50° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, neutralized with saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (1.1 g, yield 99%) as a brown amorphous solid from a fraction eluted with ethyl acetate:hexane=50:50. MS: 406(MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].Cl.N[CH2:22]C(OCC)=O>N1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][CH3:22])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: CCOC(=O)CN
Reactant: COc1cc(N)c(C(=O)c2ccccc2)cc1OC
Agent: Cl
Solvent: c1ccncc1
Product: CCOc1cc(C(=O)c2ccccc2)c(N)cc1OC
Yield: 46.1 %

Procedure:
Heat under reflux for 36 hours under an inert atmosphere a mixture of 4.5 g (17.6 mmol) of (2-amino-4,5-dimethoxyphenyl)(phenyl)methanone (XXIaa), 5 g (36 mmol) of ethyl glycinate hydrochloride, and 30 ml of anhydrous pyridine. Add four 2.5 g (18 mmol) fractions of ethyl glycinate hydrochloride, every 6 hours. Allow to equilibrate to room temperature. Evaporate to dryness. Add 200 ml of water. Extract three times with 300 ml of dichloromethane. Dry the organic fractions on Na2SO4 Purify by chromatography (AcOEt 3/hexane 1/3% triethylamine). Recrystallize in EtOH/EtO2. One obtains 2.2 g of the abovenamed product in the form of colorless crystals. Yield: 43%. M:248–250° C. 1H-NMR (CDCl3, 200 MHz): d 3.71 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 4.31 (s, 2H, CH2), 6.64 (s, 1H Ar), 6.70 (s, 1H Ar), 7.27–7.59 (m, 5H Ar), 9.40 (s, 1H exchangeable, —NH).