Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([C:7]1[C:8]([N+:16]([O-])=O)=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])(=[O:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+]>[Fe].O>[C:10]([OH:12])(=[O:11])[CH3:9].[OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]=1[NH2:16])(=[O:6])=[O:5]
Reactant: O=C(O)c1cccc(S(=O)(=O)CCO)c1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)O
Product: Nc1c(C(=O)O)cccc1S(=O)(=O)CCO
Reaction time: 0.5 h

Procedure:
75 parts of 3-hydroxyethylsulfonyl-2-nitrobenzoic acid are added at a steady rate over a period of 30 minutes with stirring to a mixture of 40 parts of iron powder and 200 parts of water heated to 80° to 85° C., and the reaction temperature of the mixture is maintained at 80° to 85° C. during the addition. After the addition is completed, the mixture is stirred for 30 minutes, brought to a pH of 8.5 with aqueous sodium carbonate solution and is clarified while hot by filtering off precipitated iron hydroxide. The filter residue is washed twice with a small amount of hot water. The combined filtrates are then acidified with 25 parts of glacial acetic acid, concentrated in vacuo to 150 parts by volume and subsequently cooled to 0° to 5° C. with stirring. The slightly brownish precipitate is isolated on a nutsche filter, washed with a small amount of icewater and dried at 60° C. in vacuo. This gives 78 parts of 3-hydroxyethylsulfonylanthranilic acid acetate of the formula ##STR15## of melting point 286° to 289° C. and a purity (by diazotization) of 99.5%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:24]([CH3:26])[CH3:25])[N:11](/[CH:20]=[CH:21]/[CH:22]=[O:23])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:27]([O:33][CH3:34])(=[O:32])[CH2:28][C:29]([CH3:31])=[O:30].[H-].[Na+].C([Li])CCC>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:24]([CH3:26])[CH3:25])[N:11](/[CH:20]=[CH:21]/[CH:22]([OH:23])[CH2:31][C:29](=[O:30])[CH2:28][C:27]([O:33][CH3:34])=[O:32])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/C=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Product: COC(=O)CC(=O)CC(O)/C=C/n1c(C(C)C)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1

Procedure:
From (E)-3-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-2-propenal (0.100 g), methyl acetoacetate (0.028 ml), sodium hydride (0.031 g, washed with dry THF(3×3 ml)) and n-butyl lithium (1.4M in, hexanes, 0.26 ml) by the process as described for the preparation of Intermediate (10a) to afford a dark orange oil which was purified by FCC eluting with System A (2:3, 1:1) to afford the title compound (0.054 g) as an orange solid, Rf (System A 2:3) 0.18;
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][NH:53][CH2:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][N:53]([CH2:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCCc2ccccc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.2 %

Procedure:
To a solution of 120 mg (0.74 mmol) of 1H-indole-7-carboxylic acid and 240 mg of TBTU (0.74 mmol) in 8 ml DMF, were added 0.64 ml (3.72 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 280 mg (0.74 mmol) of (4-tert-butyl-benzyl)-(3-phenyl-propyl)-amine were added. After stirring for 4 h at rt, the reaction mixture was diluted with 80 ml water and extracted with EtOAc (2×). The combined organic phases were washed with brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:4) to give 205 mg white solid (63%). MS (ISP) 425.5 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:14]2([CH3:20])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:23]2[C:30]([CH3:31])=[CH:29][NH:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:14]2([CH3:20])[CH2:15][CH2:16][N:17]([C:22]3[C:23]4[C:30]([CH3:31])=[CH:29][NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:18][CH2:19]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: CC1(C(=O)Nc2cccc(C(C)(C)C)c2)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)Nc4cccc(C(C)(C)C)c4)CC3)c12
Temperature: 100 °C
Yield: 50 %

Procedure:
N-(3-tert-Butylphenyl)-4-methylpiperidine-4-carboxamide from step B (0.33 g, 1.07 mmol), 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.18 g, 1.07 mmol), N,N-diisopropylethylamine (0.69 g. 5.34 mmol), and isopropanol (7 mL) were combined in a pressure rated sealed tube and heated at 100° C. for 18 hours. The mixture was concentrated and taken up in dichloromethane from which a precipitate (0.18 g) was collected. The solution was chromatographed (SiO2, 0-2% MeOH:CH2Cl2), and the columned material (0.15 g) was combined with the precipitate and dissolved in methanol (15 mL) at 60° C. Water was added (5.0 mL), and the mixture was cooled. The resultant precipitate was filtered, washed with water, and dried to give the title compound in 50% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[F:9]
Reactant: O=[N+]([O-])[O-]
Reactant: Fc1ccc(Cl)c(F)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc(Cl)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-chloro-2,4-difluorobenzene (0.829 g, 5.58 mmol) in concd H2SO4 (8.0 mL) at 0° C., KNO3 (0.565 g, 5.59 mmol) was added in one portion. The resulting solution was allowed to warn to room temperature and stirred overnight at room temperature. It was then poured into ice (80 g) and extracted with ethyl acetate (75 mL). The ethyl acetate was dried over anhydrous Na2SO4, removed under vacuum, and the resulting oil was dried further under vacuum to afford 1.007 g (93%) pure (1H NMR) title compound as a light red oil; 1H NMR (CDCl3) δ 7.17 (dd, 1H, J1=9.9 Hz, J2=8.4 Hz), 8.24 (t, 1H, J=7.5 Hz).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:18]([NH:20][C@H:21]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])[CH2:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4].[CH3:35][C:36]([O:39][C:40]([NH:42][C@H:43]([C:59](ON1C(=O)CCC1=O)=[O:60])[CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])=[O:41])([CH3:38])[CH3:37].CN1CCOCC1>CN(C=O)C>[NH:42]([C:40]([O:39][C:36]([CH3:38])([CH3:37])[CH3:35])=[O:41])[C@H:43]([C:59]([NH:1][CH2:2][C:3]([NH:5][C@H:6]([C:18]([NH:20][C@H:21]([C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])[CH2:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4])=[O:60])[CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:49]([O:51][CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)=[O:50]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)CN)C(=O)OCc1ccccc1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)CNC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 46.3 %

Procedure:
A solution of 583 mg of H-Gly-Asp(OBzl)-Val-OBzl (Example 15Bb) and 477.5 mg of Boc-Lys(Z)-O Su in 10 ml of DMF is adjusted to pH 8.5 with N-methylmorpholine. After stirring for 18 hours the mixture is concentrated and the residue is partitioned between ethyl acetate and water. The organic phase is washed with saturated NaHCO3 solution, 5% KHSO4 /10% K2SO4 solution and saturated NaCl solution, dried and filtered. The filtrate is concentrated and the residue is crystallized from ether. There are obtained 385 mg of Boc-Lys(Z)-Gly-Asp(OBzl)-Val-OBzl, m.p. 95°-101° C.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[N:34]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=1)=[C:35]=O.[F:47][C:48]1[CH:56]=[CH:55][C:54]2[N:53]3[CH2:57][CH2:58][NH:59][CH2:60][C:52]3=[CH:51][C:50]=2[CH:49]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:14]=[C:35]([N:59]1[CH2:58][CH2:57][N:53]3[C:54]4[CH:55]=[CH:56][C:48]([F:47])=[CH:49][C:50]=4[CH:51]=[C:52]3[CH2:60]1)[N:34]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=1)[CH:8]2[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: Fc1ccc2c(c1)cc1n2CCNC1
Reactant: COC(=O)/C=C/c1cccc(F)c1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCn3c(cc4cc(F)ccc43)C2)N1c1cccc(C(F)(F)F)c1

Procedure:
Starting with 546 mg (1.2 mmol) of the iminophosphorane from Example 12A, 402 mg (1.2 mmol) of 1-isocyanato-3-(trifluoromethyl)benzene and 240 mg (1.3 mmol) of 8-fluoro-1,2,3,4-tetrahydropyrazino[1,2-a]indole from Example 36A, the general procedure [M] gives 610 mg (86% of theory) of product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][N:12]=[C:13]([N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)[CH:14]=2)[NH:9][CH:8]=1)[CH3:2].[H][H]>[Pd].CO>[N:16]1([C:13]2[CH:14]=[C:15]3[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:21])=[CH:8][NH:9][C:10]3=[CH:11][N:12]=2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1c[nH]c2cnc(-n3cncn3)cc12
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1c[nH]c2cnc(-n3cncn3)cc12
Yield: 88.6 %

Procedure:
Ethyl-3-(5-(1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)prop-2-enoate (0.5 g, 1.8 mmol) was hydrogenated over palladium on carbon (10%, 0.2 g) in methanol (75 mL) at 45 psi of hydrogen for 90 min. The catalyst was removed by filtration and the solvent evaporated in vacuo to give the title compound (0.455 g, 90%) as a colourless solid. mp 129°-131° C. 1H NMR (360 MHz, CDCl3) δ 1.24 (3H, t, J=7.1Hz), 2.72 (2H, t, J=7.4Hz), 3.13 (2H, t, J=7.4Hz), 4.14 (2H, q, J=7.1Hz), 7.31 (1H, d, J=2.3Hz), 8.08 (1H, s), 8.11 (1H, s), 8.54-8.60 (2H, m) and 9.15 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH2:5]P(=O)(OCC)OCC.O=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.O1CCCC1.[H-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:5]=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(Cl)c1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccc([N+](=O)[O-])c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Diethyl 3-chloro-4-nitrobenzylphosphonate (2.80 mmol, 0.86 g), tert-butyl 4-oxopiperidine-1-carboxylate (2.80 mmol, 0.557 g) and tetrahydrofuran (4.89 mL) were stirred and sodium hydride (4.19 mmol, 0.168 g) was added. The reaction was stirred overnight at room temperature. Water was added and the reaction extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated under vacuum to afford the intermediate tert-butyl 4-(3-chloro-4-nitrobenzylidene)-piperidine-1-carboxylate (0.85 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1.CI.[C:20](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cl-].[Na+].O>[CH3:20][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[S:2][CH3:1]
Reactant: CSc1ccccc1-c1nc2ccccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccccc1-c1nc2ccccc2n1C

Procedure:
The product of step (a) above (3.25 g), methyl iodide (1.92 g) and potassium carbonate (5.2 g) were stirred together in dry dimethylformamide (50 ml) at room temperature for 24 hours. The reaction mixture was poured into brine and extracted into ethyl acetate, the extract was washed with excess brine, dried over magnesium sulphate and evaporated to dryness in vacuo and the residue was purified by flash chromatography (SiO2 /CH2Cl2 9:1 ethyl acetate) to afford the sub-title compound as yellow solid, MS MW 254 bp 239.
Reaction SMILES: [Cl:1][C:2]1[N:6]=[C:5](Cl)[S:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C([O-])([O-])=O.[K+].[K+].CC#N>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:6]=[C:5]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH3:8])[S:4][N:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: Clc1nsc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccccc1-c1nc(Cl)ns1
Temperature: 100 °C

Procedure:
A mixture of 3,5-dichloro-1,2,4-thiadiazole (0.14 g, 0.93 mmol), 2-methoxyphenylboronic acid (0.16 g, 1.0 mmol), Pd(PPh3)4 (11 mg, 9.3 μmol), K2CO3 (0.26 g, 1.9 mmol), and CH3CN (3 mL containing 10% H2O) was sealed in a microwave vessel and heated by microwave irradiation at 100° C. for three minutes. The reaction was cooled to room temperature, diluted with water, and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to yield 3-chloro-5-(2-methoxyphenyl)-1,2,4-thiadiazole. LC/MS: m/z 227 (M+H)+ at 3.45 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[C:5]3[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]=3[CH:13]=[CH:14][CH:15]=2.[H-].[Na+].BrC[CH2:20][CH2:21][CH2:22][C:23]#[N:24].CCOCC>CN(C)C=O>[CH3:1][S:2][C:3]1[C:4]2[C:5]3[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[C:7](=[O:12])[C:6]=3[CH:13]=[CH:14][CH:15]=2
Reactant: N#CCCCCBr
Reactant: CSc1ccc2c3c(cccc13)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CSc1ccc2c3c(cccc13)C(=O)N2CCCC#N
Temperature: 50 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
A mixture of 2.15 g of 6-(methylthio)-benz-[cd]indol-2(1H)-one (Example 2), 0.6 g of 60% sodium hydride in 70 ml of N,N-dimethylformamide is heated at 50° C. for 30 minutes then cooled. A solution of 2.22 g of 1-bromo-4-cyano-butane in 25 ml of N,N-dimethylformamide is added dropwise to the reaction mixture and stirring continued for 3 hours. The reaction mixture is quenched in 400 ml of ice water and extracted with (2×300 ml) of ethyl acetate. The organic layer is dried with magnesium sulfate and evaporated to afford a solid which is stirred with ether, filtered and dried to yield 2.5 g of the desired product as a solid, m.p. 120°-122° C.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.O.O[N:15]1[C:19]2C=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=N1.[CH2:24]([NH:26][C:27](=[O:45])[NH:28][C:29]1[N:34]=[C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:32]([C:42]([OH:44])=O)=[CH:31][N:30]=1)[CH3:25].NC1C=NC=CC=1>CN(C)C=O.O>[CH2:24]([NH:26][C:27](=[O:45])[NH:28][C:29]1[N:34]=[C:33]([NH:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:32]([C:42]([NH:17][C:18]2[CH:19]=[N:15][CH:21]=[CH:22][CH:23]=2)=[O:44])=[CH:31][N:30]=1)[CH3:25]
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)Nc1ncc(C(=O)O)c(Nc2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1cccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1ncc(C(=O)Nc2cccnc2)c(Nc2ccccc2)n1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 48.2 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.096 g, 0.500 mmol) and 1-hydroxybenzotriazole monohydrate (0.077 g, 0.500 mmol) were added to a stirred solution of 2-(3-ethylureido)-4-(phenylamino)pyrimidine-5-carboxylic acid (v) (0.100 g, 0.330 mmol) in dimethylformamide (3 mL) at room temperature. After 15 min, 3-aminopyridine (0.047 g, 0.500 mmol) was added and the reaction mixture stirred at 40° C. for 24 h. The mixture was cooled to room temperature, treated with water (2 mL) and the resulting off-white precipitate filtered, washed with water, air-dried and triturated with hot EtOH to give Compound 6 (0.060 g, 0.159 mmol, 48%) as a colourless powder. 1H NMR (300 MHz, DMSO-d6): δ 10.67 (1H, br s), 10.52 (1H, br s), 9.89 (1H, br s), 8.91-8.84 (3H, m), 8.35 (1H, dd, J 1.0 and 4.6), 8.12 (1H, dt, J 2.0 and 8.7), 7.67 (2H, d, J 8.2), 7.46-7.38 (3H, m), 7.20 (1H, t, J 7.2), 3.10 (2H, dq, J 5.6 and 7.2), 0.93 (3H, t, J 7.2); [M+H]+ m/z=378.2.
Reaction SMILES: O.O.[Sn](Cl)Cl.[F:6][C:7]([S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-])=O)([F:9])[F:8]>Cl.C(O)C>[F:6][C:7]([S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17])([F:9])[F:8]
Reactant: O=[N+]([O-])c1ccccc1SC(F)(F)F
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccccc1SC(F)(F)F
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 75.7 %

Procedure:
A solution of 25.53 g of tin(II) chloride dihydrate in 40 ml of concentrated hydrochloric acid was added dropwise to a stirred solution of 5.05 g of 2-nitrophenyl trifluoromethyl sulfide, obtained according to Example 1, in 30 ml of ethanol. After the addition had ended, the mixture was heated to 100° C. and stirred at this temperature for 1.5 hours. The mixture was cooled, ethanol was evaporated off under reduced pressure, and the residue was poured into a mixture of 150 g of ice and 150 ml of 40% strength by weight aqueous sodium hydroxide solution. The product was extracted with ether. The combined ether extracts were dried over magnesium sulfate and concentrated under reduced pressure. Vacuum distillation of the residue gave 3.31 g (75.7% of theory) of 2-aminophenyl trifluoromethyl sulfide (boiling point 102-104° C. at 50 mbar, melting point: 30-31° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][C:17]=3[Cl:18])[O:10][N:9]=2)=[CH:4][C:3]=1[NH2:19].[CH2:20]([OH:22])[CH3:21].C([CH2:25][C:26](OBr)=[O:27])C.C(N(CC)CC)C>C(OCC)(=O)C>[CH2:20]([O:22][C:26](=[O:27])[CH2:25][NH:19][C:3]1[CH:4]=[C:5]([C:8]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][C:17]=3[Cl:18])[O:10][N:9]=2)[CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:21]
Reactant: Nc1cc(-c2noc(-c3sccc3Cl)n2)ccc1Cl
Reactant: CCO
Reactant: CCCC(=O)OBr
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)CNc1cc(-c2noc(-c3sccc3Cl)n2)ccc1Cl
Yield: 94 %

Procedure:
To a 10 mL microwave reaction flask reaction charged with a magnetic stir bar, was added 2-chloro-5-[5-(3-chlorothiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-phenylamine (0.100 g, 0.320 mmol), anhydrous ethanol (1.3 mL), bromo ethylacetate (0.241 g, 1.44 mmol) and triethylamine (67 μL, 0.48 mmol). The suspension was reacted at 120° C., for 15 min in a microwave set at 70 watts. The resulting yellow suspension was diluted with ethyl acetate (50 mL) and the organic layer was then washed with H2O (2×15 mL), brine (10 mL), dried over MgSO4, and the solvent was removed by evaporation. The white solid was then purified by flash column chromatography (silica gel, elution with EtOAc:hexanes, 1:5) to yield 0.119 g (94%) of the title compound as a white solid. 1H NMR (CDCl3): 7.59 (dd, 1H, J=5.2 and 1.4 Hz), 7.47 (dd, 1H, J=8.3 and 1.7 Hz), 7.38 (dd, 1H, J=8.3 and 1.1 Hz), 7.27 (d, 1H, J=1.7 Hz), 7.10 (dd, 1H, J=5.2 and 1.4 Hz), 5.11 (t, 1H, J=5.0 Hz), 4.29 (q, 2H, J=7.1 Hz), 4.05 (d, 2H, J=5.2 Hz), 1.33 (t, 3H, J=7.1 Hz).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:5][CH:6]=1.C(N(CC)CC)C.[CH3:21][C:22]1([CH3:31])[C:26]([CH3:28])([CH3:27])[O:25][B:24]([CH:29]=[CH2:30])[O:23]1.C(OCC)(=O)C>CN(C=O)C>[CH3:27][C:26]1([CH3:28])[C:22]([CH3:31])([CH3:21])[O:23][B:24](/[CH:29]=[CH:30]/[C:2]2[N:3]=[C:4]([CH2:7][N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[S:5][CH:6]=2)[O:25]1
Reactant: Brc1csc(CN2CCOCC2)n1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)OB(/C=C/c2csc(CN3CCOCC3)n2)OC1(C)C
Temperature: 120 °C

Procedure:
To a solution of 4-((4-bromothiazol-2-yl)methyl)morpholine (125 mg, 0.5 mmol) and triethylamine (0.2 mL, 1.5 mmol) in DMF (1.5 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.15 mL, 1 mmol) and Pd(Ptert-Bu3)2 (8 mg, 0.002 mmol). The mixture was heated to 120° C. under microwave irradiation for 1 h. Ethyl acetate (50 mL) was added and the solution was washed with water (2×10 mL) and brine (10 mL), dried over MgSO4 and concentrated to an orange oil (165 mg, 99%). 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J=18.0 Hz, 1H), 7.19 (s, 1H), 6.40 (d, J=18.0 Hz, 1H), 3.84 (s, 2H), 3.74 (bs, 4H), 2.61 (bs, 4H), 1.29 (s, 12H); MS ESI 337.1 [M+H]+, calcd for [C16H25BN2O3S+H]+ 337.2. [α]22.8°D=−169° (c 0.42, Methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[I:12]Cl>C(Cl)(Cl)Cl>[I:12][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([S:8]([NH2:11])(=[O:9])=[O:10])[CH:4]=1
Reactant: ClI
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: ClC(Cl)Cl
Product: Nc1ccc(I)cc1S(N)(=O)=O
Temperature: 25 °C
Yield: 91.6 %

Procedure:
To a cold (0° C.) stirred solution of 2-aminobenzenesulfonamide (17.2 g; 100 mmol) in CHCl3 (200 ml) was added a solution of iodine monochloride (17.1 g; 105 mmol) in CHCl3 (50 ml) over 1 h. The reaction mixture was slowly warmed up to rt. and left with stirring over night. The reaction mixture was filtered and the isolated solid was washed on the filter with CHCl3 (3×20 ml), NaHCO3 (sat. aq., 1×20 ml), H2O (4×50 ml). The isolated solid was air dried to give 27.3 g (92%) of product.
Reaction SMILES: CI.[CH:3]([C:5]1[S:13][C:12]2[C:11](=[O:14])[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][NH:8][C:7]=2[CH:6]=1)=[O:4].[C:20](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:3]([C:5]1[S:13][C:12]2[C:11](=[O:14])[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:8]([CH3:20])[C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c[nH]c2cc(C=O)sc2c1=O
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2cc(C=O)sc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
Methyl iodide (1.2 mL, 19.3 mmol) was added to a mixture of ethyl 2-formyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate (3.0 g, 11.9 mmol), potassium carbonate (2.5 g, 18.1 mmol) in DMF (30 mL) at 0° C. After the addition of methyl iodide, the mixture was stirred at room temperature for 1 hr. The mixture was diluted with water (40 mL), stirred at room temperature for 15 minutes, and then filtered. The collected solid was washed with water and dried in vacuo, leaving a solid (1.3 g, 41%). The aqueous phase was extracted with methylene chloride (2×50 mL). The organic layers were combined, washed with water (50 mL) and brine (50 mL), and dried over magnesium sulfate. Removal of the solvent gave a second crop of product (0.34 g).