Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[O:40][CH3:41])[C:26]3[S:27][CH:28]=[CH:29][N:30]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.[CH2:42]([Sn](CCCC)(CCCC)CCCC)[CH:43]=[CH2:44]>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.CN(C=O)C>[CH2:44]([C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[O:40][CH3:41])[C:26]3[S:27][CH:28]=[CH:29][N:30]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1)[CH:43]=[CH2:42]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Br)nccc3c2)c(OC)c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3nccs3)ccc12
Temperature: 90 °C

Procedure:
A microwave vial was charged with 1-(2-bromo-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (see Example 70, step 3; 0.185 g, 0.278 mmol), Pd(PPh3)4 (0.016 g, 0.014 mmol), and DMF (0.557 ml). Allyltributyltin (0.104 ml, 0.334 mmol) was added and the reaction was heated in a microwave reactor at 90° C. for 30 minutes. The reaction was concentrated and purified via column chromatography (40 g silica gel column, gradient elution 0 to 50% EtOAc:Heptane) to afford 1-(2-allyl-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light pink solid. m/z (ESI) 626.3 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])(C)[O:7]2)[CH:3]=[N:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][C:23](=[O:26])[CH2:24][CH3:25]>CN(C)C=O>[CH3:13][C:11]1([CH3:12])[CH:8]([CH3:10])[O:7][B:6]([C:4]2[CH:5]=[N:1][N:2]([CH2:22][C:23](=[O:26])[CH2:24][CH3:25])[CH:3]=2)[O:14]1
Reactant: CCC(=O)CBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC(=O)Cn1cc(B2OC(C)C(C)(C)O2)cn1
Temperature: 90 °C
Yield: 14.8 %

Procedure:
Pyrazole-4-boronic acid pinacol ester (1 g, 1 equiv, 5.15 mmol) was dissolved in dimethylformamide (15 mL) followed by the addition of Cs2CO3 (0.86 g, 1.5 equiv, 7.73 mmol) and 1-bromo-2-butanone (1.1 equiv, 5.67 mmol, 0.86 g). The mixture was heated at 90° C. overnight. The reaction was extracted into ethyl acetate and washed with water (3×) and brine (3×). The filtrate was concentrated in vacuo onto silica gel and purified by flash chromatography (SiO2, CH2Cl2:CH3OH 100:0-80:20) to return the title compound (0.19 g, 14% yield). 1H NMR 500 MHz (DMSO) δ 0.97 (3H, t) 1.26 (12H, s), 2.50 (2H, q), 4.71 (2H, s), 7.65 (1H, s), 8.04 (1H, s). MS m/z 265 (M+H+)+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[OH:30]>>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[O:30][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1
Reactant: COc1ccc(-c2nnc(Cl)cc2-c2ccccc2)cc1
Reactant: Oc1ccc(F)cc1F
Product: COc1ccc(-c2nnc(Oc3ccc(F)cc3F)cc2-c2ccccc2)cc1

Procedure:
In a similar manner as in Example 2, 6-chloro-3-(4-methoxyphenyl)-4-phenylpyridazine (215 mg, 0.725 mmol) and 2,4-difluorophenol were reacted as starting materials at 150° C. for 20 hours and post-treatment was then conducted, whereby the title compound was obtained as colorless needles (169.7 mg, 60.0%). Melting point: 169.0-169.9° C. (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.S(Cl)(Cl)=O.C(N(C(C)C)C(C)C)C.[CH3:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[NH:39][CH2:38][CH2:37][CH2:36]2>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[C:7]([C:8]([N:39]2[C:40]3[C:35](=[CH:34][C:33]([CH3:32])=[CH:42][CH:41]=3)[CH2:36][CH2:37][CH2:38]2)=[O:10])=[CH:11][CH:12]=[CH:13][N:14]=1
Reactant: Cc1ccc2c(c1)CCCN2
Reactant: O=C(O)c1cccnc1Oc1ccc(F)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: Cc1ccc2c(c1)CCCN2C(=O)c1cccnc1Oc1ccc(F)c(Cl)c1
Temperature: 140 °C
Yield: 7.8 %

Procedure:
A solution of 2-(3-chloro-4-fluoro-phenoxy)-nicotinic acid (32.1 mg, 0.12 mmol, 1.0 equiv) in thionyl chloride (57 mg, 35 pt, 0.48 mmol, 4.0 equiv; [CAS RN 7719-09-7]) was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure, remaining thionyl chloride removed by azotropic distillation with toluene and the residue dissolved in anhydrous DMF (1 mL). To this solution was added N-ethyldiisopropylamine (77.6 mg, 102 μL, 0.60 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and 6-methyl-1,2,3,4-tetrahydro-quinoline (21.2 mg, 0.14 mmol, 1.2 equiv; [CAS RN 91-61-2]) and the reaction mixture heated by microwave irradiation to 140° C. for 15 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 auto sampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 3.7 mg (8%) of the title compound. MS (ISP): 397.0 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH3:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([CH3:20])=[CH:17][CH:18]=2)[C:13]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[C:12]([C:27]#[N:28])[C:11]1=[O:29]>N1C=CC=CC=1>[CH3:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([CH3:20])=[CH:17][CH:18]=2)[C:13]([N:21]2[CH2:26][CH2:25][N:24]([C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:23][CH2:22]2)=[C:12]([C:27]#[N:28])[C:11]1=[O:29]
Reactant: Cc1ccc2c(c1)c(N1CCNCC1)c(C#N)c(=O)n2C
Reactant: O=C(Cl)c1cccs1
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)c(N1CCN(C(=O)c3cccs3)CC1)c(C#N)c(=O)n2C
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
2-Thiophene carbonyl chloride (160 μL, 1.5 mmol) was added to a stirred solution of Compound 28 (282 mg, 1.0 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 277 mg (70%) of white solids. M.P. 214° C. 1H NMR (DMSO-d6): δ 2.41 (s, 3H), 3.55 (s, 3H), 3.63 (m, 4H), 3.92 (m, 4H), 7.16 (t, J=4.1 Hz, 1H), 7.47 (m, 2H), 7.56 (d, J=8.7 Hz, 1H), 7.68 (s, 1H), 7.80 (d, J=4.9 Hz, 1H). EIMS m/z 393 (M+1), 415 (M+23). Anal. (C21H20N4O2S) C,H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([CH:12]=NN=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[O:11])=[CH:5][CH:4]=1.N([O-])=[O:35].[Na+].Cl>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([CH:12]=[O:35])=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)C=NN=P(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CC(=O)C=O)cc1
Reaction time: 0.5 h

Procedure:
A solution of 1.82 g of 1-(4-methoxyphenyl)-3-(triphenylphosphoranylidene-hydrazono)-acetone in 12 ml of tetrahydrofuran is mixed with 0.84 g of pulverized sodium nitrite and the mixture is diluted with 5 ml of water. The resulting suspension is cooled to 0°-5°, treated dropwise over the course of 7 minutes with 8.8 ml of 2N hydrochloric acid and then kept for a further 30 minutes at 0°-5°. The aqueous phase is twice washed with methylene chloride; the combined organic solutions are washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The oily residue is chromatographed on 40 g of acid-washed silica gel. A small quantity of a by-product is eluted with benzene and, using 1200 ml of a 95:5-mixture of benzene and ethyl acetate, the 4-methoxybenzylglyoxal is obtained in the form of the hydrate, which is an oily product; infra-red absorption spectrum (in methylene chloride): characteristic bands at 2.96μ, 5.79-5.84μ, 6.23μ and 6.63μ. The anhydrous product melts at 139°-140° after recrystallisation from a mixture of chloroform and hexane; ultra-violet absorption spectrum:λmax 333 mμ (in ethanol or hydrochloric acid/ethanol) and λmax 367 mμ (in potassium hydroxide/ethanol); ethanol); infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.00μ, 5.97μ, 6.09μ, 6.24μ, 6.61μ and 7.15μ.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH:9]=2)=O.[NH2:26][CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CCO>[CH2:32]([O:31][C:29](=[O:30])[C:28]([CH3:35])([CH3:34])[CH2:27][NH:26][C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH:9]=2)=[O:2])[CH3:33]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3cccc(Cl)c3)ccc2c1O
Reactant: CCOC(=O)C(C)(C)CN
Solvent: CCO
Product: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3cccc(Cl)c3)ccc2c1O

Procedure:
7-(3-Chloro-phenoxy)-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (25 mg, 0.07 mmol) and ethyl 3-amino-2,2-dimethylpropanoate (41 mg, 0.28 mmol) in EtOH (3 mL) were heated at 150° C. in a microwave for 1.5 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 26 mg. MS: (−) m/z 466.42 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10](/[N:17]=[CH:18]/[N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][CH2:26][CH:25]([O:29][C:30]2[CH:31]=[C:32](CN)[CH:33]=[CH:34][CH:35]=2)[CH2:24]1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([CH2:21][C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([O:29][CH:25]5[CH2:26][CH2:27][CH2:28][N:23]([CH3:22])[CH2:24]5)[CH:35]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CN1CCCC(Oc2cccc(CN)c2)C1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Solvent: CO
Product: CN1CCCC(Oc2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)c2)C1
Temperature: 120 °C

Procedure:
Methyl 5-(4-chlorophenyl)-3-{[(1E)-(dimethylamino)methylene]amino}thiophene-2-carboxylate (180 mg, 0.558 mmol) and 1-{3-[(1-methylpiperidin-3-yl)oxy]phenyl}methanamine (135 mg, 0.613 mmol) were dissolved in MeOH (2 ml). The reaction was heated in a microwave at 120° C. for 15 minutes, MeOH added, the resulting precipitate filtered and washed with MeOH to yield the title compound as a white solid. Yield: 140 mg (54%). 1H NMR (400 MHz, d6-DMSO) δ 8.66 (s, 1H), 7.92-7.87 (m, 3H), 7.57 (m, 2H), 7.25 (t, 1H, J=8.0 Hz), 6.94 (m, 1H), 6.89 (m, 2H), 5.18 (s, 2H), 4.36 (m, 1H J=4.3 Hz), 3.30 (d, 1H, J=9.6 Hz), 2.81 (d, 1H, J=10.7 Hz), 2.15 (s, 3H), 2.04-1.88 (m, 3H), 1.73-1.67 (m, 1H), 1.57-1.45 (m, 1H), 1.36-1.25 (m, 1H). MS (ESI+) 465.93 (M+1H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][NH:11][CH2:10][C@@:9]2([N:14]([CH3:25])[C:15](=[O:24])[O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:13])=[CH:4][CH:3]=1.[C:26]([N:31]1[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]1)(=[O:30])[CH:27]([CH3:29])[CH3:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][C:15](=[O:24])[N:14]([C@:9]2([CH3:13])[C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:12][N:11]([C:37]([CH:34]3[CH2:33][CH2:32][N:31]([C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH2:36][CH2:35]3)=[O:38])[CH2:10]2)[CH3:25])=[CH:22][CH:21]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@]1(C)CNC[C@@H]1c1ccc(Cl)cc1
Reactant: CC(C)C(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C(=O)N1CCC(C(=O)N2C[C@H](c3ccc(Cl)cc3)[C@@](C)(N(C)C(=O)Oc3ccc(F)cc3)C2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 34 mg (0.093 mmol) rac-4-fluorophenyl (3R,4S)-4-(4-chlorophenyl)-3-methylpyrrolidin-3-yl(methyl)carbamate, 14.9 mg (0.075)mmol 1-isobutyrylpiperidine-4-carboxylic acid, 34.2 (0.09 mmol) HATU and 58 mg (0.45 mmol) DIPEA in 2 mL DMF was shaken for 3 h at room temperature. The mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions 26.8 (66%) of the title compound as light yellow viscous oil. MS m/e: 544.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:5]([O:7]CC)=O.[Cl:14][C:15]1[N:20]=[C:19]([CH3:21])[CH:18]=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH2:21][C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:14])[N:20]=2)[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: CCOC(=O)c1ccc(Cl)c(Br)c1
Reactant: Cc1cccc(Cl)n1
Product: O=C(Cc1cccc(Cl)n1)c1ccc(Cl)c(Br)c1

Procedure:
In a similar manner as described in Example 1 from ethyl 3-bromo-4-chlorobenzoate (42.6 g, 171 mmol) and 6-chloro-2-picoline (18.7 mL, 171 mmol), 1-(3-bromo-4-chlorophenyl)-2-(-6-chloro-2-pyridinyl)ethanone was obtained as a pale yellow solid existing as a mixture of ketone and enol tautomers. 1H NMR (CDCl3) of ketone: δ 8.30 (d, 1H), 7.92 (dd, 1H), 7.69–7.54 (m, 2H), 7.24 (m, 2H), 4.42 (s, 2H); MS m/z 344 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[CH:11][O:10][N:9]=2)=[N:6][CH:7]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:21]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][CH:11]=3)=[N:19][C:18]=2[CH3:20])=[O:23])[CH2:26][CH2:25]1
Reactant: NC1CC1
Reactant: Cc1nc(/C=C/c2conc2-c2ccc(F)cn2)sc1C(=O)O
Product: Cc1nc(/C=C/c2conc2-c2ccc(F)cn2)sc1C(=O)NC1CC1
Yield: 48 %

Procedure:
As described for example 90 g, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (99 mg, 0.3 mmol) was converted, using cyclopropylamine instead of 4-aminotetrahydropyran, to the title compound (53 mg, 48%) which was obtained as a yellow solid. MS: m/e=371.1 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@:18]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]#[N:28])[CH2:23][CH2:22]4)([CH3:20])[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH:29][NH:30][C:31](=N)[CH2:32][CH2:33][CH3:34]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C:18]([CH3:20])([CH:21]4[CH2:22][CH2:23][N:24]([C:27]5[O:29][N:30]=[C:31]([CH2:32][CH2:33][CH3:34])[N:28]=5)[CH2:25][CH2:26]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CCCC(=N)NO
Reactant: C[C@@]1(C2CCN(C#N)CC2)Cc2cc(-c3ccc(S(C)(=O)=O)cc3)ncc2O1
Product: CCCc1noc(N2CCC(C3(C)Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O3)CC2)n1

Procedure:
The title compound is prepared from (S)-4-[5-(4-methanesulfonyl-phenyl)-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile (Intermediate 33; the configuration of the stereocenter is arbitrarily assigned) and N-hydroxy-butyramidine following a procedure analogous to that described in Example 2. LC (method 6): tR=1.25 min; Mass spectrum (ESI+): m/z=483 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH2:27][OH:28])[CH2:3][N:4]1[C:24](=[O:25])[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[S:13][C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:19]=4[N:6]([C:7]=23)[C:5]1=[O:26].C(Cl)(Cl)Cl.C[OH:34]>>[OH:1][CH:2]([CH2:27][OH:28])[CH2:3][N:4]1[C:24](=[O:25])[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[S:13](=[O:34])[C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][C:19]=4[N:6]([C:7]=23)[C:5]1=[O:26]
Reactant: CO
Reactant: O=c1c2cccc3c2n(c(=O)n1CC(O)CO)-c1cc(C(F)(F)F)ccc1S3
Solvent: ClC(Cl)Cl
Product: O=c1c2cccc3c2n(c(=O)n1CC(O)CO)-c1cc(C(F)(F)F)ccc1S3=O

Procedure:
Reaction of 2-(2,3-dihydroxypropyl)-10-trifluoromethyl-1H-pyrimido[5,4,3-kl] phenothiazine-1,3(2H)-dione and m-chloroperbenozic acid according to the procedure of Example 6 gave the title compound, m.p. 224°-225° (chloroform-methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]([NH:11][NH:12][CH:13]=O)=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CN(C=O)C>[N:11]1[N:12]=[CH:13][N:1]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH:9]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=CNNC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Oc1ccc(-n2cnnc2)cc1

Procedure:
4-aminophenol (1 g, 9.16 mmol) and bisformyl hydrazine (888 mg, 10.08 mmol) were dissolved in a mixture of toluene (30 mL) and DMF (3 mL), followed by addition of pTSA (1.92 g, 10.08 mmol). The mixture was heated under reflux for 3 hours. Upon cooling, the mixture separated to two layers. The upper toluene layer was discarded. The lower dark DMF layer was directly purified by column chromatography using a 115 gram biotage silica gel cartridge eluting with 20-40 ethyl acetate/hexanes (gradient) to give the product as pale yellow solid. LRMS tale: 161.1; obs: 162.4 (M+1).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH2:13]([C:15]1[S:19][CH:18]=[C:17]([C:20]([OH:22])=O)[CH:16]=1)[CH3:14].[CH3:23][C:24]12[CH2:31][CH:28]([NH:29][CH2:30]1)[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2.O>C(Cl)Cl>[CH2:13]([C:15]1[S:19][CH:18]=[C:17]([C:20]([N:29]2[CH2:30][C:24]3([CH3:23])[CH2:31][CH:28]2[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]3)=[O:22])[CH:16]=1)[CH3:14]
Reactant: CC1(C)CC2CC(C)(CN2)C1
Reactant: CCc1cc(C(=O)O)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCc1cc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cs1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61.6 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.06 g; 1.2 eq) was added to a solution of 5-ethyl-thiophene-3-carboxylic acid (0.04 g; 1 eq.) in DCM (1 mL/100 mg of starting material). This mixture was stirred at room temperature for 5 minutes, then 1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane (0.043 g; 1.1 eq.) added and the mixture allowed to stir for 18 hours. Water (1 mL/100 mg of starting material) was then added and the organic layer separated, dried and evaporated to give the crude product which was purified by column chromatography (EtOAc/iso-hexane) to give the title compound (0.046 g). LCMS m/z 292 [M+H]+ RT=4.28 min (Analytical Method 3).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[C:6]([CH2:12]Cl)=[N:7]2.O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[C:6]([CH2:12][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)=[N:7]2
Reactant: O=c1c2c(Cl)cccc2nc(CCl)n1-c1ccccc1F
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cl)cccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1F
Yield: 84.1 %

Procedure:
Prepared according to Procedure C using Intermediate 2k (210 mg, 0.650 mmol), 6-mercaptopurine monohydrate (122 mg, 0.715 mmol), K2CO3 (99 mg, 0.715 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 240 mg of an off-white solid (84%), mp 244.0° C. 1H NMR (DMSO-d6) δ: 13.56 (br s, 1H); 8.50 (s, 1H); 8.45 (s, 1H); 7.81 (t, J=8.0 Hz, 1H); 7.74 (t, J=7.7 Hz, 1H); 7.67 (d, J=8.1 Hz, 1H); 7.62 (d, J=7.7 Hz, 1H); 7.46-7.55 (m, 1H); 7.29-7.42 (m, 2H); 4.47-4.59 (m, 2H). 13C NMR (DMSO-d6) ppm: 158.4, 157.3 (d, J=249 Hz), 156.4, 153.8, 151.0, 149.1, 143.2, 135.0, 132.9, 131.8 (d, J=8.0 Hz), 130.8, 129.9, 126.7, 125.3 (d, J=3.5 Hz), 123.6 (d, J=13 Hz), 117.0, 116.2 (d, J=19 Hz), 31.7. MS (ES): m/z 439.0 (M+). Anal. calcd. for C20H12ClFN6OS: C, 54.74; H, 2.76; Cl, 8.08; N, 19.15; S, 7.31. Found: C, 54.42; H, 2.88; Cl, 8.08; N, 18.87; S, 7.08.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:9]=[CH:10][C:11]([N+:28]([O-:30])=[O:29])=[C:12]([N:14]2[C:19](=[O:20])[NH:18][C:17](=[O:21])[N:16]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:15]2=[O:27])[CH:13]=1.[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[OH:39].Cl>CN(C)C=O.C(OCC)(=O)C>[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[O:39][C:8]1[CH:9]=[CH:10][C:11]([N+:28]([O-:30])=[O:29])=[C:12]([N:14]2[C:19](=[O:20])[NH:18][C:17](=[O:21])[N:16]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:15]2=[O:27])[CH:13]=1
Reactant: COC(=O)Cn1c(=O)[nH]c(=O)n(-c2cc(F)ccc2[N+](=O)[O-])c1=O
Reactant: Oc1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)[nH]c(=O)n(-c2cc(Oc3ccc(Cl)cc3Cl)ccc2[N+](=O)[O-])c1=O
Temperature: 38 °C
Reaction time: 72 h

Procedure:
Potassium carbonate (1.14 g, 8.25 mmol) is added to a solution of methyl 3-(5-fluoro-2-nitrophenyl)tetrahydro-2,4,6-trioxo-s-triazine-1(2H)-acetate (0.93 g, 2.74 mmol) and 2,4-dichlorophenol (0.66 g, 4.07 mmol) in N,N-dimethylformamide at 38° C. The reaction mixture is stirred at 38° C. for 3 days, cooled to room temperature and poured into 1M hydrochloric acid. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain an orange oil. Column chromatography of the oil using silica gel and 30% to 40% ethyl acetate in hexanes solutions gives the title product as a yellow foam which is identified by NMR spectral analysis.
Reaction SMILES: [C:1](Cl)([Cl:3])=O.Cl.Cl.Cl.[NH2:8][C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][C:10]=1[O:16][CH2:17][CH:18]([OH:32])[CH2:19][NH:20][CH2:21][CH2:22][NH:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:31]>O>[ClH:3].[N:15]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([O:16][CH2:17][CH:18]([OH:32])[CH2:19][NH:20][CH2:21][CH2:22][NH:23][C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:31])[C:9]=2[NH:8][CH:1]=1
Reactant: Cc1cccc(C)c1NCCNCC(O)COc1cccc(N)c1N
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: O
Product: Cc1cccc(C)c1NCCNCC(O)COc1cccc2nc[nH]c12

Procedure:
Phosgene is passed into a solution of 21.5 g. 2,3-diamino-1-{2-hydroxy-3-[2-(2,6-dimethylphenylamino)-ethylamino]-propoxy}-benzene trihydrochloride in 400 ml. water for 45 minutes, while cooling (internal temperature 20° to 25° C.). After flushing with nitrogen, the aqueous supernatant is decanted off and the precipitate recrystallized from ethanol/methanol (1:1 v/v), with the addition of active charcoal. There are obtained 6.6 g. (35% of theory) of the desired compound; m.p. 248°-250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][S:20]([CH3:22])=[O:21])=[O:15])=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24].C1C=C(Cl)C=C(C(OO)=[O:35])C=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][S:20]([CH3:22])(=[O:35])=[O:21])=[O:15])=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24]
Reactant: CS(=O)CCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CS(=O)(=O)CCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 35 from 5-((3,5-dichloropyridin-4-yl)thio)-N-(3-(methylsulfinyl)propyl)-4-nitrothiophene-2-carboxamide (60.0 mg, 0.13 mmol) and MCPBA (67.0 mg, 0.39 mmol). The titled product was obtained as a white solid (45.0 mg, 74% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, m), 8.91 (1H, m), 8.41 (1H, s), 3.28 (2H, m), 3.13 (2H, m), 2.95 (3H, s), 1.90 (2H, m). MS m/z: 470.11, 472.06 [M+H]+.