Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[C:16](=[O:17])[CH:15]=[C:14](O)[C:13]([C:19]([NH2:21])=O)=[N:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)([Cl:24])=O>CC#N>[Cl:24][C:14]1[C:13]([C:19]#[N:21])=[N:12][N:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:16](=[O:17])[CH:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-n2nc(C(N)=O)c(O)cc2=O)cc1OC
Solvent: CC#N
Product: COc1ccc(-n2nc(C#N)c(Cl)cc2=O)cc1OC
Reaction time: 19 h

Procedure:
The starting amide (30) (190 mg) was dissolved in 1 ml of CH3CN, treated with 1 ml of phosphorus oxychloride, and heated to reflux. After 18-20 hours the reaction was complete by HPLC. The reaction mixture was poured into ice and stirred for one hour. The product was extracted with ethyl acetate, the organic phase dried over magnesium sulfate, filtered, and concentrated to dryness. This material was then purified by normal phase column SiO2 chromatography affording 90 mg of desired nitrile chloride (31) as a solid. MS+: m/e=292.0 (M+H), 1H-NMR (500 MHz, MeOH-d4): δ 7.40 (s, 1H), 7.18 (s, 1H), 7.12 (d, 1H), 7.08 (d, 1H), 3.90 (s, 3H), 3.85 (s, 3H), ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:20][C:12]3=[N:13][CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1F.[CH3:21][O:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][O:28][CH3:29]>CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:20][C:12]3=[N:13][CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[N:25]([CH2:26][CH2:27][O:28][CH3:29])[CH2:24][CH2:23][O:22][CH3:21]
Reactant: COCCNCCOC
Reactant: O=[N+]([O-])c1cnc2[nH]c(-c3ccc(F)c(F)c3)nc2c1
Solvent: CN1CCCC1=O
Product: COCCN(CCOC)c1ccc(-c2nc3cc([N+](=O)[O-])cnc3[nH]2)cc1F
Reaction time: 18 h

Procedure:
0.5 g 2-(3,4-Difluoro-phenyl)-6-nitro-3H-imidazo[4,5-b]pyridine, 0.1 ml NMP and 0.51 g bis(2-methoxyethyl)-amine were heated to 170 C with stirring for 18 hrs. Volatile materials were removed under vacuum and the residue purified by chromatography, first on silica in dichloromethane/methanol mixtures, and subsequently by preparative HPLC.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH3:16][O:17][CH2:18][CH2:19][N:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[C:28]([NH2:31])[CH:29]=[CH:30][C:23]=2[CH2:22][CH2:21]1.Cl[C:33]1[N:38]=[C:37]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[S:46]([N:49]([CH3:51])[CH3:50])(=[O:48])=[O:47])[C:36]([Cl:52])=[CH:35][N:34]=1.C(=O)([O-])[O-]>C(O)(C)C>[Cl:52][C:36]1[C:37]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[S:46]([N:49]([CH3:51])[CH3:50])(=[O:48])=[O:47])=[N:38][C:33]([NH:31][C:28]2[CH:29]=[CH:30][C:23]3[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][O:17][CH3:16])[CH2:26][CH2:25][C:24]=3[CH:27]=2)=[N:34][CH:35]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)cc2CC1
Reaction time: 1 h

Procedure:
10-Camphorsulfonic acid (53 mg, 0.23 mmol) was added to 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (48 mg, 0.22 mmol) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide (72 mg, 0.21 mmol) in Isopropyl alcohol (2 mL). The mixture was irradiated in a CEM microwave (140° C., 30 min). MP-Carbonate (2.69 mmol/g loading; 0.18 g, 0.47 mmol) was added and the mixture stirred for 1 h and filtered, washing with DCM. The filtrate was conc. in vacuo. The residue was taken up in DCM with a few drops of MeOH and chromatographed (ISCO, 2×12 g, 0-12% MeOH:DCM) to afford 2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N,N-dimethyl-benzenesulfonamide as a colorless wax (83 mg, 75%). LCMS 531 (M+H), 1H-NMR (CDCl3): 9.42 (s, 1H), 8.54 (d, 1H, J=8.4 Hz), 8.12 (s, 1H), 7.86 (d, 1H, J=7.5 Hz), 7.55 (dd, 1H, J=7.5, 8.2 Hz), 7.24 (m, 3H), 7.02 (d, 1H, J=7.8 Hz), 6.90 (s, 1H), 3.55 (m, 2H), 3.37 (s, 3H), 2.90 (m, 4H), 2.74 (m, 12H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[S:55]1[CH:59]=[CH:58][N:57]=[C:56]1[C:60](Cl)=[O:61]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:60]([C:56]2[S:55][CH:59]=[CH:58][N:57]=2)=[O:61])[CH2:49][CH2:48]1
Reactant: O=C(Cl)c1nccs1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2nccs2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 37 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1,3-thiazole-2-carbonyl chloride as starting materials in 37% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.04 (s, 1H), 9.41 (m, 2H), 9.02 (s, 1H), 8.30 (m, 2H), 8.20 (s, 1H), 8.00 (m, 2H), 7.65 (s, 1H), 7.30 (d, 1H), 7.05 (d, 1H), 5.20 (m, 1H), 4.48 (m, 1H), 3.22 (m, 2H), 2.98 (m, 4H), 2.32 (m, 2H), 2.12 (m, 1H), 1.80 (m, 2H), 1.25 (m, 2H). LCMS for C28H28ClN8O2S (M+H)+: m/z=575.2.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(Cl)Cl.Cl.[OH:12][C:13]1[CH:36]=[CH:35][C:34]([O:37][CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:33][C:14]=1[C:15]([NH:17][C:18]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])=[O:16]>N1C=CC=CC=1>[C:1]([N:41]1[CH2:40][CH2:39][CH:38]([O:37][C:34]2[CH:35]=[CH:36][C:13]([OH:12])=[C:14]([CH:33]=2)[C:15]([NH:17][C:18]2[CH:26]=[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:24]=[CH:23][C:19]=2[C:20]([OH:22])=[O:21])=[O:16])[CH2:43][CH2:42]1)(=[O:3])[CH3:2]
Reactant: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(OC2CCNCC2)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCC(Oc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under ice-cooling, pyridine (0.30 mL) and acetic anhydride (6.7 μL) were sequentially added to a methylene chloride (1 mL) suspension of 2-(2-hydroxy-5-(piperidin-4-yloxy)benzamido)-4-phenylbenzoic acid hydrochloride (0.030 g), followed by stirring at room temperature for 1 hour. Pyridine (0.20 mL) and acetic anhydride (5.4 μL) were sequentially added to the reaction mixture, followed by stirring at room temperature for 1 hour and 30 minutes. The solvent was evaporated under reduced pressure, and methanol (0.5 mL) and a 2 mol/L aqueous solution of sodium hydroxide (0.19 mL) were added to the residue, followed by stirring at room temperature for 1 hour. To the reaction mixture, 1 mol/L hydrochloric acid (5 mL) and ethyl acetate were added. The organic layer was separated, washed with 1 mol/L hydrochloric acid, water, and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Dioxane (0.5 mL), methanol (0.5 mL), and a 2 mol/L aqueous solution of sodium hydroxide (0.32 mL) were added to the obtained residue, followed by stirring at 70° C. for 30 minutes. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure, and water was added to the obtained residue. After adjusting the pH to 3 with 6 mol/L hydrochloric acid, the solid substance was collected by filtration to obtain 0.022 g of 2-(5-(1-acetylpiperidin-4-yloxy)-2-hydroxybenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9].I[CH3:19].O>C1COCC1>[CH3:3][O:4][CH2:5][CH2:6][N:7]([CH3:19])[S:8]([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: CI
Reactant: COCCNS(=O)(=O)c1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCN(C)S(=O)(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.5 %

Procedure:
Sodium hydride (144 mg, 3.6 mmol) was added in portions to a solution of N-(2-methoxyethyl)-4-iodobenzenesulphonamide (Method 40, 1 g, 3 mmol) in THF (10 ml) and the mixture stirred at ambient temperature for 15 minutes. Iodomethane (230 μl, 3.6 mmol) was added and the reaction stirred for 18 hours. Water (30 ml) was added cautiously and the mixture extracted with ether (40 ml). The combined organics were washed with brine (50 ml), dried and the volatiles evaporated. The residue was purified by flash chromatography on silica gel eluting with iso-hexane/EtOAc (100:0 increasing in polarity to 10:1) to give the title compound (730 mg, 69%) as a clear oil. NMR 2.78 (s, 3H), 3.16 (t, 2H), 3.22 (s, 3H), 3.45 (t, 3H), 7.42 (d, 2H), 7.80 (d, 2H); m/z 356.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:21]([NH2:23])=[N:20][CH:19]=[N:18][C:17]=3[NH:16][CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(=O)O[CH2:27][CH2:26][O:25]1.[OH-].[Na+]>CN(C)C=O>[NH2:23][C:21]1[C:22]2[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)=[CH:15][N:16]([CH2:27][CH2:26][OH:25])[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: O=C1OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2CCO

Procedure:
A mixture of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (0.50 g), ethylene carbonate (0.16 g), N,N-dimethylformamide (20 ml) and a catalytic amount of sodium hydroxide powder was boiled under reflux for 1 hour. The mixture was evaporated under reduced pressure and the residue was triturated with water (30 ml). The mixture was filtered to give a solid which was purified by flash column chromatography on silica using ethyl acetate/industrial methylated spirit (9:1) as the mobile phase to give 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]ethanol, m.p. 144.5-145° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1.O1CCCC1.[OH:26][CH:27]([CH2:30][OH:31])[CH2:28][SH:29]>CO>[OH:26][CH:27]([CH2:30][OH:31])[CH2:28][S:29][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:2]([NH:3][C:11]1[CH:16]=[CH:15][C:14]([S:17](=[O:19])(=[O:18])[NH2:20])=[CH:13][CH:12]=1)=[O:1]
Reactant: NS(=O)(=O)c1ccc(-n2sc3ccccc3c2=O)cc1
Reactant: OCC(O)CS
Solvent: CO
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(NC(=O)c2ccccc2SSCC(O)CO)cc1

Procedure:
This compound was prepared according to the method of Example 132 using a suspension of 0.46 g (1.5 mmol) of 4-(3-oxo-3H-benzo[d]isothiazol-2-yl) benzenesulfonamide in a mixture of 15 mL of methanol, and 15 mL of tetrahydrofuran and 2,3-dihydroxy-1-propanethiol. The product was washed with ether and dried in vacuo to give 0.61 g of the title compound, mp >260° C.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.S(=O)(=O)(O)O.[CH3:20][CH2:21]O>>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:10]([O:12][CH2:20][CH3:21])=[O:11])=[CH:13][CH:14]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C(O)c1ccc(-n2cccn2)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(-n2cccn2)cc1
Reaction time: 71 h

Procedure:
To a solution of 4-(1H-pyrazol-1-yl)benzoic acid (CAS 160209-00-0, 678 mg, 3.60 mmol) in absolute EtOH (10 mL) was added sulfuric acid (0.1 mL) at room temperature. The reaction mixture was heated to reflux and stirred for 71 h, then concentrated under reduced pressure. The residue was partitioned between sat. aq. NaHCO3 (60 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound as an off white solid (711 mg, 91%): 1H NMR (400 MHz, CDCl3, δ in ppm) 8.14 (d, J=8.6 Hz, 2H), 8.01 (d, J=2.5 Hz, 1H), 7.78 (d, J=8.8 Hz, 2H), 7.78-7.75 (m, 1H), 6.51 (t, J=1.8 Hz, 1H), 4.39 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[Br-].[C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:16])=[O:15]>C1COCC1>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][C:14]([OH:16])=[O:15])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C=O)cc1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCOc1ccc(C=CCCCCC(=O)O)cc1
Yield: 60 %

Procedure:
This compound was synthesized from p-propoxybenzaldehyde (3.26 g, 20 mmol, prepared from 1-bromopropane and 4-hydroxybenzaldehyde) and 5-carboxypentyltriphenylphosphonium bromide (9.50 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization (petroleum ether) afforded the product (3.15 g, 60%) as white crystals (mp: 52-53° C.). IR: 3450-2500, 1730 cm-1 ; 1H-NMR: 1.00 (t, 3H), 1.48 (m, 2H), 1.67 (m, 2H), 1.82 (m, 2H), 2.35 (m, 4H), 3.92 (t, 2H), 5.72+6.05 (m, 1H), 6.35 (d, 1H), 7.05 (q, 4H), 10.40 (bs, 1H). Anal. Calcd. for C16H22O3 : C, 73.25, H, 8.45%. Found: C, 73.15, H, 8.45%. Z:E=30:70.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:13])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].N1C(C)=CC=CC=1C.Br[CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C1(C)C=CC=CC=1>[C:28]([O:27][C:25](=[O:26])[CH2:24][CH2:23][NH:13][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]([F:11])([F:12])[F:10])=[C:2]([Cl:1])[CH:3]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: Nc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)CCBr
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC(=O)CCNc1ccc(OC(F)(F)F)c(Cl)c1
Reaction time: 48 h
Yield: 66.6 %

Procedure:
A solution of 9.26 g (42.4 mmol) of 3-chloro-4-trifluoromethoxy-phenylamine and 4.39 ml (42.4 mmol) of 2,6-lutidine in 50 ml of toluene was treated slowly with 7.30 ml (42.4 mmol) of tert-butyl 3-bromopropionate and stirred 2 days at reflux temperature. The reaction was then partitioned between aqueous 10% KHSO4 and EtOAc (3×). The organic phases were washed with 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (n-heptane:EtOAc 9:1) to yield 9.59 g (60%) of the title compound as brown liquid. MS: 339 (M+, Cl).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19](=[O:28])(=[O:27])[CH2:18][CH2:17]2)[CH:3]=1.[O:29]1[CH2:32][C:31]([CH2:35][NH2:36])([CH2:33][NH2:34])[CH2:30]1>>[NH2:34][CH2:33][C:31]1([CH2:35][NH:36][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=3)[N:5]=[C:4]([N:16]3[CH2:22][C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[S:19](=[O:28])(=[O:27])[CH2:18][CH2:17]3)[CH:3]=2)[CH2:32][O:29][CH2:30]1
Reactant: COC(=O)c1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCC1(CN)COC1
Product: COC(=O)c1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(CN)COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 6-1 in Scheme 52 by using methyl 4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 497, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.57 (d, 1 H), 7.95 (d, 1 H), 7.85 (m, 2 H), 7.71 (t, 1 H), 7.61 (m, 1 H), 7.46-7.38 (m, 2 H), 6.18 (s, 1 H), 5.07 (s, 2 H), 4.32 (m, 6 H), 3.80 (s, 3 H), 3.55 (m, 4 H), 2.95 (s, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][C:23](=[O:25])[CH3:24])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: OC(Cn1cncn1)c1ccc(Cl)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)OC(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-p-Chlorophenyl-2-(1,2,4-triazol-1-yl)-ethanol (2.24 g) and triethylamine (1.1 g) in dry diethyl ether (50 ml) were treated with acetyl chloride (0.8 g) in dry diethyl ether (5 ml) and the mixture was stirred for 3 hours at room temperature to give a white solid which was filtered off and washed with ether. The solvent was removed from the filtrate to give a brown oil. The oil was distilled to give the title compound as a semi-solid which could not be purified further.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:10](=[O:11])[C:9]([C:12]3[N:16]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[N:15]=[CH:14][CH:13]=3)=[C:8]([CH3:25])[N:7]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:6]2=[O:36])[CH2:2]1.[CH2:37]=O>>[CH3:25][C:8]1[N:7]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=2)[C:6](=[O:36])[N:5]([CH:3]2[CH2:2][N:1]([CH3:37])[CH2:4]2)[C:10](=[O:11])[C:9]=1[C:12]1[N:16]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[N:15]=[CH:14][CH:13]=1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(C2CNC2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: C=O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(C2CN(C)C2)c(=O)n1-c1cccc(C(F)(F)F)c1

Procedure:
The intended compound was obtained by using 4-(5-(3-(azetidin-3-yl)-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 112) and formaldehyde according to the similar reaction and treatment method to those described in Example 69.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](N(OC)C)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:16]1([Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CON(C)C(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)c1ccccc1
Reaction time: 3 h
Yield: 83.8 %

Procedure:
Under N2, to a mixture of 2-(3,4-dichlorophenyl)-N-methoxy-N-methylacetamide (440 mg, 1.8 mmol) in anhydrous THF was added phenylmagnesium bromide (4.4 mL, 4.4 mmol) at −78° C., and the mixture was stirred for 3 hours. When TLC indicated that the starting material was consumed, the reaction mixture was diluted with EtOAc, washed with water and brine, concentrated, and purified by column chromatography (PE:EtOAc=20:1) to give Intermediate 6 (400 mg, yield 85%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([S:12]([NH:15][CH3:16])(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>>[Cl:1][C:2]1[C:11]([S:12]([NH:15][CH3:16])(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CNS(=O)(=O)c1cccc(C(=O)OC)c1Cl
Agent: [Na+]
Agent: [OH-]
Product: CNS(=O)(=O)c1cccc(C(=O)O)c1Cl

Procedure:
To a solution of methyl 2-chloro-3-(chlorosulfonyl)benzoate (608 mg, 2.26 mmol) and K2CO3 (770 mg, 5.6 mmol) in 10 mL benzene was added a 2M solution of methylamine in THF (5.6 mL, 11.2 mmol). Purification of the product (2:1 hex:EtOAc) provided methyl 2-chloro-3-[(methylamino)sulfonyl]benzoate (430 mg, 72%) as a solid. 1H NMR (400 MHz, CDCl3), δ 8.23 (dd, 1H, J=7.9, 1.7 Hz), 7.90 (dd, 1H, J=7.8, 1.7 Hz), 7.48 (t, 1H, J=7.9 Hz), 5.16 (q, 1H, J=5.2 Hz), 3.94 (s, 3H), 2.62 (d, 3H, J=5.3 Hz); ESI-MS 264 (M+H). Methyl 2-chloro-3-[(methylamino)sulfonyl]benzoate was hydrolyzed using aqueous NaOH to provide 2-chloro-3-[(methylamino)sulfonyl]benzoic acid as a solid, which was used without further purification. ESI-MS 250 (M+H), 272 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([NH2:9])=[N:6][C:7]=1[I:8].O.O.[Sn](Cl)Cl.O.[F-].[K+]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[N:6][C:7]=1[I:8]
Reactant: Nc1nc(I)c(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [F-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)c(I)nc1N
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5-chloro-6-iodo-3-nitropyridin-2-amine (18.9 g, 63.1 mmol) in EtOH (100 mL) was added tin (II) chloride dihydrate (57 g, 252 mmol). The mixture was heated at 70° C. for 0.5 h. The r×n was warmed to rt and treated with a slurry of 150 mL water and 60 g KF and stirred for 0.5 h. The mixture was then partitioned between ethyl acetate (300 mL) and water (300 mL). The ethyl acetate layer was washed with brine, dried over magnesium sulfate and filtered through a 100 g pad of silica gel. The filtrate was concentrated and dried under vacuum to give an off-white solid, which was used in next step without further purification. LC-MS: calculated for C5H5ClIN3 269.47, observed m/e: 269.99 (M+H)+ (Rt 1.35/5 min).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][S:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29](Cl)=[O:30])[CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19].Cl>O1CCCC1.O>[OH:3][NH:2][C:29](=[O:30])[CH:28]=[CH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([S:18](=[O:20])(=[O:19])[NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])[CH:22]=1
Reactant: COc1ccccc1NS(=O)(=O)c1cccc(C=CC(=O)Cl)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1NS(=O)(=O)c1cccc(C=CC(=O)NO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.36 g, 5.20 mmol) in tetrahydrofuran (6 ml) a saturated NaHCO3 solution (4.5 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-[3-(2-methoxy-phenylsulfamoyl)-phenyl]-acryloyl chloride (16c) (0.37 g,1.05 mmol) in tetrahydrofuran (5 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was poured into water, the obtained solution was acidified with 2N HCl and extracted with ethyl acetate. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was crystallised from ethyl acetate and washed with diethyl ether affording the title compound (0.23 g, 64%). M.p. 181° C. 1H NMR (DMSO-d6, HMDSO) δ: 3.45 (3H, s); 6.49 (1H, d, J=16.0 Hz); 6.76-7.96 (9H, m); 9.09 (1H, br s); 9.54 (1H, s); 10.78 (1H, br s). HPLC analysis on Symmetry C8 column: impurities 1.3% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 35:65; sample concentration 0.15 mg/min; flow rate 1.2 ml/min; detector UV 230 nm). Anal. Calcd for C16H16N2O5S, % N C 55.16, H 4.63, N 8.04. Found, %: C 55.14, H 4.52, N 7.99.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[CH2:18]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[CH3:19].Cl.N1C=CC=CC=1.C(OCCO)C>>[CH2:18]([C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[CH:22][CH:21]=1)[CH3:19]
Reactant: CCc1ccc(N)cc1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: CCc1ccc(Nc2c(C#N)cnc3cc(OC)c(OC)cc23)cc1
Temperature: 139 °C
Yield: 97.5 %

Procedure:
A mixture of 0.248 g (1 mmol)of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.14 ml (1.1 mmol) of 4-ethylaniline, 0.116 g (1 mmol) pyridine hydrochloride and 12 ml of 2-ethoxyethanol was heated in a 138-140° C. oil bath for 1 hour; progress of the reaction was monitored by TLC. When TLC indicated the disappearance of starting material, the reaction was cooled and concentrated in vacuo to a thick oil. To this oil was added 50 ml of water followed by 5 ml of 1M NaHCO3, approximately pH 8. The resulting precipitate was collected, washed with water and diethyl ether, and dried in vacuo at 65° C. to give 0.325 g (97.5%) of the desired product as light cream crystals. MP 248-250° C.;: mass spectrum (electrospray, m/e,): 333.1462.