Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([C:8]([OH:10])=O)[N:7]=1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[CH:28]=[C:29]([CH:46]=[CH:47][CH:48]=1)[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([N:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[N:39]=2)[CH:36]=1>CN(C)C=O.CN(C)C(=O)C>[CH:43]1([C:41]([NH:40][C:38]2[N:39]=[C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]4[CH:28]=[C:27]([NH:26][C:8]([C:6]5[N:7]=[C:3]([CH2:1][CH3:2])[O:4][C:5]=5[C:11]([F:14])([F:13])[F:12])=[O:10])[CH:48]=[CH:47][CH:46]=4)=[CH:36][N:35]3[N:37]=2)=[O:42])[CH2:44][CH2:45]1
Reactant: CCc1nc(C(=O)O)c(C(F)(F)F)o1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCc1nc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c(C(F)(F)F)o1
Yield: 48.8 %

Procedure:
In the same manner as in Example 18-4 and using 2-ethyl-5-(trifluoromethyl)-1,3-oxazole-4-carboxylic acid (314 mg, 1.50 mmol), tetrahydrofuran (7 mL), oxalyl chloride (143 μL, 1.65 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (309 mg, 1.00 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (244 mg, 49%) was obtained as a white solid.
Reaction SMILES: S1C(C=[O:7])=CC=C1C=O.C(O)(=O)C.[CH2:14]([CH:16]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([NH:26][OH:27])=[CH:22][CH:21]=1)[CH3:15]>O>[CH2:14]([CH:16]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:17][O:18][C:19](=[O:28])[C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:7])=[O:27])=[CH:24][CH:25]=1)[CH3:15]
Reactant: O=Cc1ccc(C=O)s1
Reactant: CCCCC(CC)COC(=O)c1ccc(NO)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCCCC(CC)COC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 160.6 %

Procedure:
To a 250 ml 3-necked flask was added 0.5 gm 2,5-thiophenedicarboxaldehyde, 30 ml acetic acid, 5.6 gm 2-ethylhexylesterphenyl hydroxylamine 3 and stirred for 20 hrs at room temperature. To the reaction mixture, 100 ml water was added and the mixture was filtered. The filtered product was washed with water and dried. A yield of about 1.6 gm of 2, 5-thiophene bis-2-ethylhexylesterphenyl dinitrone of Ex.2 was obtained with a HPLC purity of 98% (DSC: 205° C.).
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.ClC(Cl)(O[C:19](=[O:25])OC(Cl)(Cl)Cl)Cl.[NH2:27][C:28]1[N:33]=[C:32]([C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[C:36]([F:42])[CH:35]=2)[CH:31]=[C:30]([N:43]2[CH2:48][CH2:47][CH2:46][C@@H:45]([NH2:49])[CH2:44]2)[N:29]=1>C(Cl)Cl>[CH:1]1([O:5][C:19](=[O:25])[NH:49][C@@H:45]2[CH2:46][CH2:47][CH2:48][N:43]([C:30]3[CH:31]=[C:32]([C:34]4[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[C:36]([F:42])[CH:35]=4)[N:33]=[C:28]([NH2:27])[N:29]=3)[CH2:44]2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@@H](N)C3)nc(N)n2)cc1F
Reactant: OC1CCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-c2cc(N3CCC[C@@H](NC(=O)OC4CCC4)C3)nc(N)n2)cc1F
Reaction time: 1 h

Procedure:
A premixed solution of cyclobutanol (30.5 μl, 0.389 mmol) and Hunig's base (57 uL) in CH2Cl2 (1 mL) was slowly added to a solution of triphosgene (38.5 mg, 0.130 mmol) in CH2Cl2 (1 mL), and the resulting solution was stirred for 1 hour. A premixed solution of 4-{2-amino-6-[(3R)-3-amino-1-piperidinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (125 mg, 0.324 mmol) and Hunig's base (226 uL) in CH2Cl2 (5 mL) was added, and the reaction mixture was stirred at room temperature overnight. The reaction was concentrated, then loaded on a Biotage SNAP 10 g column and purified with a gradient of 0 to 55% EtOAc in Hexane over 25 min. LC-MS (ES) m/z=411 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=2)=[CH:8][CH:7]=1.[F:25][C:26]([F:36])([F:35])[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=O.[OH-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:23]([CH3:24])=[CH:22][C:21]2[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:26]([F:36])([F:35])[F:25])[C:7]3[C:6](=[CH:11][C:10]4[C:27]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)([C:26]([F:35])([F:25])[F:36])[C:18]5[C:13]([O:12][C:9]=4[CH:8]=3)=[CH:14][C:15]([CH3:20])=[C:16]([CH3:19])[CH:17]=5)[O:5][C:4]=2[CH:3]=1
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: Cc1ccc(Oc2ccc(Oc3ccc(C)c(C)c3)cc2)cc1C
Agent: *CC*
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc2c(cc1C)C(c1ccccc1)(C(F)(F)F)c1cc3c(cc1O2)C(c1ccccc1)(C(F)(F)F)c1cc(C)c(C)cc1O3
Temperature: 120 °C
Reaction time: 8 h
Yield: 21.4 %

Procedure:
A mixture of 45.7 g (0.144 mole) 1,4-bis(3,4 dimethylphenoxy)benzene, 50.0 g (0.288 mole) trifluoroacetylbenzene, and 90 g (4.5 mole) HF was shaken in an autoclave at 120° C. for 8 hours. The clave contents were transferred to a polyethylene jar, half filled with ice-water, and containing 250 ml 50% NaOH. Methylene chloride was added, the slurry was filtered through Celite®, the organic layer was separated and the extracts were stripped. The residue was stirred with acetone and filtered, yielding 19.4 g of white solid. Because of its low solubility in methylene chloride, some product was lost on the Celite® pad. The IR was sharp, and the NMR was consistent with structure: m 7.33-7.45, 2 s 6.85, 2 s 6.67, s 6.55, 2 s 2.21, s 2.07 ppm in 5:1:1:1:3:3 ratio, indicating presence of cis-trans isomers. Analysis: calc. for C38H28F6O2 : C 72.4; H 4.44; found: C 71.3; H 4.57%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH3:11].C(O[C:15](=O)[CH:16]([CH3:20])[C:17]([CH3:19])=[O:18])C.C(OCC)(=[O:24])C>CCCCCC>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:11])=[C:2]([NH:1][C:19](=[O:24])[C:17](=[O:18])[CH:16]([CH3:20])[CH3:15])[CH:7]=1)[CH3:10]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: CCOc1ccc(C)c(N)c1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CCOc1ccc(C)c(NC(=O)C(=O)C(C)C)c1
Temperature: 150 °C
Reaction time: 4 h

Procedure:
A mixture of 2-amino-4-ethoxytoluene (590 mg, 3.99 mmol) and ethyl-2-methylacetoacetate (560 mg, 3.88 mmol) was stirred in a bath of 150° C. for 4 hours. The resultant mixture was subjected to silica gel column chromatography (developer: ethyl acetate--n-hexane), and the fraction containing the target substance was condensed, followed by recrystallizing from a solvent mixture of chloroform--n-hexane. As a result, 252 mg of the title compound was obtained as yellow powder (25.9%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[N+:22]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23].C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>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.C(O)C>[CH3:8][C:7]1[C:2]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:22]([O-:24])=[O:23])[CH:30]=2)=[CH:3][C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1I
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
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: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 101.4 %

Procedure:
To N-(3-iodo-4-methylphenyl)-3-(trifluoromethyl)benzamide (400 mg, 0.99 mmol) was added (3-nitrophenyl)boronic acid (180 mg, 1.1 mmol) followed by toluene (8.2 mL), ethanol (1.1 mL), and K2CO3 (270 mg, 2.0 mmol in 1.1 mL water). The resulting mixture was degassed with N2, then tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.05 mmol) was added. The mixture was degassed again, then heated under reflux condenser and N2 atmosphere at 90° C. until LCMS and TLC indicated complete reaction, typically 16 hours. The reaction was then cooled to ambient temperature and transferred to a separatory funnel and partitioned between water and EtOAc. The phases were separated and the organic phase was washed with water, then saturated aqueous NaCl. The washed organic phase was then dried (MgSO4) and evaporated to dryness to leave the crude product, which was purified by column chromatography to give the product (402 mg, 102%). 1H NMR (400 MHz, CDCl3): δ 8.23 (m, 2H), 8.12 (s, 1H), 8.07 (d, 1H), 7.88 (bs, 1H), 7.82 (d, 1H), 7.6 (m, 4H), 7.32 (d, 1H), 2.27 (s, 3H). MS (EI) m/z=401 (M+H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C@H:7]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH:8]([OH:22])[CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(O)=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[CH2:15]([O:14][C:12]([NH:11][CH2:10][CH2:9][CH:8]([OH:22])[CH:7]([N:6]1[CH2:5][CH2:4][C:1]1=[O:2])[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)CCN[C@H](C(=O)OCc1ccccc1)C(O)CCNC(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C(NCCC(O)C(C(=O)OCc1ccccc1)N1CCC1=O)OCc1ccccc1
Yield: 99.8 %

Procedure:
Benzyl N2 -(β-carboxyethyl)-N5 -benzyloxycarbonyl-3-hydroxyornithinate (227 mg, 0.51 mmol) in distilled acetonitrile (50 ml) was heated under reflux with recrystallised 2,2'-dipyridyl disulphide (135 mg, 0.61 mmol) and triphenylphosphine (160 mg, 0.61 mmol) for eight hours. The acetonitrile was removed under vacuum and the residue chromatographed over silica gel (Merck Art. 9385) repeatedly using the following solvents as eluants ether/ethanol (49:1), ethyl acetate/isopropyl alcohol (19:1) and hexane/acetone/isopropyl alcohol (8:8:1) to yield the slow-moving diastereoisomer of the title compound as an oil (217 mg, 64%) which slowly crystallised m.p. 66°-68° (ethyl acetate/hexane); [Rf 0.22 on thin layer chromatography, silica gel plates (Merck Art. 5719) eluting with dichloromethane/ethyl acetate/ethanol (60:10:1)]. νmax (KBr) 1725, 742, and 698 cm-1 ; δH (CDCl3, 250 MHz) 1.85 (2H, m), 2.98 (2H, t, J 4.2 Hz), 3.40 (4H, m), 4.09 (1H, d, J 3.3H), 4.17 (1H, m), 4.69 (1H, d, J4.1Hz) (exchanges with D2O), 5.10 (2H, s) 5.22 (3H, m) and 7.36 (10 H, m). [Found: C, 64.81; H, 6.12; N, 6.55 %; MH+ (p.i. F.A.B. thioglycerol) 427. C23H26N2O7 requires C, 64.77; H, 6.15; N, 6.57%; M, 426].
Reaction SMILES: OO.[CH3:3][O:4][CH2:5][CH2:6][N:7]([CH3:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12]1[N:13]=[N+:14]([O-:25])[C:15]2[CH:24]=[C:23]3[C:19]([CH2:20][CH2:21][CH2:22]3)=[CH:18][C:16]=2[N:17]=1.C(O)(C(F)(F)F)=[O:28].N>C(Cl)Cl.C(Cl)(Cl)Cl>[O-:25][N+:14]1[C:15]2[CH:24]=[C:23]3[C:19](=[CH:18][C:16]=2[N+:17]([O-:28])=[C:12]([NH:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:6][CH2:5][O:4][CH3:3])[CH3:26])[N:13]=1)[CH2:20][CH2:21][CH2:22]3
Reactant: O=C(O)C(F)(F)F
Reactant: COCCN(C)CCCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COCCN(C)CCCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCC3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 4.7 %

Procedure:
H2O2 (70%, 3.0 mL, ca. 60.4 mmol) was added dropwise to a stirred solution of TFM (8.4 mL, 60.4 mmol) in DCM (80 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., and added to a solution of 1-oxide 52 (2.0 g, 6.04 mmol) and TFA (1.0 mL, 13.0 mmol) in CHCl3 (80 mL) at 0° C. and the solution stirred at 20° C. for 18 h. The solution was made basic with dilute aqueous NH3 solution and extracted with CHCl3 (3×100 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-18%) of MeOH/DCM, to give 1,4-dioxide 53 (99 mg, 5%) as a red solid: mp 77-79° C.; 1H NMR δ 8.12 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.26 (br s, 1H, NH), 3.66 (t, J=6.3 Hz, 2H, CH2), 3.59 (t, J=5.6 Hz, 2H, CH2), 3.36 (s, 3H, OCH3), 3.03-3.12 (m, 4H, H-6, H-8), 2.66-2.71 (m, 4H, 2×CH2), 2.39 (s, 3H, NCH3), 2.19 (p, J=7.4 Hz, 2H, H-7), 1.91 (p, J=6.6 Hz, 2H, CH2); 13C NMR δ 155.6, 149.5, 145.7, 138.0, 129.7, 115.8, 111.6, 70.5, 58.9, 56.8, 55.9, 42.5, 40.5, 33.4, 32.4, 25.9, 25.6; HRMS (FAB+) calcd for C17H26N5O3 (MH+) m/z 348.2036, found 348.2032.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[O:34]1[CH2:39][CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH2:36][CH2:35]1.O1CCOCC1>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.CO.O>[O:34]1[CH2:35][CH:36]=[C:37]([C:2]2[CH:3]=[C:4]3[C@:15]4([CH2:19][S:18][C:17]([NH2:20])=[N:16]4)[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:21]5[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=5)[CH:13]=4)[O:8][C:5]3=[N:6][CH:7]=2)[CH2:38][CH2:39]1
Reactant: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
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: CO
Solvent: O
Solvent: C1COCCO1
Product: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1ncc(C3=CCOCC3)cc12
Temperature: 100 °C
Yield: 81.5 %

Procedure:
A microwave vessel was charged with (S)-3-bromo-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (0.12 g, 0.27 mmol), potassium carbonate (0.19 g, 1.35 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.11 g, 0.54 mmol), tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), dioxane (1.81 mL) and water (0.90 mL). The reaction was heated in a microwave at 100° C. for 45 min. After cooling to rt, the organic layer was separated with a separatory funnel, dried over sodium sulfate, filtered, and concentrated to afford a yellow oil which was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-100% EtOAc in 90/10 CH2Cl2:CH3OH to provide a white solid, (S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (0.1 g, 0.22 mmol, 83% yield). MS m/z=447.2 [M+H]+. Calc'd for C24H19FN4O2S: 446.5.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[S:12][C:13](SC2C=CC=CC=2)=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Cl[C:30]1[CH:35]=[CH:34][CH:33]=[C:32](C(OO)=O)[CH:31]=1.[S:40]([O-:44])([O-])(=[O:42])=S.[Na+].[Na+]>CN(C)C=O>[CH3:1][N:2]([CH2:10][C:11]1[S:12][C:13]([S:40]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:44])=[O:42])=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Reactant: CN(Cc1nc(-c2ccccc2)c(Sc2ccccc2)s1)C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1nc(-c2ccccc2)c(S(=O)(=O)c2ccccc2)s1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of tert-butyl methyl{[4-phenyl-5-(phenylthio)-1,3-thiazol-2-yl]methyl}carbamate (0.27 g) in N,N-dimethylformamide (3 mL) was added 3-chloroperbenzoic acid (0.57 g) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in acetic acid (2 mL), 3-chloroperbenzoic acid (0.96 g) was added thereto, and the mixture was stirred at room temperature for 30 min. Aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=2:1) to give the title compound as a pale-yellow oil (yield 0.18 g, 63%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:10][NH:11][C:12]2[C:16]([C:17](O)=[O:18])=[CH:15][NH:14][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.B.O1CCCC1.CO>C1COCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:10][NH:11][C:12]2[C:16]([CH2:17][OH:18])=[CH:15][NH:14][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(CNc2n[nH]cc2C(=O)O)cc1OC1CCCC1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CNc2n[nH]cc2CO)cc1OC1CCCC1
Temperature: -15 °C
Reaction time: 72 h
Yield: 86.6 %

Procedure:
Pure 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-pyrazolecarboxylic acid (compound 3) (1.32 g, 4.0 mmol) was dissolved in 50 ml of THF and cooled to −15° C. under nitrogen. Borane-tetrahydrofuran (30 ml of 1M solution, 30 mmol) was added over 30 minutes and the resulting solution was stirred for 72 hours at room temperature. Methanol (30 ml) was added to the reaction and the solvent was evaporated under reduced pressure. The residue was treated with 160 ml of methanol and evaporated again. The crude product was treated with 30 ml of 10% aqueous ammonia and some brine and then extracted with three 50 ml portions of ethyl acetate. Evaporation of the solvent afforded 1.1 g of crude 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-hydroxymethylpyrazole which was purified by flash chromatography on 30 g of flash chromatography silica gel. Elution with ethyl acetate/hexane (1:4) afforded a small amount of material which was discarded. Elution with 60 ml of 1:1 ethyl acetate/hexane gave 600 mg of 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-hydroxymethylpyrazole which was recrystallized from 2 ml of toluene to give 500 mg of pure 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-hydroxymethylpyrazole (compound 4) mp 129-130° C.
Reaction SMILES: CNC.[N:4]1[CH:9]=[CH:8]C=[CH:6][CH:5]=1.[C:10]1([CH3:17])[CH:15]=[CH:14]C(Cl)=[CH:12][CH:11]=1.Cl.CCCCCC.C([O:28][CH2:29][CH3:30])(=O)C>C(Cl)Cl>[CH2:5]([N:4]([CH2:9][CH3:8])[C:29](=[O:28])[C:30]1[CH:12]=[CH:11][C:10]([CH3:17])=[CH:15][CH:14]=1)[CH3:6]
Reactant: CCOC(C)=O
Reactant: c1ccncc1
Reactant: Cc1ccc(Cl)cc1
Agent: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: CCN(CC)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Dimethyl amine (13.00 g, 177.87 mmol, 18.40 mL) and pyridine (38.37 g, 485.10 mmol, 39.23 mL) were dissolved in 500 mL of anhydrous DCM under argon and cooled to 0EC. p-Tolyl chloride (25.00 g, 161.70 mmol), dissolved in 75 mL of anhydrous DCM, was added to the solution slowly. On completion of addition the solution was slowly warmed to room temp and stirred for 12 h. The reaction mixture was poured into 1N HCl and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (4:1 hexane/ethyl acetate) Yield 25.36 g.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[C:7](=O)[CH:8]=O.[CH2:12]([NH2:15])[CH2:13][NH2:14].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[CH:7]1[CH2:8][NH:15][CH2:12][CH2:13][NH:14]1
Reactant: NCCN
Reactant: O=CC(=O)c1cc(Cl)sc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Clc1cc(C2CNCCN2)c(Cl)s1
Reaction time: 3 h

Procedure:
A 10.45 g portion of the above aldehyde was suspended in 200 ml of ethanol, cooled to 0°-5° C. and a solution of 3.3 g of ethylenediamine in 20 ml of ethanol added dropwise with stirring. The mixture was allowed to ccme to room temperature over 3 hours, then 3.8 g of sodium borohydride was added and the mixture was evaporated to dryness. The residue was dissolved in dichloromethane, water washed, filtered, dried and evaporated. The resulting gum was triturated with ether producing an oil. The oil was purified by chromatography, eluting with chloroform:methanol (9:1), giving an oil which crystallized, giving 3.3 g of 2-(2,5-dichloro-3-thienyl)piperazine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH:29]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:28]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:27]2[CH2:32][CH2:31][O:30][CH:29]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:28]2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)CCC1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCOC(CCC(=O)O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 49.1 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.7 g, 1.4 mmol) was reacted with 3-(morpholin-2-yl)propanoic acid (0.22 g, 1.4 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.40 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[BrH:17].BrBr>CC(O)=O>[Br:17][CH:3]1[CH2:4][CH2:5][C:6]2[N:7]=[C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])[S:9][C:10]=2[C:2]1=[O:1]
Reactant: CCNC(=O)Nc1nc2c(s1)C(=O)CCC2
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: CCNC(=O)Nc1nc2c(s1)C(=O)C(Br)CC2
Temperature: 45 °C
Yield: 166.9 %

Procedure:
A solution of 1-(7-oxo-4,5,6,7-tetrahydro-2-benzothiazolyl)-3-ethyl-urea 4 (1.00 g, 4.18 mmol) and 48% HBr (aq) (0.24 mL, 2.09 mmol, 0.5 eq) in AcOH (18 mL) was treated dropwise with a solution of Br2 (0.23 mL, 4.39 mmol, 1.05 eq) in AcOH (1 mL) with stirring. The reaction mixture was heated at about 45° C. with stirring for about 16 hours with a condensor on top of the reaction flask. An orange colored suspension was obtained. The solid was filtered off and washed with AcOH (5 mL), toluene (2×3 mL) and Et2O (2×5 mL). After drying under vacuum, 1.11 g (83%) of the desired compound 7 was obtained. 1H NMR (DMSO) δ 11.15 (br s, 1H, NH), 6.73 (br s, 1H, NH), 4.87 (t, 1H, J=4.6 Hz, CH), 3.17 (m, 2H, CH2), 2.87 (dd, 2H, J=7.2, 4.4 Hz, CH2), 2.61–2.54 (m, 1H, CH2), 2.39–2.33 (m, 1H, CH2), 1.08 (t, 3H, J=7.2 Hz, CH3); LC/MS 318 (MH+); RP-HPLC RT 2.68 minutes.