Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[OH:36])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].N1C=CC=CC=1>ClCCl>[C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[O:36][S:38]([CH3:37])(=[O:40])=[O:39])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OC1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: -30 °C
Reaction time: 17 h
Yield: 96.5 %

Procedure:
To a suspension of 3-hydroxy-7beta-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester (2) in dichloromethane (18 parts) cooling at -30° C. are dropwise added methanesulfonyl chloride (6 equivalents) and then pyridine (6 equivalents). The mixture is let stand at 0° to 5° C. for 17 hours. The reaction mixture is diluted with ice-water, the organic layer is taken, washed with hydrochloric acid and water, dried, and concentrated. The residue is crystallized from a mixtue of ethyl acetate and hexane to give 3-methanesulfonyloxy-7beta-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester (3c). Yield: 96.5%. mp. 151°-152° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]=[CH:11]C[O:9]2)=[CH:4][CH:3]=1.[H][H]>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][O:9]2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Brc1ccc(C2CC=CCO2)cc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1ccc(C2CCCO2)cc1
Yield: 37.6 %

Procedure:
A solution of 2-(4-bromophenyl)-3,6-dihydro-2H-pyran (140 mg, 0.586 mmol) in toluene/ethanol (10 mL, v/v=1/1) was charged into a hydrogenation Parr bottle followed by tris(triphenylphosphine)rhodium(I) chloride (55 mg, 0.0586 mmol). The mixture was set up for 45 psi of hydrogen at 80° C. overnight. The mixture was filtered through celite and the filtrate was concentrated. The residue was purified by silica gel chromatography to give the title compound (50 mg, 35%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.46 (d, 2H) 7.23 (d, 2H) 4.29 (d, 1H) 4.13 (m, 1H) 3.60 (t, 1H) 1.95 (m, 1H) 1.81 (d, 1H) 1.60 (m, 3H) 1.27 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[CH2:8][C:9](=O)[CH:10]=1)=[O:4].Cl.[NH2:23][OH:24].N1C=CC=CC=1>CO>[CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[CH2:8][C:9](=[N:23][OH:24])[CH:10]=1)=[O:4]
Reactant: COC(=O)C1=CC(=O)CC(c2ccc(Cl)c(OC)c2F)N1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: COC(=O)C1=CC(=NO)CC(c2ccc(Cl)c(OC)c2F)N1
Yield: 83.7 %

Procedure:
6-(4-Chloro-2-fluoro-3-methoxyphenyl)-4-oxo-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (16, 5.19 g, 16.5 mmol) was slurried in methanol (160 mL). Hydroxylamine hydrochloride (3.35 g, 48.3 mmol) was added, followed by pyridine (10.0 mL, 123 mmol). The reaction mixture was stirred at reflux for 120 min. Methanol was evaporated under vacuum. H2O (200 mL) was added, and the residue was extracted into ether (4×150 mL). The combined extracts were washed with brine, dried (MgSO4) and evaporated under vacuum to give 6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-hydroxyimino-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (18; 4.54 g, 80%) as a white solid: mp 136-138° C. A 1:1 mixture of syn and anti isomers was observed by NMR spectroscopy and HPLC. 1H NMR (400 MHz, C6D6) δ 8.34 (br, 1H, NOH), 8.25 (br, 1H, NOH), 7.00 (s, 1H, H3), 6.71 (dd, JF-H=1.5 Hz, JH-H=9 Hz, 1H, aromatic), 6.69 (dd, JF-H=1.8 Hz, JH-H=9 Hz, 1H, aromatic), 6.57 (dd, JF-H=JH-H=7.5 Hz, 1H, aromatic), 6.53 (s, 1H, H3), 6.50 (dd, JF-H=JH-H=7.5 Hz, 1H, aromatic), 4.72 (s, 1H, NH), 4.52 (s, 1H, NH), 4.38 (dd, JH-H=3.6, 10.2 Hz, 1H, H6, isomer A), 4.23 (dd, JH-H=3.9, 11.4 Hz, 1H, H6, isomer B), 3.53 (s, 6H, CO2Me), 3.24 (s, 3H, OMe), 3.23 (s, 3H, OMe), 3.30 (dd, JH-H=4.2, 16.8 Hz, 1H, H5, isomer B), 2.63 (dd, JH-H=4.2, 15.3 Hz, 1H, H5, isomer A), 2.44 (dd, JH-H=10.5, 15.3 Hz, 1H, H5, isomer A), 2.33 (dd, JH-H=11.1, 16.8 Hz, 1H, H5, isomer B); 13C{1H} NMR (CDCl3) δ 164.2 (CO2Me), 163.9 (CO2Me), 153.7 (d, JF-C=250 Hz, C2′), 153.6 (d, JF-C=251 Hz, C2′), 152.6 (C4), 149.6 (C4), 144.3 (d, JF-C=3 Hz, C3′), 144.1 (d, JF-C=3 Hz, C3′), 139.2, 138.3, 128.6 (d, JF-C=12 Hz), 127.9 (d, JF-C=11 Hz), 127.8 (d, JF-C=3 Hz), 127.7 (d, JF-C=3 Hz), 125.3, 121.7, 101.7 (C3), 92.6 (C3), 61.42, 61.38, 52.7, 52.6, 49.3, 48.3, 33.6 (C5), 28.7 (C5). HRMS-ESI (m/z) calcd for C14H14ClFN2O4, 328.0621. found, 328.0620. Anal. Calcd for C14H14ClFN2O4: C, 51.15; H, 4.29; N, 8.52. Found: C, 51.31; H, 4.34; N, 8.40.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([OH:16])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>CCO>[C:2]1([C:1]2[C:9]3[CH:13]=[CH:12][S:11][C:10]=3[C:14](=[O:16])[NH:18][N:19]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccccc1)c1ccsc1C(=O)O
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2ccccc2)c2ccsc12
Yield: 102.8 %

Procedure:
A solution of 3-benzoylthiophene-2-carboxylic acid (0.497 g, 2.14 mmol) (Alfa Aesar) and hydrazine hydrate (0.50 mL, 8.8 mmol) in EtOH (6 mL) was stirred at 85° C. for 4 hours, concentrated, and azeotroped with toluene to give the title compound (0.50 g, 2.2 mmol) as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 8.28 (d, 1H), 7.69-7.75 (m, 2H), 7.51-7.59 (m, 4H).
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][N:3]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[OH:24])N.C([N:27](CC)CC)C>>[Br:16][C:17]1[CH:18]=[C:19]([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]=[C:4]([NH2:27])[N:3]=2)[CH:21]=[CH:22][C:23]=1[OH:24]
Reactant: Nc1ccc(O)c(Br)c1
Reactant: CCN(CC)CC
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Product: COc1cc2nc(N)nc(-c3ccc(O)c(Br)c3)c2cc1OC

Procedure:
A mixture of 448 mg (2 mmol) of 4-chloro-6,7-dimethoxy-quioazoline (7) and 2.5 mmol of 3-bromo-4-hydroxyaniline in 20 ml of alcohol (EtOH or MeOH) was refluxed for 8 hours. After cooling, triethylamine was added to basify the solution, and the solvent was concentrated to give material that was recrystallized from DMF to give compound (2); 89.90%; m.p. 233.0-233.5° C.; 1H NMR(DMSO-d6): δ 10.08(s, 1H, —NH), 9.38(s, 1H, —OH), 8.40(s, 1H, 2-H), 7.89(d, 1H, J2′,5′=2.7 Hz, 2′-H), 7.75(s, 1H, 5-H), 7.55(dd, 1 H, J5′,6′=9.0 Hz, J2′,6′=2.7 Hz, 6′-H), 7.14(s, 1H, 8-H), 6.97(d, 1H, J5′,6′=9.0 Hz, 5′-H), 3.92(s, 3H, —OCHER), 3.90(s, 3H, —OCH3). UV(MeOH)λmax(e): 203.0, 222.0, 250.0, 335.0 nm. IR(KBr)umax: 3431(br), 2841, 1624, 1498, 1423, 1244 cm−1. GC/MS m/z 378( M+ +2, 90.68), 377(M+ +1,37.49), 376(M+, 100.00), 360(M+3.63), 298(18.86), 282 (6.65).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=N[C:34]2[CH:35]=[CH:36][CH:37]=[N:38][C:33]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C1(CN)CCC1>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:38][CH2:37][CH:36]4[CH2:35][CH2:34][CH2:33]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)NCC4CCC4)cn3)c2O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Combined 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (200 mg, 0.654 mmol) and HATU (372 mg, 0.98 mmol) in DMF (3 mL) was added triethylamine (198 mg, 1.961 mmol). Then cyclobutylmethanamine (0.784 mmol) was added and the reaction was stirred at room temperature for 4 h. The reaction mixture was purified by preparative HPLC to give the title compound as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.90 (s, 1H), 8.70-8.65 (m, 2H), 8.45-8.40 (m, 2H), 8.13 (d, J=7.6 Hz, 2H), 7.78 (d, J=7.6 Hz, 2H), 3.31 (m, 2H), 2.56-2.53 (m, 1H), 2.05-2.00 (m, 2H), 1.85-1.82 (m, 2H), 1.75-1.72 (m, 2H). MS m/Z [M+H]+ 374.1.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([Cl:23])[CH:15]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O.Cl>[Fe].C(O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([Cl:23])[CH:15]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)c2ccc([N+](=O)[O-])c(Cl)c2)cc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)c2ccc(N)c(Cl)c2)cc1
Yield: 1304.3 %

Procedure:
Iron powder (2.5 g) was added to a stirred mixture of 4-(4-acetamidophenyl-sulphonyl)-2-chloro-nitrobenzene (Method 13) (0.67 g), water (2 ml), concentrated hydrochloric acid (0.5 ml) and ethanol (10 ml). The mixture was heated under reflux for 1 hour then evaporated to near dryness and partitioned between ethyl acetate and water. The organic layer was separated the aqueous layer was extracted with ethyl acetate (3×15 ml). The organic extracts were combined and dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-2% methanol/DCM to give the title compound (0.1 8 g) as a solid. NMR: 2.05 (s, 3H), 6.4 (s, 2H), 6.8 (d, 1H), 7.5 (d, 1H), 7.6 (d, 1H), 7.8 (q, 4H), 10.3 (brs, 1H); MS (ESP−): 323.
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)=[N:26][C:21]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:19])[CH3:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:22][CH:23]=1
Reactant: COc1cc2c(cc1N)CCN(CC(C)(F)F)CC2
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3-n3cccn3)n1)CCN(CC(C)(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-propyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine in an analogous manner to Example 61e. Product isolated as an off-white foam (0.029 g, 27%). MP: 114-121° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 10.15 (s, 1H), 8.52 (d, 1H, J=8.3 Hz), 8.06-8.04 (m, 2H), 7.85 (s, 1H), 7.82-7.80 (m, 1H), 7.46 (s, 1H), 7.40-7.32 (m, 2H), 7.19 (t, 1H, J=7.7 Hz), 6.63 (s, 1H), 6.52-6.50 (m, 1H), 3.86 (s, 3H), 2.90-2.73 (m, 10H), 1.69 (t, 3H). MS: 540.43 (H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:27]=[CH:26][C:14]([O:15][C:16]2[C:21]([F:22])=[C:20](F)[C:19]([F:24])=[C:18]([F:25])[N:17]=2)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:28]([C:31]1[C:36]([F:37])=[C:35]([F:38])[C:34]([OH:39])=[C:33]([F:40])[C:32]=1F)([O-:30])=[O:29].C(=O)([O-])[O-:43].[K+].[K+].C(=O)([O-])O.[K+]>CS(C)=O>[N+:28]([C:31]1[C:36]([F:37])=[C:35]([F:38])[C:34]([O:39][C:20]2[C:19]([F:24])=[C:18]([F:25])[N:17]=[C:16]([O:15][C:14]3[CH:13]=[CH:12][C:11]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])=[CH:27][CH:26]=3)[C:21]=2[F:22])=[C:33]([F:40])[C:32]=1[OH:43])([O-:30])=[O:29]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1c(F)c(F)c(O)c(F)c1F
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2nc(F)c(F)c(F)c2F)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)c1ccc(Oc2nc(F)c(F)c(Oc3c(F)c(O)c([N+](=O)[O-])c(F)c3F)c2F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
40 g of 2-(4-benzyloxycarbonylphenoxy)-3,4, 5, 6-tetrafluoropyridine prepared as described in Example 7 (0.106 mol) and 22.4 g of 4-nitrotetrafluorophenol prepared as described in Example 4 (0.106 mol) are dissolved in 400 ml of dimethyl sulfoxide. 30 g of potassium carbonate (0.22 mol) are added in portions to the solution. The mixture is then stirred at room temperature for 24 hours and then heated at 60° C. for 24 hours, and 15 g of potassium hydrogen carbonate (0.15 mol) are then added. The reaction solution is then cooled to room temperature and filtered through a fluted filter. The crude product is washed by shaking with 300 ml of ethyl acetate and 700 ml of water, and the organic phase is washed three times with water and evaporated in a rotary evaporator until the reaction product precipitates out. The reaction product is then recrystallized from a mixture of ethyl acetate and n-hexane (volume ratio 1:1) and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (Yield: 92%).
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6](=[O:23])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:12]([CH3:22])[CH:11]=1)=[O:8].C(O)(C(F)(F)F)=O>CC(O)=O>[OH:23][C:6]1[C:7](=[O:8])[N:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([OH:21])([CH3:19])[CH3:20])=[C:12]([CH3:22])[CH:11]=2)[CH:3]=[CH:4][N:5]=1
Reactant: COC(CNC(=O)C(=O)Nc1ccc(OCC(C)(C)O)c(C)c1)OC
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1cc(-n2ccnc(O)c2=O)ccc1OCC(C)(C)O
Yield: 73.1 %

Procedure:
A solution of N1-(2,2-dimethoxyethyl)-N2-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)oxalamide (11.4 g, 32.2 mmol) and TFA (2.97 mL, 38.6 mmol) in AcOH (120 mL) was stirred at 135° C. in a seal tube for 60 min. After cooling and concentration under vacuum, addition of CH2Cl2 (300 ml) produced a precipitate which was collected by filtration and was washed with CH2Cl2 (150 ml) to yield 3-hydroxy-1-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)pyrazin-2(1H)-one (7.19 g, 23.53 mmol, 73.1% yield) as brown solid. MS (M+1=226). 1H NMR (500 MHz, methanol-d3) δ ppm 7.13-7.26 (2H, m), 6.98 (1H, d, J=8.52 Hz), 6.50 (1H, d, J=5.77 Hz), 6.41 (1H, d, J=6.05 Hz), 3.82 (2H, s), 2.29 (3H, s), 1.35 (6H, s).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=1.Cl.[O:17]1[CH2:22][CH2:21][NH:20][C@@H:19]2[CH2:23][CH2:24][C:25]3[C:30]([C@@H:18]12)=[CH:29][CH:28]=[CH:27][CH:26]=3.C(N(CC)CC)C>O1CCCC1>[O:17]1[CH2:22][CH2:21][N:20]([C:2]2[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][N:11]=3)[N:3]=2)[C@@H:19]2[CH2:23][CH2:24][C:25]3[C:30]([C@@H:18]12)=[CH:29][CH:28]=[CH:27][CH:26]=3
Reactant: c1ccc2c(c1)CC[C@H]1NCCO[C@H]21
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCO[C@@H]3c4ccccc4CC[C@H]32)nc(-c2ccncn2)cc1=O
Yield: 17 %

Procedure:
A solution of 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.25 g, 1.12 mmol), (4aRS,10bRS)-trans-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazine hydrochloride (0.3 g, 1.33 mmol) and triethylamine (0.4 g, 3.95 mmol) in tetrahydrofuran (15 ml) was stirred for 48 hours at 100° C. The mixture was partitioned between water and chloroform, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to give 2-((4aRS,10bRS)-trans-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (72 mg, 0.19 mmol, 16%) as pale white crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([O:36][C:37]2[CH:42]=[C:41]([F:43])[C:40]([C:44]([F:47])([F:46])[F:45])=[CH:39][C:38]=2[C:48]2[CH:53]=[CH:52][N:51]=[N:50][CH:49]=2)=[CH:11][C:12]([F:35])=[C:13]([S:15]([N:18](CC2C=CC(OC)=CC=2OC)[C:19]2[S:20][CH:21]=[N:22][N:23]=2)(=[O:17])=[O:16])[CH:14]=1.C(Cl)Cl>>[Cl:8][C:9]1[C:10]([O:36][C:37]2[CH:42]=[C:41]([F:43])[C:40]([C:44]([F:45])([F:46])[F:47])=[CH:39][C:38]=2[C:48]2[CH:53]=[CH:52][N:51]=[N:50][CH:49]=2)=[CH:11][C:12]([F:35])=[C:13]([S:15]([NH:18][C:19]2[S:20][CH:21]=[N:22][N:23]=2)(=[O:16])=[O:17])[CH:14]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(F)c(C(F)(F)F)cc3-c3ccnnc3)cc2F)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2cc(F)c(C(F)(F)F)cc2-c2ccnnc2)cc1F
Reaction time: 0.33 h
Yield: 34.7 %

Procedure:
Trifluoroacetic acid (500 uL, 6 mmol) was added to a solution of 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-[5-fluoro-2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (22 mg) in methylene chloride (5 mL, 70 mmol). After stirring 20 min, the reaction mixture was concentrated onto diatomaceous earth and purified by automated flash chromatography (4 g SiO2, methylene chloride to 9:1 methylene chloride-methanol) to afford the product as a tan solid (6 mg, 9%).
Reaction SMILES: [H-].[Na+].Br[C@H:4]1[C@H:9](O)[C:8]2[C:11]([O:15][CH3:16])=[CH:12][CH:13]=[CH:14][C:7]=2[O:6][CH2:5]1.[O:17]1CCCC1>>[CH3:16][O:15][C:11]1[C:8]2[CH2:9][C:4](=[O:17])[CH2:5][O:6][C:7]=2[CH:14]=[CH:13][CH:12]=1
Reactant: C1CCOC1
Reactant: COc1cccc2c1[C@@H](O)[C@H](Br)CO2
Agent: [H-]
Agent: [Na+]
Product: COc1cccc2c1CC(=O)CO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5.0 g sodium hydride in 100 ml of dry tetrahydrofuran is added with stirring a solution of 13 g of trans-3-bromo-4-hydroxy-5-methoxy-3,4-dihydro-2H-[1]benzopyran in 150 ml of dry tetrahydrofuran in a dropwise fashion. After 30 minutes stirring at room temperature, the reaction mixture is filtered through filter-cel and the solvent is removed in vacuo. The residue is dissolved in 150 ml of toluene, 1.0 g of anhydrous zinc iodide is added and the mixture is refluxed for 15 minutes. The reaction mixture is filtered through 120 g of silica gel with methylene chloride as the eluent to afford 5-methoxy-3,4-dihydro-2H-[1]-benzopyran-3-one (5-methoxychroman-3-one) as an oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][C@@:8]([CH3:16])([C:12]([F:15])([F:14])[F:13])[C:9](O)=[O:10].[Br:17][C:18]1[CH:24]=[C:23]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:19]=1[NH2:20].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>ClCCl.CN(C=O)C>[Br:17][C:18]1[CH:24]=[C:23]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:19]=1[NH:20][C:9](=[O:10])[C@:8]([OH:7])([CH3:16])[C:12]([F:15])([F:14])[F:13]
Reactant: C[C@@](O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(Sc2ccccc2)cc1Br
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@](O)(C(=O)Nc1ccc(Sc2ccccc2)cc1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.1 %

Procedure:
Oxalyl chloride (0.052 ml) was added to a stirred suspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (Method 9) (0.095 g) in dichloromethane (3 ml) containing DMF (1 drop). The mixture was stirred at ambient temperature for 2 hours and was then added to a solution of 2-bromo-4-phenylthioaniline (Method 17) (0.135 g) and 2,6-di-tert-butylpyridine (0.14 ml) in dichloromethane (5 ml) and stirred a further 3 hours. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-30% ethyl acetate/hexane to give the title compound (0.061 g) as a waxy solid. NMR: 1.59 (s, 3H), 7.25-7.50 (bm, 6H), 7.59 (s, 1H), 7.82 (bs, 1H), 7.98 (d,1H), 9.79 (s, 1H); MS: 420 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:14])[CH2:10][CH2:11][C:12]=1[CH3:13].N1C=CC=CC=1.[C:21]1([CH3:33])[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1[S:29](Cl)(=[O:31])=[O:30].Cl>C(Cl)Cl>[C:21]1([CH3:33])[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1[S:29]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:14])[CH2:10][CH2:11][C:12]=1[CH3:13])(=[O:30])=[O:31]
Reactant: CC1=C(c2ccccc2N)C(=O)CC1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1=C(c2ccccc2NS(=O)(=O)c2c(C)cc(C)cc2C)C(=O)CC1

Procedure:
0.500 g (2.67 mmol) of 2-(2-aminophenyl)-3-methyl-2-cyclopenten-1-one, 0.253 g (3.204 mmol) of pyridine, 0.584 g (2.67 mmol) of 2-mesitylenesulfonyl chloride), and 2 mL of M.C (methylene chloride) were loaded to a 20 mL vial, and then reacted for 12 hours. 10 mL of M.C and 4 mL of 2 N HCl were added to the reaction product. The resultant organic layer is collected and then dried over MgSO4 to remove water. The solvent contained in the dried product was removed using a rotary vacuum evaporator. The obtained solid was washed with 10 mL of diethyl ether and filtered using a glass filter. The filtered product was dried in vacuum to remove the solvent that had remained therein (0.790 g, 80%).
Reaction SMILES: [F:1][C:2]([F:19])([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][C@H:4]([N:9]=[C:10]=[O:11])[C:5]([O:7][CH3:8])=[O:6].[CH2:20]1[C:24]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>ClCCl>[CH2:23]1[C:24]2([CH2:29][CH2:28][N:27]([C:10]([NH:9][C@@H:4]([CH2:3][C:2]([F:19])([F:1])[CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:5]([O:7][CH3:8])=[O:6])=[O:11])[CH2:26][CH2:25]2)[CH2:20][CH2:21][CH2:22]1
Reactant: C1CCC2(C1)CCNCC2
Reactant: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)N=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCC2(CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (S)-4,4-difluoro-2-isocyanato-5-phenylpentanoate (425 mg, 1.58 mmol) were dissolved in 25 ml of dichloromethane. 8-Azaspiro[4.5]decane (220 mg, 1.58 mmol, 1 eq.) and DIPEA (269 μl, 204 mg, 1.58 mmol, 1 eq.) were added to this solution which was stirred at RT overnight. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (gradient: acetonitrile/water and addition of 0.05% TFA). The product-containing fractions were combined and freed from the solvent under reduced pressure.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].[OH2:24]>>[CH2:16]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:24].[CH2:12]([CH2:11][CH2:10][NH2:9])[CH2:13][CH2:14][CH2:15][NH2:7]
Reactant: NCCCCCCCCCCCC(=O)O
Reactant: O=C1CCCCCN1
Reactant: O
Product: NCCCCCCN
Product: O=C(O)CCCCCCCCCCC(=O)O
Temperature: 260 °C

Procedure:
An autoclave was charged with 5.0 kg of ε-caprolactam, 9.5 kg of 12-aminododecanoic acid and 1.0 kg of water, the temperature was increased gradually to 260° C. and then the internal pressure was adjusted to 4 kg/cm2 2 hours thereafter. After 2 hours of reaction at 260° C., generated steam was gradually removed, and the pressure was adjusted to atmospheric pressure and then to a reduced pressure for 1.5 hours of reaction, thereby obtaining a nylon 6/12 polymer.