Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[C:9]([NH2:14])(=[O:13])[C:10]([CH3:12])=[CH2:11].O>C(Cl)(Cl)Cl>[C:1]([NH:14][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)Cl
Reactant: C=C(C)C(N)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=C(C)C(=O)NC(=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.8 %

Procedure:
Into the same reaction vessel as used in Example 1, ethoxalyl chloride (12.3 g; 0.09 mol) was charged, and the reaction vessel was cooled in an ice bath. A solution of methacrylamide (20.3 g; 0.24 mol) in chloroform (90.0 ml) was dropwise added thereto in 30 minutes, followed by stirring at room temperature for 3 days. The reaction mixture was shaken with chloroform (500 ml) and water (500 ml), and the chloroform layer was separated and dried over anhydrous magnesium sulfate, followed by removal of chloroform. Hydroquinone (0.01 g) was added thereto, and distillation under reduced pressure was carried out to give N-ethoxalylmethacrylamide (4.8 g). Yield, 29%.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Cl:19][C:20]1[S:21][C:22]([Cl:29])=[CH:23][C:24]=1[S:25](Cl)(=[O:27])=[O:26]>>[Cl:19][C:20]1[S:21][C:22]([Cl:29])=[CH:23][C:24]=1[S:25]([NH:18][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[F:17])(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)c1cc(Cl)sc1Cl

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene 1,2-diamine was reacted with 2,5-dichlorothiophene-3-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.41 (dd, J=1.5 & 10.5 Hz, 1H), 7.28-7.20 (m, 2H), 7.08 (dd, J=9.0 & 17.4 Hz, 2H), 6.99 (s, 1H), 6.03 (dt, J=2.1, 8.7 & 17.4 Hz, 1H), 5.56 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:18][CH3:19])[CH:12]=3)=[CH:9][N:8]([CH:20]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:27](Cl)(=[O:36])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1.ClCCl>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:27](=[O:36])[CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:13]([O:18][CH3:19])[CH:12]=3)=[CH:9][N:8]([CH:20]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1cc(-c2cn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)CCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1NC(=O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a solution of 4-[4-amino-5-(4-amino-3-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-cyclohexanone (0.8 g, 2.3 mmol) in pyridine (13 mL) and dichloromethane (32 mL) at 0° C. was added hydrocinnamoylchloride (0.57 g, 3.4 mmol) in dichloromethane (5 mL) under nitrogen. The solution was stirred at 0° C. for 2 hr, warmed to room temperature and quenched by addition of saturated aqueous citric acid solution (50 mL). The organic layer was washed with saturated aqueous citric acid solution (2×50 mL), dried (sodium sulphate), filtered and evaporated to leave N1-{4-[4-amino-7-(4-oxocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-3-phenylpropanamide (1.0 g, 92% crude) as a brown foam. 1H NMR (d6 DMSO, 400 MHz):9.17(1H, s), 8.18(1H, s), 8.06(1H, d), 7.51(1H, s), 7.18-7.29(6H, m), 7.09(1H, m), 6.99(1H, d), 6.21(2H, bs), 5.18 (1H, m), 3.88(3H, s), 1.99-2.93(12H, m). HPLC: (5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min.) tr=14.48 min, 92.2%.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:10])([CH2:8][CH3:9])[CH2:6][CH:5]([OH:11])[CH:4]([CH3:12])[C:3]1([CH3:15])[CH2:13][CH3:14].C(N(CC)CC)C.[CH3:23][Si:24]([CH3:27])([CH3:26])Cl>O1CCOCC1>[CH3:1][N:2]1[C:7]([CH3:10])([CH2:8][CH3:9])[CH2:6][CH:5]([O:11][Si:24]([CH3:27])([CH3:26])[CH3:23])[CH:4]([CH3:12])[C:3]1([CH3:15])[CH2:13][CH3:14]
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1C
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCC1(C)CC(O[Si](C)(C)C)C(C)C(C)(CC)N1C

Procedure:
21.1 g of 1,2,3,6-tetramethyl-2,6-diethyl-4-hydroxypiperidine and 20 g of triethylamine are dissolved in 250 ml of dioxane. By addition of 10.9 g of trimethylchlorosilane and using the same procedure of reaction and isolation as described in the previous examples there is obtained 1,2,3,6-tetramethyl-2,6-diethyl-4-(trimethylsiloxy)-piperidine (Compound No. 6), b.p. 78°-79° C./0.35 mm Hg.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([C:27]([CH3:31])([CH3:30])[C:28]#[N:29])[CH2:24]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C([O-])([O-])=[O:33].[Na+].[Na+].O>OS(O)(=O)=O>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([CH:23]5[CH2:24][N:25]([C:27]([CH3:31])([CH3:30])[C:28]([NH2:29])=[O:33])[CH2:26]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(C(C)(C)C#N)C3)cc1OCC2
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(C(C)(C)C(N)=O)C3)cc1OCC2
Reaction time: 3.25 h
Yield: 54 %

Procedure:
2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionitrile (0.17 g, 0.41 mmol) was dissolved in conc. H2SO4, (2 mL) and the mixture allowed to stand at room temperature for 3.25 hr before adding to ice. The resultant solution was basified with Na2CO3, further water added, and the mixture extracted with 10% MeOH in DCM. The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) to give 205 as a white solid (97 mg, 54%). 1H NMR δ (ppm) (CDCl3): 8.46 (1 H, d, J=8.29 Hz), 7.84 (1 H, s), 7.61 (1 H, s), 7.13 (1 H, s), 7.08 (1 H, d, J=8.39 Hz), 6.95 (1 H, s), 6.01-5.91 (1 H, m), 5.27 (1 H, s), 4.50-4.40 (4 H, m), 3.62 (3 H, s), 3.33 (2 H, s), 1.56 (6 H, d, J=6.63 Hz), 1.23 (6 H, s). LCMS: RT=2.53 min, M+H+=436
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[NH2:19][CH2:20][CH2:21][CH2:22][C:23]1[C:24]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[N:25][C:26]([NH2:30])=[N:27][C:28]=1[CH3:29].[C:37]1([CH2:47][C:48](O)=[O:49])[CH:42]=[CH:41][C:40]([CH2:43][C:44]([OH:46])=[O:45])=[CH:39][CH:38]=1>C1COCC1.CCOC(C)=O>[NH2:30][C:26]1[N:27]=[C:28]([CH3:29])[C:23]([CH2:22][CH2:21][CH2:20][NH:19][C:48](=[O:49])[CH2:47][C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44]([OH:46])=[O:45])=[CH:39][CH:38]=2)=[C:24]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[N:25]=1
Reactant: O=C(O)Cc1ccc(CC(=O)O)cc1
Reactant: CCCCCNc1nc(N)nc(C)c1CCCN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCNc1nc(N)nc(C)c1CCCNC(=O)Cc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of T3P (1.591 ml, 1.57M in THF) was added to a mixture of the product from example 1 step (v) (0.2 g), TEA (0.333 ml) and 2,2′-(1,4-phenylene)diacetic acid (0.463 g) in THF (15 mL) and the mixture stirred at rt overnight. The reaction was diluted with EtOAc, washed with water, dried and evaporated under reduced pressure. Used crude in next step.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[C:16]([C:24](=[O:26])[CH3:25])[CH:17]=[CH:18][C:19]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:3]=1[CH3:27].[O:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[C:36]([NH2:40])[CH:37]=[N:38][CH:39]=2)[CH2:30][CH2:29]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:40][C:36]1[CH:37]=[N:38][CH:39]=[C:34]([N:31]3[CH2:32][CH2:33][O:28][CH2:29][CH2:30]3)[CH:35]=1)=[C:3]([CH3:27])[C:4]([C:14]1[CH:15]=[C:16]([C:24](=[O:26])[CH3:25])[CH:17]=[CH:18][C:19]=1[S:20]([CH3:23])(=[O:21])=[O:22])=[N:5]2
Reactant: CC(=O)c1ccc(S(C)(=O)=O)c(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Reactant: Nc1cncc(N2CCOCC2)c1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(S(C)(=O)=O)c(-c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)c1

Procedure:
Essentially prepared according to Procedure H using 1-(3-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-4-(methylsulfonyl)phenyl)ethanone (150.0 mg, 0.35 mmol) and 5-morpholinopyridin-3-amine in toluene to give 1-(3-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)-4-(methylsulfonyl)-phenyl)ethanone. 1H NMR (CDCl3) δ ppm 8.17-8.35 (3H, m), 7.94-8.13 (2H, m), 7.76 (1H, s), 7.54-7.66 (1H, m), 7.17 (1H, ddd, J=13.0, 8.5, 2.4 Hz), 6.73 (1H, s), 3.72-3.88 (4H, m), 3.18-3.33 (4H, m), 3.10 (3H, s), 2.70 (3H, s), 1.96 (3H, s). Mass Spectrum (ESI) m/e=553.2 (M+1).
Reaction SMILES: CN([CH2:4][C:5]1C=C(O)C=C[CH:10]=1)C.[CH3:12][N:13]([CH2:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][CH:27]=1)[O:19][CH2:20][CH2:21][CH2:22][CH:23]=[O:24])[CH3:14]>>[N:13]1([CH2:15][C:16]2[CH:17]=[C:18]([CH:25]=[CH:26][CH:27]=2)[O:19][CH2:20][CH2:21][CH2:22][CH:23]=[O:24])[CH2:14][CH2:10][CH2:5][CH2:4][CH2:12]1
Reactant: CN(C)Cc1cccc(O)c1
Reactant: CN(C)Cc1cccc(OCCCC=O)c1
Product: O=CCCCOc1cccc(CN2CCCCC2)c1

Procedure:
Similarly prepared from 3-[(dimethylamino)methyl]phenol (12.08 g) was 4-[3-[(dimethylamino)methyl]phenoxy]butanal (1.05 g) as a colourless oil b.p. 150°, 0.06 mm; tlc System A, Rf 0.59.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.NC1C=CC=CC=1.[CH:37]1[N:41]=[CH:40][N:39]([C:42](N2C=NC=C2)=[NH:43])[CH:38]=1>C1COCC1>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:42]([N:39]3[CH:38]=[CH:37][N:41]=[CH:40]3)=[NH:43])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: N=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Product: N=C(Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)n1ccnc1
Yield: 1.6 %

Procedure:
To imidazole (65 mg, 9.760 mmol) in CH2Cl2 (10 ml) at room temperature under nitrogen atmosphere bromonitrile (500 mg, 4.71 mmol) was added. The resulting mixture was heated at reflux for 1 hr. Cooling to room temperature, filtration and concentration in vacuo to a volume of approximately 10 ml. The resulting pale liquor was let stand at 0° C. for 15 hrs. Filtration afforded a pale white powder for C-(di-imidazol-1-yl)-methyleneamine (210 mg, 28% yield). To [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone (132 mg, 3.389 mmol), aniline (213 mg, 2.347 mmol) and C-(di-imidazol-1-yl)-methyleneamine (420 mg, 2.608 mmol) in THF (20 mg) was heated at reflux for 2.5 hrs. Concentration in vacuo and RP-HPLC (gradient water:acetonitrile) afforded the title compound as a yellow powder (20 mg, 14% yield). MS (ESI) m/z 486.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1.[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[OH:34]>>[Cl:27][C:28]1[CH:29]=[C:30]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:21][CH2:22]2)[CH:31]=[CH:32][C:33]=1[OH:34]
Reactant: OB(O)c1ccc(O)c(Cl)c1
Reactant: CN(C)CC1CCN(c2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CN(C)CC1CCN(c2c(C(=O)C3CC3)cnc3ccc(-c4ccc(O)c(Cl)c4)cc23)CC1
Yield: 58.5 %

Procedure:
Following general procedure D, (6-bromo-4-{4-[(dimethylamino)methyl]piperidin-1-yl}quinolin-3-yl)(cyclopropyl)methanone (25 mg, 0.060 mmol) was reacted with 3-chloro-4-hydroxyphenylboronic acid (21 mg, 0.120 mmol) to afford the desired product (16.3 mg, 59%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 8.74 (s, 1H), 8.28 (s, 1H), 8.05-7.98 (m, 2H), 7.70 (d, J=2.3 Hz, 1H), 7.53 (dd, J=8.4, 2.3 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 3.53 (d, J=12.7 Hz, 2H), 3.21 (t, J=11.5 Hz, 2H), 2.60-2.51 (m, 1H), 2.43 (d, J=6.8 Hz, 2H), 2.35 (s, 6H), 2.00-1.84 (m, 3H), 1.65-1.53 (m, 2H), 1.34-1.28 (m, 2H), 1.28-1.17 (m, 2H); ESI MS m/z 464 [C27H30ClN3O2+H]+; HPLC>99% (AUC), tR=10.38 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O>CN(C=O)C>[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][N:9]=[CH:10][C:2]=1[F:1])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccncc1F
Reactant: Nc1ccccc1OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1OCc1ccccc1)c1ccncc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.2 %

Procedure:
To a mixture of 3-fluoroisonicotinic acid (2.20 g, 15.6 mmol), 2-(benzyloxy)aniline (2.84 g, 14.2 mmol) and BOP (6.94 g, 15.6 mmol) in DMF (20.0 mL) was added TEA (4.4 mL, 31.2 mmol). The reaction mixture was stirred at room temperature for 20 min and poured into water. The aqueous layer was extracted with ethyl acetate (2×). The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo to a quarter volume. The resulting solid was found to be the desired compound. The filtrate was concentrated in vacuo to dryness. The residue was triturated in 30% ethyl acetate in hexanes and the 2 solids were combined to afford compound 24 (4.45 g, 97%) as a white solid. LRMS (ESI): (calc) 322.11 (found) 323.2 (MH)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6].C(OCC)(=O)C.[C:18]12([CH2:28][S:29](O)(=[O:31])=[O:30])[C:25]([CH3:27])([CH3:26])[CH:22]([CH2:23][CH2:24]1)[CH2:21][C:19]2=[O:20]>C(O)C>[CH3:26][C:25]1([CH3:27])[CH:22]2[CH2:23][CH2:24][C@@:18]1([CH2:28][S:29]([O:6][C@H:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH2:4][CH2:3][NH:2][CH3:1])(=[O:31])=[O:30])[C:19](=[O:20])[CH2:21]2
Reactant: CNCC[C@H](O)c1cccs1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCC[C@H](OS(=O)(=O)C[C@]12CCC(CC1=O)C2(C)C)c1cccs1
Temperature: 30 °C
Reaction time: 0.25 h
Yield: 92.7 %

Procedure:
A mixture of (S)-3-methylamino-1-thiophen-2-yl-propan-1-ol (34.2 g, 200 mmol) and ethyl acetate (400 mL) is heated to 30° C., then a mixture of (+)-camphor-10-sulfonic acid (46.4 g, 200 mmol), ethyl acetate (100 mL) and ethanol (100 mL) is added dropwise at 30° C. in 40 minutes. At the end of the addition, the resulting solution is heated to 50° C., stirred for 15 minutes at that temperature, then cooled to 25° C. Once cold, the reaction mixture is concentrated to dryness and ethyl acetate (500 mL) is added to the residue. The resulting mixture is then heated to reflux, kept at that temperature for 15 minutes, then cooled to 25° C. in 30 minutes while seeding the reaction mixture when the temperature reaches about 40° C. Once cold, the resulting suspension is stirred for 30 additional minutes. Afterwards, the precipitate is filtrated, washed with ethyl acetate (2×50 mL) and dried at 40° C. under vacuum (20 mbar) for 15 h affording a white solid (71.5 g, 89%); 1H-NMR (CDCl3, 400 MHz): 7.2 (1H, dm), 7.0 (1H, m), 6.9 (1H, m), 5.21 (1H, t), 3.3 (3H, m), 2.82 (1H, d), 2.75 (3H, s), 2.50 (1H, m, symm.), 2.3 (3H, m), 2.1 (1H, m), 2.0 (1H, m), 1.85 (1H, d), 1.74 (1H, m, symm.), 1.4 (1H, m), 1.04 (3H, s), 0.82 (3H, s).
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]/[C:4]([O:6]CC)=O.[H-].[Na+].[F:15][C:16]1([F:34])[O:21][C:20]2[CH:22]=[C:23]([F:29])[C:24]([N:26]=[C:27]=[O:28])=[CH:25][C:19]=2[N:18]([CH2:30][C:31]#[CH:32])[C:17]1=[O:33]>CN(C=O)C.C1(C)C=CC=CC=1>[F:12][C:9]([F:10])([F:11])[C:2]1[NH:1][C:27](=[O:28])[N:26]([C:24]2[C:23]([F:29])=[CH:22][C:20]3[O:21][C:16]([F:15])([F:34])[C:17](=[O:33])[N:18]([CH2:30][C:31]#[CH:32])[C:19]=3[CH:25]=2)[C:4](=[O:6])[CH:3]=1
Reactant: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(N=C=O)cc21
Reactant: CCOC(=O)/C=C(/N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (E)-ethyl 3-amino-4,4,4-trifluorobut-2-enoate (4.24 g, 23.2 mmol) was added dropwise at 5° C. under N2 to a stirred solution of sodium hydride (1.01 g of a 55% suspension in mineral oil, 23.2 mmol) in dry DMF. The light yellow suspension was stirred for 1 hour, while allowing the reaction mixture to warm to room temperature. After that period, a solution of 2,2,7-trifluoro-6-isocyanato-4-(prop-2-ynyl)-2Hbenzo[b][1,4]oxazin-3(4H)-one (6.54 g, 23.2 mmol) in toluene was added dropwise, after which the mixture was heated at 80° C. overnight under nitrogen. As LC/MS indicated that the reaction was not fully complete, heating was continued for a further 3 hours at 100° C., after which the light brown solution was concentrated in vacuo. The dark residue was partitioned between ethyl acetate and aqueous ammonium chloride solution, and the aqueous phase was extracted with additional ethyl acetate. The combined organic fractions were washed with brine and dried over Na2SO4. Filtration and evaporation of the solvent gave 10.68 g crude brown oil. This was purified by column chromatography (EtOAc:heptane, 20-60%) to give three fractions in which the desired product was the major component (present as a mixture of keto and enol tautomers). These three fractions were combined and further purified by column chromatography, eluting with di-isopropyl ether, to give the product (3.0 g) as an off-white fluffy solid (94% purity according to NMR, with ca. 20% existing as the enol tautomer).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH2:7]Br)=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[CH3:13][S-:14].[Na+].O>O1CCCC1>[Br:1][C:2]1[O:6][C:5]([CH2:7][S:14][CH3:13])=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1
Reactant: C[S-]
Reactant: COC(=O)c1cc(Br)oc1CBr
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Br)oc1CSC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of methyl 5-bromo-2-(bromomethyl)furan-3-carboxylate (8.9 g) in tetrahydrofuran (50 mL) was added sodium methanethiolate (2.5 g) at 0° C., and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 10% ethyl acetate/hexane) to give the title compound (6.7 g, 84%) as an oil.
Reaction SMILES: [CH2:1](O)COCCOCCO.C(Cl)(Cl)=O.C1(C)C=CC=CC=1.[CH2:22]([OH:40])[CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][OH:39]>CCOC(C)=O>[CH3:1][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][OH:40]
Reactant: OCCOCCOCCOCCOCCOCCO
Reactant: OCCOCCOCCO
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCCOCCOCCOCCOCCOCCO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The following description refers to the scheme illustrated in FIG. 10. Non-polydispersed activated hexaethylene glycol monomethyl ether was prepared analogously to that of non-polydispersed triethylene glycol in Example 39 above. A 20% phosgene in toluene solution (35 mL, 6.66 g, 67.4 mmol phosgene) was chilled under a N2 atmosphere in an ice/salt water bath. Non-polydispersed hexaethylene glycol 50 (1.85 mL, 2.0 g, 6.74 mmol) was dissolved in 5 mL anhydrous EtOAc and added to the phosgene solution via syringe. The reaction mixture was kept stirring in the ice bath for one hour, removed and stirred a further 2.5 hours at room temperature. The phosgene, EtOAc, and toluene were removed by vacuum distillation, leaving non-polydispersed compound 51 as a clear, oily residue.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.S(Cl)([Cl:12])=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([Cl:12])=[O:9])[S:5][CH:6]=1
Reactant: O=C(O)c1cc(Br)cs1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(Br)cs1

Procedure:
According to the procedure of Example 32, 2.48 g (12.0 mmoles) of 4-bromo-2-thiophenecarboxylic acid (prepared according to Lawesson, S. O., Arkiv. for Kemi. 11:317 (1957)) and 10 ml of thionyl chloride were combined and heated. The reaction gave 2.99 g of 4-bromo-2-thiophenecarbonyl chloride as a dark oil. Following the procedure of Example 32, the acid chloride, 2.11 g (10.0 mmoles) of 5-chloro-2-oxindole-1-carboxamide and 3.67 g (30.0 mmoles) of 4-(N,N-dimethylamino)pyridine were reacted in N,N-dimethylformamide to give 4.03 g of a crude orange solid. Recrystallization gave 2.67 g (6.68 mmoles, 66.8% yield) of title compound as a yellow crystalline solid, m.p. 217°-219° C. (dec.) (2-butanone).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH2:14][CH2:13][CH2:12][O:11][CH:10]([CH3:15])[C:9]2=O)=[CH:5][CH:4]=1.CO.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:14][CH2:13][CH2:12][O:11][CH:10]([CH3:15])[CH2:9]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(CN2CCCOC(C)C2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CN2CCCOC(C)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a solution of 4-(4-methoxy-benzyl)-2-methyl-[1,4]oxazepan-3-one (2.00 g, 8.02 mmol) in tetrahydrofuran (24 ml) was added 1M borane-tetrahydrofuran complex in tetrahydrofuran (27.3 ml, 27.3 mmol) at 0° C. The mixture was stirred at room temperature for 3 hours. After cooling to 0° C., methanol (20 ml) and 6N sodium hydroxide (20 ml) was added carefully. The resulting mixture was refluxed for 2 hours and cooled to room temperature. The solvent was removed under reduced pressure. The residue was partitioned between saturated ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=1/1) to afford 4-(4-methoxybenzyl)-2-methyl-[1,4]oxazepane as colorless oil (1.66 g, 88%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][NH:15][CH3:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6](=[O:13])[NH:5]2.[N+:17]([O-])([O-:19])=[O:18].[K+]>OS(O)(=O)=O>[CH3:1][C:2]1[C:3]([CH2:14][NH:15][CH3:16])=[C:4]2[C:9](=[CH:10][C:11]=1[N+:17]([O-:19])=[O:18])[NH:8][C:7](=[O:12])[C:6](=[O:13])[NH:5]2
Reactant: CNCc1c(C)ccc2[nH]c(=O)c(=O)[nH]c12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CNCc1c(C)c([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12
Reaction time: 8 h

Procedure:
To a cooled (10° C.) solution of 6-methyl-5-methylaminomethyl-1,4-dihydro-quinoxaline-2,3-dione (10° C.) of (1.23 g, 5.6 mmol) in concentrate H2SO4 (5 mL), KNO3 (0.606 g, 6 mmol) was added. Reaction mixture stirred overnight and quenched with ice. Green ppt filtered and washed with ice-cold water and dried (0.77 g, 42%); mp 260-261° C.