Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([NH2:17])=[N:11][NH:12]2>N1C=CC=CC=1>[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([NH:17][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[N:11][NH:12]2
Reactant: Nc1n[nH]c2cccc(Cl)c12
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1n[nH]c2cccc(Cl)c12
Temperature: 10 °C
Reaction time: 17 h

Procedure:
0.23 cm3 of butyryl chloride is added to 1 g of 4-chloro-1H-indazole-3-amine, prepared as described in patent EP 90 972, in 10 cm 3 of pyridine, cooled to about 10° C. The temperature is allowed to return to about 19° C. over 17 hours. The reaction medium is evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 25 cm3 of ethyl acetate and 25 cm3 of distilled water. The organic phase is washed with 2×25 cm3 of distilled water and with 25 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4 cm), eluting with a dichloromethane/methanol mixture (99/1 by volume) and collecting 30 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). 80 mg of N-[4-chloro-1H-indazol-3-yl]butanamide are thus obtained in the form of a white solid melting at 198° C.
Reaction SMILES: [C:1]([O-:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=[O:7].[CH3:11][C:12](NC1C=CC(NC2C3C(C4C(C(=O)C=3C(N)=C(S(O)(=O)=O)C=2)=CC=CC=4)=O)=CC=1)=O.[Na+]>>[C:1]([O-:10])(=[O:9])[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.[C:1]([O-:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=[O:7]
Reactant: CC(=O)Nc1ccc(Nc2cc(S(=O)(=O)O)c(N)c3c2C(=O)c2ccccc2C3=O)cc1
Agent: O=C([O-])CCCCC(=O)[O-]
Agent: [Na+]
Product: O=C([O-])c1ccc(C(=O)[O-])cc1
Reaction time: 0.08 h

Procedure:
This material is then spun to a 14-filament yarn at a block temperature of 249°C. at a windup speed of 119 yards (108.8 meters) per minute. The yarn has a relative viscosity of 14.4 and contains 0.057% nitrogen and 6 mole % adipate units. The yarn is drawn 5.6X with a feed roll temperature of 68°C. and a draw roll temperature of 90°C. After relaxing at 180°C. for 5 minutes, the yarn has a tenacity of 2.5 grams per denier and an elongation of 51%. The relaxed yarn dyes to a medium shade when dyed 90 minutes at 100°C. at pH 4.5 with 3% owy Acid Blue 40 (C.I. 62125), using a bath-to-yarn weight ratio of about 100.1.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([I:18])[C:7]([F:19])=[C:6]([Cl:20])[CH:5]=1)(=[O:3])[CH3:2].[CH2:21](O)[CH2:22][OH:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:20][C:6]1[CH:5]=[C:4]([C:1]2([CH3:2])[O:23][CH2:22][CH2:21][O:3]2)[C:9]([O:10][CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([I:18])[C:7]=1[F:19]
Reactant: OCCO
Reactant: CCOC(=O)C(C)Oc1c(C(C)=O)cc(Cl)c(F)c1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(C)Oc1c(C2(C)OCCO2)cc(Cl)c(F)c1I
Yield: 56.8 %

Procedure:
A solution of ethyl 2-(6-acetyl-4-chloro-3-fluoro-2-iodophenoxy)propanoate (3.58 g, 8.63 mmol) and 1,2-ethanediol (1.20 mL, 21.6 mmol) in toluene (16.3 mL) was treated with p-toluenesulfonic acid monohydrate (246 mg, 1.30 mmol) and heated at reflux in a flask fitted with a Dean-Stark trap filled with sieves. The reaction mixture was cooled and poured into saturated sodium bicarbonate (150 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography (100% hexanes to 10% EtOAc/hexanes) gave the desired product (2.25 g, 57%) as a mixture of enantiomers. LCMS calculated for C15H18ClFIO5 (M+H)+: m/z=459.0; found: 459.0.
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[CH2:8]([NH:10][C:11]([NH2:13])=[NH:12])[CH3:9].S([O-])([O-])(=O)=O.[Na+].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][CH:23]=1>CC(C)=O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:13][C:11]([NH:10][CH2:8][CH3:9])=[NH:12])=[O:30])=[CH:24][CH:23]=1
Reactant: CCNC(=N)N
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCNC(=N)NC(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
A mixture of a 50% aqueous solution of sodium hydroxide (8.80 g), ethylguanidine sulfate (14.98 g), and 100 ml of acetone is stirred for 21/2 hrs at RT. The reaction mixture is treated with anhydrous sodium sulfate (6.0 g) and stirred for 1 hr. A solution of 4-chlorophenylacetylchloride (9.45 g) in 50 ml acetone is added to the reaction mixture dropwise and the mixture stirred overnight. The mixture is filtered, and the filtrate diluted with 100 ml of saturated aqueous sodium bicarbonate and the acetone evaporated in vacuo. The aqueous mixture is diluted with 100 ml of H2O and extracted with two 100 ml portions of methylene chloride. The combined extracts are dried with sodium sulfate, filtered and evaporated in vacuo. The resulting solution is treated with ethereal hydrochloric acid, and the solvent evaporated in vacuo. The residue is stirred with 200 ml of diethyl ether for 1/2 hr. The diethyl-ether insoluble solid is collected and dried in air. The product is recrystallized from CH3CN to afford 6.03 g of white crystalline solid, M.P. 146°-147° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]([OH:15])=O)=[CH:10][C:5]=2[N:4]=[CH:3]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:37][CH2:38][CH:39]([OH:51])[CH2:40][N:41]1[CH2:50][CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42]1>CN(C=O)C>[CH2:42]1[C:43]2[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:49][CH2:50][N:41]1[CH2:40][CH:39]([OH:51])[CH2:38][NH:37][C:13](=[O:15])[CH2:12][O:11][C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[CH:3]=[N:4][C:5]=2[CH:10]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: Cn1cnc2cc(OCC(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cn1cnc2cc(OCC(=O)NCC(O)CN3CCc4ccccc4C3)ccc21
Temperature: 29 °C
Reaction time: 16 h
Yield: 4.3 %

Procedure:
To a solution of 2-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)acetic acid (160 mg, 0.776 mmol) in DMF (4 ml) was added TEA (336 mg, 3.33 mmol), HOBt (157 mg, 1.164 mmol), EDCI (223 mg, 1.164 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (192 mg, 0.931 mmol) at 29° C. The reaction mixture was stirred for 16 h at 29° C. until TLC showed the reaction to be complete. After evaporation of the solvent, the mixture was purified by preparative HPLC to give the title compound (13.1 mg, 4.2%) as colorless oil. 1H NMR (400 MHz, MeOD) δ 8.05 (s, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.21 (d, J=2.0 Hz, 1H), 7.09-6.97 (m, 5H), 4.59 (s, 2H), 4.03-3.97 (m, 1H), 3.84 (s, 3H), 3.65 (dd, J1=14.8 Hz, J2=30.4 Hz, 2H), 3.47-3.42 (m, 2H), 2.88 (t, J=5.6 Hz, 2H), 2.72 (t, J=5.6 Hz, 2H), 2.53-2.51 (m, 2H). LCMS (m/z): 395.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12](C(OCC)=O)[CH2:11]2)=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1.[OH-].[K+]>C(O)(C)C>[NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: CCOC(=O)N1CCOC(CNC(=O)c2cc(Cl)c(N)cc2OC)C1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CNCCO1
Reaction time: 3 h
Yield: 28.5 %

Procedure:
A mixture of 4-amino-5-chloro-N-[(4-ethoxycarbonyl-2-morpholinyl)methyl]-2-methoxybenzamide (6.1 g), potassium hydroxide (10.1 g), and isopropyl alcohol (60 ml) is refluxed with stirring for 3 hours. The reaction mixture is concentrated under reduced pressure, and the residue is diluted with water and extracted with chloroform. The organic layer is washed successively with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is recrystallized from isopropyl alcohol to give the title compound (1.4 g), mp 161°-162° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH:10]=O)[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br-].[CH2:13]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O1CCCC1.[C].[Pd].CN(C)C=O>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)c1cc(C=O)[nH]n1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CCc2ccccc2)[nH]n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 83.2 %

Procedure:
A mixture of 3-tert-butyl-1H-pyrazole-5-carbaldehyde (1.52 g, 10.0 mmol), benzyltriphenylphosphonium bromide (6.50 g, 15.0 mmol), potassium carbonate (2.76 g, 20.0 mmol) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 14 hr. The reaction mixture was poured into 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was purified by silica gel column chromatography (5%-80% ethyl acetate/hexane) to give pale-yellow crystals. The obtained crystals were dissolved in a mixed solvent of ethanol (50 mL) and tetrahydrofuran (50 mL), and 10% palladium-carbon (50% water-containing product, 2.0 g) was added. The mixture was stirred under an atmospheric hydrogen atmosphere for 3 hr. The insoluble material was filtered off, and the filtrate was concentrated to give the title compound (1.90 g, yield 83%) as colorless crystals. 1H NMR (CDCl3) δ: 1.31 (9H, s), 2.90-2.99 (4H, m), 5.89 (1H, s), 7.18-7.33 (5H, m).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:19]=[CH:18][C:17]2[O:16][C:15]3[C:10](=[CH:11][C:12]([C:20](=[O:24])[CH2:21][CH2:22]Cl)=[CH:13][CH:14]=3)[CH2:9][C:8]=2[CH:7]=1)=[O:5].[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([N:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][C:4]([C:6]3[CH:19]=[CH:18][C:17]4[O:16][C:15]5[C:10](=[CH:11][C:12]([C:20](=[O:24])[CH2:21][CH2:22][N:34]6[CH2:35][CH2:36][N:31]([C:25]7[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=7)[CH2:32][CH2:33]6)=[CH:13][CH:14]=5)[CH2:9][C:8]=4[CH:7]=3)=[O:5])[CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(CCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCl)ccc1O2
Reactant: c1ccc(N2CCNCC2)cc1
Product: O=C(CCN1CCN(c2ccccc2)CC1)c1ccc2c(c1)Cc1cc(C(=O)CCN3CCN(c4ccccc4)CC3)ccc1O2

Procedure:
Prepared from compound 17 and 4-phenyl-piperazine according to General Procedure C to give a solid. Mp 206-208° C. 1H NMR (CDCl3, 400 MHz) δ7.91-7.86 (m 4H), 7.29 (t, J=10 Hz, 4H), 7.14 (d, J=10 Hz, 2H), 6.96-6.91 (m, 6H), 4.16 (s, 2H), 3.51-3.46 (m, 12H), 3.38-3.10 (m, 12H). Anal. (C39H42N4O3.).
Reaction SMILES: Br[CH:2]([CH2:19][CH3:20])[C:3]([NH:5][C:6]1[S:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][N:10]=1)=[O:4].[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>CN(C)C=O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[S:7][C:6]([NH:5][C:3](=[O:4])[CH:2]([N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])[CH2:19][CH3:20])=[N:10][CH:9]=1
Reactant: CCNCC
Reactant: CCC(Br)C(=O)Nc1ncc(Cc2ccccc2Cl)s1
Solvent: CN(C)C=O
Product: CCC(C(=O)Nc1ncc(Cc2ccccc2Cl)s1)N(CC)CC

Procedure:
2-Bromo-N-[5-(2-chloro-benzyl)-thiazol-2-yl]-butyramide (37 mg, 0.10 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide containing diethylamine (146 mg, 2.00 mmol). The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80° C. The crude mixture was evaporated to dryness and purified by reverse-phase preparative liquid chromatography (14 mg, 0.038, 38%). ESI-MS m/z calc. 365.1, found 366.2 (M+1)+ Retention time 2.18 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:52])([CH3:51])[C:29]([F:50])([F:49])[C@:30]([C:33]3[CH:38]=[C:37](B4OC(C)(C)C(C)(C)O4)[CH:36]=[CH:35][C:34]=3[F:48])([CH3:32])[N:31]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Cl[C:54]1[S:55][C:56]2[CH:62]=[C:61]([Cl:63])[CH:60]=[CH:59][C:57]=2[N:58]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:52])([CH3:51])[C:29]([F:49])([F:50])[C@:30]([C:33]3[CH:38]=[C:37]([C:54]4[S:55][C:56]5[CH:62]=[C:61]([Cl:63])[CH:60]=[CH:59][C:57]=5[N:58]=4)[CH:36]=[CH:35][C:34]=3[F:48])([CH3:32])[N:31]=2)([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(B4OC(C)(C)C(C)(C)O4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4nc5ccc(Cl)cc5s4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 75.6 %

Procedure:
Reaction of [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-6,6-difluoro-5-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl}-amine (intermediate B10.2) (35 mg, 49 μmol) with 2,6-dichlorobenzo[d]thiazole (13.4 mg, 63.7 μmol) yielded the [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-5-[5-(6-chloro-benzothiazol-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl}-amine (28 mg, 76% yield) as a light yellow solid. MS (ISP): m/z=756.4 [M+H]+ and 758.3 [M+2+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH2:12][OH:13])[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:20][C:21]1[C:22](F)=[CH:23][C:24]([F:34])=[C:25]([CH:33]=1)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].Cl>CS(C)=O>[Cl:20][C:21]1[C:22]([O:13][CH2:12][C:2]2([CH3:1])[CH2:11][CH2:10][C:5]3([O:6][CH2:7][CH2:8][O:9]3)[CH2:4][CH2:3]2)=[CH:23][C:24]([F:34])=[C:25]([CH:33]=1)[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: CC1(CO)CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)CCC2(CC1)OCCO2
Temperature: 70 °C
Reaction time: 16 h
Yield: 45.3 %

Procedure:
To a solution of (8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)methanol (0.301 g, 1.65 mmol) in anhydrous dimethylsulfoxide (3 mL) were added cesium carbonate (1.07 g, 3.30 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (0.37 g, 1.49 mmol) and the reaction mixture was stirred at 70° C. for 16 hours. The reaction mixture was cooled down to room temperature and acidified to pH=1 with 5% aqueous hydrochloric acid solution and extracted with diethyl ether (2×15 mL). The combined organic layers were washed with brine (15 mL); dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography (0 to 10% ethyl acetate in hexanes) afforded the title compound (0.28 g, 45%). 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J=7.67 Hz, 1H), 6.60 (d, J=12.13 Hz, 1H), 3.96-3.89 (m, 4H), 3.72 (s, 1H), 1.98-1.37 (m, 17H), 1.12 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:7](=[O:10])[CH2:8][CH3:9])[NH:5][CH:6]=1.I[CH2:12][C:13]([F:16])([F:15])[F:14].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([C:7](=[O:10])[CH2:8][CH3:9])[N:5]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH:6]=1
Reactant: CCC(=O)c1cc(I)c[nH]1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC(=O)c1cc(I)cn1CC(F)(F)F
Temperature: 60 °C

Procedure:
A mixture of 1-(4-Iodo-1H-pyrrole-2-yl)-propan-1-one (3.8 g, 15.3 mmol), 2-Iodo-1,1,1-trifluoroethane (3.83 g, 18.3 mmol) and Cs2CO3 (5.96 g, 183 mmol) in 20 ml DMF is heated with stirring to 60° C. for until the reaction is finished (TLC). The mixture then is cooled to room temperature and partitioned between water (200 ml) and ether (100 ml), the ether phase is separated and dried with MgSO4. The product is purified by flash chromatography with solvent EtOAc/hexane (10/90) to afford the product as an oil which solidified upon standing 1.8 g (35%). 1HNMR (DMSO-d6): δ (ppm) 1.00 (t, 3H), 2.79 (q, 2H), 5.29 (q, 2H), 7.36 (s, 1H), 7.39 (s, 1H).
Reaction SMILES: [N:1]12[C:7](=[O:8])[CH2:6][CH:5]1[CH2:4][C:3](=[O:9])[CH:2]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(CC)CC)C.[CH2:27]=[C:28]=[O:29]>>[C:28]([O:9][C:3]1[CH2:4][CH:5]2[N:1]([C:7](=[O:8])[CH2:6]2)[C:2]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:29])[CH3:27]
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Reactant: C=C=O
Solvent: CCN(CC)CC
Product: CC(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1

Procedure:
A solution of benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (13 mg, 0.05 mmol) in anhydrous CH2CL2 (1 ml) is cooled in an ice-bath and treated with triethylamine (Et3N) (7 μl, 0.05 mmol). Ketene is passed through the resulting solution for 10 mins. The solvent and excess ketene are removed in vacuo to leave crude benzyl 3-acetoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate
Reaction SMILES: CON(C)[C:4](=[O:14])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[CH3:16][Mg]Br>O1CCCC1.CCCCCCC>[CH3:6][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[C:4](=[O:14])[CH3:16]
Reactant: CON(C)C(=O)C(C)(C)c1ccccc1
Reactant: C[Mg]Br
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(=O)C(C)(C)c1ccccc1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To 2.1 g (10.1 mmol) of N-Methoxy-N-methyl-2-phenyl-isobutyramide in 80 ml of dry tetrahydrofuran at ambient temperature was added 6.7 ml (20.2 mmol) of 3M methymagnesium bromide in heptane, and the solution was warmed to 60° C. After 6 hours, the mixture was allowed to cool to ambient temperature and was quenched with 1M HCl. The resulting mixture was partitioned between water and ether, and the phases were separated. The ether phase was washed once each with 1M HCl and brine, dried over Na2SO4, filtered, and concentrated in vacuo to an oil. The oil was chromatographed to give the title compound as a clear oil: 1H NMR CDCl3 δ (ppm): 1.49 (s, 6H), 1.93 (s, 3H), 7.24-7.34 (m, 5H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][CH2:28][C@@H:29]([OH:33])[C@H:30]([OH:32])[CH3:31])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[OH:33][C@@H:29]([C@H:30]([OH:32])[CH3:31])[CH2:28][O:27][C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)[N:26]=1
Reactant: C[C@@H](O)[C@H](O)COc1nc(N2CCN(C(=O)OCc3ccccc3)CC2)nc2ccccc12
Agent: [Pd]
Solvent: CO
Product: C[C@@H](O)[C@H](O)COc1nc(N2CCNCC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.4 %

Procedure:
2-[4-(Benzyloxycarbonyl)piperazin-1-yl]-4-[(2R,3R)-(2,3-dihydroxybutan-1-yl)oxy]quinazoline (1.3 g) is dissolved in methanol (20 ml), and thereto is added 10% palladium/carbon (0.4 g), and the mixture is stirred under hydrogen atmosphere and under atmospheric pressure at room temperature for 16 hours. The reaction mixture is filtered, and the filtrate is evaporated to dryness under reduced pressure to give 4-[(2R,3R)-(2,3-dihydroxybutan-1-yl)oxy]-2-(1-piperazinyl)quinazoline (0.9 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])=[CH:6][C:3]=1[C:4]#[N:5].[F:19][CH:20]([C:23]1[CH:32]=[CH:31][C:26]2[C:27](=[O:30])[O:28][CH2:29][C:25]=2[CH:24]=1)[CH:21]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:21][CH:20]([F:19])[C:23]3[CH:32]=[CH:31][C:26]4[C:27](=[O:30])[O:28][CH2:29][C:25]=4[CH:24]=3)[CH2:14][C:13]2=[O:18])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(CCN2CCNCC2=O)ccc1F
Reactant: O=CC(F)c1ccc2c(c1)COC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cc(CCN2CCN(CC(F)c3ccc4c(c3)COC4=O)CC2=O)ccc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a flask charged with 2-Fluoro-5-[2-(2-oxopiperazin-1-yl)ethyl]benzonitrile (53 mg, 0.25 mmol) and Fluoro(1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (20 mg, 0.10 mmol) was added NaBH(OAc)3 (153 mg, 0.72 mmol). The mixture was stirred at RT for 12 hours. Then the reaction was diluted with DCM (120 mL), washed with brine (15 mL), dried over Na2SO4 and concentrated. The residue was purified with prep-TLC (MeOH/DCM=1:15) to obtain the title product. 1H-NMR (400 MHz, MeOD) δ ppm 7.88 (d, J=8.0 Hz, 1H), 7.55-7.65 (m, 4H), 7.25 (t, J=9.0 Hz, 1H), 5.90 (dd, J=7.6, 3.2 Hz, 1H), 5.78 (dd, J=7.6, 3.2 Hz, 1H), 5.39 (s, 2H), 3.59 (d, J=7.6, 7.0 Hz, 2H), 2.80-2.95 (m, 6H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(OO)(=[O:18])C>ClCCl>[CH2:14]([O:13][C:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][CH:2]=[N+:1]2[O-:18])=[CH:6][CH:7]=1)=[O:12])[CH3:15]
Reactant: CC(=O)OO
Reactant: CCOC(=O)c1ccc2cccnc2c1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2ccc[n+]([O-])c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of ethyl quinoline-7-carboxylate (1.02 g, 5.05 mmol) in dichloromethane (20 mL) was added peracetic acid (2.13 mL, 10.1 mmol, 32 wt % in acetic acid). The reaction was stirred at room temperature overnight. The reaction was partitioned between water and dichloromethane. The layers were separated and the aqueous was extracted with dichloromethane (4×). The combined organics were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The solid was concentrated from heptanes and ethyl acetate several times, then dried under vacuum to give the title compound (1.01 g, 92%) as a yellow solid. +ESI (M+H) 218.2; 1H NMR (400 MHz, CDCl3, δ): 9.40 (s, 1H), 8.65 (d, J=6.05 Hz, 1H), 8.27 (dd, J=8.58, 1.56 Hz, 1H), 7.95 (d, J=8.39 Hz, 1H), 7.82 (d, J=8.58 Hz, 1H), 7.42 (dd, J=8.49, 6.15 Hz, 1H), 4.47 (q, J=7.02 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5](O)=O.[NH2:12][NH:13][C:14]([NH2:16])=[S:15].P(Cl)(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH:2]1([NH:16][C:14]2[S:15][C:5]([C:4]3[CH:3]=[C:2]([OH:1])[C:10]([OH:11])=[CH:9][CH:8]=3)=[N:12][N:13]=2)[CH2:3][CH2:4][CH2:8][CH2:9][CH2:10]1
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: NNC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: Oc1ccc(-c2nnc(NC3CCCCC3)s2)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a mixture of 3,4-dihydroxybenzoic acid (2.885 mmol, 0.445 g), thiosemicarbazide (5b) (2.885 mmol, 0.500 g) in anhydrous dioxane (10 mL) was added phosphorus oxychloride (3.751 mmol, 0.350 mL) at 90° C., and the mixture of sodium bicarbonate to pH 7 then stirred at RT overnight. The precipitate was filtered, washed with hexane, then dried to give the title compound. Yield: 71%.