Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].O.[F:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][C:26]=1[F:27]>O1CCCC1>[C:15]([O:14][C:12]([NH:7][C@H:6]([CH2:10][CH2:9][C:8]([C:24]1[CH:23]=[CH:22][C:21]([F:20])=[C:26]([F:27])[CH:25]=1)=[O:11])[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Fc1ccc([Mg]Br)cc1F
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H](CCC(=O)c1ccc(F)c(F)c1)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (6.0 g) in tetrahydrofuran (100 mL), 3,4-difluorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran; 50 mL) was added dropwise at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. to 0° C. for two hours. Water was added to the solution in small portions, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 8.3 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][C:5]2[CH:22]=[CH:23][CH:24]=[CH:25][C:4]=2[CH2:3]1.[Br:26][CH:27]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45])[C:28](O)=[O:29].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl>[C:14]([O:13][C:11](=[O:12])[CH:10]([N:7]1[C:8](=[O:9])[CH:2]([NH:1][C:28](=[O:29])[CH:27]([Br:26])[CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[C:39](=[O:40])[C:38]3=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]3[C:36]2=[O:45])[CH2:3][C:4]2[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=2[CH2:6]1)[CH2:18][CH:19]([CH3:21])[CH3:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)CC(C(=O)OC(C)(C)C)N1Cc2ccccc2CC(N)C1=O
Reactant: O=C(O)C(Br)CCCCN1C(=O)c2ccccc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)CC(C(=O)OC(C)(C)C)N1Cc2ccccc2CC(NC(=O)C(Br)CCCCN2C(=O)c3ccccc3C2=O)C1=O
Reaction time: 17 h

Procedure:
Combine 2-(4-amino-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valeric acid, tert-butyl ester (0.34 mmol), 2-bromo-6-phthalimidohexanoic acid (0.189 g, 0.56 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.106 g, 0.55 mmol), and 1-hydroxybenztriazole hydrate ((75 mg, 0.56 mmol) in dicloromethane (8 mL). After 17 hours, evapoarte in vacuo to give a residue, partition the residue between ethyl aceate and an aqueous 5% sulfuric acid solution (about 20 mL). Separate the layers, extract the organic layer with a saturate aqueiosu sodium bicarbonate solution and then brine, dry over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([C:12]1[CH:25]=[CH:24][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=2)=[C:14]([CH2:26][CH2:27][CH3:28])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].ClC1C=CC=[C:34]([C:38]([O:40]O)=[O:39])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO>[C:38]([O:40][CH2:23][C:19]1[CH:18]=[C:17]([O:16][C:15]2[CH:24]=[CH:25][C:12]([C:3]([O:8][CH2:9][O:10][CH3:11])([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:29])[F:30])=[CH:13][C:14]=2[CH2:26][CH2:27][CH3:28])[CH:22]=[CH:21][N:20]=1)(=[O:39])[CH3:34]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccnc(C)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccnc(COC(C)=O)c1
Temperature: 140 °C
Yield: 55.6 %

Procedure:
To a solution of 4-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)-2-methylpyridine (780 mg, 1.78 mmol) in chloroform (2 mL), m-chloroperbenzoic acid (2.05 g) was added at room temperature and the resultant mixture was stirred. After completion of the reaction, the reaction solution was added with an aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and then dried using sodium sulfate. After filtration, the filtrate was concentrated in vacuo. The obtained residue was added with acetic anhydride and heated at a surrounding temperature of 140° C. After completion of the reaction, the reaction solution was added with methanol (4 mL) at room temperature, then neutralized by adding a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and then concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (490 mg, yield 56%) was obtained as a colorless oil.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([O:27]C)=[O:26])=[N:23][CH:24]=2)[C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.[OH-].[Na+]>O1CCCC1>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[N:23][CH:24]=2)[C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2sc3ccccc3c2C)C2CCCCC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)O)nc2)C2CCCCC2)sc2ccccc12
Reaction time: 8 h

Procedure:
To a mixture of methyl 5-{[cyclohexyl(3-methyl-1-benzothiophen-2-yl)methyl]amino}pyridine-2-carboxylate (460 mg) synthesized above, ethanol (5 mL) and tetrahydrofuran (5 mL) was added 1N aqueous sodium hydroxide solution (5.00 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), 1N hydrochloric acid (5.00 mL) was added at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (452 mg, quantitative) as a pale-brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:13][C:14]([CH3:19])=[CH:15][C:16](Cl)=[O:17].N1C=CC=CC=1.Cl>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:9]([CH:10]([CH3:12])[CH3:11])[C:16](=[O:17])[CH:15]=[C:14]([CH3:19])[CH3:13])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(C)=CC(=O)Cl
Reactant: Cc1ccc(NC(C)C)cc1Br
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)=CC(=O)N(c1ccc(C)c(Br)c1)C(C)C
Temperature: 0 °C
Reaction time: 5 h

Procedure:
(3-Bromo-4-methyl-phenyl)-isopropyl-amine (Compound 41, 36.78 g, 161.2 mmol) was dissolved in dichloromethane (200 mL) and the solution was cooled to 0° C. and treated with 3,3-dimethylacryloyl chloride (28.6 g, 241.8 mmol) and then pyridine (36 mL). The solution was stirred at 0° C. for 1 hour and at room temperature for 5 hours. The mixture was poured into separatory funnel containing dichloromethane and 10% aqueous HCl. The layers were separated and the aqueous layer extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried with MgSO4, filtered, and concentrated under reduced pressure to give the title compound, which was used directly for the next reaction without further purification, as a solid: Rf=0.48, 20% ethyl acetate in hexane:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Li]CCCC.[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:27]([CH:28]=[O:29])=[C:26]([CH3:30])[O:25][N:24]=2)=[N:21][CH:22]=1>C1COCC1>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:27]([CH:28]([OH:29])[CH2:1][C:2]3[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=3)=[C:26]([CH3:30])[O:25][N:24]=2)=[N:21][CH:22]=1
Reactant: Cc1onc(-c2ccc(F)cn2)c1C=O
Reactant: Cc1nc(C)c(C(=O)O)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(CC(O)c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Temperature: 25 °C
Yield: 50.8 %

Procedure:
To a stirred solution of 2,4-dimethyl-thiazole-5-carboxylic acid (650 mg, 7.0 mmol) in THF (33 mL) at −70° C. and under argon was added BuLi (1.6M in hexanes, 4.94 mL, 7.9 mmol) dropwise. After 2 h a solution of 3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazole-4-carbaldehyde (814 mg, 3.95 mmol) in THF (12 mL) was added dropwise. After 2 h the reaction mixture was quenched with citric acid solution (5%, 25 mL) then warmed to room temperature and extracted with ethyl acetate. The combined extracts were washed with brine, water, dried over sodium sulfate, filtered and concentrated. Purification by recrystallization (ethyl acetate) afforded the title compound (729 mg, 51%) as a light yellow solid. MS: m/e=362.2 [M+H]+.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].I[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.C(N(CC)CC)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[C:9]1([CH3:12])[CH:10]=[CH:11][C:6]([C:3]#[C:2][CH2:1][OH:4])=[CH:7][CH:8]=1
Reactant: Cc1ccc(I)cc1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C#CCO)cc1
Temperature: 35 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
Bis(triphenylphosphine)palladium(II) chloride (120 mg; 0.171 mmol) was added to a stirred solution of propargyl alcohol (5.38 g; 95.88 mmol, 1.02 eq), 1-iodo-4-methylbenzene (20.50 g; 94.0 mmol, 1 eq), triethylamine (18.99 g; 188 mmol, 2 eq), and copper iodide (60 mg; 0.32 mmol) in THF (50 mL). The mixture was stirred at 35° C. for 12 h under a nitrogen atmosphere. The mixture was then filtered through a bed of celite and the filtrate was washed with ethyl acetate. The filtrate was then concentrated at 35° C. (vac.=28 in Hg) using a rotary evaporator. The residue was purified using a silica gel column (4:1 heptane/ethyl acetate→2:1 heptane/ethyl acetate) to give the desired product as a light yellow oil (9.62 g; 65.8 mmol; 70%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.34 (s, 3 H) 4.48 (s, 2H) 7.11 (d, 2H) 7.33 (d, 2H).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].S(=O)(=O)(O)O.[CH2:11]([O:13][C:14]([C:16]1([CH3:35])[C:24]2[C:19](=[CH:20][C:21]([NH:25][C:26]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[O:27])=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:34])=[O:15])[CH3:12].N>>[CH2:11]([O:13][C:14]([C:16]1([CH3:35])[C:24]2[C:19](=[CH:20][C:21]([NH:25][C:26]([C:28]3[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=3)=[O:27])=[C:22]([N+:1]([O-:4])=[O:2])[CH:23]=2)[NH:18][C:17]1=[O:34])=[O:15])[CH3:12]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)C1(C)C(=O)Nc2cc(NC(=O)c3ccncc3)ccc21
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)C1(C)C(=O)Nc2cc(NC(=O)c3ccncc3)c([N+](=O)[O-])cc21
Reaction time: 1 h

Procedure:
A solution of 3.9 g. (0.038 mol) potassium nitrate in 30 ml. concentrated sulphuric acid is added dropwise, while cooling, to a solution of 13 g. (0.038 mol) 3-ethoxycarbonyl-3-methyl-6-(4-pyridinoylamino)-indolin-2-one in 90 ml. concentrated sulphuric acid. The reaction mixture is further stirred for about 1 hour, poured on to ice, adjusted to pH 8 with a concentrated aqueous solution of ammonia, while cooling, and the crystals obtained are filtered off with suction and recrystallised from ethanol/methylen chloride. Yield: 12.81 g. (82% of theory); m.p. 217°-219° C.
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[CH:8]=1)([CH3:6])[CH2:4][F:5].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH2:35][CH2:36][O:37][CH3:38])[N:30]=[CH:29][N:28]=[C:27]2[S:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43]>CN(C)C1C=CN=CC=1.C1COCC1>[F:5][CH2:4][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13]([NH:43][C:42]2[CH:44]=[CH:45][CH:46]=[C:40]([S:39][C:27]3[C:26]4[C:31](=[CH:32][C:33]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[C:24]([O:23][CH3:22])[CH:25]=4)[N:30]=[CH:29][N:28]=3)[CH:41]=2)=[O:21])[CH:8]=1)([CH3:6])[CH2:2][F:1]
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)on4)c3)c2cc1OC
Yield: 23 %

Procedure:
The title compound was prepared as described in Example 162B, using phenyl 5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate as described in Example 162A (0.089 g, 0.3 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline from the previous step (0.107 g, 0.3 mmol), and 4-(dimethylamino)pyridine (0.03 g) in THF (6 mL), to afford 1-[5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}urea as solid (0.038 g, 23%). 1H NMR (300 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.02 (s, 1H), 8.69 (s, 1H), 7.84 (m, 1H), 7.28-7.54 (m, 5H), 6.78 (s, 1H), 4.72 (s, 2H), 4.56 (s, 2H), 4.33 (m, 2H), 3.99 (s, 3H), 3.77 (m, 2H), 3.34 (s 3H), 1.29 (s, 3H); LC-MS (ESI) m/z 560 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][CH2:10][CH:11]=O>>[CH3:8][O:9][CH2:10][CH2:11][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: COCC=O
Product: COCCNc1ccccc1

Procedure:
The title compound was prepared from aniline and methoxyacetaldehyde by the same method as described for Example 5, part A. The residue was purified by flash chromatography on silica gel (ethyl acetate:hexanes/1:15) to give a pale yellow oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:16]=[CH:15][C:7]2[C:8](=[O:14])[NH:9][C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=1.Cl[CH2:18][O:19][CH3:20]>C1COCC1>[F:3][C:4]1[CH:16]=[CH:15][C:7]2[C:8](=[O:14])[N:9]([CH2:18][O:19][CH3:20])[C:10]([CH3:12])([CH3:13])[O:11][C:6]=2[CH:5]=1
Reactant: CC1(C)NC(=O)c2ccc(F)cc2O1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCN1C(=O)c2ccc(F)cc2OC1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.3 %

Procedure:
Sodium hydride (60% dispersion in oil) (45 mg, 1.13 mmol) was added to a solution of 7-fluoro-2,2-dimethyl-2,3-dihydro-4H-1,3-benzoxazin-4-one (0.2 g, 1.02 mmol) in THF (4 mL) at 0° C., under argon then allowed to warm to RT and chloromethylmethyl ether (0.086 mL, 1.13 mmol) added. The reaction was stirred at RT for 4 hours then poured into ice/water (50 mL) and extracted into ethyl acetate (50 mL). The organics were washed with brine (50 mL), dried (MgSO4), and the solvent removed in vacuo. The crude oil was chromatographed on silica, eluting with 10-50% ethyl acetate in isohexane, to give the desired compound as a white solid (0.13 g). 1H NMR δ (CDCl3): 1.66 (s, 6H), 3.31 (s, 3H), 5.00 (s, 2H), 6.53 (d, 1H), 6.67-6.72 (m, 1H), 7.89 (dd, 1H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH4+:23].[OH-]>CN(C=O)C.C(Cl)Cl>[CH2:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:23])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Cc2ccccc2)c1
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the product from Step A (0.0119 moles) was added 150 mL of CH2Cl2, one drop of DMF, 10 mL of oxalyl chloride, and the mixture was stirred at room temperature for 3 hours. After cooling to 10° C., 30 mL of NH4OH (exothermic) was added and the mixture was stirred for 30 min. The reaction mixture was then concentrated and the resulting residue diluted with ethyl acetate. The organic layer was washed with 1N NaOH, brine, dried over Na2SO4, and concentrated to give the 3-(benzyl)benzamide as a white solid, which was used without further purification.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]([F:32])([F:31])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]3[NH:27][CH:28]=[CH:29][C:22]=23)=[C:16]([F:30])[CH:15]=1)=[O:12].C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:29]1[C:22]2[C:23](=[N:24][CH:25]=[CH:26][C:21]=2[O:20][C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[C:10]([F:31])([F:9])[F:32])=[CH:15][C:16]=2[F:30])[NH:27][CH:28]=1
Reactant: O=C(Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1)C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc3[nH]cc(Cl)c23)c(F)c1)C(F)(F)F
Reaction time: 8 h

Procedure:
233 mg (1.75 mmol) of N-chlorosuccinimide are added to a solution of 540 mg (1.59 mmol) of 2,2,2-trifluoro-N-[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]acetamide in anhydrous tetrahydrofuran (20 ml). The solution is stirred overnight. 20 ml of a saturated sodium bicarbonate solution are added, and the mixture is extracted with ethyl acetate (two times 20 ml). The combined organic phases are washed with a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. This gives a solid which is not purified any further.
Reaction SMILES: [CH:1]1([N:7]([CH3:17])[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][CH:30]([OH:33])[CH2:31][OH:32])(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[CH:1]1([N:7]([CH3:17])[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][CH:30]([OH:33])[CH2:31][OH:32])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(S(=O)(=O)NCC(O)CO)cc1
Reactant: CN(c1cc(C(=O)O)ncn1)C1CCCCC1
Solvent: ClCCl
Product: CN(c1cc(C(=O)Nc2ccc(S(=O)(=O)NCC(O)CO)cc2)ncn1)C1CCCCC1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(methyl)amino]pyrimidine-4-carboxylic acid (Intermediate 10) and 4-amino-N-(2,3-dihydroxypropyl)benzenesulfonamide (Intermediate 14), the title compound was obtained as a white solid after trituration in DCM.
Reaction SMILES: [CH3:1][CH:2]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14]([CH3:20])=[N:15]3)[CH2:6][CH2:5]1.[C:28](O)(=[O:30])[CH3:29]>>[CH3:1][CH:2]([C:21]1[CH:22]=[C:23]([NH:24][C:28](=[O:30])[CH3:29])[CH:25]=[CH:26][CH:27]=1)[CH2:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14]([CH3:20])=[N:15]3)[CH2:8][CH2:9]1
Reactant: CC(=O)O
Reactant: Cc1ccc2c(N3CCN(CC(C)c4cccc(N)c4)CC3)cccc2n1
Product: CC(=O)Nc1cccc(C(C)CN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Yield: 75 %

Procedure:
The title compound was prepared in 75% yield according to the general procedure for the preparation of amides (Method C) starting from 3-{1-methyl-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D21) and acetic acid.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH:9]1[C:21]2[CH:20]([CH2:22][OH:23])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:9]1[C:21]2[CH:20]([CH2:22][O:23][C:5]([CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])=[O:6])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: OCC1c2ccccc2-c2ccccc21
Reactant: O=C1CCCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(O)CCCC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 60.6 %

Procedure:
To a solution of glutaric anhydride (1.0 g, 8.76 mmol) and (9H-fluoren-9-yl)methanol (1.56 g, 7.97 mmol) in CH2Cl2 (44 mL) was added DMAP (107 mg, 0.88 mmol) and the mixture was stirred for 20 h at room temperature. The reaction mixture was concentrated, diluted with H2O and saturated NaHCO3 solution and washed with ethyl acetate. The organic layer was extracted with saturated NaHCO3 solution (3×). The combined aqueous layers were acidified to pH=2 with conc. HCl solution, extracted with a 4:1 mixture of CHCl3/i-PrOH (3×′). The organic layers were combined, dried over MgSO4, filtered and concentrated to dryness, yielding acid 151 as a white solid (1.5 g, 61%). 1H NMR (400 MHz, CDCl3) δ 1.95 (quint, J=7.3 Hz, 2H), 2.40 (t, J=7.3 Hz, 2H), 2.47 (t, J=7.3 Hz, 2H), 4.21 (t, J=6.9 Hz, 1H), 4.43 (d, J=7.0 Hz, 2H), 7.32 (dt, J=7.4, 1.1 Hz, 2H), 7.41 (t, J=7.4 Hz, 2H), 7.59 (d, J=7.5 Hz, 2H), 7.78 (d, J=7.5 Hz, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:23]=[CH:22][C:6]2[C:7]([CH:10]3[CH2:15][NH:14][CH2:13][CH2:12][N:11]3[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[N:8][O:9][C:5]=2[CH:4]=1.C(O)(=O)C>CN(C=O)C>[N:19]1[CH:18]=[CH:17][C:16]([N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH:10]2[C:7]2[C:6]3[CH:22]=[CH:23][C:3]([OH:2])=[CH:4][C:5]=3[O:9][N:8]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc2c(C3CNCCN3c3ccncc3)noc2c1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Oc1ccc2c(C3CNCCN3c3ccncc3)noc2c1
Yield: 65.8 %

Procedure:
A stirred solution of 6-methoxy-3-[1-(4-pyridyl)piperazinyl]-1,2-benzisoxazole (1.75 g) and sodium ethylthiolate (0.79 g) in DMF (30 ml) was heated to 105°-107° C. under N2 for 3 hours. TLC (silica gel 30% MeOH/CH2Cl2) showed no presence of starting material. Glacial acetic acid (5 ml) was added and the solvent was removed in vacuo. The residue was flash chromatographed (silica gel) eluting with 10% MeOH/CH2Cl2 to afford 1.1 g of material. The material was further purified through recrystallization from pyridine to afford 1.0 g of the product, m.p. >250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[S-:19][C:20]#[N:21].[K+]>Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:17][CH:18]=2)[C:20]([NH2:21])=[S:19])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(CNc2ccc(Cl)cc2)cc1
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Product: NC(=S)N(Cc1ccc(C(=O)O)cc1)c1ccc(Cl)cc1
Yield: 74.1 %

Procedure:
A mixture of 4-[(4-chlorophenylamino)methyl]benzoic acid (33.3 g, 127 mmol) and potassium thiocyanate (37 g, 382 mmol) in 1 N hydrochloric acid (500 mL) was refluxed for 16 hours. The suspension was filtered and washed with water. The solid was mixed with potassium thiocyanate (37 g, 382 mmol) and 1 N hydrochloric acid (500 mL) and the mixture was again refluxed for 16 hours. Filtration, washing with water and re-submission to the reaction conditions above afforded 30.2 g (70%) of 4-[1-(4-chlorophenyl)thioureidomethyl]benzoic acid as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12](Cl)(=[O:15])[CH:13]=[CH2:14].O>O1CCCC1>[NH2:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12](=[O:15])[CH:13]=[CH2:14])=[CH:3][CH:4]=1)(=[O:9])=[O:10]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In 100 mL of tetrahydrofuran was dissolved 17 g of p-aminobenzenesulfonamide. This solution was cooled to 0° C. on an ice bath. To this solution was dropwise added 5 g of acryloyl chloride. After completion of the addition, the ice bath was removed and the reaction mixture was warmed to room temperature and stirred for 1 hour. Subsequently, the reaction mixture was heated at 60° C. for 1 hour. After completion of the reaction, the reaction mixture was poured into 1 L of distilled water. Thus, N-(p-aminosulfonylphenyl)acrylamide was obtained as precipitated white particles.