Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)(=[O:27])=[O:26])[CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[C:34](Cl)([CH3:36])=[O:35]>C(Cl)Cl.O>[C:34]([N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)(=[O:26])=[O:27])[CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1)(=[O:35])[CH3:36]
Reactant: CC(=O)Cl
Reactant: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCNCC4)c3n2)c1)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCC(Oc2ncnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)nc23)CC1
Reaction time: 2 h
Yield: 7.8 %

Procedure:
To a solution of N-(5-(4-(piperidin-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzene-sulfonamide (0.082 g, 0.177 mmol) in DCM (0.886 ml) was added TEA (0.062 ml, 0.443 mmol) at room temperature. After stiffing for 2 hours at room temperature, AcCl (0.019 ml, 0.266 mmol) was added to the mixture at 0° C. After stiffing overnight at room temperature, the reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep TLC (DCM:MeOH=20:1) to give N-(5-(4-(1-acetylpiperidin-4-yloxy)-pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide (0.007 g, 7%) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.05-2.18 (2H, m), 2.19 (3H, s), 3.53-3.59 (2H, m), 3.65-3.76 (2H, m), 3.89-3.40 (2H, m), 5.74-8.79 (1H, m), 7.44-7.48 (2H, m), 7.53-7.57 (1H, m), 7.86-7.89 (2H, m), 8.23 (1H, d, J=8.8 Hz), 8.36 (1H, d, J=8.8 Hz), 8.46 (1H, d, J=2.8 Hz), 8.53 (1H, d, J=2.4 Hz), 8.84 (1H, s), 9.12 (1H, d, J=1.6 Hz). m/z=505.1 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:1]=[CH:2][CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1
Reactant: O=C(O)CCCOc1ccc(CCCO)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCCc1ccc(OCCCC(=O)O)cc1
Reaction time: 4 h

Procedure:
A 1.19 g (5.00 mmol) sample of 4-[4-(3-hydroxypropyl)phenoxy]butanoic acid is dissolved with stirring in 250 mL of methylene dichloride. Next, 3.77 g (17.49 mmol) of pyridinium chlorochromate is added, the mixture is stirred for 4 hours, and then filtered through a celite pad. The reaction mixture is then diluted with an equal volume of ether, precipitating out salts. This mixture is then filtered through a silica gel pad, and the filtrate evaporated, giving a brown solid. The solid is recrystallized from an ether-hexane mixture producing 0.21 (18%) of 4-[4-(3-oxopropyl)phenoxy]butanoic acid as off-white crystals: m.p. 100°-03° C.; IR (KBr) 1715 cm-1 ; 1H-NMR (CDCl3) is consistent with the desired product; MS (CI) m/e 237 (M+ +H). Analysis calculated for C13H16O4 : C, 66.09; H, 6.83; O, 27.09. Found: C, 65.91; H, 6.72; O, 27.35.
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH:3]([OH:5])O.S([O-])([O-])(=O)=O.[Na+].[Na+].Cl.[NH2:16][OH:17].Cl.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[N:16](=[CH:2][C:3]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:5])[OH:17]
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: Nc1ccccc1
Reactant: NO
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(C=NO)Nc1ccccc1

Procedure:
25 mL H2O was added to chloral hydrate (1.49 g, 9 mmol) and anhydrous sodium sulfate (7.62 g, 54 mmol), and the mixture was rapidly stirred until clear. Hydroxylamine hydrochloride (6.84 g, 42 mmol) was added into dilute hydrochloric acid (9 mL H2O: 1 mL concentrated HCl), and then, aniline (1.23 g, 8 mmol) was added. The mixture was stirred to form a suspension. The suspension was added into an aqueous solution of chloral hydrate. After stirring for 5 min, the mixture was transferred to an oil bath at 45° C. and heated for 2 h. The reaction was finished by TLC detection, and the reaction system was stirred and cooled in an ice bath, filtered and dried, to obtain a solid oximino acetanilide.
Reaction SMILES: [CH2:1]([N:5]([CH3:11])[C:6](=O)[N:7]([CH3:9])[CH3:8])[CH2:2][CH2:3][CH3:4].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH2:1]([N:5]([CH3:11])[C:6]([N:7]([CH3:9])[CH3:8])=[N:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccccc1N1CCOCC1
Reactant: CCCCN(C)C(=O)N(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCCCN(C)C(=Nc1ccccc1N1CCOCC1)N(C)C

Procedure:
Reaction of 3-n-butyl-1,1,3-trimethylurea (7 g) in benzene (60 ml) with 4-(2-aminophenyl)morpholine (7.2 g) in benzene (30 ml) in the presence of phosphorus oxychloride (4 ml) for 18 hours at 80°-85° C. gave 1-n-butyl-2-(2-morpholinophenyl)-1,3,3-trimethyl guanidine (bp. 162°-163° C. at 0.7 mm Hg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:32])=[C:13]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C:16]2=[O:31])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]=[O:34].[OH-].[Na+]>O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:32])=[C:13]([C:15]2([CH2:33][OH:34])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C:16]2=[O:31])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(c2cc(OCc3ccccc3)ccc2O)c2ccccc2N1Cc1ccc(Cl)s1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1N(Cc2ccc(Cl)s2)c2ccccc2C1(CO)c1cc(OCc2ccccc2)ccc1O
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a mixture of 3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chlorothiophen-2-yl)methyl]-1,3-dihydro-2H-indol-2-one (2.80 g, 6.07 mmol), para-formaldehyde (0.73 g, 24.3 mmol) in tetrahydrofuran (10.0 mL) was added an aqueous solution of sodium hydroxide (0.97 g, 24.3 mmol) in water (10.0 mL) at 0° C. The reaction solution was stirred for 2 h, then quenched by the addition of 10% aqueous hydrochloric acid solution (30.0 mL). The reaction mixture was extracted with ethyl acetate (3×50 mL). The combined organic solution was washed with saturated ammonium chloride (3×50 mL), brine (50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was triturated with diethyl ether, filtered and dried to afford 3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chlorothiphen-2-yl)methyl]3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (2.71 g, 91%) as a colourless solid: MS (ES+) m/z 494.2 (M+1), 492.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccccc2)nc1
Temperature: 50 °C
Yield: 88.3 %

Procedure:
2,5-dibromopyridine (7.11 g, 30 mmol), toluene (130 mL), phenylboronic acid (4.57 g, 37.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.73 g, 1.5 mmol) were weighed into a reaction vessel, and the reaction mixture was dissolved with stirring at 50° C. in a nitrogen stream. To this solution, a 2 M aqueous sodium carbonate solution (30 mL) was added, and the mixture was stirred at 80° C. for 6 hours. The organic layer of the obtained reaction solution was collected and washed with an aqueous sodium carbonate solution and a saturated brine. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness. This residue was purified by silica gel column chromatography (hexane/toluene). The eluate was evaporated to obtain 5-bromo-2-phenylpyridine (6.21 g, 26.5 mmol).
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)C=1.[Cl:12][C:13]1[C:14]([S:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[NH:31][C:32](=[O:34])[O-:33])=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.[OH2:35]>C(Cl)Cl>[Cl:12][C:13]1[C:14]([S:23]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[NH:31][C:32](=[O:33])[O:34][CH3:2])=[O:35])=[N:15][CH:16]=[C:17]([C:19]([F:20])([F:22])[F:21])[CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O
Reactant: O=C([O-])Nc1ccccc1CSc1ncc(C(F)(F)F)cc1Cl
Solvent: ClCCl
Product: COC(=O)Nc1ccccc1CS(=O)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 20 h

Procedure:
0.41 g of m-chloroperbenzoic acid was added little by little to a solution of 0.75 g of N-[2-(3-chloro-5-trifluoromethyl-2-pyridylthiomethyl)phenyl]carbamate obtained in the same manner as Synthesis Example 1 (Compound No. 1) in 20 ml of methylene chloride under stirring At room temperature. After completion of the addition, the reaction was continued at room temperature for 20 hours. The reaction mixture was poured into water, subjected to extraction with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was washed with hexane. The precipitated solid was filtered off to obtain 0.66 g of the desired product (Compound No. 60) having a melting point of 160° to 162° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2].[NH:31]1[CH:35]=[C:34]([C:36]2[CH:37]=[C:38]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=2)[NH2:39])[CH:33]=[N:32]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CC(=O)OCC>N1C=CC=CC=1.O>[NH:31]1[CH:35]=[C:34]([C:36]2[CH:37]=[C:38]([NH:39][C:27](=[O:28])[CH2:26][C:23]3[CH:24]=[CH:25][C:20]([C:6]4[CH:7]=[N:8][C:9]([O:10][CH2:11][C:12]5[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=5)=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=4)=[CH:21][C:22]=3[F:30])[CH:40]=[C:41]([C:43]([F:45])([F:46])[F:44])[CH:42]=2)[CH:33]=[N:32]1
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Reactant: Nc1cc(-c2cn[nH]c2)cc(C(F)(F)F)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(-c4cn[nH]c4)cc(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a mixture of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (15 mg, 0.036 mmol) in pyridine (3 mL) were added 3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)aniline (8.28 mg, 0.036 mmol) and T3P® (EA solvate) (0.5 mL, 0.036 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was added to water and concentrated to afford N-(3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (50 mg, 0.024 mmol, 66.3% yield). TLC (DCM/MeOH=15:1, Rf=0.5): 1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.82 (s, 1H), 7.58 (s, 1H), 7.37 (s, 2H), 7.32-7.30 (m, 4H), 7.25-7.23 (m, 2H), 6.89-6.86 (m, 3H), 5.36 (s, 2H), 4.15-4.09 (m, 2H), 3.83 (s, 2H), 3.77 (s, 3H), 1.46 (t, J=6.8 Hz, 3H). ES-LCMS m/z 621.2 (M+H).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:44])[C@H:11]([N:20]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]2[O:41][CH2:42][O:43][C:37]=2[CH:36]=1)[S:21]([C:24]1[C:29]([CH3:30])=[CH:28][C:27]([O:31][CH3:32])=[CH:26][C:25]=1[CH3:33])(=[O:23])=[O:22])[CH2:12][O:13]C1CCCCO1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([O:8][NH:9][C:10](=[O:44])[C@H:11]([N:20]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]2[O:41][CH2:42][O:43][C:37]=2[CH:36]=1)[S:21]([C:24]1[C:29]([CH3:30])=[CH:28][C:27]([O:31][CH3:32])=[CH:26][C:25]=1[CH3:33])(=[O:23])=[O:22])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](COC2CCCCO2)C(=O)NOCc2ccccc2)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CO)C(=O)NOCc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.6 %

Procedure:
To a solution of N-benzyloxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-(tetrahydropyran-2-yloxy)propionamide (1.7 g, 4.3 mmol) in methanol (100 mL) at 0° C. was added p-toluenesulfonic acid monohydrate (150 mg). After 12 h, the reaction mixture was warmed to room temperature and stirred for an additional 5 h. The reaction mixture was concentrated and the residue was chromatographed (Biotage 40M; 20% to 50% ethyl acetate-hexanes) to afford N-benzyloxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-hydroxypropionamide (1.60 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[NH:15][C@@H:14]([C:16](=[O:18])[CH3:17])[CH2:13][O:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[CH3:19][Mg]Br>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[F:9][C:6]1[CH:5]=[C:4]([C@H:10]2[NH:15][C@@H:14]([C:16]([OH:18])([CH3:19])[CH3:17])[CH2:13][O:12][CH2:11]2)[CH:3]=[C:2]([F:1])[C:7]=1[F:8]
Reactant: C[Mg]Br
Reactant: CC(=O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1

Procedure:
To a solution of 1-[(3R,5R)-5-(3,4,5-trifluorophenyl)morpholine-3-yl]ethanone (529 mg) in tetrahydrofuran (25 mL) was, under a nitrogen atmosphere, dropwise added methylmagnesium bromide (0.97 M tetrahydrofuran solution, 4.63 mL) at 0° C. The resultant solution was stirred for 1 hour at the same temperature, and then diluted with aqueous ammonium chloride and ethyl acetate. The organic layer was partitioned, washed with brine, and then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane/ethyl acetate), to thereby obtain the titled compound (330 mg). The physical properties of this crude product were as follows.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][CH:6]([CH2:10][CH3:11])[C:7](Cl)=[O:8].[C:12]1([S:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C(Cl)(Cl)Cl>[CH3:19][S:18][C:12]1[CH:17]=[CH:16][C:15]([C:7](=[O:8])[CH:6]([CH3:5])[CH2:10][CH3:11])=[CH:14][CH:13]=1
Reactant: CCC(C)C(=O)Cl
Reactant: CSc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC(C)C(=O)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of AlCl3 (35.4 g) in CHCl3 (500 mL) at −10° C. was added dropwise 2-methylbutyryl chloride (3.13 g) followed by thioanisole (31.2 mL). The mixture was then stirred at r.t. for 20 min. and was then cooled back to 0° C. Water (200 mL) was then added over 30 min. The CHCl3 layer was separated and dried over MgSO4. After filtration and removal of the solvent, the residue was dried under vacuum at 80° C. for 2 h to give 35 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH2:36]([NH2:41])[CH2:37][CH2:38][CH2:39][CH3:40].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28]([NH:41][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:34]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: CCCCCN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was dissolved in chloroform (5 ml) and triethylamine (1 ml), and a solution of triphosgene (45 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, amylamine (26 μl) was added to the reaction solution, and the mixture was stirred at room temperature for additional 30 min. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 33 mg (yield 49%) of the title compound.
Reaction SMILES: C[O-].[Na+].O=[C:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:6][CH2:7][CH:8]=O.[CH:17]1[CH2:21][CH:20]=[CH:19][CH:18]=1.C(Cl)Cl>CO>[CH2:10]([C:5]1[CH:6]=[CH:7][CH:8]=[C:17]2[C:18]=1[CH:19]=[CH:20][CH2:21]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCC(=O)CCC=O
Reactant: C1=CCC=C1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCc1cccc2c1C=CC2
Temperature: 0 °C
Reaction time: 3 h
Yield: 33.5 %

Procedure:
20.4 ml of a 30 percent strength solution of sodium methanolate (111 mmol) in methanol were initially introduced into the reaction vessel at 0° C., and a mixture of 9.0 g (44.5 mmol) of 4-oxoundecylaldehyde and 4.0 ml (49 mmol) of cyclopentadiene was added in the course of 30 minutes. After the mixture had been stirred at 0° C. for 2 hours and at room temperature for a further 3 hours, it was hydrolyzed, methylene chloride was added and the mixture was filtered over Corolite. The organic phase was separated off, dried over MgSO4 and evaporated. Column chromatography with hexane as the mobile phase gave 3.2 g (34%) of the indene 17. For the NMR data, see Table 1.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Cl:7][C:8]1[C:9](I)=[CH:10][C:11]([OH:18])=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14]>C(N(CC)CC)C.[Cu]I.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>[Cl:7][C:8]1[C:9]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:10][C:11]([OH:18])=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(Cl)c(I)cc1O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)cc1O
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 95.3 %

Procedure:
A solution of copper (I) iodide (1.1 g, 5.8 mmol) in triethylamine (32 mL) was degassed with nitrogen, treated with (trimethylsilyl)acetylene (4.5 mL, 32 mmol), degassed with nitrogen, and stirred at 20° C. for 10 minutes. The reaction mixture was treated with bis(triphenylphosphine)palladium(II) chloride (0.56 g, 0.80 mmol), degassed with nitrogen, and stirred at 20° C. for 30 minutes. The reaction mixture was treated with methyl 5-chloro-2-hydroxy-4-iodobenzoate (5.0 g, 16 mmol), degassed with nitrogen, and stirred at 75° C. for 2 hours. The reaction mixture was filtered over celite, washed with ethyl acetate, and concentrated to a crude residue. Purification via flash column chromatography using ethyl acetate in hexanes (0%-20%) gave the desired product (4.31 g, 95%). LCMS for C13H16ClO3Si (M+H)+: m/z=283.1; Found: 282.9.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[N:9]([CH3:10])[C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[N:6]=2)[CH2:2]1.[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[C:18]([CH3:23])[N:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O.CCOC(C)=O>[Cl:15][C:16]1[N:17]=[C:18]([CH3:23])[N:19]=[C:20]([N:1]2[CH2:4][CH:3]([C:5]3[N:9]([CH3:10])[C:8]4[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=4[N:6]=3)[CH2:2]2)[CH:21]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: Cn1c(C2CNC2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)cc(N2CC(c3nc4ccccc4n3C)C2)n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
Intermediate 1 (8.2 g, 43.8 mmol), 4,6-dichloro-2-methylpyrimidine 2-1 (8.2 g, 50.4 mmol) and Cs2CO3 (21.4 g, 65.7 mmol) were suspended in DMA (100 mL) and the mixture was stirred at 50° C. for 3 h. The mixture was cooled to rt, diluted with EtOAc (200 mL), and washed sequentially with water, brine, and water (150 mL each). The combined aqueous phase was back extracted with EtOAc (2×100 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated to give a brownish solid. The solid was triturated with a diethyl ether/DCM mixture (95/5) and then filtered and dried under vacuum to give Intermediate 3 as a light brown solid (10.2 g, 74%). MS: m/z=314.2 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:31]=[C:30]([C:32]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([OH:42])[CH:37]=2)=[O:33])[CH:29]=[C:28]([CH3:43])[C:10]=1[C:11]([NH:13][C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:15][NH:16]C(OC(C)(C)C)=O)=[O:12].Cl.C(#N)C>ClCCl>[ClH:8].[NH2:16][CH2:15][C@@H:14]([C:24]([O:26][CH3:27])=[O:25])[NH:13][C:11](=[O:12])[C:10]1[C:28]([CH3:43])=[CH:29][C:30]([C:32]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([OH:42])[CH:37]=2)=[O:33])=[CH:31][C:9]=1[Cl:8]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: Cl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CN)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (20 mL) was added to a solution of N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-6-methylbenzoyl]-3-[[(1,1-dimethylethoxy)carbonyl]amino]-L-alanine, methyl ester (800 mg, 1.54 mmol) in dichloromethane (20 mL). The solution was stirred at room temperature for 1 h. The reaction mixture was concentrated, azeotroped three times with dichloromethane/hexanes, and then held under high vacuum for 35 min. 1 M HCl (4.6 mL, 4.6 mmol) was added, along with acetonitrile (4 mL) and the mixture was freeze-dried overnight to give crude 3-amino-N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-6-methylbenzoyl]-L-alanine, methyl ester hydrochloride (0.85 g, 120% of the theoretical amount).
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:37])[NH:11][C:12]2[C:13]([CH3:36])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([C:32](=[NH:35])[NH:33][OH:34])[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:46](OCC)=[O:47]>C(Cl)Cl>[C:1]1([C@H:7]([O:9][C:10](=[O:37])[NH:11][C:12]2[C:13]([CH3:36])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([C:32]5[NH:33][O:34][C:46](=[O:47])[N:35]=5)[CH2:30][CH2:31]4)=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=N)NO)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1noc(-c2ccc(-c3ccc(C4(c5nc(=O)o[nH]5)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (5-{4′-[1-(N-hydroxycarbamimidoyl)-cyclopropyl]-biphenyl-4-yl}-3-methyl-isoxazol-4-yl)-carbamic acid (R)-1-phenyl-ethyl ester (0.66 mmol) in CH2Cl2 (5 mL) was added triethylamine (0.19 mL, 1.32 mmol) and ethyl chloroformate (0.127 mL, 1.32 mmol), and the reaction was stirred overnight at room temperature. Additional triethylamine (0.19 mL, 1.32 mmol) was added, and the reaction was stirred for 6 hours. Additional triethylamine (0.19 mL, 1.32 mmol) was added, and the reaction was stirred until complete. The mixture was diluted with CH2Cl2 (20 mL) and washed with 10% aqueous citric acid, and then dried over MgSO4, filtered, and concentrated. The residue was dissolved in toluene (10 mL), and the solution was refluxed for 3 days. After concentrating, the crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.