Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:10][N:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][NH:12]3)[CH:5]=[CH:4][N:3]=1.IC.[C:26](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:10][N:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][N:12]3[CH3:26])[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(-c2nn3c(c2-c2ccnc(Cl)n2)CCCN3)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCCc2c(-c3ccnc(Cl)n3)c(-c3ccc(F)cc3)nn21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(2-chloro-4-pyrimidinyl)-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-b]pyridazine (i.e. the product of Step A) (50.0 mg, 0.15 mmol), iodomethane (0.019 mL, 0.31 mmol) and potassium carbonate (63 mg, 0.46 mmol) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 2 h, followed by at 50° C. for 1 h and then at 100° C. for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The combined organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by medium pressure liquid chromatography using 20-80% ethyl acetate in hexanes as eluant to give 37.4 mg of the title product, a compound of the present invention, as a white solid.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[C:23]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16](=[N:24]O)[C:15]=4[CH:14]=[CH:13][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[F:26]>[Ni].C(O)C.O1CCCC1>[F:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[C:23]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH:16]([NH2:24])[C:15]=4[CH:14]=[CH:13][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[F:26]
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2c(F)c(F)ccc2[nH]1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: NC1c2ccccc2-c2c(-c3nc4c(F)c(F)ccc4[nH]3)cccc21
Yield: 26 %

Procedure:
The procedure used in Example 6 is followed, but starting from 4 g of 4-(4,5-difluoro-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, and 0.27 g of Raney nickel in 35 ml of ethanol and 35 ml of tetrahydrofuran for 10 hours at 60° C. under an initial hydrogen pressure of one bar. After filtration of the catalyst, and purification by forming a paste in diisopropyl ether, in this way we obtain 1 g of 4-(4,5-difluoro-1H-benzimidazol-2-yl)-9H-fluoren-9(R,S)-ylamine, in the form of a beige powder which is used as it is in the following stage.
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([N+:17]([O-:19])=[O:18])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C.Cl.O.[OH-].[Na+]>C(O)(=O)C>[NH2:4][C:5]1[CH:13]=[C:12]([N:14]([CH3:15])[CH3:16])[C:11]([N+:17]([O-:19])=[O:18])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CC(=O)Nc1cc(N(C)C)c([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CN(C)c1cc(N)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
A mixture of 2-acetylamino-4-dimethylamino-5-nitrobenzoic acid (6.5 g), concentrated hydrochloric acid (20 ml), and water (80 ml) is stirred at 100° C. for 30 minutes. After cooling, solid sodium hydroxide (5 g) and then 10% aqueous sodium hydroxide solution are added until the mixture becomes a clear solution. The resulting solution is adjusted to the pH of about 4 with acetic acid. The precipitate is collected and recrystallized from methanol to give the title compound (4.8 g), mp 240°-250° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:6]([N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[N:7]1)[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:4]=1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1cnn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Nitro-1H-indazole (1.0 g, 6.13 mmol) and potassium carbonate (1.69 g, 12.3 mmol) were added to DMF and stirred at room temperature overnight. Water (50 mL) was added and the product was extracted with ethyl acetate and dried over magnesium sulfate. Crude, brown solid was purified on silica gel using hexanes/ethyl acetate. First isolated peak (730 mg) was the desired 1-benzyl regio-isomer, as confirmed by NMR.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[Cl:59]C1C=CC(C(Cl)=O)=CC=1>>[Cl:59][C:5]1[CH:4]=[CH:3][C:2]([C:1]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]4=[O:25])=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)=[O:8])=[CH:7][CH:6]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(Cl)cc4)cc3)cc2C1=O

Procedure:
The compound of example 113 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 4-chlorobenzoyl chloride. The compound of example 113 was used directly without isolation for the preparation of compound of example 114.
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1.[CH3:22][N:23]([CH2:31][CH2:32][CH2:33][CH:34]=O)[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].S1C=CC=C1.[H][H]>CO.[Pt]>[NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:34][CH2:33][CH2:32][CH2:31][N:23]([CH3:22])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:11][C@H:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: [H][H]
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Reactant: CN(CCCC=O)C(=O)OC(C)(C)C
Agent: [Pt]
Solvent: c1ccsc1
Solvent: CO
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCCN(C)C(=O)OC(C)(C)C)C[C@H]1OC
Yield: 100 %

Procedure:
A mixture of 33 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide, 30 parts of (1,1-dimethylethyl) methyl(4-oxobutyl)carbamate, 3-parts of a solution of thiophene in methanol 4% and 400 parts of methanol was hydrogenated at normal pressure and at room temperature with 5 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 45.1 parts (100%) of (1,1-dimethylethyl) cis-[4-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinyl]butyl]methylcarbamate as a residue (interm. 8).
Reaction SMILES: [C:1]([C:3]1[C:9]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[C:8]([O:16][CH3:17])[C:7]([O:18][CH3:19])=[CH:6][C:4]=1[NH2:5])#[N:2].[C:20]([N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[CH2:25][CH2:24]1)(=O)[CH3:21]>ClCCl.CO>[CH3:17][O:16][C:8]1[C:9]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[C:3]([C:4]([N:5]=[C:20]([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[O:31])[CH2:25][CH2:24]2)[CH3:21])=[CH:6][C:7]=1[O:18][CH3:19])[C:1]#[N:2]
Reactant: CC(=O)N1CCCN(C(=O)N2CCOCC2)CC1
Reactant: COc1cc(N)c(C#N)c(OCC(F)(F)F)c1OC
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N=C(C)N2CCCN(C(=O)N3CCOCC3)CC2)c(C#N)c(OCC(F)(F)F)c1OC

Procedure:
The subtitle compound was prepared from 2-cyano-4,5-dimethoxy-3-(2,2,2-trifluoroethoxy)aniline and 1-acetyl-4-(4-morpholinecarbonyl)-1,4-diazepane following the procedure described in Example 10(g) (73%). Rf 0.16 (dichloromethane:methanol 95:5, v/v). MS m/z 514 (MH)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:16]I>C1(C)C=CC=CC=1.FC(F)(F)C([O-])=O.[Ag+]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([I:16])=[C:11]([OH:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: II
Reactant: Oc1cccc(OCc2ccccc2)c1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: Cc1ccccc1
Product: Oc1cc(OCc2ccccc2)ccc1I
Yield: 89.1 %

Procedure:
To a suspension of 3-(benzyloxy)phenol (5.00 g) and silver trifluoroacetate (5.52 g) in toluene (25 mL) was added dropwise a solution of iodine (6.35 g) in toluene (75 mL) over 30 min under ice-cooling. The reaction mixture was filtered, and to the organic layer were added saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (7.26 g).
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20]C(O)=O)[CH:17]=[CH:18][CH:19]=1>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[CH:20]=[C:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:6]1
Reactant: COc1cccc(CC(=O)O)c1
Reactant: O=C1OC(=O)c2ccccc21
Product: COc1cccc(C=C2OC(=O)c3ccccc32)c1
Temperature: 255 °C
Yield: 73.1 %

Procedure:
A mixture of phthalic anhydride (89.6 g, 0.605 mol), m-methoxyphenylacetic acid, (100.5 g, 0.605 mol), and freshly fused sodium acetate (3.0 g) is heated to 255° C. for 1 hour under a Dean-Stark receiver. The orange melt is poured onto aluminum foil and allowed to cool. The solid residue is recrystallized from absolute ethanol (2500 ml) to give 111.5 g (73%) of (3-methoxybenzal)phthalide as a yellow solid: m.p. 119°-123° C. Without further purification it (111.5 g, 0.441 mol) is hydrogenated with Raney nickel (6 tablespoons) at 25° C. and 40 psi in absolute ethanol (3000 ml). The catalyst is removed by filtration through super cel and the filtrate is evaporated to dryness under reduced pressure. The oily residue is slurried with methylene chloride (1000 ml) and extracted with aqueous saturated NaHCO3 (3×500 ml). The basic aqueous extracts are combined, warmed on a steam bath to remove excess methylene chloride, filtered, and the filtrate acidified with 6 N hydrochloric acid to give 70.9 g (63%) of 2-[2-(3-methoxyphenyl)-ethyl]benzoic acid as a white solid: m.p. 119°-122° C. Without further purification it (70.9 g, 0.276 mol) is treated with polyphosphoric acid (437 g) and heated to 100° C. After 2 hours, the reaction mixture is hydrolyzed in ice water and the aqueous phase is extracted with ether (3×300 ml). The combined etheral extracts are washed with aqueous saturated NaHCO3 (1×150 ml), H2O (2×150 ml), dried over MgSO4 and filtered, and the filtrate evaporated to dryness under reduced pressure. Treatment of the residue with ether gives 60.6 g (92%) of title compound as a light yellow solid: m.p. 74°-76° C.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:25])[C@H:7]([CH3:24])[NH:8][C:9](=[O:23])[C@@H:10]([NH:16][C@@H:17]([C:19]([O:21]C)=[O:20])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].C(O)(=O)C>CO>[CH2:1]([NH:5][C:6](=[O:25])[C@H:7]([CH3:24])[NH:8][C:9](=[O:23])[C@@H:10]([NH:16][C@@H:17]([C:19]([OH:21])=[O:20])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:13])[CH3:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@H](C)NC(=O)[C@H](CC(C)(C)C)N[C@H](C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCNC(=O)[C@H](C)NC(=O)[C@H](CC(C)(C)C)N[C@H](C)C(=O)O
Yield: 48 %

Procedure:
N-[2-(S)-N(1-(R)-Methoxycarbonylethyl)amino-4,4-dimethylpentanoyl]-L-alanine N-butylamide (65 mg) in methanol (30 ml) was treated with IN-sodium hydroxide (3 ml) at 20° for 6 h. Excess acetic acid was then added and the solvent evaporated in vacuo. The residue was chromatographed on reverse phase silica (RF 18) in a gradient of 20%-80% methanol in water. Elution in 70% methanol in water afforded the title compound (30 mg) as a freeze-dried powder, m.p. 137°-138°; (Found: [m+1]+ =344.2548. C17H34N3O4 requires [m+1]+ =344.2549); δ(D2O) 0.9 (3H,t,J=6 Hz,CH2CH3); 0.94 (9H,s,C(CH3)3); 1.2-1.8 (6H,m,(CH2)2 and CH2); 1.4 (3H,d,J=8 Hz,CH3); 1.52 (3H,d,J=7 Hz,CH 3); 3.18 (2H,t,J=6 Hz,NHCH2); 3.66 (1H,q,J=5 Hz,CHCO); 3.88 (1H,d,J=10 Hz,CHCH2) and 4.38 (1H,q,J=5 Hz,CHCH3).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][CH2:29][S:30][CH2:31][CH3:32])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=[O:43])=CC=1.ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][CH2:29][S:30]([CH2:31][CH3:32])=[O:43])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CCSCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CCS(=O)CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
A solution of N-(4-chlorobenzyl)-1-[2-(ethylsulfanyl)ethyl]-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.10 gm) from Example No. 60 in dichloromethane (2 mL) at 0° C. is added p-toluenesulfonic acid hydrate (0.04 gm) followed by m-chloroperoxybenzoic acid (˜85%) (0.045 gm). The mixture is stirred for 0.5 hrs. The reaction mixture is diluted with dichloromethane, washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by flash column chromatography eluting with 3% to 9% methanol in dichloromethane and then by recrystallization from acetonitrile to afford 0.05 gm of the title compound as a white solid.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:30](O)[CH2:31][CH2:32][CH:33]([C:35]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=2)[OH:34])[CH:20]=[C:21]([N+:27]([O-:29])=[O:28])[C:22]=1[O:23][CH2:24][CH2:25][CH3:26].O>N1C=CC=CC=1>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:30]2[CH2:31][CH2:32][CH:33]([C:35]3[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=3)[O:34]2)[CH:20]=[C:21]([N+:27]([O-:29])=[O:28])[C:22]=1[O:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCOc1c(OC)cc(C(O)CCC(O)c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: O
Product: CCCOc1c(OC)cc(C2CCC(c3cc(OC)c(OC)c(OC)c3)O2)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
A suspension of P4S10 (19.25 g, 43.3 mmol) in 250 mL of pyridine was heated at 120° C. for 75 minutes. To this suspension was then added a solution of 1-(3-methoxy-4-propoxy-5-nitrophenyl) -4-(3,4,5-trimethoxyphenyl)-butane-1,4-diol (4.65 g, 10 mmol) in 50 mL of pyridine. The temperature was reduced to 90° C. and stirring continued for an additional 90 minutes. After cooling, ice and water were added, the mixture was extracted with methylene chloride. The organic layer was washed with water, 5% HCl, water, sodium bicarbonate and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and evaporated.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-Boc-4-hydroxypiperidine (32.2 g, 0.160 mol) in DCM (400 mL) were added triethylamine (26.8 mL, 0.192 mol), methanesulfonyl chloride (13.6 mL, 0.176 mol) and 4-dimethylaminopyridine (0.20 g, 0.0016 mol) at 0° C. undernitrogen atmosphere. The resulting mixture was slowly warmed to rt and stirred at rt overnight. The mixture was washed with sat. aq. NaHCO3 (3×80 mL), brine (2×80 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated to give the title compound as a white solid. It was used in the next step without further purification. 1H NMR (CDCl3): δ=1.47 (s, 9H), 1.80-1.85 (m, 2H), 1.95-1.99 (m, 2H), 3.05 (s, 3H), 3.28-3.34 (m, 2H), 3.68-3.74 (m, 2H), 4.89 (mc, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[NH2:14][C:15]1[C:23]([C:24](=[O:32])[NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].O>N1C=CC=CC=1>[O:18]=[C:17]1[O:6][C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[C:2]([F:13])([F:12])[F:1])=[N:14][C:15]2[C:23]([C:24]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:32])=[CH:22][CH:21]=[CH:20][C:16]1=2
Reactant: Nc1c(C(=O)O)cccc1C(=O)Nc1ccccn1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccccn1)c1cccc2c(=O)oc(-c3ccccc3C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.7 %

Procedure:
2-(trifluoromethyl)benzoyl chloride 24 (180 mg, 0.88 mmol) was added to a suspension of 2-amino-3-(pyridin-2-ylcarbamoyl)benzoic acid 23 (150 mg, 0.58 mmol) in pyridine (8 mL). The reaction mixture was stirred at room temperature for 12 h then poured into ice cooled H2O. The resulting precipitate was collected by filtration, rinsed with H2O, and dried under vacuum to give 25 (90 mg, 38% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].O.ON1C2C=CC=CC=2N=N1.[Br:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=1[CH2:46][CH2:47][NH2:48].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[Br:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=1[CH2:46][CH2:47][NH:48][C:17]([C:16]1[CH:20]=[CH:21][C:13]([O:12][C:11]2[CH:10]=[C:9]3[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]3)=[CH:3][C:2]=2[Cl:1])=[CH:14][CH:15]=1)=[O:19]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NCCc1ccc(Cl)cc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4Br)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.9 %

Procedure:
To a stirred solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1; 1.32 g; 3.52 mmol), 1-hydroxybenzotriazole hydrate (0.59 g; 3.85 mmol) and 2-(2-bromo-4-chlorophenyl)ethanamine (Preparation 5; 0.904 g; 3.85 mmol) in dry dimethylformamide (10 mL) was added 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.806 g; 4.02 mmol) at ambient temperature. After stirring at ambient temperature for 5 hours, the solution was diluted with 100 mL of water, stirred for 10 minutes longer and then extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage 40M), eluting with hexane and ethyl acetate to provide ethyl 7-(4-(2-bromo-4-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate as a white solid (1.21 g). MS (apci, pos) m/z=594.
Reaction SMILES: F[C:2]1[C:3]([CH3:14])=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:15][O-:16].[K+]>C1COCC1.CO>[CH3:15][O:16][C:2]1[C:3]([CH3:14])=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1C(=O)O
Reactant: C[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])c(C(=O)O)c1C
Temperature: 100 °C

Procedure:
To a stirring solution of 3-Fluoro-2-methyl-6-nitro-benzoic acid (4.2 g, 21 mmol) in THF (40 mL) and methanol (40 mL) is added potassium methoxide in methanol (15 g, 63 mmol) and the solution is heated to 100° C. for 2 hours. The reaction mixture is cooled to room temperature and then the mixture is quenched with a 1N HCl solution and partitioned between ethyl acetate. The organic layer is washed with brine and then concentrated to give 3-Methoxy-2-methyl-6-nitro-benzoic acid (4.3 g) in quantitative yields. 1H-NMR (400 MHz, δ, ppm) CDCl3: 2.32 (s, 3H), 3.98 (s, 3H), 6.95 (d, 1H), 8.15 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13]O.OS(O)(=O)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]2[CH2:13][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[NH:6][CH2:5][C:4]=2[CH:15]=[CH:16][CH:17]=1.[Br:1][C:2]1[CH:17]=[CH:16][C:15]2[CH2:13][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[NH:6][CH2:5][C:4]=2[CH:3]=1
Reactant: OCc1ccccc1NCc1cccc(Br)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Brc1ccc2c(c1)CNc1ccccc1C2
Product: Brc1cccc2c1Cc1ccccc1NC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of [2-(3-bromo-benzylamino)-phenyl]-methanol (0.180 mol) in DCM (50 mL) was added over a 5 hr period to a cooled (±−10 to −20° C.) solution of concentrated H2SO4 (500 mL). The ice-bath was then removed, and the mixture was stirred for one hour at rt. The reaction mixture was added to ice-water, cooled on ice, and alkalized with a 50% aqueous NaOH solution. The resulting mixture (±3 L) was extracted with DCM. The organic layer was separated, dried on MgSO4, filtered and the filtrate was concentrated in vacuo. A part (8 g) of this residue was purified via Supercritical Fluid Chromatography (SFC, column: Diacel AD-H 30×250 mm, mobile phase: 55% MeOH/45% CO2+0.2% isopropylamine, 40° C., 100 bar) to give 2 g of 10-bromo-6,11-dihydro-5H-dibenzo[b,e]azepine and 4.65 g of 8-bromo-6,11-dihydro-5H-dibenzo[b,e]azepine.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:6]=1[O:12][CH:13]([CH3:15])[CH3:14])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)C>CO.C1COCC1.[Li+].[OH-]>[I:11][C:9]1[CH:8]=[CH:7][C:6]([O:12][CH:13]([CH3:15])[CH3:14])=[C:5]([OH:4])[CH:10]=1
Reactant: CC(=O)Oc1cc(I)ccc1OC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: CC(C)Oc1ccc(I)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
To a solution of 5-iodo-2-isopropoxyphenyl acetate (10 mmol) in MeOH (5 mL) and THF (15 mL), LiOH (1.0 M, 15 mL) was added at 0° C. After the mixture was stirred at rt for 3.0 h, 5% citric acid (30 mL) and diethyl ether (150 mL) was added. The organic extract was washed with brine, dried over Na2SO4 and evaporated to give 5-iodo-2-isopropoxyphenol (2.3 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:38])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([C:26](=[O:37])[C:27]#[C:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=1>>[CH3:9][O:10][C:11](=[O:38])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)/[C:27](=[C:28](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])/[C:26]2=[O:37])[CH:13]=1
Reactant: Clc1ccc(I)cc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2OC)c2ccccc2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(/c3ccc(Cl)cc3)c3ccccc3OC)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodo-benzene (commercially available) and 3-({[3-(2-methoxy-phenyl)-propynoyl]-phenyl-amino}-methyl)-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 7.99 (s, 1H), 7.92 (d, 1H), 7.26-7.49 (m, 7H), 6.93-7.15 (m, 4H), 6.72 (t, 1H), 6.61-6.64 (m, 2H), 4.93 (dd, 2H), 3.90 (s, 3H), 3.63 (s, 3H).