Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([O:8][C:9]1[CH:14]=[C:13]([C:15](=[O:23])[NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:12]=[C:11]([O:24][CH3:25])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH2:27]([O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH:33]=O)[CH3:28].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:26])[C:5]([O:8][C:9]1[CH:10]=[C:11]([O:24][CH3:25])[CH:12]=[C:13]([C:15](=[O:23])[NH:16][CH:17]2[CH2:18][CH2:19][N:20]([CH2:33][C:32]3[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:30]([O:29][CH2:27][CH3:28])[CH:31]=3)[CH2:21][CH2:22]2)[CH:14]=1)([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: CCOC(=O)C(C)(C)Oc1cc(OC)cc(C(=O)NC2CCNCC2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C)Oc1cc(OC)cc(C(=O)NC2CCN(Cc3ccc(OC)c(OCC)c3)CC2)c1

Procedure:
In analogy to the procedure described in example 50k), 2-[3-methoxy-5-(piperidin-4-ylcarbamoyl)-phenoxy]-2-methyl-propionic acid ethyl ester (example 66b) was reacted with 3-ethoxy-4-methoxybenzaldehyde, sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as off-white amorphous solid. MS: 529.3 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.C(CC([NH:23][CH:24](C#N)[C:25]([O-:27])=[O:26])=O)C.Cl>>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([C:6]2[CH:16]=[CH:17][C:3]([CH2:2][C@@H:24]([C:25]([OH:27])=[O:26])[NH2:23])=[CH:4][CH:5]=2)=[O:8])=[CH:10][CH:11]=1
Reactant: CCCC(=O)NC(C#N)C(=O)[O-]
Reactant: O=C(c1ccc(O)cc1)c1ccc(CCl)cc1
Agent: Cl
Product: N[C@@H](Cc1ccc(C(=O)c2ccc(O)cc2)cc1)C(=O)O

Procedure:
FIG. 1 is a schematic showing the synthesis of HBPA. 4-(Chloromethyl)benzoyl chloride (II) is made by refluxing 4-(chloromethyl)benzoic acid with oxalyl chloride in benzene. Mixing this compound with pyridine with gentle heating using a steam bath followed by ice quench gave 4-chloro-methylbenzoic anhydride (III). 4-Chloromethylbenzoic anhydride (III) is reacted with phenol in polyphosphoric acid to give the 4-chloromethylbenzoyl ester of 4-chloromethyl-4'-hydroxybenzophenone (IV). Reacting IV with ethylacetamidocyanoacetate and subsequent hydrolysis with concentrated HCl gives racemic p-(4-hydroxybenzoyl)phenylalanine (HBPA, VI). D,L-HBPA is derivatized using standard Fmoc chemistry for incorporation into the peptide (e.g., at position 8 of substance P) by solid-phase synthesis. Radioiodination of L-HBPA8 -SP is accomplished using Chloramine-T. See "Experimental Procedures" for details. HBPA can also be prepared by procedures disclosed in Horner and Medem., Chem. Ber., 85:520 (1952), the teachings of which are incorporated herein by reference.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:8][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])=[N:4][CH:5]=[N:6][CH:7]=1.F[C:16]1[CH:21]=[C:20]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])[C:19]([F:35])=[CH:18][C:17]=1[N+:36]([O-:38])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:35][C:19]1[C:20]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:21][C:16]([O:1][C:2]2[C:3]([O:8][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])=[N:4][CH:5]=[N:6][CH:7]=2)=[C:17]([N+:36]([O-:38])=[O:37])[CH:18]=1
Reactant: COC(=O)C(C)Oc1ncncc1O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ncncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-hydroxy-4-{1-(methoxycarbonyl)ethoxy}pyrimidine, 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and N,N-dimethylformamide is added potassium carbonate, and the mixture is stirred for 1 hour at 70° C. The reaction solution is cooled to room temperature, then, poured into ice water, and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-4-{1-(methoxycarbonyl)ethoxy}pyrimidine.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]O)=C.[CH3:11][O:12][C:13](=[O:25])/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O1CCCC1.C1(C)C=CC=CC=1.S(=O)(=O)(O)O.CO>[CH3:11][O:12][C:13](=[O:25])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][OH:3])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: COC(=O)/C=C/c1ccc(O)c(OC)c1
Reactant: C=COCCCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=S(=O)(O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C=Cc1ccc(OCCCCCCO)c(OC)c1
Temperature: 0 °C
Reaction time: 22.5 h
Yield: 82.8 %

Procedure:
3.92 ml (25.2 mmol) of 1,6-hexanediol vinyl ether were added to a solution of 5.0 g (24.0 mmol) of (E)-4-hydroxy-3-methoxycinnamic acid methyl ester and 6.61 g (25.2 mmol) of triphenylphosphine in 150 ml of tetrahydrofuran. The colourless solution was subsequently cooled to 0° C. and then 11.5 ml (25.3 mmol) of a 40% solution of azodicarboxylic acid diethyl ester in toluene were added dropwise thereto in the course of 30 minutes. The mixture was subsequently allowed to react first for minutes at 0° C. and then for 22.5 hours at room temperature. 150 ml of methanol and 10 drops of concentrated sulfuric acid were then added to the reaction solution and the mixture was stirred for 1.5 hours. The reaction mixture was then partitioned between ethyl acetate and water; the organic phase was washed with a saturated sodium bicarbonate solution and repeatedly with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated by evaporation. Chromatography of the residue on 470 g of silica gel using toluene:ethyl acetate 1:1 and subsequent crystallisation from ethyl acetate:hexane 3:5 yielded 6.13 g of 4-(6-hydroxyhexyloxy)-3-methoxycinnamic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1.[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1)=[O:16]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1ccc(C#N)cc1
Product: COC(=O)c1nc(C)sc1-c1ccc(C#N)cc1

Procedure:
prepared by reaction of 3-chloro-3-(4-cyano-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.92 min; [M+H]+=259.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:38]=[CH:37][O:36][N:35]=2)=[CH:30][CH:29]=1>CN(C)C=O>[O:36]1[CH:37]=[N:38][C:34]([C:31]2[CH:32]=[CH:33][C:28]([CH2:27][N:11]([C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[CH2:18][OH:19])[S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])=[CH:29][CH:30]=2)=[N:35]1
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)cc1
Reactant: BrCc1ccc(-c2ncon2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncon2)cc1)[C@@H]1CCCC[C@H]1CO
Reaction time: 2 h
Yield: 15.2 %

Procedure:
A suspension of 4-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (300 mg, 1.0 mmol), cesium carbonate (390 mg, 1.2 mmol), and 3-(4-(bromomethyl)phenyl)-1,2,4-oxadiazole (280 mg, 1.2 mmol) in dimethylformamide (5 mL) was stirred for 2 h. The reaction was concentrated and purified by flash chromatography on a 40 g silica gel column using a gradient of 0 to 80% ethyl acetate in hexane, then by preparative HPLC to give N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-4-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (70 mg, 15%). 1H NMR (400 MHz, MeOD) δ ppm 9.23 (s, 1H), 8.00 (d, J=8.30 Hz, 2H), 7.75 (d, J=8.81 Hz, 2H), 7.54 (d, J=8.00 Hz, 2H), 7.51 (d, J=8.60 Hz, 2H), 4.55 (d, J=15.61 Hz, 1H), 4.36 (d, J=15.86 Hz, 1H), 3.52 (br. s., 1H), 3.31-3.38 (m, 1H), 3.14 (dd, J=11.08, 7.30 Hz, 1H), 1.87 (d, J=12.34 Hz, 1H), 1.53-1.75 (m, 2H), 1.30-1.53 (m, 3H), 0.98-1.22 (m, 3H). LC/MS R.T.=2.72 min; [M+H]+=462. HRMS [M+H]+ calc'd 462.1254, found 462.1241.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([O:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[CH:7]=1.C(=O)([O-])O.[K+].[CH2:23]([OH:25])[CH3:24]>>[CH2:23]([O:25][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([O:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[CH:7]=1)[CH3:24]
Reactant: CCO
Reactant: Cc1cc(Oc2cc(F)ccc2[N+](=O)[O-])n[nH]1
Agent: O=C([O-])O
Agent: [K+]
Product: CCOc1ccc([N+](=O)[O-])c(Oc2cc(C)[nH]n2)c1
Yield: 59.8 %

Procedure:
Reaction of 3-(5-fluoro-2-nitrophenyloxy)-5-methylpyrazole with ethanol was carried out in the presence of potassium hydrogencarbonate in the same manner as in Example 40, to give a yellow viscous substance of 3-(5-ethoxy-2-nitrophenyloxy)-5-methylpyrazole (yield: 59.8%). 1H-NMR (CDCl3, TMS, ppm): δ 1.39 (t, J=7.0 Hz, 3H), 2.28 (s, 3H), 4.04 (q, J=7.0 Hz, 2H), 5.72 (s, 1H), 6.68 (dd, J=2.6 and 9.1 Hz, 1H), 6.73 (d, J=2.6 Hz, 1H), 8.04 (d, J=9.1 Hz, 1H), 9.62 (br s, 1H).
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](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[F:27][C:28]([F:40])([F:39])[S:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][NH2:38])=[CH:32][CH:31]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl>[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](=[O:18])[NH:38][CH2:37][CH2:36][C:33]3[CH:32]=[CH:31][C:30]([S:29][C:28]([F:39])([F:27])[F:40])=[CH:35][CH:34]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NCCc1ccc(SC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(SC(F)(F)F)cc4)cc3)c(Cl)cc21
Reaction time: 16 h
Yield: 92 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl) chroman-7-yloxy)benzoic acid (Preparation 1) (50.7 mg, 0.137 mmol), in 1:1 DCM:DMF (0.1 M) was sequentially treated with 2-(4-(trifluoromethylthio)phenyl)ethanamine (32.7 mg, 0.148 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31.0 mg, 0.161 mmol), 1-hydroxy-7-azabenzotriazole (5.49 mg, 0.0404 mmol), and N,N-Diisopropylethylamine (26.1 mg, 0.202 mmol) at ambient temperature. After 16 hours the reaction was applied directly to a silica gel column and eluted with a gradient (15% to 60%) of ethyl acetate-hexanes to provide the title compound (73.3 mg, 0.126 mmol, 93.9% yield) as a white solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[N:15]2[N:16]=[CH:17][CH:18]=[C:14]2[N:13]=[C:12]([CH3:19])[C:11]=1[CH2:20][CH2:21][Cl:22]>C(Cl)(Cl)Cl>[Br:1][C:18]1[CH:17]=[N:16][N:15]2[C:10]([Cl:9])=[C:11]([CH2:20][CH2:21][Cl:22])[C:12]([CH3:19])=[N:13][C:14]=12
Reactant: Cc1nc2ccnn2c(Cl)c1CCCl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(Br)cnn2c(Cl)c1CCCl
Reaction time: 0.5 h
Yield: 98 %

Procedure:
2.35 g (13.2 mmoles) of N-bromosuccinimide was added to a solution of 2.53 g (11 mmoles) of 7-chloro-6-(2-chloroethyl)-5-methylpyrazolo[1,5-a]pyrimidine (prepared as described in Example 3) dissolved in 20 ml of chloroform, and the mixture was heated under reflux, with stirring, for 30 minutes. At the end of this time, the reaction mixture was washed with a 2N aqueous solution of potassium hydroxide and then with water, after which it was dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through alumina (eluted with chloroform) and recrystallized from diisopropyl ether to afford 3.33 g (yield 98%) of the title compound as colorless needles, melting at 128.5°-129.5° C.
Reaction SMILES: [Cl-].[NH4+].[CH3:3][C:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[NH:7][C:6]([CH3:13])([CH3:12])N=1.CC(C)=[O:16]>>[CH3:12][C:6]1([CH3:13])[NH:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4](=[O:16])[CH2:3]1
Reactant: CC(C)=O
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Agent: [Cl-]
Agent: [NH4+]
Product: CC1(C)CC(=O)CC(C)(C)N1

Procedure:
17.2 g of acetonine hydrate, 30 g of acetone and 0.5 g of ammonium chloride are heated in a sealed tube for 6 hours at 45° C. After this period of time, it is shown by gas-chromatographical analysis that at least 95% of the employed acetonine has been reacted to form triacetoneamine, which is then isolated by distillation.
Reaction SMILES: C[O-].[Na+].CO.[SH:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[CH:12]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)=[CH2:13]>C(O)C>[N:17]1[CH:18]=[CH:19][C:14]([CH2:12][CH2:13][S:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:15][CH:16]=1
Reactant: COC(=O)CS
Reactant: C=Cc1ccncc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: COC(=O)CSCCc1ccncc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
Under a nitrogen atmosphere, sodium methoxide (1.62 g., 0.03 mole) is dissolved in 36 ml. of stirring methanol and the solution cooled in an ice bath. Methyl 2-mercaptoacetate (3.18 g., 0.03 mole) in 6 ml. of methanol is added over approximately 5 minutes. Finally, 4-vinylpyridine (3.22 g., 0.03 mole) in approximately 20 ml. of absolute ethanol is added over 15 minutes. The reaction mixture is allowed to warm to room temperature and stirred for 23 hours. The reaction mixture is concentrated to dryness in vacuo. The residue is added slowly to a stirred mixture of water and chloroform. The chloroform phase is separated and the aqueous phase further extracted with chloroform. The combined chloroform phases are extracted with saturated sodium chloride, dried over anhydrous sodium sulfate, and stripped to yield title product.
Reaction SMILES: [CH2:1]([C:8]1[C:13]2[O:14][CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH:16]3[C:12]=2[CH:11]=[C:10]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([C:8]1[C:13]2[O:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH:16]3[C:12]=2[CH:11]=[C:10]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2Oc3c(Cc4ccccc4)cc(-c4ccc(Cl)cc4Cl)cc3C2C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(-c2cc(Cc3ccccc3)c3c(c2)C2CNCCC2O3)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl 6-benzyl-8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate (0.137 g, 0.270 mmol) was dissolved in CH2Cl2 (5 mL). Trifluoracetic acid (0.44 mL, 5.670 mmol) was added and the reaction mixture was stirred at rt under N2 for 4 h. The reaction mixture was cooled to 0° C. and 25% aqueous NaOH (15 mL) was added. The reaction mixture was partitioned between CH2Cl2 and water. The water layer was extracted with CH2Cl2 (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography (1% NH4OH, 5.95% CH3OH, 93.05% CH2Cl2), and Example 250 was obtained in 86% yield. MS (ESI+) for C24H21Cl2NO m/z 410.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7].COC1C=C(C=CC=1C)C(O)=O.ClC1C=C(C=CC=1C[C:38]([C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][C:41]=1[OH:47])=[O:39])C(OC)=O>>[OH:47][C:41]1[CH:42]=[C:43]([OH:46])[CH:44]=[CH:45][C:40]=1[C:38](=[O:39])[CH2:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc(CC(=O)c2ccc(O)cc2O)c(Cl)c1
Reactant: COC(=O)c1ccc(C)c(OC)c1
Agent: COc1cc(C(=O)O)ccc1C
Product: COC(=O)c1ccc(CC(=O)c2ccc(O)cc2O)c(OC)c1

Procedure:
Synthesis of methyl 3-methoxy-4-methylbenzoate, starting with 3-methoxy-4-methylbenzoic acid (see step 1 of Intermediate F). MS (ESI): m/z 181.1 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:21]=[C:22]([C@@H:26]([NH2:28])[CH3:27])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1.C(Cl)CCl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([NH:28][C@H:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([N:17]3[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]3)[CH:21]=2)[CH3:27])=[O:10])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Reactant: C[C@H](N)c1cccc(N2CCN(C)CC2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C[C@H](NC(=O)C=Cc1ccc(F)cc1)c1cccc(N2CCN(C)CC2)c1
Yield: 73.5 %

Procedure:
A solution of 4-fluorocinnamic acid (17 mg, 0.1 mmol), (S)-1-[3-(4-methylpiperazin-1-yl)-phenyl]ethylamine (preparation 42, 24 mg, 0.11 mmol), EDC (28 mg, 0.15 mmol), DMAP (12 mg, 0.1 mmol) and triethylamine (40 mg, 0.4 mmol) in dichloromethane (2 ml) was stirred overnight. The reaction mixture was purified by fresh chromatography over silica gel with 5% methanol in dichloromethane to give the title compound as a solid (27 mg 74% yield).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH3:4][S:5][C:6](SC)=[CH:7][C:8]([C:10]1[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=1[Cl:21])=O>C(O)C>[Cl:21][C:11]1[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:15]([Cl:16])[C:10]=1[C:8]1[N:2]([CH3:1])[N:3]=[C:6]([S:5][CH3:4])[CH:7]=1
Reactant: CSC(=CC(=O)c1c(Cl)cc(C(F)(F)F)cc1Cl)SC
Reactant: CNN
Solvent: CCO
Product: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n(C)n1
Yield: 33.9 %

Procedure:
Methylhydrazine (1.9 g) was added dropwise to a solution of 5.0 g of 3,3-bis[methylthio]-1-(2,6-dichloro-4-trifluoromethylphenyl)-2-propen-1-one (22) in 50 ml of ethanol at room temperature, followed by refluxing for 3 hours. The solvent was distilled off under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel, giving 1.6 g of the desired compound in the form of a brown oil (yield 28.5%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N+:17](/[CH:20]=[CH:12]/[C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[O:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([O-:19])=[O:18]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cccc(OCc2ccccn2)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1cccc(OCc2ccccn2)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 71.4 %

Procedure:
A mixture of 3-(pyridin-2-ylmethoxy)-benzaldehyde (2.98 g, 14 mmol) described in Manufacturing Example 60-1-1, nitromethane (1.51 mL, 28 mmol), ammonium acetate (1.62 g, 21 mmol) and acetic acid (30 mL) was stirred for 6 hours at 100° C. This mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-2:1-1:1) to obtain the title compound (2.56 g, 71%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:6]([CH2:27][C:28]([OH:30])=[O:29])=[C:7]3[N:12]([C:13]=2[CH:14]=1)[CH2:11][CH:10]([N:15]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH3:16])[CH2:9][CH2:8]3>CO.[Pd]>[F:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:15]([CH3:16])[CH:10]2[CH2:9][CH2:8][C:7]3[N:12]([C:4]4[N:3]=[CH:2][CH:14]=[CH:13][C:5]=4[C:6]=3[CH2:27][C:28]([OH:30])=[O:29])[CH2:11]2)(=[O:18])=[O:19])=[CH:25][CH:24]=1
Reactant: CN(C1CCc2c(CC(=O)O)c3cnc(Cl)cc3n2C1)S(=O)(=O)c1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: CN(C1CCc2c(CC(=O)O)c3cccnc3n2C1)S(=O)(=O)c1ccc(F)cc1

Procedure:
A solution of (±)-{3-chloro-6-[(4-fluoro-benzenesulfonyl)-methyl-amino]-5,6,7,8-tetrahydro-2,4b-diaza-fluoren-9-yl}-acetic acid (2 mg) and 2 mg of Pd/C (20%) in 0.5 mL of MeOH was stirred under Hz (balloon pressure) for 8 h. The suspension was filtered through celite and the filtrate was concentrated to give the title compound. MS (ES): 418.0 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:32])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]3[N:23]=[C:24]([NH:26][C:27]([CH:29]4[CH2:31][CH2:30]4)=[O:28])[N:25]=[C:21]3[CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)(C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[NH2:7][CH2:8][C:9]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]3[N:23]=[C:24]([NH:26][C:27]([CH:29]4[CH2:30][CH2:31]4)=[O:28])[N:25]=[C:21]3[CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:32]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: NCC(=O)Nc1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Reaction time: 8 h

Procedure:
({4-[2-(Cyclopropanecarbonyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-phenylcarbamoyl}-methyl)-carbamic acid tert-butyl ester (0.08 g, 0.17 mmol) was dissolved in dichloromethane (3 ml), microporous p-toluenesulfonic acid (0.16 g, 0.51 mmol) was added and the mixture was shaken overnight. The resin was washed several times with methanol, and then the product was cleaved from the resin using a 2M ammonia/methanol solution. This solution was concentrated in vacuo to give clean product. LCMS method: 2, RT: 1.86 min, MI: 351 [M+1]. NMR (1H, DMSO, 300 MHz): 11.04 (brs, 1H), 8.02 (d, 2H), 7.82 (d, 2H), 7.66 (m, 2H), 7.28 (dd, 1H), 3.34 (brs, 2H), 2.03 (brs, 1H), 0.82 (d, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:13][CH2:14][CH:15]=[CH2:16])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH:12]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:13][CH2:14][CH:15]=[CH2:16])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: C=CCCC(=C1C(=O)Nc2cc(Cl)ccc21)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CCCC(c1cccc(Cl)c1)C1C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a yellow slurry of 6-chloro-3-(1-(3-chlorophenyl)pent-4-enylidene)indolin-2-one (Example 62, Step B) (12.81 g, 37.2 mmol) in MeOH (200 mL) at room temperature was slowly added sodium borohydride (1.689 g, 44.7 mmol). Evolution of gas was observed. The yellow reaction mixture was stirred at room temperature for 30 min. Additional sodium borohydride (1.689 g, 44.7 mmol) was slowly added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water (200 mL). A precipitate formed and the mixture was sonicated for 15 min then filtered. The filtrate was concentrated under reduced pressure to 36 mL and then extracted with EtOAc twice. The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure to provide the title compound.