Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Cl[C:13]1[CH:22]=[C:21]([Cl:23])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:24][CH3:25])[CH:19]=2)[N:14]=1>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.CN(C=O)C>[Cl:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:24][CH3:25])[CH:19]=2)[N:14]=[C:13]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:22]=1
Reactant: COc1ccc2nc(Cl)cc(Cl)c2c1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc2nc(-c3ccc(C#N)cc3)cc(Cl)c2c1
Temperature: 100 °C

Procedure:
Followed Scheme 2, Step 1 starting from 4-cyanophenylboronic acid and 2,4-dichloro-6-methoxyquinoline, where the solvent used was DMF, and the catalyst used was Pd(PPh3)4. The mixture was heated to 100° C. for 3 h, allowed to cool, and then poured into ice water. The resulting solid was isolated by filtration, washed with water, and dried followed by recrystallization from methanol to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>>[NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]=[CH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Nc1cccc(Nc2ncc(F)c(Nc3cccc(N)c3)n2)c1
Product: CC(C)(C)OC(=O)C=Nc1cccc(Nc2nc(Nc3cccc(N)c3)ncc2F)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and tert-butyl bromoacetate were reacted together to give N2-(3-aminophenyl)-N4-(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 18.82 min.; purity: 85.8%; MS (m/e): 369.11 (MH+).
Reaction SMILES: [OH:1][N:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]1=[S:8].C(=O)([O-])O.[Na+].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[C:14]([O:1][N:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]1=[S:8])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1csc(=S)n1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1csc(=S)n1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.735 parts of 3-hydroxy-4-methylthiazol-2(3H)-thione were stirred in 50 parts of water and 0.84 parts of sodium hydrogen carbonate. The solution was screened and 0.9 parts of benzoyl chloride were added. The reaction mixture was stirred overnight at room temperature. A precipitate was formed which was separated by filtration, washed with cold water and recrystallised from ethanol to give 3-benzoyloxy-4-methylthiazol-2(3H)-thione, m.pt. 100°-102° C. By analysis the composition was found to be C 52.4% wt; H 3.6% wt; N 5.6% wt and S 25% wt. C11H9NO2S2 requires C 52.6% wt; H 3.6% wt; N 5.6% wt and S 25.5% wt.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH2:15][C:16](Cl)=[O:17].[OH-].[Na+]>[N+](C1C=CC=CC=1)([O-])=O>[Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5]2[O:6][CH2:15][C:16](=[O:17])[C:7]=2[CH:8]=1
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1COc2cc(O)c(Cl)cc21
Temperature: 40 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
A solution of 4-chlororesorcinol (4.34 g, 30.0 mmol) in nitrobenzene (60 mL) was added with aluminum chloride (10.2 g, 90.0 mmol) at room temperature. Then, the mixture was added with chloroacetyl chloride (2.87 mL, 36.0 mmol) under ice cooling. The mixture was stirred at 40° C. for 2 hours, and then added with 2 N aqueous sodium hydroxide (60 mL), and then the aqueous layer was separated. The separated aqueous layer was added with concentrated hydrochloric acid and thereby adjusted to pH 3, and the precipitated solid was collected by filtration to obtain the objective 5-chloro-6-hydroxybenzofuran-3(2H)-one (0.995 g, 17%).
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH2:24][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=4)[CH:26]=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[C:36]1([Mg]Cl)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl.[Cl-].[NH4+].C(OCC)(=O)C>[CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH2:24][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=4)[CH:26]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[OH:27])[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:3])=[O:4]
Reactant: CSc1ccc(C(C=O)Cc2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)cc1
Reactant: Cl[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CSc1ccc(C(Cc2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)C(O)c2ccccc2)cc1
Temperature: 21 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methylsulfanyl-phenyl)-propionaldehyde from Step 2 (150 mg, 0.3 mmol) in CH2Cl2 (6 mL) at 21° C. was added phenylmagnesium chloride (2M, TBF, 0.45 mL, 0.9 mmol) dropwise. The resulting reaction mixture was stirred 0.5 h at 21° C. then diluted with a saturated ammonium chloride solution and ethyl acetate. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated. The crude oil was used as such in the next step.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C([O-])(O)=O.[Na+]>C(O)C.O>[C:5]1([C:3]2[N:11]=[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]3[CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc(-c2cn3ccccc3n2)cc1
Yield: 79 %

Procedure:
Stir a solution of 2-bromoacetophenone (1 g, 5.024 mmol) and 2-aminopyridine (591 mg, 6.280 mmol) in ethanol (4 mL) containing NaHCO3 (658 mg, 7.837 mmol) at room temperature for 6 hours. Dilute the mixture with water (15 mL) and extract with ether (3×20 mL). Wash the combined organic layers with saturated aqueous sodium chloride (25 mL), dry (MgSO4) and concentrate in vacuo. Purify the residue by flash chromatography (SiO2; eluent:hexane/EtOAc 4:1) to give a white solid, 79% yield. MS(ES+): m/z=195.1 (M+H)+
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][CH:4]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10].O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][CH:2]([CH3:26])[CH2:3][CH:4]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10]
Reactant: COC(=O)c1ccc(NC(CC(C)C)c2oc3ccccc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(CC(C)C)Nc2ccc(C(=O)O)cc2)oc2ccccc12
Yield: 80 %

Procedure:
To a mixture of methyl 4-{[3-methyl-1-(3-methyl-1-benzofuran-2-yl)butyl]amino}benzoate (1.38 g) synthesized above, tetrahydrofuran (20 mL) and ethanol (20 mL) was added 1N aqueous sodium hydroxide solution (20 mL), and the mixture was stirred with heating under reflux overnight. In addition, 1N aqueous sodium hydroxide solution (20 mL) was added, and the mixture was stirred with heating under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid (40 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title object compound (1.06 g, 80%) as a white solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.S(=O)(=O)(O)[OH:26].[OH-].[NH4+]>>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH2:22])=[O:26])=[CH:23][CH:24]=3)=[O:16])[CH2:6][C:5]=12
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(5H,11H-Pyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-benzonitrile (0.5 g) from Example 44 was added to concentrated sulfuric acid (5 ml) and the mixture was stirred for 18 hours at room temperature to yield a bright yellow solution. The solution was poured onto ice and made basic with the addition of concentrated ammonium hydroxide. The resultant solid was filtered, dissolved in dichloromethane, and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (5.05 g), m.p. 226-228° C.
Reaction SMILES: Cl.NO.C([N:6](C(C)C)C(C)C)C.[CH3:13][O:14][C:15]1[C:16]([NH:21][C:22]([NH:24]C(OCC)=O)=S)=[N:17][CH:18]=[CH:19][CH:20]=1>C(O)C.CO>[CH3:13][O:14][C:15]1[C:16]2[N:17]([N:6]=[C:22]([NH2:24])[N:21]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1ncccc1OC
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CO
Product: COc1cccn2nc(N)nc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
To a solution of 21.8 g (313.7 mmol) hydroxylamine hydrochloride and 32.2 ml (188.2 mmol) N-ethyldiisopropylamine in a mixture of 130 ml methanol ethanol 1:1 was added 16 g (62.7 mmol) N-(3-methoxy-2-pyridinyl)-N′-carboethoxy-thiourea and stirred for 2 h at room temperature and subsequently for 3 h at 60° C. The volatiles were removed under reduced pressure and the residue was triturated with 100 ml water. The collected precipitate was washed with 25 ml methanol/diethyl ether 4:1 and afterwards with 25 ml diethyl ether. After drying under high vacuum 8 g (78%, 48.7 mmol) of the title compound was collected as off-white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=1[F:17].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COCCOC>[Cl:1][C:2]1[N:3]=[C:4]([Cl:9])[CH:5]=[C:6]([C:13]2[CH:14]=[CH:15][C:16]([F:17])=[C:11]([Cl:10])[CH:12]=2)[N:7]=1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Fc1ccc(-c2cc(Cl)nc(Cl)n2)cc1Cl

Procedure:
Combine 2,4,6-trichloropyrimidine (9.15 g, 0.05 mol), 3-chloro-4-fluorophenylboronic acid (8.7 g, 0.05 mol), 1,2-dimethoxyethane (300 mL), and 2M aqueous sodium carbonate (25 mL) and let stir under nitrogen for 10 minutes. Add palladium acetate (56 mg, 0.25 mmol) and PPh3 (131 mg, 0.5 mmol) and reflux the mixture for 16 hours. Evaporate, add water (100 mL), and extract twice with DCM (25 mL each). Dry the organic layer with sodium sulfate and evaporate, giving a yellow gum. The mixture is chromatographed with 20:1 hexanes/EtOAc, affording 2,4-dichloro-6-(3-chloro-4-fluoro-phenyl)-pyrimidine as a white solid.
Reaction SMILES: C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1.I[C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1.[SH:47][C:48]1[CH:53]=[CH:52][C:51]([CH:54]([CH2:63][CH:64]2[CH2:69][CH2:68][O:67][CH2:66][CH2:65]2)[C:55]([NH:57][C:58]2[S:59][CH:60]=[CH:61][N:62]=2)=[O:56])=[CH:50][CH:49]=1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:43]1[CH:44]=[CH:45][CH:46]=[C:41]([S:47][C:48]2[CH:53]=[CH:52][C:51]([CH:54]([CH2:63][CH:64]3[CH2:69][CH2:68][O:67][CH2:66][CH2:65]3)[C:55]([NH:57][C:58]3[S:59][CH:60]=[CH:61][N:62]=3)=[O:56])=[CH:50][CH:49]=2)[CH:42]=1
Reactant: Ic1cccnc1
Reactant: O=C(Nc1nccs1)C(CC1CCOCC1)c1ccc(S)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Nc1nccs1)C(CC1CCOCC1)c1ccc(Sc2cccnc2)cc1
Temperature: 105 °C

Procedure:
A solution of Pd2dba3 (18 mg, 20 μmol) and DPEPhos (24 mg, 45 μmol) in anhydrous PhMe (4 mL) was stirred at 20° C. for 3 min. 3-Iodopyridine (107 mg, 522 μmol), 2-(4-mercaptophenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide (see EXAMPLE 146, 173 mg, 500 μmol), and t-BuOK (65 mg, 579 μmol) were added, then the mixture was heated at 105° C. (bath) for 2.5 h. On cooling to 20° C., the mixture was diluted with CH2Cl2 (10 mL) and filtered through Celite, washing with CH2Cl2 (5 mL) and EtOAc (10 mL). Solvent evaporation and flash chromatography (IH-EtOAc, 3:1 to 0:1) afforded the title compound: RTB=1.37 min; m/z (ES+)=426.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:15][C:16]([Cl:21])([Cl:20])[C:17](Cl)=[O:18].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:15][C:16]([Cl:21])([Cl:20])[C:17]([N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)=[O:18]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: COc1ccccc1N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1N1CCN(C(=O)C(Cl)(Cl)Cl)CC1
Reaction time: 18 h
Yield: 91 %

Procedure:
A solution of 1-(2-methoxyphenyl) piperazine (7.0 g) in dichloromethane (30 ml) was added over 15 minutes to a stirred solution of trichloroacetyl chloride (4.06 ml) in dichloromethane (40 ml) at room temperature under argon. Diisopropylethylamine (5.95 ml) was then added and the whole was stirred for 18 hours. The reaction mixture was washed with water (2×100 ml), dried (Na2SO4) and concentrated to give the title compound (D1) as an oil (11.2 g, 91%), MH+337/339.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5](F)=[C:6]([CH:18]=1)[C:7]([N:9]([CH3:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[O:8].[CH3:21][O:22][Na].CO>>[Br:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]([O:22][CH3:21])=[C:6]([CH:18]=1)[C:7]([N:9]([CH3:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[O:8]
Reactant: CO[Na]
Reactant: Cc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1F
Solvent: CO
Product: COc1cc(Cl)c(Br)cc1C(=O)N(C)c1ccccc1C

Procedure:
A mixture of 5-bromo-4-chloro-2-fluoro-N-methyl-N-o-tolyl-benzamide (2.5 g, 7.0 mmol) was heated in MeONa/MeOH (20 mL, 25%) at 55° C. for 12 hrs, then was concentrated and partitioned between DCM and water. The organic layer was then separated, washed with 3N HCl, sat NaHCO3 and brine, dried over MgSO4, and concentrated. Purification by silica gel column chromatography eluting with ethyl acetate in hexanes (1/4) gave 5-bromo-4-chloro-2-methoxy-N-methyl-N-o-tolyl-benzamide (2.75 g). MS: 367.8 (M+H)+; tR=2.51 min (method 1).
Reaction SMILES: C(O[C:6](=[O:25])[CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[CH:9]=1)(C)(C)C.C(C1NC=CN=1)(C1[NH:29]C=CN=1)=O.N>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:24][N:21]1[CH2:20][CH2:19][N:18]([C:10]2[CH:9]=[C:8]([CH2:7][C:6]([NH2:29])=[O:25])[C:13]([C:14]([F:16])([F:15])[F:17])=[CH:12][N:11]=2)[CH2:23][CH2:22]1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CN1CCN(c2cc(CC(=O)OC(C)(C)C)c(C(F)(F)F)cn2)CC1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2cc(CC(N)=O)c(C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
[2-(4-Methyl-piperazin-1-yl)-5-trifluoromethyl-pyridin-4-yl]-acetic acid tert-butyl ester (475 mg, 1.32 mmol) is dissolved in a mixture of TFA and CH2Cl2 (10 ml/10 ml) and stirred at RT. After 1.5 h at RT, TLC analysis indicated complete conversion of starting material. The solvent is removed by rotary evaporation, and replaced by dry DMF (5 ml). Under an atmosphere of argon, carbonyl diimidazole (236 mg, 1.46 mmol) is added. After 3 h at RT, TLC analysis indicated complete conversion of the carboxylic acid. An aqueous solution of ammonia (25%, 20 ml) is added at RT. After 15 minutes at RT, solvents are removed under high vacuum. The residue is dissolved in CH2Cl2/MeOH (9:1) and purified by FCC (CH2Cl2/MeOH, slow gradient from 90:10 to 40:60) to yield the title compound. 1H NMR (d6-DMSO, 400 MHz): δ 2.69 (s, 3H), 2.93-3.18 (m, broad, 4H), 3.54 (s, 2H), 3.59-3.98 (m, broad, 4H), 6.95 (s, 1H), 7.02 (s, broad, 1H), 7.47 (s, broad, 1H), 8.45 (s, 1H). ES+−MS: 303.2 [M+H]+.
Reaction SMILES: [C:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)#[N:2].BrN1C(=[O:24])CCC1=O.O>C(Cl)Cl>[C:1]([N:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[CH:6]([OH:24])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CN1c2ccccc2CCc2ccccc21
Solvent: ClCCl
Solvent: O
Product: N#CN1c2ccccc2CC(O)c2ccccc21
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 60.9 %

Procedure:
13.2 g (0.060 mols) of (I) are dissolved at room temperature in 80 ml of CH2Cl2 under stirring, then 11.8 g (0.066 mols) of N-bromosuccinimide of purity above 98% and 0.70 g (0.003 mols) of di-tert-butyl-peroxalate are added under stirring. The reaction mixture is subjected to mild nitrogen stream for 5 minutes, then heated to 45° C. and stirred at this temperature for 85 minutes. The resulting suspension is added with 100 ml of demineralized water and 3 grams of polyethylene glycol with average molecular weight 400, then refluxed for 5 hours under strong stirring. After decanting at 30° C., the organic phase is separated, dried over 4 g of Na2SO4, filtered and the resulting solution is concentrated to 20 ml, added with 10 ml of hexane, cooled to 0-5° C. for 2 hours and filtered to obtain 8.64 g (61%) of (VI), m.p. 110-112° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([NH:28][C:29]([C@@H:31]2[CH2:35][CH2:34][CH2:33][N:32]2C(OC(C)(C)C)=O)=[O:30])=[CH:23][CH:22]=3)=[O:18])=[C:11]([F:43])[C:10]=1[O:44][C:45]1[CH:50]=[C:49]([C:51]#[N:52])[CH:48]=[C:47]([Cl:53])[CH:46]=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([NH:28][C:29](=[O:30])[C@@H:31]2[CH2:35][CH2:34][CH2:33][NH:32]2)=[CH:23][CH:22]=3)=[O:18])=[C:11]([F:43])[C:10]=1[O:44][C:45]1[CH:50]=[C:49]([C:51]#[N:52])[CH:48]=[C:47]([Cl:53])[CH:46]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(NC(=O)[C@@H]5CCCN5)ccc4[nH]3)c2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
Trifluoroacetic acid (0.25 mL, 3.24 mmol) was added to a suspension of 1,1-dimethylethyl(2S)-2-{[(2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino}carbonyl]-1H-indol-5-yl)amino]carbonyl}-1-pyrrolidinecarboxylate (0.013 g, 0.020 mmol) in dichloromethane (1 mL). The resulting solution was stirred at RT for 1 h. The solvent was evaporated to give the title compound (0.013 g, 98%) an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.67 (s, 1H), 10.38 (s, 1H), 9.24 (s, 1H), 9.02 (s, 1H), 8.66 (s, 1H), 7.95 (s, 1H), 7.81 (s, 1H), 7.46-7.55 (m, 2H), 7.36-7.44 (m, 1H), 7.28 (dd, 1H), 7.15 (d, 1H), 4.57 (s, 2H), 4.30 (m, 1H), 3.28 (m, 2H), 1.75-2.14 (m, 4H). MS: m/z 566 (M).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[CH2:22][CH2:23][O:24][C:25]4[CH:31]=[CH:30][C:29]([C:32]5[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=5)=[CH:28][C:26]=4[CH:27]=3)=[O:20])=[CH:14][CH:13]=2)=[N:7][CH:8]=[CH:9][CH:10]=1.ClC1C=CC=C(C(OO)=[O:47])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[O-:47][N+:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:6]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([C:21]2[CH2:22][CH2:23][O:24][C:25]3[CH:31]=[CH:30][C:29]([C:32]4[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=4)=[CH:28][C:26]=3[CH:27]=2)=[O:20])=[CH:16][CH:17]=1
Reactant: COCOc1cccnc1Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(C)cc4)ccc3OCC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc[n+]([O-])c1Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(C)cc4)ccc3OCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.6 %

Procedure:
To a solution of N-[4—(3-methoxymethoxypyridin-2-ylmethyl)phenyl]-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (300 mg) in tetrahydrofuran (10 ml) was added 3-chloroperbenzoic acid (70%, 0.22 g) at 0° C., and the mixture was stirred at room temperature for 18 hours. To the mixture was added sodium thiosulfate, and the mixture was stirred for a few minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:15→1:10), and recrystallized from ethanol to give N-[4—(1-oxido-3-methoxymethoxypyridin-2-ylmethyl)phenyl]-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 173) (203 mg) as colorless crystals.
Reaction SMILES: C(N(CC)CC)C.CO[C:10]([C@@H:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11].Cl[C:21]1[C:26]([N+:27]([O-])=O)=[CH:25][CH:24]=[CH:23][N:22]=1>CCCCCCC.CC(C)=O.C(OC)(C)(C)C>[C:13]1([CH:12]2[NH:19][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][N:22]=3)[NH:27][C:10]2=[O:11])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: COC(=O)[C@@H](N)c1ccccc1
Solvent: CC(C)=O
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: O=C1Nc2cccnc2NC1c1ccccc1

Procedure:
In analogy to Example 2, but using only one mole equivalent of triethylamine, 4.45 g (27 mmol) of D/L-phenylglycine methyl ester were reacted with 3.51 g (22 mmol) of 2-chloro-3-nitropyridine. Working up and column chromatography (n-heptane/acetone/methyl t-butyl ether=5:1:1) resulted in 3.27 g (42%) of N-(3-nitro-2-pyridyl)-(D/L)-phenylglycine methyl ester of melting point 70° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12](O)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[K+].[Br-]>C(Cl)(Cl)Cl.CO>[C:13]1([C:12]2[O:11][C:3]3[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=3[N:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc2oc(-c3ccccc3)nc2c1
Yield: 85 %

Procedure:
Prepared from 2-amino-4-nitrophenol and benzoic acid, in a manner similar to that of Example 9b. Yield: 85%; Rf (9/1 chloroform/methanol): 0.92; Elem. anal. C13H8N2O3; theory C, 65.00; H, 3.35; N, 11.66. found C, 64.54; H, 3.35; N, 11.85. IR (KBr): 1615, 1530, 1345 cm−1.