Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][CH:6]([C:11](=[O:13])[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C([O-])([O-])=O.[Cs+].[Cs+].[Na+].[I-].Cl.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29]Cl>CC#N.C(Cl)Cl>[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][O:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][CH:6]([C:11](=[O:13])[CH3:12])[C:7]([O:9][CH3:10])=[O:8]
Reactant: CN(C)CCCl
Reactant: COC(=O)C(Cc1cccc(O)c1)C(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)C(Cc1cccc(OCCN(C)C)c1)C(C)=O
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 1.5 g (6.75 mmol) of methyl 2-(3-hydroxybenzyl)-3-oxobutanoate, 6.6 g (20.25 mmol) of anhydrous Cs2CO3, 0.1 g (0.67 mmol) of NaI and 1 g (7.1 mmol) of 2-dimethylaminoethyl chloride hydrochloride in 20 mL of anhydrous CH3CN is heated for 4 hours at 90° C., and then stirred overnight at room temperature. The reaction medium is filtered and then concentrated under reduced pressure. The residue obtained is taken up in DCM (100 mL), washed with brine (30 mL), dried over Na2SO4, filtered, concentrated under reduced pressure and then purified by chromatography on a column of silica gel, eluting with a DCM/MeOH gradient of 0 to 10% MeOH. After concentrating under reduced pressure, 409 mg of methyl 2-{3-[2-(dimethylamino)ethoxy]benzyl}-3-oxobutanoate are obtained in the form of a brown wax.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1([CH2:10][CH2:11][C:12](Cl)=[O:13])[CH2:9][CH2:8][CH2:7][CH2:6]1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>ClCCCl>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:12](=[O:13])[CH2:11][CH2:10][CH:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:18][CH:17]=1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: O=C(CCC1CCCC1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25.3 %

Procedure:
Aluminum chloride (4.979 g, 37.34 mmol) was added in small portions to a solution of 3-cyclopentylpropionyl chloride (3 g, 18.67 mmol) in 1,2-dichloroethane (100 mL) cooled to 0° C. After 15 min., chlorobenzene (6.304 g, 56.01 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 48 h. It was then poured into a mixture of ice and water. The product was extracted with ethyl acetate. The organic layers were washed with saturated solution of sodium bicarbonate (1×30 mL), brine (1×20 mL) and dried over anhydrous magnesium sulfate. The solids were then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32–63 μm, 60 Å silica gel) eluting with hexanes yielded 1-(4-chloro-phenyl)-3-cyclopentyl-propan-1-one (1.12 g, 25%) as yellow oil.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15]O)[N:10]=[CH:9]2)C=CC=CC=1.[OH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH:38]2[CH2:41][CH2:40][CH2:39]2)=[O:37])=[CH:32][CH:31]=1>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]([CH:38]3[CH2:39][CH2:40][CH2:41]3)=[O:37])=[CH:34][CH:35]=2)[N:10]=[CH:9]1
Reactant: O=C(c1ccc(O)cc1)C1CCC1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: O=C(c1ccc(OCCCc2c[nH]cn2)cc1)C1CCC1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of cyclobutyl 4-hydroxyphenyl ketone are treated as described in Example 76.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[OH:10][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14]>ClCCl.ClCCCl>[OH:10][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([Cl:3])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccnc1O
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccnc1O
Temperature: 25 °C
Yield: 84.5 %

Procedure:
20 ml (270 mmol) of thionyl chloride and 1 ml of dimethylformamide are added respectively to 12.5 g (90 mmol) of 2-hydroxynicotinic acid in suspension in a mixture of 80 ml of dichloromethane and 20 ml of 1,2-dichloroethane. The suspension is stirred at reflux for 2.5 hours. The reaction mixture is cooled to room temperature and the precipitate formed is filtered to yield (11.98 g) of 2-hydroxynicotinic chloride. The solid is suspended in 150 ml of dichloromethane, and then 7.42 g (76 mmol) of N,O-dimethylhydroxylamine hydrochloride and 21.37 ml (152 mmol) of triethylamine are added successively. The reaction mixture is stirred for 2 hours at room temperature, the solvent is evaporated, and then the solid is taken up in a minimum of ethyl acetate (70 ml). The solid is filtered (triethylamine salt) and the filtrate is concentrated to yield after purification by silica gel chromatography (eluent: 10:1 dichloromethane/methanol) 10.5 g (64%) of N-methoxy-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].[NH2:14][C:15]1[S:16][C:17]([C:20]2([CH3:26])[S:25][CH2:24][CH2:23][CH2:22][S:21]2)=[N:18][N:19]=1>C1(C)C=CC=CC=1.CCCCC>[CH3:26][C:20]1([C:17]2[S:16][C:15]([NH:14][C:5](=[O:6])[C:4]3[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[CH:9][C:8]=3[O:12][CH3:13])=[N:19][N:18]=2)[S:21][CH2:22][CH2:23][CH2:24][S:25]1
Reactant: CC1(c2nnc(N)s2)SCCCS1
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: CCCCC
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1C(=O)Nc1nnc(C2(C)SCCCS2)s1
Temperature: 25 °C

Procedure:
A solution of 1.0 g of 2,6-dimethoxybenzoyl chloride in 50 ml of toluene containing 1.0 g of 2-amino-5-(2-methyl-1,3-dithian-2-yl)-1,3,4-thiadiazole was heated at reflux for fifteen hours. The reaction mixture was then cooled to room temperature and diluted with pentane, whereupon a white precipitate formed. The precipitate was collected by filtration and identified as N-[5-(2-methyl-1,3-dithian-2-yl)-1,3,4-thiadiazol-2-yl]-2,6-dimethoxybenzamide.
Reaction SMILES: [NH:1]([C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:23])[C:12]=2[C:11](S(C2C=CC(C)=CC=2)(=O)=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([NH2:38])[CH2:35][CH2:36][CH3:37]>>[NH:1]([C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:23])[C:12]=2[C:11]([NH:38][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)c2ccc(Nc3ccccc3)c3c2C(=O)c2ccccc2C3=O)cc1
Reactant: CCCCN
Product: CCCCNc1ccc(Nc2ccccc2)c2c1C(=O)c1ccccc1C2=O
Yield: 90 %

Procedure:
1-(anilino)-4-(n-butylamino)-anthraquinone was prepared by reaction of 1-(anilino)-4-tosylanthraquinone with n-butylamine. The isolated and purified reaction product has the structure illustrated below. ##STR15## The yield was 90% and m.p. 118°-120° C. Mass spectrum, m/e 370 (M+), 327 (M-C3H7), 299 (327-CO); 1H-NMR (CD2Cl2)δ12.17 (br s, 1H), 10.78 (br s, 1H), 8.37-8.27 (m, 2H) 7.76-7.39 (m, 4H), 7.33-7.10 (m, 5H), 3.65-3.05 (m, 2H), 1.72-1.38 (m, 4H), 1.07-0.92 (t, 3H); UV/VIS max (Xylenes) 388 nm (ε4000), 598 (14 200), 642 (15 600).
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][CH:10]=[C:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>N1C=CC=CC=1>[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([O:1][C@H:2]2[CH2:21][CH2:20][C@@:19]3([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]4[C@@H:18]3[C:17](=[O:23])[CH2:16][C@@:15]3([CH3:24])[C@H:8]4[CH2:9][CH:10]=[C:11]3[C:12](=[O:14])[CH3:13])[CH2:3]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: c1ccncc1
Product: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 97.6 %

Procedure:
A solution of 3β-hydroxy-5α-pregn-16-ene-11,20-dione (39.6 g) in dry pyridine (165 ml.) was treated with toluene-p-sulphonyl chloride (43.9 g.) to give 3β-toluene-p-sulphonyloxy-5α-pregn-16-ene-11,20-dione (56.7 g.) m.p. 147°-151°. A portion (10.7 g.) of this material was crystallised from ethyl acetate-petrol to give the pure toluenesulphonate (9.2 g.) as plates m.p. 154°-155°, [α]D + 42.8° (c 1.2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][O:10][CH2:11][C:12]#[CH:13]>C(N(CC)CC)C.C(OCC)(=O)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>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]#[C:12][CH2:11][O:10][CH3:9])=[N:3][CH:4]=1
Reactant: C#CCOC
Reactant: Brc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCC#Cc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
A solution of 2,5-dibromo-pyridine (41, 4.64 g, 19.6 mmol), 3-methoxy-propyne (30, 1.66 mL, 19.7 mmol), and copper(I) iodide (0.084 g, 0.44 mmol) in 61.6 mL of triethylamine was purged with nitrogen, and bis(triphenylphosphine)palladium(II) chloride (0.31 g, 0.44 mmol) was added at 0° C. The resulting mixture was stirred at 0° C. for 1 hour, then at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, then washed with water and brine. The organic layer was dried with anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The crude material was purified by silica gel flash chromatography eluting with ethyl acetate and hexane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (42, 2.64 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[Cl:5][C:6]1[CH:25]=[CH:24][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:23])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[C:8]([F:26])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([NH:10][C:9]3[CH:24]=[CH:25][C:6]([Cl:5])=[CH:7][C:8]=3[F:26])=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: BrCCBr
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCBr
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
1,2-Dibromoethane (725 mg, 4 mmol) was added by portions of 70 μl every 30 minutes to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (320 mg, 1 mmol), (prepared as described for the starting material in Example 24), and potassium carbonate (552 mg, 4 mmol) in DMF (5 ml) heated at 35° C. The mixture was stirred for a further 30 minutes after the completion of the addition and then partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with petroleum ether/ether, the solid was collected by filtration and dried under vacuum to give 7-(2-bromoethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (200 mg, 47%). 1H NMR Spectrum: (DMSOd6) 3.89(t, 2H); 3.96(s, 3H); 4.51(t, 2H); 7.23(s, 1H); 7.35(dd, 1H); 7.55(dd, 1H); 7.59(t, 1H); 7.83(s, 1H); 8.36(s, 1H); 9.57(s, 1H)
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[CH:31][N:32]([CH:34]([CH3:36])[CH3:35])[CH:33]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:39][N:38]=[N:37][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[CH:31][N:32]([CH:34]([CH3:35])[CH3:36])[CH:33]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc2c(C)cc(-c3cn(C(C)C)cn3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(-c3cn(C(C)C)cn3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[(2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[OH:24][C:25]([C:36]([O:38]CC)=O)([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26][C:27]([OH:29])=O.[NH2:41][CH2:42][C:43]([C:46]1[CH:51]=[CH:50][C:49]([Br:52])=[CH:48][CH:47]=1)([OH:45])[CH3:44]>C1COCC1.C(N(CC)CC)C.C(Cl)Cl>[Br:52][C:49]1[CH:48]=[CH:47][C:46]([C:43]([OH:45])([CH3:44])[CH2:42][N:41]2[C:27](=[O:29])[CH2:26][C:25]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])([OH:24])[C:36]2=[O:38])=[CH:51][CH:50]=1
Reactant: CC(O)(CN)c1ccc(Br)cc1
Reactant: CCOC(=O)CC(O)(CC(=O)O)C(=O)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1(O)CC(=O)N(CC(C)(O)c2ccc(Br)cc2)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.7 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.833 g, 4.34 mmol) followed by 1-hydroxybenzotriazole hydrate (0.66 g, 4.35 mmol), 3-hydroxy-3,4-bis (ethoxycarbonyl)butanoic acid (1.08 g, 4.35 mmol) in THF (50 ml) and triethylamine is added to a stirred solution of 1-amino-2-(4-bromophenyl) propan-2-ol (Preparation 19, 1 g, 4.35 mmol) in THF (45 ml). The reaction mixture is stirred at ambient temperature for 18 hrs, diluted with CH2Cl2 and washed with saturated NaHCO3 solution followed by saturated NaCl solution. The organic layer is dried over MgSO4, concentrated and purified by flash chromatography (2% MeOH/CH2Cl2) to give 1-[2-(4-bromophenyl)-2-hydroxy-propyl]-3-hydroxy-2,5-dioxopyrrolidin-3-ylacetic acid, ethyl ester (0.5 g, 28% yield); MS (FAB+ion) m/z 414/416 (M+H)+ and 4-[2-(4-bromophenyl)-2-hydroxypropylcarbamoyl]-3-hydroxy-3-methyl butyric acid ethyl ester (0.94 g, 50% yield); MS (FAB+ion) m/z 460/462 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[C]=O.[O:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1>>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:3]=[CH:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: C=CC(=O)OC
Reactant: c1ccoc1
Agent: [C]=O
Product: COC(=O)C=Cc1ccco1
Reaction time: 7 h
Yield: 39 %

Procedure:
Charged in a shaking type stainless steel autoclave having an inner capacity of 100 ml, were 30 ml of furan, 1.083 g of methyl acrylate and 0.04 g of Rh4 (CO)12, followed by supply of carbon monoxide under 25 kg/cm2. Reaction was carried out at 220° C. for 7 hours. After completion of the reaction, the obtained reddish orange reaction solution was concentrated under reduced pressure and separated and purified by silica gel column chromatography. From a fraction eluted with benzene/hexane (3/2 to 4/1) was obtained 0.74 g of methyl β-(2-furyl)acrylate (1) (the yield was 39% based on methyl acrylate).
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=[C:13]([C:14](O)=[O:15])[C:8]=2[C:7]([CH3:23])=[N:6]1)([CH3:4])[CH3:3].[NH2:24][CH2:25][C:26]1[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=1[CH3:32].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:3][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=[C:13]([C:14]([NH:24][CH2:25][C:26]3[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=3[CH3:32])=[O:15])[C:8]=2[C:7]([CH3:23])=[N:6]1)([CH3:4])[CH3:1]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1nn(C(C)(C)C)c2nc(-c3cccnc3)cc(C(=O)O)c12
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccnc3)nc3c2c(C)nn3C(C)(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 121 using 1-(1,1-dimethylethyl)-3-methyl-6-[3-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (58 mg, 0.167 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (47 mg, 0.251 mmol), N-methylmorpholine (0.092 mL, 0.836 mmol), 1-hydroxy-7-azabenzotriazole (46 mg, 0.334 mmol), EDC (64 mg, 0.334 mmol), and DMSO (1 mL). The product was collected as 73 mg (96%). LCMS E-S (M+H)=445.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.81 (s, 9 H), 2.12 (s, 3 H), 2.25 (s, 3 H), 2.42 (s, 3 H), 4.39 (d, J=5.05 Hz, 2 H), 5.89 (s, 1 H), 7.59 (dd, J=8.08, 4.80 Hz, 1 H), 7.78 (s, 1 H), 8.55 (dt, J=8.15, 1.86 Hz, 1 H), 8.68 (dd, J=4.80, 1.52 Hz, 1 H), 8.74 (t, J=5.05 Hz, 1 H) 9.38 (d, J=1.77 Hz, 1 H), 11.54 (s,1 H).
Reaction SMILES: [CH3:1][NH2:2].FC(F)(F)S(O[C:9]1[C:10]([Br:27])=[CH:11][C:12]2[CH:18]([CH3:19])[CH2:17][N:16]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:15][CH2:14][C:13]=2[N:26]=1)(=O)=O.C1COCC1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:27][C:10]1[C:9]([NH:2][CH3:1])=[N:26][C:13]2[CH2:14][CH2:15][N:16]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:17][CH:18]([CH3:19])[C:12]=2[CH:11]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2nc(OS(=O)(=O)C(F)(F)F)c(Br)cc21
Reactant: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1nc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Yield: 62 %

Procedure:
A mixture of 3-bromo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H -pyrido[2,3-d]azepin-2-ol (30.0 mg, 85.0 μmol), Tf2O (50 μl), K2CO3 (18 mg) and DCM (1 ml) was stirred for 16 h at room temperature. The mixture was extracted with sat. aq. NaHCO3, dried over Na2SO4, concentrated in vacuo and purified by column chromatography to yield 11.0 mg (26%) of 3-bromo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl trifluoromethanesulfonate. A mixture of methylamine (50 μl), 3-bromo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl trifluoromethanesulfonate (11.0 mg, 22.7 μmol), and THF (1 ml) was heated to reflux for 15 h. The reaction mixture was parted between sat. aq. NaHCO3 and EtOAc. The organic layer was dried, concentrated in vacuo and purified with column chromatography to give 5.2 mg (62%) of 3-bromo-N,5-dimethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine. MS (ESI) m/z 486.2 (M+H+). A mixture of 3-bromo-N,5-dimethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine (5.2 mg, 14.2 μmol), K2CO3 (15 mg), MeOH (1 ml) and H2O (100 μl) was heated to reflux for 10 min. The reaction mixture was concentrated in vacuo and the resulting residue was purified by column chromatography to yield 2.1 mg (55%) of 3-bromo-N,5-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine. MS (ESI) m/z 271.2 (M+H+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([C:13]([NH:15][C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:34])[C:24]4[CH:29]=[C:28](Cl)[CH:27]=[CH:26][C:25]=4[N+:31]([O-:33])=[O:32])[CH:19]=[CH:20][CH:21]=3)=[O:14])[CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:2]1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([C:13]([NH:15][C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:34])[C:24]4[CH:29]=[C:28]([N:39]5[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]5)[CH:27]=[CH:26][C:25]=4[N+:31]([O-:33])=[O:32])[CH:19]=[CH:20][CH:21]=3)=[O:14])[CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(Nc1cccc(NC(=O)c2cc(Cl)ccc2[N+](=O)[O-])c1)c1ccnc(N2CCOCC2)c1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc([N+](=O)[O-])c(C(=O)Nc3cccc(NC(=O)c4ccnc(N5CCOCC5)c4)c3)c2)CC1
Yield: 89 %

Procedure:
In an analogous procedure to that described in the fifth paragraph of the portion of Note c) which is concerned with the preparation of starting materials, N-[3-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-chloro-2-nitrobenzamide was reacted with 1-methylpiperazine to give N-[3-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-(4-methylpiperazin-1-yl)-2-nitrobenzamide in 89% yield; NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 2.41 (m, 4H), 3.5 (m, 8H), 3.71 (t, 4H), 7.07 (m, 3H), 7.31 (m, 3H), 7.48 (d, 1H), 8.03 (d, 1H), 8.16 (s, 1H), 8.26 (d, 1H), 10.35 (broad s, 1H), 10.44 (broad s, 1H); Mass Spectrum: M+H+ 546.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:7]=1[CH:8]=O)[CH2:2][CH2:3][CH3:4].C1(P(=[CH:37][C:38]([O:40][CH3:41])=[O:39])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOC(C)=O>[CH3:41][O:40][C:38](=[O:39])[CH:37]=[CH:8][C:7]1[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCOc1cc(C(F)(F)F)ccc1C=O
Solvent: CCOC(C)=O
Product: CCCCOc1cc(C(F)(F)F)ccc1C=CC(=O)OC
Yield: 90 %

Procedure:
2-Butoxy-4-trifluoromethyl-benzaldehyde (420 mg) was reacted with methyl (triphenylphosphoranylidene)acetate (679 mg) at 110° C. overnight as described above to yield title compound (464 mg) after column chromatography (Hex/EtOAc=20/1).
Reaction SMILES: C[CH2:2][N:3]=C=NCCCN(C)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=O)=[CH:15][CH:14]=1.C1C=CC2N(O)N=NC=2C=1.NC>CN(C=O)C.O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([NH:3][CH3:2])=[O:23])=[CH:15][CH:14]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CCc1ccc(Br)cc1
Agent: CN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)CCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
EDAC (1.56 g, 8.1 mmol) was added in one portion to 3-(4-bromophenyl)propanoic acid (2.5 g, 7.4 mmol) and HOBt (1.1 g, 8.1 mmol) in DMF (6 mL) and the reaction mixture was stirred for 2 h. The reaction mixture was cooled to 0° C. and NH2Me (2.0 M in MeOH, 29 mL, 58 mmol) was added dropwise. The solution was stirred at 0° C. for 30 min and 10 h at ambient temperature. The reaction mixture was diluted with water (25 mL), extracted with diethyl either (3×50 mL). The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to yield 22A (1.7 g, 67%) as an off-white solid. MS (ESI) m/z 242.22/244.22 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[F:17][C:18]([F:32])([F:31])[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([C:7]([N:28]2[CH2:27][CH2:26][N:25]([C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:31])([F:32])[F:17])=[CH:24][CH:23]=3)[CH2:30][CH2:29]2)=[O:8])[CH:10]=1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)c1cc(Br)ccc1N1CCOCC1
Product: O=C(c1cc(Br)ccc1N1CCOCC1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1

Procedure:
Example CR was prepared in analogy to Example 46 from 5-Bromo-2-morpholin-4-yl-benzoyl chloride (example BI) and 1-(4-Trifluoromethyl-phenyl)-piperazine (commercial). MS (m/e): 500.1 (M+H+, 100%).
Reaction SMILES: C([O:3][C:4](=[O:22])[C@@H:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][CH2:32][NH2:33].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][CH2:32][NH:33][C:17]([C:14]([CH3:15])([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH3:21])[C:4]([OH:3])=[O:22])=[CH:12][CH:11]=1)[CH3:16])=[O:19]
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCCc2ccc(Cl)cc2Cl)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (PREPARATION 5, step 2) and 2-(2,4-dichloro-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C22H25Cl2NO5 [M−H]−: 452, [M+H]: 454.