Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:13][C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(C=O)cc1Br
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)O)cc1Br

Procedure:
3-Bromo-4-methoxybenzaldehyde (50 g, 232 mmol), malonic acid (36.3 g, 348 mmol) and 250 ml of anhydrous pyridine are introduced into a 500 ml round-bottomed flask. Piperidine (11.4 ml, 116 mmol) is added and the medium is brought to reflux for 3 h. The pyridine is removed under vacuum and the medium is run on to 500 ml of a 1M aqueous hydrochloric acid solution. The solid is filtered off, washed with water and dried over P2O5.
Reaction SMILES: C[N+](CC)(CC)CC.[C:9]([C:11]([F:19])([F:18])[C:12]([F:17])([F:16])[C:13]([O-])=[O:14])#[N:10].S(F)(OC(F)(F)C(F)=C(F)[F:27])(=O)=O>COCCOCCOC>[C:9]([C:11]([F:19])([F:18])[C:12]([F:17])([F:16])[C:13]([F:27])=[O:14])#[N:10]
Reactant: N#CC(F)(F)C(F)(F)C(=O)[O-]
Reactant: O=S(=O)(F)OC(F)(F)C(F)=C(F)F
Agent: CC[N+](C)(CC)CC
Solvent: COCCOCCOC
Product: N#CC(F)(F)C(F)(F)C(=O)F
Reaction time: 1 h
Yield: 28.9 %

Procedure:
A solution of 53.9 g (0.2 mole) of methyltriethylammonium-3-cyanotetrafluoropropionate prepared as in Part A in 300 ml of diglyme was stirred at -10° to -5° while 46.0 g (0.20 mole) of perfluoroallyl fluorosulfate was rapidly added. The mixture was then stirred at -10° to -5° for 1 hr., and then at -5° to 0° for 4 hr. Removal of volatiles at 35° (5 mm, 6.7×10-1 kPa) through a liquid N2 trap and fractionation gave 10.0 g (29%) of 3-cyanotetrafluoropropionyl fluoride, bp 19°-20°. IR (gas phase): 2265 (CN), 1888 (COF), and 1300-1100 cm-1 (CF) with traces of CO2, SO2F2 and SiF4 present. NMR (CCl4 ; 0°); 19F 25.8 (t of t, JFF 10.1, 5.0 Hz, 1F, COF), -106.7 (d of t, JFF 5.0, 4.6 Hz, 2F, CF2CN), and -118.5 ppm (d of t, JFF 10.1, 4.6 Hz, 2F, CF2C=O).
Reaction SMILES: [I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[NH2:9][C:10]1[C:11]2[N:12]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1.[CH3:21][C:22]1[C:27]([CH2:28]Cl)=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=[CH:24][CH:23]=1>CC(C)=O>[CH3:21][C:22]1[C:27]([CH2:28][NH:9][C:10]2[C:11]3[N:12]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=3)[CH:13]=[CH:14][CH:15]=2)=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1nc2c(N)cccn2c1C
Reactant: Cc1cccc([N+](=O)[O-])c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cccc([N+](=O)[O-])c1CNc1cccn2c(C)c(C)nc12
Temperature: 25 °C
Yield: 49.5 %

Procedure:
15.0 g of sodium iodide and 31.0 g of sodium carbonate are added at RT to a solution of 8-amino-2,3-dimethylimidazo[1,2-a]pyridine (14.7 g) and 6-methyl-2-nitrobenzyl chloride (18.6 g) in 100 ml of acetone and the mixture is then heated at boiling under reflux for 6 h. After cooling the solution to RT and concentrating, the residue is dissolved in a mixture of 200 ml of ethyl acetate and 200 ml of water and the organic phase is separated off. After three further extractions with 100 ml of ethyl acetate each, the combined organic phases are dried over magnesium sulfate and then concentrated to 80 ml. 12.1 g of the title compound crystallize as a slightly yellow solid. The mother liquor is concentrated. Chromatographic purification of the residue on silica gel (eluent: toluene/dioxane=6:1) gives a further 14 g of the crystalline product. Recrystallization of both fractions from ethyl acetate gives 21.5 g (76%) of the title compound of m.p. 160-162° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[Cl:45][C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([NH:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH:53]=2)[NH:48][C:47]=1[C:63](O)=[O:64].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:45][C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([NH:55][C:56](=[O:57])[O:58][C:59]([CH3:60])([CH3:61])[CH3:62])[CH:53]=2)[NH:48][C:47]=1[C:63]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:28]=1[F:44])=[O:64]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)O)c(Cl)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)c(Cl)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
HATU (0.119 g, 0.314 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.055 g, 0.209 mmol), 3-chloro-5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylic acid (0.065 g, 0.209 mmol) and diisopropylethylamine (0.055 mL, 0.314 mmol) in DMF (1 mL). The mixture was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was triturated with methanol to give the title compound (0.033 g, 26%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (s, 1H), 9.28 (br. s., 1H), 8.44 (t, 1H), 7.78 (br. s., 2H), 7.48 (d, 2H), 7.35-7.45 (m, 2H), 7.26-7.32 (m, 1H), 7.19-7.26 (m, 1H), 4.58 (d, 2H), 1.42 (s, 9H). ES MS: m/z 601 (M−1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]([CH:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[C:12]2=[S:26])=[CH:5][CH:4]=1)#[N:2].C([Sn]([N:40]=[N+:41]=[N-:42])(CCCC)CCCC)CCC>C1(C)C(C)=CC=CC=1>[NH:40]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]3[CH:15]=[CH:14][N:13]([CH:16]4[CH2:25][CH2:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH2:17]4)[C:12]3=[S:26])=[CH:7][CH:8]=2)=[N:2][N:42]=[N:41]1
Reactant: N#Cc1ccc(CCn2ccn(C3CCc4ccccc4C3)c2=S)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: S=c1n(CCc2ccc(-c3nnn[nH]3)cc2)ccn1C1CCc2ccccc2C1
Temperature: 120 °C
Yield: 100 %

Procedure:
A mixture 3-[2-(4-cyanophenyl)ethyl]-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (0.5 g, 1.4 mmol), prepared as in Example 15, and tributyltin azide (1.39 g, 4.2 mmol) in 3 mL of xylene was heated at 120° C. under nitrogen for approximately 16 hours. The mixture was purified by chromatography on silica gel eluting with methylene chloride/methanol and the purified product was recrystallized from ethyl acetate/methanol to give 3-[2-(4 (1H)-tetrazol-5-ylphenyl)ethyl]-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (0.5 g, 1.4 mmol), m.p. 218°-220° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1.OC1C=CC(O)=CC=1C(=O)C.[Cl:31]C1C=C(C=CC=1)C=O>>[Cl:31][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Reactant: O=Cc1cccc(Cl)c1
Agent: CC(=O)c1cc(O)ccc1O
Product: O=C1CC(c2cccc(Cl)c2)Oc2ccc(O)cc21

Procedure:
2-(3-Chlorophenyl)-6-hydroxychroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 2.0 g of 2′,5′-dihydroxyacetophenone and 1.85 g of 3-chlorobenzaldehyde. The product was recrystallised from acetic acid. 1H NMR (400 MHz, d6-DMSO) δ: 9.47 (s, 1H), 7.62 (s, 1H), 7.51-7.45 (m, 3H), 7.12 (d, 1H, J 3.0 Hz), 7.05 (dd, 1H, J 8.8, 3.0 Hz), 6.98 (d, 1H, J 8.8 Hz), 5.58 (dd, 1H, J 13.1, 2.9 Hz), 3.18 (dd, 1H, J −16.9, 13.1 Hz), 2.81 (dd, 1H, J −16.9, 2.9 Hz).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7]([C:10]#[N:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([Cl:21])[C:15]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1OC(=O)[S:31][N:30]=1>ClC1C=CC=C(Cl)C=1>[Cl:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([Cl:21])[C:15]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:11]=[C:10]([S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:12])=[CH:6][CH:5]=2)(=[O:8])=[O:9])[S:31][N:30]=1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2-c2nsc(=O)o2)c1Cl
Solvent: Clc1cccc(Cl)c1
Product: Cc1ccc(S(=O)(=O)c2nc(-c3ccccc3Nc3c(Cl)ccc(C)c3Cl)ns2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 155° C. solution of p-toluenesulfonyl cyanide (420 mg, 2.32 mmols) in 5 mL of m-dichlorobenzene is added 5-[2 [(2,6-dichloro-3-methylphenyl]amino]phenyl]-1,3,4-oxathiazol-2-one (442 mg, 1.25 mmols) in three portions. Heating is continued for 1.5 hours. The solution is cooled to room temperature and directly purified by flash chromatography, eluting with 10:1 hexane:diethyl ether providing 446 mg (73%) of 2,6-dichloro-3-methyl-N-[2-[5-[(4-methylphenyl)sulfonyl]-1,2,4-thiadiazol-3-yl]phenyl]benzenamide as a bright yellow solid; mp 130.5°-135° C.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH2:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[H][H]>[Pd].C1(C)CCC(C(C)C)C(O)C1>[CH3:1][C:2]1[CH:14]=[C:13]([CH:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5]
Reactant: [H][H]
Reactant: C=C(c1ccccc1)c1ccc(C(=O)OC(C)(C)C)c(C)c1
Agent: [Pd]
Agent: CC1CCC(C(C)C)C(O)C1
Product: Cc1cc(C(C)c2ccccc2)ccc1C(=O)OC(C)(C)C
Yield: 88.5 %

Procedure:
The tert-butyl 2-methyl-4-(1-phenylvinyl)benzoate (1.8 g, 6.1 mmol), palladium 10% on carbon (0.61 mmol, 700 mg) and 30 mL menthol was stirred at room temperature under the atmosphere of hydrogen (4 atmosphere) for 24 hours. Then mixture was filtered, the filtrate was concentrated to give tert-butyl 2-methyl-4-(1-phenylethyl)benzoate (1.6 g, 90%) product. 1H-NMR (300 MHz, CD3OD) δ 7.67 (d, J=8.1 Hz, 1H), 7.24-7.08 (m, 7H), 4.02 (m, 1H), 2.48 (s, 3H), 1.59-1.61 (s, 9H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[CH2:21]([O:28][C:29]1[C:30]([CH3:46])=[C:31]2[C:36](=[C:37]([CH3:40])[C:38]=1[CH3:39])[O:35][C@@:34]([CH3:45])([CH2:41][C:42]([OH:44])=[O:43])[CH2:33][CH2:32]2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:21]([O:28][C:29]1[C:30]([CH3:46])=[C:31]2[C:36](=[C:37]([CH3:40])[C:38]=1[CH3:39])[O:35][C:34]([CH3:45])([CH2:41][C:42]([OH:44])=[O:43])[CH2:33][CH2:32]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@](C)(CC(=O)O)O2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CC(=O)O)O2

Procedure:
To a solution of 11.0 g. of diisopropylamine in 50 ml. of anhydrous tetrahydrofuran at 0° was added 50 ml. of 2N butyllithium solution. To the resultant solution of lithium diisopropylamide was added a solution of 3.54 g. of (R)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-acetic acid in 25 ml. of tetrahydrofuran. The resulting mixture was heated at 50° for 4 hours, acidified with 2N HCI and extracted with ether. The ether solutions were washed with brine, dried (Na2SO4) and stripped of solvent to give (±)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-acetic acid, αD25= ± 0°, m.p. 130° -133°.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[CH2:27][CH2:28][N:29]=[C:30]=[O:31].[H-].[Na+]>C(Cl)Cl.C1COCC1>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:27][CH2:28][NH:29][C:30]2=[O:31])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CN(CCCCN)Cc2ncccc2C(C)C)c(C)c1
Reactant: O=C=NCCCl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cnc(CN(CCCCN2CCNC2=O)Cc2ncccc2C(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a cold (0° C.) solution of N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-{3-isopropyl-pyridin-2-ylmethyl}-butane-1,4-diamine (163 mg, 0.48 mmol) in CH2Cl2 (5 mL) was added 2-chloroethylisocyanate (50 μL, 0.59 mmol) and the resultant mixture was stirred for 80 minutes then concentrated to provide a yellow oil. To a cold (0° C.) solution of the yellow oil in THF (5 mL) was added NaH (95% dry, 39 mg, 0.98 mmol). The cooling bath was removed and the resultant mixture was stirred at room temperature overnight. The mixture was treated with brine (10 mL) and extracted with CH2Cl2 (5×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2-MeOH—NH4OH) followed by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2-MeOH—NH4OH) provided 82 mg (41%) of COMPOUND 151 as a colorless oil. 1H NMR (CDCl3) δ 0.98 (d, 6H, J=6.9 Hz), 1.26-1.36 (m, 2H), 1.42-1.52 (m, 2H), 2.19 (s, 3H), 2.28 (s, 3H), 2.53 (dd, 2H, J=7.2, 7.2 Hz), 2.90-3.06 (m, 3H), 3.27-3.39 (m, 4H), 3.72 (s, 4H), 4.21 (br s, 1H), 7.—(dd, 1H, J=7.2, 4.8 Hz), 7.25 (s, 1H), 7.51 (dd, 1H, J=7.8, 1.5 Hz), 8.19 (s, 1H), 8.33 (dd, 1H, J=4.8, 1.5 Hz); 13C NMR (CDCl3) δ 18.27, 18.30, 23.51 (2 carbons), 24.36, 25.98, 27.46, 38.56, 43.75, 45.40, 54.47, 58.99, 59.59, 123.06, 132.12, 133.16, 133.61, 138.92, 144.24, 145.99, 146.57, 154.48, 156.29, 163.37; ES-MS m/z 410 (M+H). Anal. Calcd. For C24H35N5O.0.7H2O: C, 68.28; H, 8.69; N, 16.59. Found: C, 68.24; H, 8.52; N, 16.36.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[CH2:31][CH2:30][CH2:29][CH2:28][C:12]=2[C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:19][CH:18]=1)=[O:15])=[O:7].[CH:35]1([NH:38][CH:39]2[CH2:44][CH2:43][N:42]([C:45](=[O:47])[CH3:46])[CH2:41][CH2:40]2)[CH2:37][CH2:36]1>>[C:45]([N:42]1[CH2:41][CH2:40][CH:39]([N:38]([CH2:2][C:3]2[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=2)[C:6]([NH:8][C:9]2[S:10][C:11]3[CH2:31][CH2:30][CH2:29][CH2:28][C:12]=3[C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:19][CH:18]=2)=[O:15])=[O:7])[CH:35]2[CH2:37][CH2:36]2)[CH2:44][CH2:43]1)(=[O:47])[CH3:46]
Reactant: CC(=O)N1CCC(NC2CC2)CC1
Reactant: CCN(CC)c1ccc(NC(=O)c2c(NC(=O)c3cccc(CCl)c3)sc3c2CCCC3)cc1
Product: CCN(CC)c1ccc(NC(=O)c2c(NC(=O)c3cccc(CN(C4CC4)C4CCN(C(C)=O)CC4)c3)sc3c2CCCC3)cc1
Yield: 77.7 %

Procedure:
By using 5.34 g of 2-{[3-(chloromethyl)benzoyl]amino}-N-[4-(diethylamino)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide and 13.1 g of 1-[4-(cyclopropylamino)piperidin-1-yl]ethanone as starting materials, a reaction was performed under the conditions similar to Preparation Example 29, thereby obtaining 5.37 g of 2-[(3-{[(1-acetylpiperidin-4-yl)(cyclopropyl)amino]methyl}benzoyl)amino]-N-[4-(diethylamino)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide.
Reaction SMILES: [CH:1]1([NH:7][C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C(Cl)Cl>[CH:1]1([NH:7][C:8]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:38](=[O:39])[C:37]4[CH:41]=[CH:42][C:34]([Cl:33])=[CH:35][CH:36]=4)[CH:18]=3)[CH2:14][CH2:15]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cccc(CN2CCC(C(=O)NC3CCCCC3)CC2)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cccc(CN2CCC(C(=O)NC3CCCCC3)CC2)c1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 1-(3-Amino-benzyl)-piperidine-4-carboxylic acid cyclohexylamide BB-1 (80 mg, 0.25 mmol) in DCM (3 mL) is treated with DIPEA (33 mg, 43 μl, 0.25 mmol) under argon and cooled to 0° C. A solution of 4-chlorobenzoylchloride (49 mg, 0.28 mmol) in DCM (1 mL) is added and the resulting solution is stirred at 0° C. for 2 h. The mixture is diluted with DCM (25 mL) and washed twice with aq. sat. NaHCO3 (25 mL). The solvent is evaporated and the title compound is obtained by prep. LC-MS F as a colorless powder: LC-MS A: tR=0.81 min; [M+H]+=454.4. 1H-NMR (DMSO-d6): δ 1-1.3 (m, 6H), 1.5-1.7 (m, 9H), 1.8-2.1 (m, 3H), 2.8-2.9 (m, 2H), 3.4-3.5 (m, 3H), 7.03 (d, J=8, 1H), 7.29 (t, J=8, 1H), 7.5-7.7 (m, 5H), 7.98 (d, J=8, 1H), 10.2 (s, 1H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:30]=[N:29][C:17]4[NH:18][C:19]5[CH:24]=[N:23][C:22]([C:25]([NH:27][NH2:28])=[O:26])=[CH:21][C:20]=5[C:16]=4[CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31]OC(OC)OC.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(O)(=O)C>[O:26]1[CH:31]=[N:28][N:27]=[C:25]1[C:22]1[N:23]=[CH:24][C:19]2[NH:18][C:17]3[N:29]=[CH:30][C:14]([C:11]4[CH:12]=[CH:13][C:8]([CH2:7][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[CH:9][CH:10]=4)=[CH:15][C:16]=3[C:20]=2[CH:21]=1
Reactant: COC(OC)OC
Reactant: NNC(=O)c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: c1nnc(-c2cc3c(cn2)[nH]c2ncc(-c4ccc(CN5CCCCC5)cc4)cc23)o1
Yield: 10.9 %

Procedure:
A solution of 3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbohydrazide (53.8 mg, 0.134 mmol) and trimethoxymethane (1.21 mL, 11.0 mmol) in DMF (0.81 mL) was heated at 120° C. for 24 h. The mixture was cooled, treated with trimethoxymethane (1.0 mL) and a few drops of acetic acid and heated under reflux for 48 h. The mixture was allowed to cool, treated with saturated aqueous sodium bicarbonate solution, and the resultant white precipitate collected by filtration and washed with water. The filtrate was extracted with DCM, 20% methanol in DCM, and the combined organic phases dried over sodium sulfate, combined with the isolated solid and concentrated in vacuo. The resultant residue was purified by preparative HPLC [2-60% MeCN/water modified with 0.1% ammonium hydroxide] to afford a light-yellow flaky solid (6.0 mg, 27%). 1H NMR (DMSO-D6, 400 MHz): 12.77-12.69 (s, 1H), 9.41 (s, 1H), 9.26 (d, J=2.2 Hz, 1H), 9.18 (s, 1H), 9.08 (s, 1H), 9.00 (d, J=2.2 Hz, 1H), 8.31 (s, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 3.50 (s, 2H), 2.37 (m, 4H), 1.52 (m, 4H), 1.41 (m, 2H). LCMS (Method D): RT=7.69 min, M+H+=411.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl[C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16].Cl>C(O)C>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:13]1[C:14]([C:15]([OH:17])=[O:16])=[CH:18][CH:19]=[CH:20][N:21]1[C:4]2=[O:6]
Reactant: O=C(O)c1cccnc1Cl
Reactant: Nc1ccc(I)cc1C(=O)O
Agent: Cl
Solvent: CCO
Product: O=C(O)c1cccn2c(=O)c3cc(I)ccc3nc12
Temperature: 0 °C

Procedure:
A solution of 2-amino-5-iodobenzoic acid (25 g; 95.0 mmol), 2-chloronicotinic acid (14.97 g; 95.0 mmol), concentrated hydrochloric acid (3.17 ml; 38 mmol), and ethanol (150 ml) was heated at reflux for 18 hours, then cooled to 0° C. The precipitate was collected by filtration and the filter cake was washed with fresh ethanol (200 ml). The filter cake was dried in vacuo over phosphorous pentoxide to provide product as a yellow solid: 12.0 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][C:9](=O)[CH:10]=[CH:11][CH:12]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:9]1[N:8]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cccc(-c2ccccn2)[nH]1
Product: Clc1cccc(-c2ccccn2)n1

Procedure:
A mixture of 5.3 g of 2-(2-pyridinyl)-6-(1H)-pyridinone and 100 ml of phosphorus oxychloride was heated on a steam bath for 18 hours and then concentrated to dryness under vacuum. Crushed ice was added to the oil residue and the mixture made basic with solid potassium carbonate. The mixture was then extracted with dichloromethane, the extracts treated with activated carbon, filtered and concentrated, giving a solid which was purified by chromatography on silica gel with ethyl acetate as solvent, giving 4.1 g of 6'-chloro-2,2'-bipyridine as white crystals, mp 60°-62° C.
Reaction SMILES: COC1C=CC(C[N:10]2[CH:15]=[C:14]([O:16]CC3C=CC=CC=3)[C:13](=[O:24])[CH:12]=[C:11]2[C:25]([NH:27][CH2:28][CH2:29][NH:30]CC2C=CC=CC=2)=[O:26])=CC=1.[C:38]1([CH3:48])[CH:43]=[CH:42][C:41]([S:44]([OH:47])(=[O:46])=[O:45])=[CH:40][CH:39]=1.[H][H]>CO.[Pd]>[C:38]1([CH3:48])[CH:39]=[CH:40][C:41]([S:44]([OH:47])(=[O:45])=[O:46])=[CH:42][CH:43]=1.[NH2:30][CH2:29][CH2:28][NH:27][C:25]([C:11]1[NH:10][CH:15]=[C:14]([OH:16])[C:13](=[O:24])[CH:12]=1)=[O:26]
Reactant: COc1ccc(Cn2cc(OCc3ccccc3)c(=O)cc2C(=O)NCCNCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: NCCNC(=O)c1cc(=O)c(O)c[nH]1

Procedure:
1,4-Dihydro-1-[(4-methoxyphenyl)methyl]-4-oxo-5-(phenylmethoxy)-N-[2-[(phenylmethyl)amino]ethyl]-2-pyridinecarboxamide (9.95 g) and 7.7 g of p-toluenesulfonic acid in 100 ml of methanol were treated with 3 g of palladium on charcoal (10%) and hydrogen was bubbled through the reaction mixture at 45°-50° C. over six hours. A stream of argon was then bubbled through the reaction mixture for 10 minutes. Filtration and evaporation of the filtrate yielded beige crystals of the title compound which were washed first with 20 ml of cold methanol and then 50 ml of ether. Yield: 10.5 g, melting point 271° C.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]([O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([CH3:14])[CH3:13]>>[CH:12]([O:15][C:16]1[CH:21]=[C:20]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=2)[CH:19]=[CH:18][CH:17]=1)([CH3:14])[CH3:13]
Reactant: CC(C)Oc1cccc(B(O)O)c1
Reactant: Cc1cc([N+](=O)[O-])cnc1Br
Product: Cc1cc([N+](=O)[O-])cnc1-c1cccc(OC(C)C)c1
Yield: 82 %

Procedure:
Obtained (1.03 g, yield 82%) following the procedure described in Intermediate 27, starting with 2-bromo-3-methyl-5-nitropyridine (4.61 mmol, 1.0 g), 3-isopropoxyphenylboronic acid (4.61 mmol, 0.83 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:13][C:14]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:15]=1[C:16](O)=[O:17].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:16](=[O:17])[C:15]3[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:14]=3[F:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(F)c(C(=O)O)c1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)c(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)c1
Yield: 62.9 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 2-fluoro-5-methylbenzoic acid (281 mg, 1.83 mmol), BOP-Cl (465 mg, 1.83 mmol), and triethylamine (0.606 mL, 4.35 mmol) in DCM (5 mL) was processed as described in Example 62, Step A, to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-fluoro-5-methylbenzamide (200 mg, 63% yield).