Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:18]2[CH:17]=[CH:16][C:15]([S:29][C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)=[C:14]([NH:13][C:2]3[C:3]4[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:19]=2)=[CH:23][CH:24]=1
Reactant: Nc1cc(OCc2ccc(Cl)cc2)ccc1Sc1ccc(O)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc2c(Nc3cc(OCc4ccc(Cl)cc4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 1d (100 mg, 0.559 mmol) was reacted with the product from Example 143a (224 mg, 0.559 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (mg, %). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.77 (s, 3H), 5.16 (s, 2H), 6.26 (d, J=6.99 Hz, 1H), 6.65 (d, J=8.46 Hz, 2H), 7.09-7.24 (m, 5H), 7.37-7.44 (m, 3H), 7.51 (s, 1H), 7.81 (d, J=8.82 Hz, 1H), 8.40 (d, J=6.99 Hz, 1H), 8.99 (d, J=8.82 Hz, 1H), 9.80 (s, 1H), 11.04 (s, 1H); MS (ESI+) m/z 500 (M+H−TFA)+; (ESI−) m/z 498 (M−H−TFA)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.C([Mg]Cl)(C)C.[CH2:14]([O:16][C:17](=[O:31])/[C:18](=[N:23]\[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])/[C:19]([F:22])([F:21])[F:20])[CH3:15]>C1COCC1>[CH2:14]([O:16][C:17](=[O:31])[C:18]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:19]([F:22])([F:21])[F:20])[CH3:15]
Reactant: Brc1cccc(I)c1
Reactant: CCOC(=O)/C(=N\C(=O)OC(C)(C)C)C(F)(F)F
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(NC(=O)OC(C)(C)C)(c1cccc(Br)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 5.66 g (20 mmol) 1-bromo-3-iodo-benzene in 25 ml THF was stirred at −20° C. A 1.82 M solution of isopropylmagnesium chloride (12.1 ml, 22.0 mmol) in THF was added and the mixture was stirred 1 h at 0° C. The mixture was cooled to −78° C. and a solution of 5.38 g (20 mmol) 2-[(E)-tert-butoxycarbonylimino]-3,3,3-trifluoro-propionic acid ethyl ester in 50 ml of THF was added over a period of 2 h. After 20 min the mixture was quenched with 5% aqueous NH4Cl. The mixture was extracted with TBME. The organic phase was dried with Na2SO4, filtered and evaporated. Purification via chromatography on silica gel (c-hexane/0-14% EtOAc) gave the desired product as a colorless resin.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C@H:16]2[CH2:21][N:20]([CH:22]3[CH2:25][CH2:24][CH2:23]3)[CH2:19][CH2:18][N:17]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.O>[Pd].C(O)C>[CH:22]1([N:20]2[CH2:19][CH2:18][N:17]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:16]([C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])[CH2:21]2)[CH2:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCC2)C[C@@H]1C(=O)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C2CCC2)C[C@@H]1C(=O)N1CCNCC1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
10% Palladium on carbon (900 mg) was added to tert-butyl (2R)-2-[(4-benzylpiperazin-1-yl)carbonyl]-4-cyclobutylpiperazine-1-carboxylate (5.12 g) and water (10 ml). Under an argon atmosphere, ethanol (250 ml) was added and the mixture stirred at room temperature under a hydrogen filled balloon. After 4 hours the catalyst was removed by filtration and washed with a small quantity of non-flammable solvent (dichloromethane). The combined filtrate was concentrated in vacuo, azeotroped once with toluene and dried under vacuum to give tert-butyl (2R)-4-cyclobutyl-2-(piperazin-1-ylcarbonyl)piperazine-1-carboxylate as an off-white foam (4.08 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:24].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:24]
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1F
Reaction time: 0.05 h
Yield: 115.4 %

Procedure:
40% Methanolic Triton B (0.14 mL, 0.31 mM) was added to a solution of the 9-[(2-fluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (51.9 mg, 0.155 mM) in 5 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (110.5 mg, 0.72 mM) was added and the resultant mixture stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate, washed four times with H2O, once with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 72.8 mg (71%) of the {9-[(2-fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) δ 7.65 (d, 1H, J=8 Hz), 7.5 (s, 1H), 7.4-7.2 (m, 5H), 7.15 (s, 1H), 7.1 (d, 1H, J=8 Hz), 7.05 (t, 1H, J=8 Hz), 6.7 (t, 1H, J=8 Hz), 6.55 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.85 (s, 2H), and 3.7 (s, 3H). IR (CHCl3, cm−1) 3436, 1763, 1675, 1457, 1327, 1208, 1198, 1150, 1102, 772, 756, and 719. MS (FD) m/e 407.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:30]=[CH:29][C:12]2[N:13]=[C:14]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[N:15]([CH2:16][CH2:17][CH3:18])[C:11]=2[CH:10]=1.[CH3:31][N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH:37]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][N:7]([CH2:37][C:33]1[N:32]([CH3:31])[CH:36]=[CH:35][N:34]=1)[CH2:8][C:9]1[CH:30]=[CH:29][C:12]2[N:13]=[C:14]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[N:15]([CH2:16][CH2:17][CH3:18])[C:11]=2[CH:10]=1
Reactant: CCCn1c(CCCCN2CCCCC2)nc2ccc(CNCc3ncc[nH]3)cc21
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCn1c(CCCCN2CCCCC2)nc2ccc(CN(Cc3ncc[nH]3)Cc3nccn3C)cc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 105.8 %

Procedure:
The compound (429.5 mg) obtained in Example 61-4 was dissolved in methanol (21.5 ml) and added with 1-methyl-2-imidazole carboxaldehyde (173.6 mg) and sodium cyanoborohydride (132.1 mg). After the solution was adjusted to pH 4 with acetic acid, the whole was stirred at room temperature for 4 days. The reaction solution was concentrated under reduced pressure. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and a saturated saline solution. Then, the resultant was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (559.2 mg) of the subject compound as a pale-yellow solid.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[CH3:30][NH2:31]>>[CH3:5][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:1])[CH2:3][NH:31][CH3:30]
Reactant: CN
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)C=O)cn1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CNC)cn1

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide was reacted with methylamine to afford the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 19.0, 26.5, 26.6, 36.0, 37.2, 43.1, 46.0, 53.2, 58.8, 62.6, 102.6, 102.8, 103.1, 105.1, 112.3, 112.6, 131.6, 137.8, 138.8, 162.0, 164.5, 169.2, 169.3; MS m/z 422.2 (M+1).
Reaction SMILES: [CH2:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)[CH2:7][CH2:6][C:5]1=[O:22])[CH:2]=[CH2:3].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)(Cl)Cl>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][C:4]1([CH2:1][CH:2]=[CH2:3])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:12]=2)[CH2:7][CH2:6][C:5]1=[O:22])[CH3:29]
Reactant: C=CCC1C(=O)CCc2ccc(OCc3ccccc3)cc21
Reactant: CCOC(=O)CBr
Solvent: ClC(Cl)Cl
Product: C=CCC1(CC(=O)OCC)C(=O)CCc2ccc(OCc3ccccc3)cc21

Procedure:
Crude 1-allyl-7-benzyloxy-3,4-dihydro-2(1H)-naphthalenone (VIIIc), 22.9 g (78.5 mmol) was reacted with ethyl bromoacetate by the method of Example 5 to yield 25.5 g (87%) crude crystalline IXc. Recrystallization from ethanol gave 19.5 g (66%) m.p. 83°-85°. IR (CHCl3) 1725, 1710 cm-1 (ketone and ester); NMR δ, 1.05 and 3.96 (triplet and quartet and OCH2CH3) 4.8-5.8 (m, 5, olefinic and PhCH2O), 5.15 (s, 2, PhCH2O), 6.80-7.55 (m, 8, ArH).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25](I)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:34]1[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=1)CCC>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:34]5[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=5)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Reactant: Ic1ccc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2c1
Product: Cn1cncc1-c1ccc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2c1

Procedure:
Prepared in an analogous manner to Example 6 according to Procedure B from (1-Benzyl-1H-indazol-5-yl)-(6-iodoquinazolin-4-yl)-amine and 5-(tributylstannyl)-1-methylimidazole; δH [2H6]DMSO 9.98(1H,s), 8.62(1H,s), 8.55(1H,s), 8.20(1H,s), 8.15(1H,s), 7.99(1H,dd), 7.83(2H,m), 7.70(2H,m), 7.28(6H,m), 5.70(2H,s), 3.70(3H,s); m/z (M+1)+432.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH3:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+].CS(C)=O>O>[F:16][C:17]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[C:7]([C:8]3[N:9]=[C:10]([NH:14][CH3:15])[N:11]=[CH:12][N:13]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: CNc1ncnc(-c2cccnc2Cl)n1
Reactant: O=C(O)c1cc(O)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CNc1ncnc(-c2cccnc2Oc2ccc(F)c(C(=O)O)c2)n1
Temperature: 130 °C

Procedure:
To [4-(2-chloro-pyridin-3-yl)-[1,3,5]triazin-2-yl]-methyl-amine (6.90 g, 31.1 mmol), 2-fluoro-5-hydroxybenzoic acid (4.9 g, 31.1 mmol) and Cs2CO3 (20.3 g, 62.2 mmol) was added DMSO (25 mL). The mixture was heated overnight at 130° C. in a sealed tube. The cooled mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified (pH˜4) with TFA and the resulting solid was filtered, washed with water and dried to yield 2-fluoro-5-[3-(4-methylamino-[1,3,5]triazin-2-yl)-pyridin-2-yloxy]-benzoic acid. MS m/z=342 [M+1]+. Calc'd for C16H12FN5O3: 341.30.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(O)(=O)C.[CH:37](=O)[CH2:38][CH3:39].C([BH3-])#N.[Na+]>CO>[O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][N:21]([CH2:37][CH2:38][CH3:39])[CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CCC=O
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.3 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (25 mg, 0.06 mmol, Example 1) was dissolved in methanol (1 mL). Acetic acid (0.013 mL, 0.23 mmol) and propionaldehyde (4.25 μL, 0.06 mmol) was added and the reaction mixture was stirred at room temperature for 10 minutes. Sodium cyanoborohydride (3.67 mg, 0.06 mmol) was added and after 15 minutes the solvent was evaporated under reduced pressure. The crude was dissolved in few drops of dimethylformamide and acetonitrile, filtered and purified by preparative HPLC yielding 2-((2-(4-(oxazol-5-yl)phenylamino)-6-propyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (6.3 mg, 22.95%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]([C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=[CH:8][N:9]=1.Cl[CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18].C(=O)([O-])O.[Na+]>C1COCC1>[N:3]1[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:9]2[CH:8]=[CH:7][N:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=12
Reactant: O=S(=O)(Cl)CCCl
Reactant: COC(=O)c1nccnc1N
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1=NC=CN2CCS(=O)(=O)N=C12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (60%, 2.0 g) in dry THF (100 mL) were added under ice-cooling methyl 3-aminopyrazine-2-carboxylate (1.53 g) and 2-chloroethanesulfonyl chloride (2.1 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2-chloroethanesulfonyl chloride (2.1 mL), and the mixture was stirred at room temperature for 3 days. 2-Chloroethanesulfonyl chloride (2.1 mL) was added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was added dropwise to aqueous sodium hydrogen carbonate (15.1 g) solution (400 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hr. The precipitated was collected by filtration, washed successively with water and a small amount of methanol, and dried to give the title compound (1.62 g) as a pale-yellow solid.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH2:21].[I:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH:21][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([I:22])=[CH:24][CH:25]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.2 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide was prepared according to method C with triethylamine (2.23 mL; 15.90 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (1.5 g; 6.36 mmol) and 4-iodobenzoyl chloride (1.82 g; 6.68 mmol) in dichloromethane (75 mL). The mixture was stirred for 20 minutes at room temperature and was evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) to provide 1.22 g (45%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide as a white solid.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][S:13][C:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([N:25]3[CH2:30][C@@H:29]4[CH2:31][C@H:26]3[CH2:27][N:28]4[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:24])=[CH:20][CH:21]=2)[N:16]([C:39]2[N:44]=[CH:43][C:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)=[CH:41][N:40]=2)[CH:15]=1>ClCCl>[CH3:12][S:13]([C:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([N:25]3[CH2:30][C@@H:29]4[CH2:31][C@H:26]3[CH2:27][N:28]4[C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])=[O:24])=[CH:20][CH:21]=2)[N:16]([C:39]2[N:44]=[CH:43][C:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)=[CH:41][N:40]=2)[CH:15]=1)=[O:6]
Reactant: CSc1cn(-c2ncc(-c3ccccn3)cn2)c2cc(C(=O)N3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)ccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1cn(-c2ncc(-c3ccccn3)cn2)c2cc(C(=O)N3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
m-Chloroperoxybenzoic acid (0.114 g, 0.66 mmol, 0.9 eq) was added at 0° C. to a stirred solution of 244c) (0.400 g, 0.61 mmol, 1 eq) in dichloromethane (30 mL). The reaction mixture was stirred for 3 h at room temperature, then diluted with dichloromethane (50 mL) and successively washed with saturated sodium hydrogen carbonate solution (2×30 mL) and brine (30 mL). The organic layer wasdried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography [230-400 mesh silica gel, dichloromethane/methanol=95:5]. White solid. Yield: 0.290 g (71% of theory)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[CH3:19][N:20]([CH2:22][CH2:23][CH2:24]Cl)[CH3:21]>>[CH3:19][N:20]([CH2:22][CH2:23][CH2:24][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:9][CH2:10][C:11]2[CH:12]=[C:13]([C:17]#[N:18])[CH:14]=[CH:15][C:16]1=2)[CH3:21]
Reactant: N#Cc1ccc2c(c1)COC2c1ccc(F)cc1
Reactant: CN(C)CCCCl
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21

Procedure:
According to the present invention, the alkylation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (5-cyanophthalane) with N,N-dimethylaminopropylchloride may be carried out following prior art procedure, and preferably as described in U.S. Pat. No. 4,136,193. However, according to the process described in U.S. Pat. No. 4,136,193, after the completion of the alkylating reaction, the reaction mass is diluted with ice cold water and the aqueous layer is extracted into ether. The ether layer is then extracted with 20% aqueous acetic acid. The pH of the aqueous acidic layer is then adjusted to alkaline, e.g. pH 10-11, with sodium hydroxide and the citalopram base extracted into ether. The ether layer is then concentrated under reduced pressure to obtain citalopram base oil.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][N:31]([CH3:38])[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:27][N:26]([CH3:28])[C:25]([C:7]1[N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:35]4[CH2:36][CH2:37][CH:32]([N:31]([CH3:38])[CH3:30])[CH2:33][CH2:34]4)=[O:21])=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=1)=[O:29]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: CN(C)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[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: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CCC(N(C)C)CC4)cn3)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.6 %

Procedure:
To a solution of 6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (100 mg, 0.25 mmol) (Example D) in 3 mL of DMF is added dimethyl-piperidin-4-yl-amine (33 mg, 0.25 mmol), HBTU (140 mg, 0.38 mmol), and DIPEA (0.088 mL, 0.51 mmol). Alter 48 h stirring at room temperature, the resulting mixture is concentrated and diluted with saturated NaHCO3 and extracted with ethyl acetate (3×100 mL). The combine organics are dried over Na2CO3 and concentrated to give a reddish residue. Preparative HPLC to give 7-cyclopentyl-2-[5-(4-dimethylamino-piperidine-1-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (60 mg, 46%). MS(ESI) m/z 505.5 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([C@H:9]2[CH2:11][C@H:10]2[C:12](O)=[O:13])=O)=[CH:5][CH:4]=1)#[N:2].O.[NH2:18][NH2:19]>C(O)C>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]2[CH:9]3[CH:10]([C:12](=[O:13])[NH:18][N:19]=2)[CH2:11]3)=[CH:5][CH:4]=1)#[N:2]
Reactant: NN
Reactant: N#Cc1ccc(C(=O)[C@H]2C[C@H]2C(=O)O)cc1
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 66.4 %

Procedure:
2.45 g (11.4 millimoles) of cis-2-(p-cyanobenzoyl)-cyclopropanecarboxylic acid, 0.57 g (11.4 millimoles) of hydrazine hydrate and 50 ml of ethanol are refluxed for 6 hours. After filtering off the product at 10° C. and drying it under reduced pressure at 50° C., 1.6 g (67% of theory) of 2-(p-cyanophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are obtained as ocher crystals which are identical with the compound from Example 39.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH3:28]>CC(C)=O>[CH2:25]([O:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])=[CH:4][CH:3]=1)[CH2:26][CH2:27][CH3:28]
Reactant: COC(=O)CCCCC(=O)c1ccc(O)cc1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1ccc(C(=O)CCCCC(=O)O)cc1

Procedure:
A mixture of methyl 5-(4-hydroxybenzoyl)pentanoate (2 g), acetone (50 ml), potassium carbonate (2.34 g), and 1-bromobutane (2.0 ml) is gently refluxed for 4 hours. The reaction mixture is filtered and the filtrate concentrated in vacuo. The resulting brown solid is dissolved in ethanol (25 ml) and 2N sodium hydroxide (25 ml), and then refluxed for 4 hours. After washing with ether (100 ml), the aqueous layer is acidified to pH 1.0 with concentrated hydrochloric acid and the product extracted with ether (1×300 ml). The ether solution is dried over magnesium sulfate, filtered, and concentrated in vacuo. The product is recrystallized from ethanol/water to yield 5-(4-n-butoxybenzoyl)pentanoic acid (1.2 g), m.p. 95° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[CH:26][C:27]=1[Cl:28].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][C:27]([Cl:28])=[C:22]([Cl:21])[CH:23]=3)[CH2:34][CH2:33]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: Cc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)c(Cl)c4)CC3)nn2C(C)(C)C)cc1

Procedure:
99 mg (85%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (60 mg, 0.222 mmol), 1-(3,4-dichlorophenyl)piperazine (51 mg, 0.222 mmol), DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)3 (141 mg, 0.666 mmol).