Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[CH2:9][CH2:10][CH2:11][C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:15]2[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=2[N:13]=1.O.O.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31]>CN(C)C=O.O.C(OCC)C.C(O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[N:1]1([CH2:9][CH2:10][CH2:11][C:12]2[N:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:15]3[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=3[N:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: ClCCCc1nc2ccccc2n1-c1ccccc1
Reactant: c1c[nH]cn1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCOCC
Product: c1ccc(-n2c(CCCn3ccnc3)nc3ccccc32)cc1
Yield: 92.1 %

Procedure:
To a solution of imidazole (226 mg) in N,N-dimethylformamide (9 ml) was added sodium hydride (60% in oil, 140 mg) with stirring and ice-cooling. The mixture was stirred for 15 minutes at the same temperature and for 1 hour at 100° C. To the resultant mixture, after cooling, was added 2-(3-chloropropyl)-1-phenyl-1H-benzimidazole (0.9 g) and the mixture was stirred for 1 hour at 100° C. After being cooled, the reaction mixture was diluted with water and extracted with dichloromethane. The combined extract was washed with water and saturated aqueous sodium chloride in turn, and dried over magnesium sulfate. The solvent was removed under reduced pressure to give an oily residue, which was subjected to column chromatography on silica gel (9 g) eluting with a mixture of dichloromethane and methanol (50:1) to give an oil. To a solution of the oil in diethyl ether (30 ml) was added a solution of oxalic acid dihydrate (321 mg) in ethanol to give an oily precipitate. The oily precipitate was triturated in ethanol to give powder of 2-[3-(imidazol-1-yl)propyl]-1-phenyl-1H-benzimidazole oxalate (920 mg).
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[NH2:8][CH:9]([C:15](O)=[O:16])[CH2:10][CH2:11][C:12]([OH:14])=[O:13]>[OH-].[Na+]>[CH2:1]([N:5]1[C:15](=[O:16])[CH:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[NH:8][C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: NC(CCC(=O)O)C(=O)O
Reactant: CCCCN=C=O
Agent: [Na+]
Agent: [OH-]
Product: CCCCN1C(=O)NC(CCC(=O)O)C1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
n-Butyl isocyanate (7.5 g, 0.075 mole) was added dropwise to a stirred solution of DL-glutamic acid (7.35 g, 0.05 mole) in aqueous sodium hydroxide (4.0 g, in 50 ml) at 0° C. The mixture was stirred at 0° C. for 2 hours then left to rise to room temperature overnight. The mixture was filtered and the filtrate acidified with concentrated hydrochloric acid (50 ml) and heated on a steam-bath for 30 minutes. The solution was cooled whence crystals separated which were collected at the pump and recrystallised from methanol to give prisms, m.p. 130.5° C. Yield 8.7 g=76%.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[CH:8]=[N:9][NH:10][C:11]=2[C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19]C(C)(C)C)=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N:35]([C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=1)=C=O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:8]=[N:9][NH:10][C:11]=2[C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([NH:35][C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[CH:40][CH:39]=2)=[O:19])=[CH:24][CH:25]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1[nH]ncc1Cc1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCC[C@@H]1c1[nH]ncc1Cc1ccc(Cl)cc1
Reaction time: 2 h
Yield: 27.8 %

Procedure:
A solution of (R)-tert-butyl 2-(4-(4-chlorobenzyl)-1H-pyrazol-5-yl)pyrrolidine-1-carboxylate (30 mg, 0.8 mmol) was dissolved in 4M HCl in 1,4-dioxane (1 mL), stirred for 2 h and then concentrated in vacuo. The resulting residue was suspended in dicloromethane (2 mL) and DIEA (56 μL, 0.32 mmol) before 1-isocyanato-4-(trifluoromethyl)benzene (8.5 μL, 0.08 mmol) was added. After 10 min of stirring the reaction mixture was concentrated in vacuo. Purification of the resulting residue by semi-preparative HPLC afforded (R)-2-(4-(4-chlorobenzyl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethyl)phenyl)pyrrolidine-1-carboxamide (10 mg, 28%). LCMS: calculated: 448, found (MH+): 449.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:9][N:8]=[C:7]([S:20][CH3:21])[N:6]=1)=[O:4].[OH-].[Li+]>O1CCCC1>[C:14]1([S:11]([C:10]2[C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]([S:20][CH3:21])=[N:8][CH:9]=2)(=[O:13])=[O:12])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1nc(SC)ncc1S(=O)(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CSc1ncc(S(=O)(=O)c2ccccc2)c(C(=O)O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
A mixture of 5-benzenesulfonyl-2-methylsulfanylpyrimidine-4-carboxylic acid methyl ester (1.4 g) and tetrahydrofuran (20 mL) was treated with 1.0 M aqueous lithium hydroxide solution (2.2 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, pH adjusted to 4 by the addition of 0.1 M aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound as a pale yellow solid (1.3 g).
Reaction SMILES: CC(C)([O-])C.[Na+].CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.Cl[C:41]1[C:50]2[C:45](=[CH:46][C:47]([F:51])=[CH:48][CH:49]=2)[N:44]=[C:43]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=2)[C:42]=1[CH3:58].[N:59]1([C:65]2[CH:70]=[C:69]3[NH:71][CH2:72][C:73]4([CH2:76][S:75](=[O:78])(=[O:77])[CH2:74]4)[C:68]3=[CH:67][CH:66]=2)[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1>CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C1(C)C=CC=CC=1>[F:51][C:47]1[CH:46]=[C:45]2[C:50]([C:41]([N:71]3[C:69]4[C:68](=[CH:67][CH:66]=[C:65]([N:59]5[CH2:60][CH2:61][O:62][CH2:63][CH2:64]5)[CH:70]=4)[C:73]4([CH2:74][S:75](=[O:77])(=[O:78])[CH2:76]4)[CH2:72]3)=[C:42]([CH3:58])[C:43]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=3)=[N:44]2)=[CH:49][CH:48]=1
Reactant: O=S1(=O)CC2(CNc3cc(N4CCOCC4)ccc32)C1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CS(=O)(=O)C2)c2ccc(N3CCOCC3)cc21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a microwave vial was added sodium tert-butoxide (0.017 g, 0.177 mmol), ruphos (4.12 mg, 8.83 μmol), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)-quinoline (0.025 g, 0.093 mmol), 6-(4-morpholinyl)-1,2-dihydrospiro[indole-3,3′-thietane]1′,1′-dioxide (0.026 g, 0.088 mmol), and XPhos pre-catalyst (6.5 mg, 8.8 mmol) in toluene (0.6 mL). The suspension was deoxygenated with argon for 5 min then stirred at 100° C. for 1 h under microwave irradiation. Purification by column chromatography (eluting with a gradient of 0-10% MeOH in DCM) gave a yellow solid that was repurified by reverse phase HPLC (10-60% acetonitrile in water) to give 1-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2-dihydrospiro[indole-3,3′-thietane]1′,1′-dioxide as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.71 (1H, d, J=4.89 Hz), 7.99-8.05 (1H, m), 7.83-7.94 (3H, m), 7.50-7.56 (2H, m), 7.49 (1H, d, J=8.31 Hz, 6.40 (1H, dd, J=8.44, 2.08 Hz), 5.58 (1H, d, J=1.96 Hz), 4.72 (1H, dd, J=13.57, 2.32 Hz), 4.55-4.63 (3H, m), 4.35 (1H, d, J=10.03 Hz), 4.25 (1H, d, J=10.03 Hz), 3.58 (4H, t, J=4.89 Hz), 2.82-2.93 (4H, m), 2.24 (3H, s). Mass Spectrum (ESI) m/e=531.2 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:23](=[O:26])(=[O:25])[NH2:24])=[CH:13][C:12]=2[F:27])=[C:8]([C:28]#[N:29])[N:7]([C:30]2[CH:35]=[C:34]([NH:36][C:37](=[O:40])[CH2:38][CH3:39])[CH:33]=[CH:32][C:31]=2[Cl:41])[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl[C:43]([O:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:44].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>>[CH2:46]([O:45][C:43]([NH:24][S:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][N:7]([C:30]3[CH:35]=[C:34]([NH:36][C:37](=[O:40])[CH2:38][CH3:39])[CH:33]=[CH:32][C:31]=3[Cl:41])[C:8]=2[C:28]#[N:29])=[C:12]([F:27])[CH:13]=1)(=[O:26])=[O:25])=[O:44])[CH2:47][CH2:48][CH3:49]
Reactant: CCCCOC(=O)Cl
Reactant: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(C#N)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Product: CCCCOC(=O)NS(=O)(=O)c1ccccc1-c1ccc(Cc2c(CCCC)nn(-c3cc(NC(=O)CC)ccc3Cl)c2C#N)c(F)c1
Yield: 30 %

Procedure:
This material was prepared by reaction of 3-n-butyl-1-[2-chloro-5-(propionylamino)phenyl]-4-[(3-fluoro-2'-sulfamoylbiphenyl-4-yl)methyl]-1H-pyrazole-5-carbonitrile (from Example 4, Step K) according to the method of Example 6, except that n-butyl chloroformate was substituted for di-t-butyl dicarbonate, and the overnight reaction was conducted at 50° C. The crude product was purified by reverse phase HPLC, as described in Example 6, to give a 30% yield of the title compound as a nearly white solid; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 694 (M+1)+. 400 MHz 1H NMR (CDCl3) δ0.81 (t, J=7.4 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H), 1.15 (m, 2H), overlapping 1.21 (t, J=7.5 Hz, 3H), 1.38-1.46 (m, 2H), 1.72 (m, 2H), 2.38 (q, J=7.5 Hz, 2H), 2.74 (t, J=7.8 Hz, 2H), 3.97 (t, J=6.5 Hz, 2H), overlapping 4.04 (br s, 2H), 7.06-7.12 (m, 2H), 7.27-7.35 (m, 2H), 7.40-7.68 (m, 5H), 7.97 (s, 1H), 8.26 (dd, J=8.0, 1.3 Hz, 1H).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]([CH3:17])=[CH2:16])[CH:11]=[C:10]([C:18]([NH:20][CH2:21][C:22]4[C:23](=[O:30])[NH:24][C:25]([CH3:29])=[CH:26][C:27]=4[CH3:28])=[O:19])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd]>[CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([CH:15]([CH3:16])[CH3:17])[CH:11]=[C:10]([C:18]([NH:20][CH2:21][C:22]4[C:23](=[O:30])[NH:24][C:25]([CH3:29])=[CH:26][C:27]=4[CH3:28])=[O:19])[C:9]=3[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C=C(C)c1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C3CCCC3)c2c1
Agent: [Pd]
Product: Cc1cc(C)c(CNC(=O)c2cc(C(C)C)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Yield: 35 %

Procedure:
1-Cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(prop-1-en-2-yl)-1H-indazole-4-carboxamide was reduced using the standard Pd—C hydrogenation conditions and purified by prep HPLC to afford the target compound as a TFA salt (35% yield). LCMS: 407.25 (M+1)+; HPLC: 97.79% (@ 254 nm) (Rt;7.285); 1H NMR (DMSO-d6, 400 MHz) δ 11.54 (s, 1H), 8.43 (t, 1H), 8.25 (s, 1H), 7.64 (s, 1H), 7.48 (s, 1H), 5.89 (s, 1H), 5.18 (m, 1H), 4.36 (d, 2H, J=4 Hz), 3.04 (m, 1H), 2.21 (s, 3H), 2.12 (s, 3H), 2.08 (m, 2H), 1.98 (m, 2H), 1.86 (m, 2H), 1.69 (m, 2H), 1.28 (d, 6H, J=6.8 Hz).
Reaction SMILES: O.[NH2:2][C:3]1[N:8]=[C:7](Cl)[CH:6]=[C:5]([OH:10])[N:4]=1.[CH3:11][NH:12][CH3:13]>C(O)C>[NH2:2][C:3]1[N:8]=[C:7]([N:12]([CH3:13])[CH3:11])[CH:6]=[C:5]([OH:10])[N:4]=1
Reactant: Nc1nc(O)cc(Cl)n1
Reactant: CNC
Solvent: CCO
Solvent: O
Product: CN(C)c1cc(O)nc(N)n1

Procedure:
2-Amino-4-chloro-6-hydroxypyrimidine monohydrate (5.0 g) was stirred with 30% dimethylamine in ethanol (180 mL) at 100° C. in an autoclave for 16 h. The crystalline product was filtered, washed with water, acetone, ether and dried in vacuo to afford 2-amino-4-dimethylamino-6-hydroxypyrimidine, not melting under 300° C. Yield, 4.3 g (81%). For C6H10N4O (154.17) calculated 46.34% C, 6.54% H, 36.34% N; found 46.38% C, 6.65% H, 36.68% N. 1H-NMR (CD3SOCD3): 2.89 s, 6H (N—CH3); 4.51 s, 1H (H-5); 6.18 brs, 2H (NH2); 9.75 brs, 1H (OH).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:21][C:20]3[C:11](=[CH:12][C:13]4[CH2:14][C@@H:15]([C:31](O)=[O:32])[N:16]([C@H:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:23][CH3:24])[CH2:17][C:18]=4[CH:19]=3)[N:10]([CH3:34])[C:9]2=[O:35])=[CH:4][CH:3]=1.Cl.[CH3:37][O:38][C:39](=[O:56])[C@@H:40]([NH2:55])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1>>[CH3:37][O:38][C:39](=[O:56])[C@@H:40]([NH:55][C:31]([C@@H:15]1[CH2:14][C:13]2[CH:12]=[C:11]3[C:20]([O:21][C@@H:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)[C:9](=[O:35])[N:10]3[CH3:34])=[CH:19][C:18]=2[CH2:17][N:16]1[C@H:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][CH3:24])=[O:32])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(F)cc2)cc1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)N(C)C(=O)[C@H](c1ccc(O)cc1)O3
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(F)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(O)cc1)O3

Procedure:
(S)-3-(4′-Fluoro-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (57 mg, LC/MS: m/z 729) was prepared from (3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (70 mg) and (S)-2-amino-3-(4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester hydrochloride using general procedure A.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH:13]([NH:20]C(=O)OC(C)(C)C)[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1>C(OCC)(=O)C.Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH:13]([NH2:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCCC(NC(=O)OC(C)(C)C)c1nc(-c2cccc(Br)c2)c[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)CCCC(N)c1nc(-c2cccc(Br)c2)c[nH]1
Yield: 97 %

Procedure:
tert-Butyl 1-(4-(3-bromophenyl)-1H-imidazol-2-yl)-5-methylhexylcarbamate (obtained at stage 13777.2; 3.5 g; 0.008 mol) was agitated in 120 ml of an ethyl acetate solution saturated in hydrochloric acid for about 2.5 at a temperature of about 55° C. The solid obtained was filtered and washed with ether. A white powder was obtained with a yield of 97%. Melting point: 200-202° C. MH+=336.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[N:14]([CH3:40])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH:37]([CH3:39])[CH3:38])[N:16]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.CC(O)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[N:14]([CH3:40])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH:37]([CH3:38])[CH3:39])[N:16]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Reaction time: 65 h
Yield: 99.6 %

Procedure:
To a solution of 3-[2-(2-isopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene]azetidine-1-carboxylic acid tert-butyl ester (255 mg, 0.47 mmol) in EtOH (15 mL) and AcOH (5 mL) was added 10% Pd/C (55 mg) and the resulting mixture stirred under an atmosphere of H2 for 65 h. The reaction mixture was filtered through Celite®, washing with MeOH, and the filtrate concentrated in vacuo affording the title compound (256 mg, quant.). LCMS (method A): RT 3.16 min [M+H]+ 547.4
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:9][CH:8]=1.II.C(O)(=O)C.C(O)(=O)C.[I:31]C1C=CC=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>>[Br:1][C:2]1[S:3][C:4]([I:31])=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:9][CH:8]=1
Reactant: Ic1ccccc1
Reactant: CCCCC(CC)Cc1ccc(-c2ccsc2Br)cc1
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCC(CC)Cc1ccc(-c2cc(I)sc2Br)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The procedure was adapted from Yokoyama, A. Macromolecules 2004, 37, 1169. A 100-mL round bottom flask was charged with 2-bromo-3-[4-(2-ethylhexyl)-phenyl]-thiophene (2.6 g, 7.4 mmol), purged with N2, and anhydrous dichloromethane (18 mL) was added via a deoxygenated syringe. The reaction flask was cooled down to 0° C., whereupon iodine (I2) (1.04 g, 4.1 mmol) and iodobenzene diacetate (PhI(OAc)2) (1.4 g, 4.4 mmol) were added in one portion, and the mixture was stirred at ambient temperature for 4 hours. An aqueous solution of sodium thiosulfate (NaS2O3) (10%) was added to the reaction mixture; the aqueous layer was separated and extracted with diethyl ether (3×50 mL). The collected organic phase was washed with aqueous NaS2O3 (10%) and dried over anhydrous MgSO4. After filtration, the solvent and iodobenzene were removed by evaporation under reduced pressure. The crude product was purified using column chromatography on silica gel with hexane as the eluent (Rf=0.38). The compound was dried under vacuum to yield 3.35 g (95%) of slightly yellow oil.
Reaction SMILES: C(C1C=CC(S(Cl)(=O)=O)=CC=1)#N.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23](CNC)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CNCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 184 %

Procedure:
To a stirred solution of 4-cyanobenzenesulfonyl chloride (411 mg, 2.2 mmol) in CH2Cl2 (10 mL) was added 4-methylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.2 mmol) and triethylamine (0.91 mL, 6.5 mmol) and the reaction stirred at RT for 2 h after which time silica was added and solvent removed. The crude residue was purified by silica gel chromatography eluting with isohexane, and increasing the polarity to 100% EtOAc to afford 4{[4-cyano-benzenesulfonyl)-methyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester as a white solid (750 mg, 87%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:18]([Mg]Cl)#[CH:19]>C1COCC1>[OH:15][CH:14]([C:13]1[CH:16]=[CH:17][C:10]([O:9][CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[CH:11][CH:12]=1)[C:18]#[CH:19]
Reactant: C#C[Mg]Cl
Reactant: O=Cc1ccc(OCCN2CCOCC2)cc1
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(OCCN2CCOCC2)cc1

Procedure:
3-Hydroxy-3-[4-[2-(4-morpholinyl)-ethoxy]-phenyl]-1-propyne was prepared according to Method A above from 4-[2-(4-morpholinyl)-ethoxy]-benzaldehyde (0.630 g, 2.68 mmol) (see below) in THF (20 mL) and ethynylmagnesium chloride (3.0 mmol, 6 mL, 0.5M solution in tetrahydrofuran) (Aldrich). (Yield 492 mg, 70%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]([CH3:22])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CS(C)=O>[CH2:15]([N:14]([CH3:22])[C:4]1[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=[C:2]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CSc1ncnc2c(N(C)Cc3ccccc3)nc(Cl)nc12
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: CSc1ncnc2c(N(C)Cc3ccccc3)nc(N3CCNCC3)nc12

Procedure:
Prepared analogously to Example 2 from 2-chloro-4-(N-benzyl-methylamino)-8-methylthio-pyrimido[5,4-d]pyrimidine and piperazine in dimethylsulphoxide.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH3:29].C(N(CC)C(C)C)(C)C.[Cl:39][C:40]1[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:41]=1[C:42](Cl)=[O:43]>C(Cl)Cl>[Cl:39][C:40]1[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:41]=1[C:42]([NH:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH3:29])=[O:43]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(N)c(C)c1)C2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(NC(=O)c3ccc(Cl)cc3Cl)c(C)c1)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.4 %

Procedure:
To a solution of 0.30 g of ethyl 10,11-dihydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo[2,1-c]-[1,4]benzodiazepine-3-carboxylate in 20 ml of methylene chloride is added 0.15 g of N,N-diisopropylethylamine and 0.24 g of 2,4-dichlorobenzoyl chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated NaHCO3 and dried with Na2SO4. The organic layer is passed through a pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 0.24 g of solid, m.p. 174-184° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:10](Cl)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:10]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[Cl:23])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(-c2ccc(Cl)cc2)c(Cl)nn1Cc1ccccc1
Reactant: OB(O)c1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: O=c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1Cc1ccccc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
To a flame-dried round bottom flask was placed 2-benzyl-6-chloro-5-(4-chlorophenyl)pyridazin-3(2H)-one (6.0 g, 18.1 mmol), 2-chlorophenylboronic acid (5.7 g, 36.2 mmol), K3PO4 (7.7 g, 36.2 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex with CH2Cl2 (1:1) (2.96 g, 3.6 mmol). The flask was purged with argon for 15 min before degassed THF (120 mL) was added. The reaction mixture was stirred in a 70° C. oil bath under argon for 16 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (200 mL), washed with 1N aqueous NaOH (50 mL), H2O, saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (330 g) eluting with a gradient of EtOAc (0-40%) in hexanes to afford 6.5 g (88%) of the title compound as a white solid. LC/MS (method A): retention time=3.97 min, (M+H)+=407. 1H NMR (CDCl3, 400 MHz): δ 7.51 (d, 2H,J=8.0 Hz), 7.24-7.40 (m, 9H), 6.95-7.03 (m, 3H), 5.33 (s, 2H).
Reaction SMILES: C([O:8][CH:9]([C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)[CH2:10][CH2:11][CH:12]1[CH:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC=CC=3)=[CH:18][CH:17]=2)[N:14]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:13]1=[O:37])C1C=CC=CC=1>CO.[Pd]>[F:36][C:33]1[CH:32]=[CH:31][C:30]([N:14]2[CH:15]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)[CH:12]([CH2:11][CH2:10][CH:9]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[OH:8])[C:13]2=[O:37])=[CH:35][CH:34]=1
Reactant: O=C1C(CCC(OCc2ccccc2)c2ccc(F)cc2)C(c2ccc(OCc3ccccc3)cc2)N1c1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Yield: 72 %

Procedure:
10 gms of 3-[3-Benzyloxy-3-(4-fluoro-phenyl)-propyl]-4-(4-benzyloxy-phenyl)-1-(4-fluoro-phenyl)-azetidin-2-one was dissolved in 50 ml of methanol and 5 gms of 5% Pd/C was added at 20-25° C. Reaction mass was maintained about 30 minutes under hydrogen pressure. Filtered the catalyst and washed with methanol. The obtained reaction mass was distilled under vacuum at 70° C. and recrystalised from dichloromethane to produce 5 gms of 1-(4-Fluoro-phenyl)-3-[3-(4-fluoro-phenyl)-3-hydroxy-propyl]-4-(4-hydroxy-phenyl)-azetidin-2-one.