Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26](Br)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:33][O:34][C:35](=[O:72])[NH:36][CH:37]([C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH:44]1[C:48]1[NH:49][C:50]([C:53]2[CH:62]=[CH:61][C:60]3[C:55](=[CH:56][CH:57]=[C:58](B4OC(C)(C)C(C)(C)O4)[CH:59]=3)[CH:54]=2)=[CH:51][N:52]=1)=[O:42])[CH:38]([CH3:40])[CH3:39].C([O-])(O)=O.[Na+]>COCCOC.O>[CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[C:26]([C:58]2[CH:57]=[CH:56][C:55]4[C:60](=[CH:61][CH:62]=[C:53]([C:50]5[NH:49][C:48]([CH:44]6[CH2:45][CH2:46][CH2:47][N:43]6[C:41](=[O:42])[CH:37]([NH:36][C:35]([O:34][CH3:33])=[O:72])[CH:38]([CH3:40])[CH3:39])=[N:52][CH:51]=5)[CH:54]=4)[CH:59]=2)[CH:25]=[CH:24]3)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)ccc5c4)ccc3c2)[nH]1)C(C)C
Temperature: 85 °C
Reaction time: 16 h
Yield: 17.1 %

Procedure:
(1-{2-[5-(6-Bromonaphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.174 g), [2-Methyl-1-(2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (0.202 g), and NaHCO3 (0.108 g) were dissolved in a mixture of 1,2-dimethoxyethane (6 mL) and water (2 mL). The solution was degassed with nitrogen, and Pd(PPh3)4 (0.0176 g) was added. The reaction mixture was stirred at 85° C. for 16 hours and evaporated under vacuum. Solid was dissolved in ethyl acetate (10 mL) and extracted twice with water (10 mL) and once with brine (10 mL) Solution was evaporated, dissolved in DMF, purified by reverse phase HPLC (5-70% acetonitrile:water), and lyophilized, giving (1-{2-[5-(6′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-[2,2]binaphthalenyl-6-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.050 g, 16%) as a white solid: 1H-NMR: 300 MHz, (MeOH-d4) δ: 8.3 (m, 4H), 8.1 (m, 6H), 8.0 (s, 2H), 7.8 (d, J=9.4, 21-1), 5.3 (m, 2H), 4.3 (d, J=9.0, 2H), 4.1 (m, 2H), 3.9 (m, 2H), 3.7 (s, 6H), 2.6 (m, 2H), 2.2 (m, 6H), 0.9 (m, 12H); MS (ESI) m/z 839 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]([CH:9]=[CH:10][CH2:11]Cl)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:24]=2[N:25]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][N:21]([CH2:11][CH:10]=[CH:9][C:8]3[CH:13]=[CH:14][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[CH2:22][CH2:23][C:24]=2[N:25]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: CS(=O)(=O)c1ccc(C=CCCl)cc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(C=CCN2CCc3nc(N)sc3CC2)cc1
Yield: 21 %

Procedure:
Prepared from 4-methylsulphonyl-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 21% of theory, Melting point: 157°-161° C. (ether).
Reaction SMILES: [C:1]([C:5]1[C:10]2[O:11][CH2:12][CH2:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:14](O)(=[O:19])[CH2:15][CH2:16][CH2:17]C>>[C:1]([C:5]1[C:10]2[O:11][CH2:12][CH2:13][C:9]=2[CH:8]=[C:7]([C:14](=[O:19])[CH2:15][CH2:16][CH3:17])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCC(=O)O
Reactant: CC(C)(C)c1cccc2c1OCC2
Product: CCCC(=O)c1cc2c(c(C(C)(C)C)c1)OCC2

Procedure:
Substantially the method described in Example 1 is employed for the reaction between 7-tert-butyl-2,3-dihydrobenzo[b]furan and pentanoic acid, to provide 1-(7-tert-butyl-2,3-dihydrobenzo[b]furan-5-yl)-butan-1-one as a colorless oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:3][CH:2]=1.Cl[C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1.[H-].[Na+]>CN(C=O)C>[N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)=[CH:16][CH:15]=2)=[N:3][CH:2]=1
Reactant: Oc1ccc(CCNc2ncnc3nccnc23)cc1
Reactant: Clc1cnccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cnc(Oc2ccc(CCNc3ncnc4nccnc34)cc2)cn1
Temperature: 55 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a solution of 4-[2-(pteridin-4-ylamino)ethyl]phenol (0.267 g, 1.0 mmol) and 2-chloropyrazine (0.114 g, 1.0 mmol) in anhydrous DMF (7 mL) was added 60% sodium hydride (NaH) in mineral oil (0.060 g, 1.5 mmol) portionwise. The mixture was stirred at 55° C. overnight and then at 70° C. for a total reaction time of 32 h. The solvent was removed in vacuo and the residue was suspended in H2O. The solid was collected by suction filtration, washed with H2O and Et2O, dried in a vacuum oven at 55° C. overnight to afford pteridin-4-yl-{2-[4-(pyrazin-2-yloxy)-phenyl]-ethyl}-amine (0.291 g, 84%) as a light brown solid: 1H NMR (300 MHz, CDCl3) δ 9.02 (d, J=1.9 Hz, 1H), 8.82 (s, 1H), 8.63 (d, J=1.9 Hz, 1H), 8.43 (d, J=1.5 Hz, 1H), 8.26 (d, J=2.4 Hz, 1H), 8.10 (dd, J=2.4, 1.5 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 3.99 (dd, J=13.6, 6.9 Hz, 2H), 3.08 (t, J=6.9 Hz, 2H); ESIMS m/z 346.24 ([M+H]+).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1B(O)O.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:24][S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1)(=[O:14])=[O:13])(=[O:22])=[O:23]
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Reactant: OB(O)c1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccc4ccccc34)c2c1
Yield: 58 %

Procedure:
2-Methylsulfonyl-N-(3-naphthalen-1-yl-1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 59 from 0.5 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 298 mg of 2-naphthaleneboronic acid, 20 ml of dimethylformamide, 1.9 ml of a saturated aqueous sodium hydrogencarbonate solution and 24.5 mg of tetrakis(triphenylphosphine)palladium[0]. 240 mg of 2-methylsulfonyl-N-(3-naphthalen-1-yl-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of a white solid melting at 186° C. (analysis C24H19N3O4S2 % calculated C, 60.36; H, 4.01; N, 8.80; O, 13.40; S, 13.43. % found C, 59.78; H, 4.05; N, 8.76; S, 13.34).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C@@H:9]([CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[OH:10])=[O:6].[CH3:31][N:32]=[C:33]=[O:34]>ClC(Cl)C>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C@@H:9]([CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[O:10][C:33](=[O:34])[NH:32][CH3:31])=[O:6]
Reactant: CN=C=O
Reactant: CCCCCCCCCCCCCCCCCCOC[C@@H](O)COC(=O)CCCCl
Solvent: CC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC[C@H](COC(=O)CCCCl)OC(=O)NC

Procedure:
A solution of 0.33 g of (R)-1-O-(4-chlorobutyryl)-3-O-octadecylglycerine in 10 ml of dichloroethane is treated at 80° C. with 10 ml of methyl isocyanate. The solution is evaporated and the residue is chromatographed on silica gel while eluting with ether. There is obtained (R)-1-O-(4-chlorobutyryl)-2-O-(methylcarbamoyl)-3-O-octadecylglycerine of melting point 61°-62° C. (dec.).
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[F:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:21])[C:14]([OH:20])=[CH:15][N:16]2[CH3:19])=[CH:11][CH:10]=1.ClCCl>C(N(CC)CC)C>[CH3:1][CH:2]([S:4]([O:20][C:14]1[C:13](=[O:21])[C:12]2[C:17](=[CH:18][C:9]([F:8])=[CH:10][CH:11]=2)[N:16]([CH3:19])[CH:15]=1)(=[O:6])=[O:5])[CH3:3]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cn1cc(O)c(=O)c2ccc(F)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)Oc1cn(C)c2cc(F)ccc2c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Propanesulphonyl chloride (1.74 ml) was added to a stirred mixture of 7-fluoro-3-hydroxy-1-methyl-4quinolone (3.0 g), obtained as described in Example 3 a-f, triethylamine (4.35 ml) and dry dichloromethane (180 ml) and the mixture stirred at ambient temperature for 24 hours. Further quantities of 2-propanesulphonyl chloride (1.75 ml then 1 ml) and triethylamine (4.35 ml then 2.5 ml) were added after stirring for 24 hours and 48 hours respectively. After stirring for a further 24 hours, the mixture was filtered and the filter bed was washed with dichloromethane (30 ml). The combined filtrate and washing were washed with water (200 ml), saturated aqueous sodium bicarbonate (2×200 ml), then water (200 ml) and then dried over magnesium sulphate. The dichloromethane was removed by distillation to give a residue which was purified by flash chromatography on a silica gel column eluted with dichloromethane: industrial methylated spirit (19:1) followed by crystallisation from 2-propanol (25 ml) to give the novel compound 7-fluoro-1-methyl-4-oxo-1,4-dihydroquinol-3-yl 2-propanesulphonate, m.p. 130°-133°.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([CH2:11]O)=[N:9][S:10][C:6]=2[CH:5]=[C:4]([CH3:13])[CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:34]>C(Cl)Cl>[Br:34][CH2:11][C:8]1[C:7]2[C:2]([CH3:1])=[CH:3][C:4]([CH3:13])=[CH:5][C:6]=2[S:10][N:9]=1
Reactant: Cc1cc(C)c2c(CO)nsc2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(C)c2c(CBr)nsc2c1
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of (4,6-Dimethyl-1,2-benzisothiazol-3-yl)-methanol (100 mg, 0.5 mmol) in CH2Cl2 (15 mL) were added PPh3 (200 mg, 0.78 mmol) and CBr4 (340 mg, 1 mmol) at room temperature. The solution was stirred at the same temperature for 1 hour. The solution was concentrated and the residue was purified by CombiFlash with 10% EtOAc in Hexane as the eluent to afford the desirable product 3-Bromomethyl-4,6-dimethyl-1,2-benzisothiazole (90 mg, 68%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[N:17]=[N:18][N:19]([CH2:21][CH2:22][NH:23]C(OC(C)(C)C)=O)[N:20]=3)[CH2:15][C@@:9]1([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C@H:10]([O:31][CH2:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.ClCCl>[NH2:23][CH2:22][CH2:21][N:19]1[N:18]=[N:17][C:16]([C@@H:14]2[CH2:15][C@:9]3([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C@H:13]2[CH2:12][CH2:11][C@H:10]3[O:31][CH2:32][C:33]2[CH:34]=[C:35]([C:43]([F:44])([F:45])[F:46])[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=2)=[N:20]1
Reactant: CC(C)(C)OC(=O)NCCn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Yield: 96.6 %

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-{2-[2-(t-butoxycarbonylamino)ethyl]-2H-tetrazol-5-yl}-1-phenyl-8-azabicyclo[3.2.1 ]octane (Example 140; 0.54 g) was stirred in 20% trifluoroacetic acid/dichloromethane for 90 minutes. The mixture was concentrated in vacuo. The residue was partitioned between saturated sodium carbonate and dichloromethane. The organic layer was separated, dried (MgSO4), filtered and concentrated to yield the title compound (0.45 g, 96%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[N:14][OH:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:17]([C:19]1[C:20]([NH2:26])=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=1)#[CH:18].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:26])=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=3)[O:15][N:14]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C#Cc1ccc(N)nc1N
Reactant: CCCCOc1ccc(CC(Cl)=NO)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(Cc2cc(-c3ccc(N)nc3N)on2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 115.7 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-butoxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.621 mmol) described in Manufacturing Example 67-1-4 and 3-ethynyl-pyridin-2,6-diamine (52.8 mg, 0.396 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (216 μL, 1.55 mmol). This mixture was stirred for 4 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1˜ethyl acetate) to obtain the title compound (155 mg, 74%).
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[N:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]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.[OH:68][C:69]1[CH:83]=[C:82]2[C:72]([NH:73][CH:74]=[C:75]2[CH2:76][C@@H:77]([C:79]([OH:81])=[O:80])[NH2:78])=[CH:71][CH:70]=1>CN(C=O)C>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([NH:78][CH:77]([CH2:76][C:75]4[C:82]5[C:72](=[CH:71][CH:70]=[C:69]([OH:68])[CH:83]=5)[NH:73][CH:74]=4)[C:79]([OH:81])=[O:80])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:23]=[N:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Reactant: N[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC(Cc1c[nH]c2ccc(O)cc12)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 203 (100 mg, 0.22 mmol) was activated in 2 mL DMF with 92 mg (0.24 mmol) HBTU and 85 μL DIEA for 10 minutes at room temperature. 56 mg 5-hydroxy-L-tryptophane, dissolved in 1 mL DMF was added followed by 44 μL DIEA. The mixture was stirred at room temperature for 1 h, then evaporated to dryness. The oil was purified using RP-HPLC column to give Compound 234.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[C@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1.[C:45]1([CH3:57])[CH:50]=[C:49]([CH3:51])[CH:48]=[C:47]([CH3:52])[C:46]=1[S:53](Cl)(=[O:55])=[O:54].N1C=CC=CC=1>ClCCCl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[O:26])[C:14](=[O:44])[N:11]2[CH2:12][CH2:13][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][S:53]([C:46]3[C:47]([CH3:52])=[CH:48][C:49]([CH3:51])=[CH:50][C:45]=3[CH3:57])(=[O:55])=[O:54])[CH2:9][CH2:10]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2N)CC1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1cc(C)c(S(=O)(=O)Nc2ccccc2C2CCN(C(=O)[C@@H](Cc3ccc(Cl)cc3)NC(=O)[C@@H]3Cc4ccccc4CN3C(=O)OC(C)(C)C)CC2)c(C)c1
Yield: 73.1 %

Procedure:
The title compound was prepared according to the procedure described in Example 21 (Step a) by treating tert-butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)piperidyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl}carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Example 20) (154 mg, 0.25 mmol) with 2-mesitylenesulfonyl chloride (Aldrich) (55 mg, 0.25 mmol) and pyridine (0.03 mL, 0.375 mmol) in 1,2-dichloroethane (10 mL). Purification by silica gel chromatography (100% EtOAc) provided the title compound as a white foam (146 mg). MS (ESI, pos. ion) m/z: 799 (M+1); MS (ESI, neg. ion) m/z: 797 (M−1) Calc'd for C44H51ClN4O6S: 798.32.
Reaction SMILES: [CH3:1][Si:2]([CH3:8])([CH3:7])[CH2:3][C:4]#[C:5][NH2:6].C(N(CC)CC)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)C>[CH3:1][Si:2]([CH3:8])([CH3:7])[C:3]#[C:4][CH2:5][NH:6][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[Si](C)(C)CC#CN
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#CCNC(=O)c1ccccc1

Procedure:
To 8.2 g (0.07 M) of 3-trimethylsilylprop-1-ynylamine in 150 ml of diethyl ether containing 6.6 g (9.1 ml) of triethylamine at 0° C is added 9.1 g (0.07 M) of benzoyl chloride in 30 ml of ether. After 1 hour at 25° C the solution is washed well with brine and the ether extract dried over magnesium sulfate, filtered and the filtrate concentrated. The residue is recrystallized from methanol to give N-(3-trimethylsilylprop-2-ynyl)benzamide.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7](O)=[O:8])[CH2:5][CH2:4][N:3]1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1.[CH3:28][NH2:29]>>[CH3:28][NH:29][C:7]([CH:6]1[CH2:5][CH2:4][N:3]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[C:2]1=[O:1])=[O:8]
Reactant: CN
Reactant: O=C(O)C1CCN(c2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)C1=O
Product: CNC(=O)C1CCN(c2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)C1=O

Procedure:
The title compound is prepared in analogy to Example 6d) from (RS)-2-oxo-1-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid and methylamine. Yield: 6% of a colorless solid. MS: m/e=393.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[CH3:26][N:27]1[C:31](=[O:32])[CH2:30][NH:29][C:28]1=[O:33]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:29]4[CH2:30][C:31](=[O:32])[N:27]([CH3:26])[C:28]4=[O:33])=[CH:3][C:4]=3[F:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: CN1C(=O)CNC1=O
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CC(=O)N(C)C4=O)cc3F)CC2)c(C)c1
Yield: 65.2 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (163 mg) described in Preparation Example 211 and 3-methylimidazolidine-2,4-dione (68 mg) described in Preparation Example 214 and by the reaction and treatment in the same manner as in Example 536, the title compound (115 mg) was obtained.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1.[N:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[F:28])=[N+:16]=[N-:17]>CO>[F:28][C:19]1[CH:20]=[C:21]([C:24]([F:26])([F:27])[F:25])[CH:22]=[CH:23][C:18]=1[N:15]1[C:13]([NH2:14])=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH3:4])=[CH:7][CH:8]=2)[N:17]=[N:16]1
Reactant: [N-]=[N+]=Nc1ccc(C(F)(F)F)cc1F
Reactant: COc1ccc(CC#N)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2nnn(-c3ccc(C(F)(F)F)cc3F)c2N)cc1
Yield: 1.7 %

Procedure:
To a stirred and ice-cooled solution of sodium methoxide (1.659 g, 30.7146 mmol) in methanol (50 ml), 4-methoxyphenylacetonitrile (3.728 g, 24.5717 mmol) and 1-azido-2-fluoro-4-trifluoromethyl-benzene (4.200 g, 20.4764 mmol) are added portion wise and the mixture is allowed attain room temperature spontaneously and refluxed overnight. The resulting reaction mixture is concentrated, added water, and extracted with chloroform (3×100 mL). The combined organic layers are dried over MgSO4, filtered and concentrated to afford a brownish gummy material (5.900 g, 82% mass balance). The crude residue is purified by column chromatography over silica gel (230-400 mesh), eluting with 15% ethylacetate in hexane, to obtain the title compound as a grey solid (0.120 g, 1.5% yield). A major impurity isolated and characterized is 5-(4-methoxy-phenyl)-3-(2-methoxy-4-trifluoromethyl-phenyl)-3H-[1,2,3]triazol-4-ylamine (2.400 g, ˜33% yield).
Reaction SMILES: [CH:1]1([N:7]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CS(O[CH2:34][CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][N:45]2[CH2:49][C@@H:48]([C:50]3[CH:61]=[CH:60][C:53]4[O:54][C:55]([CH3:59])([CH3:58])[O:56][CH2:57][C:52]=4[CH:51]=3)[O:47][C:46]2=[O:62])=[CH:39][CH:38]=1)(=O)=O.P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH:1]1([N:7]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][CH2:34][CH2:35][O:36][C:37]3[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][N:45]4[CH2:49][C@@H:48]([C:50]5[CH:61]=[CH:60][C:53]6[O:54][C:55]([CH3:58])([CH3:59])[O:56][CH2:57][C:52]=6[CH:51]=5)[O:47][C:46]4=[O:62])=[CH:39][CH:38]=3)[CH:12]=2)(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCN(C1CCCCC1)S(=O)(=O)c1cccc(CO)c1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOS(C)(=O)=O)cc4)C(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(S(=O)(=O)N(COCC[Si](C)(C)C)C6CCCCC6)c5)cc4)C(=O)O3)ccc2O1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A solution of N-cyclohexyl-3-(hydroxymethyl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (207 mg) in DMF (5 ml) under nitrogen was treated with sodium hydride (60% dispersion in mineral oil, 24 mg) and the mixture stirred at 20° C. for 15 min. A solution of 2-(4-{2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethyl methanesulfonate [Example 15 i)] (170 mg) in DMF (3 ml) was added and the mixture stirred at 20° C. for 18 h. Phosphate buffer solution (pH 6.5, 15 ml) and water (15 ml) were added and the mixture was extracted with EtOAc. The combined extracts were washed with water and dried (Na2SO4). Solvent evaporation in vacuo gave a residue which was purified by “Flashmaster” chromatography on silica gel. Elution with EtOAc-cyclohexane (2:3) gave the title compound (125 mg). LCMS RT=4.35 min.