Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[C:12]1([C:22](O)=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:22]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)=[O:23])[CH2:2]1)[CH2:8]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1cccc2ccccc12
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cccc2ccccc12

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 1-naphthoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.94-2.71 (m, 7H), 3.46-3.93 (m, 6H), 4.56 (s, 1H), 7.50-7.59 (m, 3H), 7.61-7.68 (m, 1H), 7.90-7.96 (m, 1H), 7.97-8.03 (m, 1H), 8.11-8.18 (m, 1H); MS (APCI/NH3) m/z 307 (M+H)+.
Reaction SMILES: [CH:1]1[C:2]([I:10])=[CH:3][C:4]([I:9])=[C:5]([OH:8])[C:6]=1[I:7].[F:11][C:12]([F:23])([C:16]([F:22])([Br:21])[C:17]([F:20])([F:19])[Br:18])[C:13](Cl)=[O:14]>N1C=CC=CC=1>[I:7][C:6]1[CH:1]=[C:2]([I:10])[CH:3]=[C:4]([I:9])[C:5]=1[O:8][C:13](=[O:14])[C:12]([F:11])([F:23])[C:16]([F:22])([Br:21])[C:17]([F:20])([F:19])[Br:18]
Reactant: O=C(Cl)C(F)(F)C(F)(Br)C(F)(F)Br
Reactant: Oc1c(I)cc(I)cc1I
Solvent: c1ccncc1
Product: O=C(Oc1c(I)cc(I)cc1I)C(F)(F)C(F)(Br)C(F)(F)Br
Temperature: 50 °C
Yield: 45.2 %

Procedure:
100 grams of triiodophenol were dissolved in 100 ml of pyridine with warming to 50° C. 75 grams of 2,2,3,4,4-pentafluoro-3,4-dibromo-butyryl chloride were added dropwise through a dropping funnel with stirring at such a rate that the temperature did not rise above 65° C. The mixture was stirred at 50° C. for an additional 30 minutes, then overnight at room temperature. The mixture was washed in a separatory funnel three times with 500 ml of DI water, then filtered through a column of silica and the solvent evaporated. The material was then chromatographed on a column of silica using FREON 113 (trichlorotrifluroethane) as eluent. Chromatography on silica gave 75.5 grams of material 99% pure. The material solidified at room temperature and has a melting point of 50° C. I.R.(ν, in cm-1)=3050, 3090 (Ar--H); 1800 (C=O); 1570, 1415 (Ar C=C). m/e 62 (47, C5H2); 69 (18%, CF3); 129 (22, CF2Br); 131 (70, CF2Br and C3F5); 189 (60%, C5H2I); 344 (56%, 471 (100%, C6H2I3O).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(#N)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)=[O:10])=[N:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(Br)cn1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1CCN(C(=O)c2ccc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 25 %

Procedure:
To a toluene solution (300 ml) at −78° C. in which 2,5-dibromopyridine (4.7 g) was dissolved, n-butyl lithium hexane solution (1.6 M) was added dropwise, followed by stirring at −78° C. for 3 hours. To the reaction mixture, dry ice (ca. 50 g) was added, and followed by further stirring at room temperature for 10 hours. Water (100 ml) was added, and the aqueous layer washed with ethyl acetate (100 ml×2) was neutralized with 5M−HCl aqueous solution under ice cooling, and the resulting precipitate was filtered and dried, to obtain 5-bromo-pyridine-2-carboxylic acid as a colorless powder (2.0 g, 50%). Then, 5-bromo-pyridine-2-carboxylic acid (202 mg), N-methylpiperazine (124 μl), WSCI (230 mg), HOBt (149 mg) and triethylamine (140 μl) were dissolved in acetonitrile (10 ml), followed by stirring at room temperature for 10 hours. To the reaction mixture, water (10 ml) was added, followed by extraction with ethyl acetate (10 ml). The organic layer was washed with saturated aqueous sodium chloride solution, followed by drying over sodium sulfate. After filtering off the sodium sulfate, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by amino silica gel column chromatography (dichloromethane), to obtain (5-bromo-pyridin-2-yl)-(4-methyl-piperazin-1-yl)-methanone as a yellow oil (70 mg, 25%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])=[N:25][CH:26]=[N:27]2)=[CH:22][C:21]=1OC)(O)=[O:14].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.CN([CH:50]=[O:51])C>CN(C)C1C=CN=CC=1>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:24]2[C:23]3[C:28](=[CH:29][C:20]([O:19][CH2:18][CH2:17][CH2:16][C:13]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[O:14])=[CH:21][CH:22]=3)[N:27]=[C:26]([O:51][CH3:50])[N:25]=2)=[C:32]([F:38])[CH:33]=1
Reactant: CN(C)C=O
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCC(=O)O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: COc1nc(Nc2ccc(Cl)cc2F)c2ccc(OCCCC(=O)N3CCOCC3)cc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46 %

Procedure:
1-(3-Dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (94 mg, 4.9 mmol) was added to a mixture of 7-(3-carboxypropoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (164 mg, 0.4 mmol), morpholine (0.11 g; 1.26 mmol) and 4-dimethylaminopyridine (200 mg, 1.64 mmol) in DMF (5 ml). The reaction mixture was stirred at ambient temperature for 24 hours and the volatiles were removed by evaporation. Water was added to the residue and the aqueous mixture was extracted with methylene chloride (3×30 ml). The extracts were combined and the solvent removed by evaporation. The residue was triturated with ether and the precipitate was collected by filtration. The solid was purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (100/8/1). The purified product was triturated with acetone, collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-methoxy-7-(3-morpholinocarbonylpropoxy)quinazoline (88 mg, 46%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]([O:11]CC)=O.O.[NH2:15][NH2:16]>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]([NH:15][NH2:16])=[O:11]
Reactant: CCOC(=O)CCc1ccccn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)CCc1ccccn1

Procedure:
To a stirring 5 mL EtOH solution of 0.58 g (3.2 mmol) of ethyl 3-(2-pyridinyl)propanoate (4), prepared as described above in Example 4, was added 0.32 g (6.5 mmol) of hydrazine hydrate. The reaction was heated at reflux for three weeks. Although the reaction was still incomplete, the solvent was removed under vacuum. The resulting gum was triturated with diethyl ether (Et2O). The product remained a gum. The yield of 3-(2-pyridyl)propanoic acid, hydrazide (5) was 0.22 g (42%). This product was used immediately in the manner described in Example 6 below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](OC)=[O:13])[CH:6]=[CH:5]2.Cl.O>CCOCC.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][OH:13])[CH:6]=[CH:5]2
Reactant: COC(=O)c1ccc2cc(Cl)ccc2c1
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: OCc1ccc2cc(Cl)ccc2c1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A solution of the methyl 6-chloro-2-naphthoate (111 g.) in ether (2.5 l.) is added, dropwise below 25° C. under nitrogen, to a stirred mixture of ether (250 ml.) and a 70% solution (250 ml.) of sodium dihydro-bis-(2-methoxyethoxy)aluminate in benzene during 1 hour. The mixture is stirred for a further 30 minutes and 2N-hydrochloric acid (250 ml.) is added cautiously. The solution is decanted from undissolved solid, and concentrated hydrochloric acid is added to the solid until it dissolves. The two solutions thus obtained are combined, and ether (1 l.) and a mixture of ice and water (1 l.) are added. The ethereal layer is separated, and the aqueous phase extracted with ether. The ethereal solutions are combined, washed with water, dried and evaporated to give 6-chloro-2-hydroxymethylnaphthalene (95 g.) which may be further purified by crystallisation from toluene to give material of m.p. 134°-137° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[CH3:9])=[CH:4][CH:3]=1.[CH3:11][S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].C(N(C(C)C)CC)(C)C>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:18]2[CH2:19][CH2:20][N:15]([S:12]([CH3:11])(=[O:14])=[O:13])[CH2:16][CH2:17]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(Cl)c1ccc(Br)cc1
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccc(Br)cc1)N1CCN(S(C)(=O)=O)CC1
Temperature: 65 °C

Procedure:
1-Bromo-4-(1-chloroethyl)benzene (3.46 g, 15.8 mmol), 1-methanesulfonylpiperazine (5.19 g, 31.6 mmol) and diisopropylethylamine (11.8 mL, 79 mmol) were stirred in acetonitrile (125 mL) and heated to 65° C. for 3 d. The reaction mixture was concentrated in vacuo, dissolved in EtOAc and washed with sat. NaHCO3 (aq.). The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography using silica gel and eluting with 100% isohexanes to 100% EtOAc to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.Br[CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(OC([O-])=O)([O-])=O.[K+].[K+]>CN(C=O)C.O>[Si:17]([O:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: COc1cc(O)ccc1C=O
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])OC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1C=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
The mixture of 4-hydroxy-2-methoxybenzaldehyde (10.0 g), (3-bromopropoxy)-tert-butyldimethylsilane (25.0 g), and potassium dicarbonate (13.6 g) in DMF (100 mL) was stirred at RT for 5 h. The mixture was diluted with water and extracted with EtOAc. And the combined organic solutions were washed with water and brine, dried and concentrated. The residue was purified by silica gel chromatography eluting with hexane/EtOAc to give 21.3 g of the subtitle compound as a yellow oil [as a mixture with (3-bromopropoxy)-tert-butyldimethylsilane].
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([C:8](=[O:18])[CH:9]([CH3:17])[C:10](=O)[C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][CH:7]=1.[Li+].C[Si]([N-:25][Si](C)(C)C)(C)C.C(OCC)(=O)C(OCC)=O>CCOCC>[Cl:1][C:2]1[C:3]([F:19])=[C:4]([C:8]2[O:18][N:25]=[C:10]([C:11]([OH:13])=[O:12])[C:9]=2[CH3:17])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)C(=O)C(C)C(=O)c1cccc(Cl)c1F
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(=O)C(=O)OCC
Product: Cc1c(C(=O)O)noc1-c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 6 %

Procedure:
Ethyl 4-(3-chloro-2-fluorophenyl)-3-methyl-2,4-dioxobutanoate: To the solution of LiHMDS (1 M in THF) (3.19 mL, 3.19 mmol) in ether (12 mL) at −78° C. was added dropwise a solution of Intermediate 47B (0.59 g, 3.16 mmol) in ether (2 mL). After 45 min., diethyl oxalate (0.492 mL, 3.60 mmol) was added in one portion, and the reaction was warmed to rt. After 18 h, the reaction mixture was filtered, washing with ether. The filtrate was diluted with EtOAc, washed with 1 N HCl, brine, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography yielded the desired product (0.057 g, 6%) as a yellow oil. MS(ESI) m/z: 241.0 (M-OEt)+. 1H NMR (500 MHz, CDCl3) δ 7.80 (ddd, J=8.0, 6.3, 1.7 Hz, 1H), 7.65 (ddd, J=7.8, 7.0, 1.9 Hz, 1H), 7.23 (td, J=8.0, 0.8 Hz, 1H), 4.91 (q, J=7.2 Hz, 1H), 4.31 (qd, J=7.2, 0.8 Hz, 2H), 1.46 (dd, J=7.2, 0.8 Hz, 3H), 1.34 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C(N(CC)CC)C.[C:21]([C:23]1[C@@H:28]([C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)[N:27]2[N:37]=[C:38]([NH:40][C:41](=[O:50])[O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:39]=[C:26]2[N:25]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:60])([F:59])[F:58])[CH:52]=2)[C:24]=1[CH3:61])#[N:22]>CN(C1C=CN=CC=1)C.ClCCl>[C:21]([C:23]1[C@@H:28]([C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)[N:27]2[N:37]=[C:38]([N:40]([C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[C:41]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:50])[N:39]=[C:26]2[N:25]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:60])([F:59])[F:58])[CH:52]=2)[C:24]=1[CH3:61])#[N:22]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(C(=O)OCc3ccccc3)C(=O)Oc3ccc([N+](=O)[O-])cc3)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 5 h

Procedure:
Under an atmosphere of argon protective gas and at 0° C., 4-nitrophenyl chloroformate (27.2 mg, 135 μmol, 2.5 eq.), triethylamine (11.1 mg, 140 μmol, 2.6 eq.) and DMAP (0.7 mg, 5.4 μmol, 0.1 eq.) were added to a solution of benzyl {(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}carbamate (30 mg, 54 μmol; Example 38) in dry dichloromethane (2 ml), and the mixture was then stirred for 5 h. This reaction solution was used as such without further purification for subsequent reactions.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.N1C=CC=CC=1.Cl[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15].O>O1CCCC1>[NH:1]1[CH:5]=[N:4][C:3]([NH:6][C:14](=[O:15])[O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[N:2]1
Reactant: Nc1nc[nH]n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1nc[nH]n1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
To a solution of 1H-1,2,4-triazole-3-amine (1.00 g, 11.9 mmol) and pyridine (1.16 ml, 14.3 mmol) in tetrahydrofuran (40 ml) was added 2,2,2-trichloroethyl chloroformate (1.97 ml, 14.3 mmol) with ice-cooling and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product (1.38 g, 44.5%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Sb](F)(F)[F:18]>[Sb](Cl)(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=[CH:7][C:3]=1[C:4]([F:18])=[O:5]
Reactant: F[Sb](F)F
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)c(Cl)c1Cl
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Product: O=C(F)c1ccc(OC(F)(F)F)c(Cl)c1Cl
Yield: 123.2 %

Procedure:
2,3-Dichloro4-trifluoromethoxybenzoyl chloride (17.2 g) was added to a mixture of antimony trifluoride (10.6 g) and antimony pentachloride (1 g). The mixture was heated at reflux for 10 mins then flash distilled to give crude 2,3-dichloro-4-trifluoromethoxybenzoyl fluoride (20 g) as a semi-solid bp 211°-215° C.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:38][C:39]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:40]=1[CH2:41][NH2:42]>>[CH3:38][C:39]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:40]=1[CH2:41][NH:42][C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: Cc1ccc(CN)c(C)c1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4ccc(C)cc4C)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 2,4-dimethyl benzylamine, m.p. 161-162° C. MS [(+)ESI, m/z]: 570 [M+H]+ Anal. Calcd for C37H35N3O3: C, 78.01; H, 6.19; N, 7.38. Found: C, 77.86; H, 6.40; N, 7.20.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=3)[CH2:18][CH2:19]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)C2CCNCC2)cc1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(S(=O)(=O)C2CCN(c3cc(C(F)(F)F)ccn3)CC2)cc1
Yield: 39.1 %

Procedure:
Using the procedure from Example 7A, 4-[(4-tert-butylphenyl)sulfonyl]piperidine (100 mg, 0.36 mmol) was reacted with 2-chloro-4-(trifluoromethyl)pyridine (94 μl, 0.72 mmol), DIEA (0.25 ml, 1.44) and 1,4-dioxane (0.3 ml) at 185° C. to afford the title compound (60 mg), an off-white solid, in 39% yield.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C=O.[C:41](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH:20]=3)[CH3:41])[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCOC(=O)CC(c1cccc(CNc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)CC(c1cccc(CN(C)c2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)propanoate (203 mg), formaldehyde solution (88 μL) and acetic acid (67 μL) in acetonitrile (3.9 mL) was added sodium triacetoxyborohydride (125 mg) at 0° C., and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated sodium hydrogen carbonate solution at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (148 mg) as a colorless transparent oil.
Reaction SMILES: [NH2:1][C@H](C(O)=O)CC1N=CNC=1.C([S:15][CH2:16][CH:17]([CH2:32][C:33]([O:35]C)=O)[C:18]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=N)[NH2:27])=[O:19])(=O)C>>[SH:15][CH2:16][CH:17]([CH2:32][C:33](=[O:35])[NH2:1])[C:18]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][C:23]1[N:27]=[CH:26][NH:25][CH:24]=1)=[O:19]
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Product: NC(=O)CC(CS)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
By substituting Nα -[3-(acetylthio)-2-methoxycarbonylmethyl)propanoyl]-L-histidine for the Nα -[3-(acetylthio)-2-(methoxycarbonylmethyl)propanoyl]-L-arginine in the procedure of Example 19, Nα -[3-mercapto-2-(carbamoylmethyl)-propanoyl]-L-histidine is obtained.
Reaction SMILES: S(=O)(=O)(O)O.[As].[CH2:7]([C:13]1[CH:19]=[CH:18][CH:17]=[C:15]([OH:16])[C:14]=1[OH:20])[CH2:8][CH2:9][CH2:10][CH2:11]C>[Cu]>[CH2:13]=[CH:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:15]1([C:14](=[CH:13][CH:19]=[CH:18][CH:17]=1)[OH:20])[OH:16]
Reactant: CCCCCCc1cccc(O)c1O
Agent: [Cu]
Agent: O=S(=O)(O)O
Agent: [As]
Product: C=CCCCC
Product: Oc1ccccc1O

Procedure:
100 ml of an aqueous solution containing sulfuric acid (200 g/l), copper (45 g/l) and arsenic (5.9 g/l) were poured into a 250 ml separatory funnel. Then a 0.3M solution of n-hexylpyrocatechol (100 ml), (a mixture of the two position isomers obtained from the reaction of 1-hexene with excess of pyrocatechol), was added into ESCAID 100; the mixture was strongly stirred for 10' and made then to settle for 30'.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>CN1CCCC1=O>[N:9]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: C1COCCN1
Reactant: Nc1cc(Cl)ccn1
Solvent: CN1CCCC1=O
Product: Nc1cc(N2CCOCC2)ccn1

Procedure:
A solution of 4-chloro-pyridin-2-ylamine (800 mg, 6.22 mmol) and morpholine (8.1 mL, 93.34 mmol) in N-methyl-2-pyrrolidone (NMP) (2 mL) was heated in a microwave (Emry's Optimizer) at 200° C. for 10 minutes. The resulting solution was directly purified by flash chromatography (SiO2, 95:5:0.5/DCM:MeOH:NH4OH) to give 4-morpholin-4-yl-pyridin-2-ylamine (Int-1). MS found for C9H13N3O as (M+H)+ 180.39. A solution of Int-1 (418 mg, 2.34 mmol) and 3-chloro-pentane-2,4-dione (0.3 mL, 2.45 mmol) in NMP (2.5 mL) was added and heated in a microwave (Emry's Optimizer) at 150° C. for 30 minutes. The resulting solution was directly purified by flash chromatography (SiO2, 96:4:/DCM:MeOH) to give 1-(2-methyl-7-morpholin-4-yl-imidazo[1,2-a]pyridin-3-yl)-ethanone (Int-2). MS found for C14H17N3O2 as (M+H)+ 260.39. A mixture of Int-2 (293 mg, 1.13 mmol) and DMF.DMA (2.3 mL) was heated at 150° C. for 10 hours. The mixture was concentrated and used further without purification. MS found for C17H22N4O2 as (M+H)+ 315.23. A solution of 1-(2-methyl-7-morpholin-4-yl-imidazo[1,2-a]pyridin-3-yl)-ethanone (263 mg, 0.84 mmol), 4-guanidinobenzoic acid hydrochloride (180 mg, 0.841) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.25 mL, 1.67 mmol) in DMF (3 mL) was heated in a microwave (Emry's Optimizer) at 150° C. for 30 minutes. The reaction mixture was then diluted with water and acetonitrile and purified by preparative HPLC affording 4-[4-(2-methyl-7-morpholin-4-yl-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-2-ylamino]-benzoic acid after lyophilization. MS found for C23H22N6O3 as (M+H)+ 431.46. To the above carboxylic acid (10 mg, 0.023 mmol) in DMF (1 mL), was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (13 mg, 0.034 mmol), 1,2-phenylenediamine (5 mg, 0.046 mmol), DIPEA (0.01 mL, 0.068 mmol), and stirred at room temperature for 16 hours. The reaction mixture was diluted with water and acetonitrile and directly purified by preparative HPLC affording the title compound after lyophilization. MS found for C29H28N8O2 as (M+H)+ 521.28. 1H NMR (400 MHz, dmso-d6): δ 9.54 (d, J=8.0 Hz, 1H); 8.41 (d, J=5.6 Hz, 1H); 7.90 (d, J=8.4 Hz, 2H); 7.79 (d, J=8.4 Hz, 2H); 7.11 (d, J=7.6 Hz, 1H); 7.02-6.97 (m, 2H); 6.83 (d, J=7.6 Hz, 2H); 6.71-6.67 (m, 2H); 3.76 (m, 4H); 3.29 (m, 4H); 2.58 (s, 3H).