Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].[CH2:17]([NH2:31])[CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH2:29][NH2:30].C(N)(N)OOOCCCCCCCCC.[K+].[Br-]>CO.C(N(CC)CC)C.CN(C=O)C>[NH2:30][CH2:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][CH2:17][NH:31][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1
Reactant: NCCCOCCOCCOCCCN
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: CCCCCCCCCOOOC(N)N
Agent: [Br-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: NCCCOCCOCCOCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Biotin TFP ester (5 g, 12.8 mmol) was added to a dry flask containing 200 mL anhydrous DMF. In another dry flask containing 28 g (128 mmol) 4,7,10-trioxa-1,13-tridecanediamine, 8, was added 4 mL of triethylamine. Both flasks were cooled to 0-5° C. with ice-water baths. The TFP ester of biotin was added dropwise to the tri-oxatridecanediamine solution over the period of 1 h. The reaction was stirred at room temperature for 30 min and the solvent was removed under vacuum. The resulting oil was triturated in 500 mL ether and was stirred for 30 min. The solid was filtered, then dissolved in methanol:ethyl acetate (4:1), and loaded onto a silica column (2.5 cm×35 cm). The column was eluted with the same solvent mixture. Fractions containing product were collected, and solvent was removed under vacuum. The isolated product was dried under vacuum to yield 4.5 g (79%) of, 9, as a colorless solid, mp 104-106° C. 1H NMR (MeOH, ( ): 1.46 (m, 2H), 1.6-1.8 (m, 9H), 2.2 (t, 2H), 2.7 (d, 1H), 2.75-2.9 (m, 3H), 3.2-3.3 (m, 5H), 3.5-3.6 (m, 14H), 4.3 (m, 1H), 4.5 (m, 1H); IR (KBr, cm-1): 3280, 2910, 2850, 1690, 1640, 1110, 940. Analysis calc. for C20H38N4O5S.H2O: C, 51.70; H, 8.68; N, 12.06. Found: C, 51.95; H, 7.98; N, 11.65.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:19]=[CH:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]1C=C(O)[CH:37]=[CH:36][CH:35]=1>>[C:5]([O:4][C:1]1[CH:19]=[CH:20][CH:21]=[C:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH2:32][CH:33]=[CH:34][CH2:35][CH:36]=[CH2:37])[CH:2]=1)(=[O:7])[CH3:6]
Reactant: C=CC/C=C\C/C=C\CCCCCCCc1cccc(O)c1
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CCC=CCC=CCCCCCCCc1cccc(OC(C)=O)c1
Reaction time: 0.5 h

Procedure:
A mixture of acetic anhydride (0.1 mol, 15 ml) and p-toluenesulphonic acid (PTSA, 3.15 mol %, 0.6 g) were taken in a two necked RB flask and double distilled cardanol (0.1 mol, 30 g) was added dropwise with stirring over a period of 30 minutes at ambient conditions. The reaction was continued for 8-12 h. The product (AC) was washed free of acetic acid and catalyst with water and dried.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([CH3:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])(O)(O)=[O:19].[Na+].S(=O)(=O)(O)N.Cl([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+].Cl>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]([OH:19])=[O:14])=[C:11]([CH3:17])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)ccc1C=O
Reactant: O=P([O-])(O)O
Agent: Cl
Agent: NS(=O)(=O)O
Agent: O=S([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(OCc2ccccc2)ccc1C(=O)O
Temperature: 10 °C
Reaction time: 0.33 h

Procedure:
A solution of 4-benzyloxy-2-methylbenzaldehyde (20 g) in 1,4-dioxane (300 mL) was mixed with sodium dihydrogen phosphate (42.4 g) and sulfamic acid (13.7 g) and, while cooling, a solution of sodium chlorite (11.2 g) in water (200 mL) was added in such a way that the temperature did not rise above 10° C. After 20 minutes, sodium sulfite (14.5 g) was added, and the mixture was stirred at 10° C. for a further 15 minutes. The reaction mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH:6]=O.O=CC1C=CC(O)=C(OC)C=1.[C:29]([CH:32]1[CH2:37][CH2:36][C:35]([CH3:44])([C:38]([O:40][CH2:41][CH:42]=[CH2:43])=[O:39])[CH2:34][CH2:33]1)(=[O:31])[CH3:30].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH:6]=[CH:30][C:29]([CH:32]1[CH2:37][CH2:36][C:35]([CH3:44])([C:38]([O:40][CH2:41][CH:42]=[CH2:43])=[O:39])[CH2:34][CH2:33]1)=[O:31]
Reactant: COc1cc(C=O)ccc1OC1CCCCO1
Reactant: C=CCOC(=O)C1(C)CCC(C(C)=O)CC1
Agent: COc1cc(C=O)ccc1O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=CCOC(=O)C1(C)CCC(C(=O)C=Cc2ccc(OC3CCCCO3)c(OC)c2)CC1
Yield: 39.2 %

Procedure:
A solution of 1.5 g of 3-methoxy-4-(2-tetrahydropyranyloxy)benzaldehyde, derived from vanillin by the introduction of tetrahydropyranyl group thereinto, 1.5 g of allyl 4-acetyl-1-methyl-1-cyclohexanecarboxylate (Example 37), and 8 ml of sodium hexamethyldisilazide (THF 1M solution), mixed in 50 ml of THF, was reacted for 4 hours under an argon stream, while it was refluxed. After reaction, 100 ml of an aqueous ammonium chloride solution was added to the reaction solution. The solution was extracted three times with 50 ml of ethyl acetate. The organic layer obtained was washed three times with an aqueous sodium chloride solution and dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo. The oily substance obtained was subjected to column chromatography using 50 g of silica gel. From the fraction eluted with hexane and ethyl acetate=4:1, the solvent was removed in vacuo, yielding 1.1 g of allyl 4-[3-methoxy-4-(2-tetrahydropyranyloxy)cinnamoyl]-1-methyl-1-cyclohexanecarboxylate (a compound of the present invention) as a yellow oil, which had the following physiochemical properties:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[CH2:10][CH2:9][CH2:8][NH:7]2)=[CH:2]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: c1cc(C2CCCN2)cs1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1ccsc1

Procedure:
The title compound, white solid, m.p. 120° C. and MS: m/e=328.1 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-thien-3-yl-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: C1(O[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)C=CC=CC=1.[BrH:23].C(O)(=O)C>O>[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][Br:23])=[CH:10][C:11]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Br
Reactant: Fc1ccc(COc2ccccc2)cc1Oc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: Fc1ccc(CBr)cc1Oc1ccccc1

Procedure:
A mixture of 14.7 g (0.05 mol) of 4-fluoro-3-phenoxybenzyl phenyl ether, 50 ml of 32% strength aqueous hydrobromic acid and 60 ml of glacial acetic acid was heated to the reflux temperature for 10 hours, while stirring. The reaction mixture was then poured into 200 ml of water and extracted twice with 200 ml of methylene chloride each time. The combined methylene chloride phases were then extracted twice by shaking with 100 ml of 10% strength sodium hydroxide solution each time. The organic phase was subsequently dried over magnesium sulphate and the solvent was then stripped off under a waterpump vacuum. The residue was freed from the last residues of solvent by incipient distillation at a bath temperature of 60° C./3 mbars. 4-Fluoro-3-phenoxy-benzyl bromide was thus obtained as a viscous oil.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[C:17]2[C:24]([I:25])=[CH:23][NH:22][C:18]=2[N:19]=[CH:20][N:21]=1.[C:26]([N:33]1[CH2:37][CH2:36][C@@H:35](O)[CH2:34]1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:15][C:16]1[C:17]2[C:24]([I:25])=[CH:23][N:22]([C@H:36]3[CH2:35][CH2:34][N:33]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:37]3)[C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](n2cc(I)c3c(Cl)ncnc32)C1
Reaction time: 1 h
Yield: 64.8 %

Procedure:
DIAD (1.41 ml) was added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.00 g), (R)—N-Boc-3-pyrrolidinol (1.01 g), and triphenylphosphine (1.88 g) in tetrahydrofuran (40 ml), and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated and washed with ethyl acetate to obtain the title compound as a white solid (1.04 g). Physical properties: m/z [M+H]+ 448.9
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH3:19])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[N-:46]=[N+:47]=[N-:48].[Na+]>C(Cl)(Cl)(Cl)Cl.[Cl-].[Na+].O>[N:46]([CH2:19][C:12]1[CH:13]=[CH:14][C:15]([N+:16]([O-:18])=[O:17])=[C:10]([O:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:11]=1)=[N+:47]=[N-:48]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc([N+](=O)[O-])c(OCC(=O)OC(C)(C)C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)COc1cc(CN=[N+]=[N-])ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
A mixture of 3-tert-butoxycarbonylmethoxy-4-nitrotoluene (36.1 g, 120 mmol), N-bromosuccinimide (21.3 g, 120 mmol), and benzoyl peroxide (4 g) in carbon tetrachloride (500 mL) was refluxed for 18 h. The insoluble material formed was removed by filtration and the filtrate was concentrated. The residue was dissolved in DMF (10 mL) and sodium azide (5.2 g, 80 mmol) was added. The mixture was stirred for 2 h at 50° C., poured into brine, and extracted with a 1:1 mixture of toluene and ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 9:1 to 7:3 hexane/ethyl acetate to give 13.4 g of the title compound (36%).
Reaction SMILES: CS(O[C@H:6]([CH3:28])[CH2:7][O:8]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=O)=O.Cl.[CH:30]12[NH:36][CH:33]([CH2:34][CH2:35]1)[CH2:32][CH2:31]2>>[CH:33]12[N:36]([C@@H:6]([CH3:28])[CH2:7][OH:8])[CH:30]([CH2:35][CH2:34]1)[CH2:31][CH2:32]2
Reactant: C1CC2CCC1N2
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)OS(C)(=O)=O
Agent: Cl
Product: C[C@@H](CO)N1C2CCC1CC2

Procedure:
The title compound was synthesized as described in Intermediate 39 (steps 2-3) using (R)-1-(trityloxy)propan-2-yl methanesulfonate and 7-azabicyclo[2.2.1]heptane hydrochloride as starting materials. 1H NMR (DMSO-d6): δ 4.36 (t, 1H), 3.42 (m, 3H), 3.07 (m, 1H), 2.26 (m, 1H), 1.54 (m, 4H), 1.18 (m, 4H), 0.96 (d, 3H).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:13]2[CH:28]=[CH:29][CH:30]=[CH:31][C:12]1=2)C(=O)C.Cl[C:42]([O:44][CH3:45])=[O:43]>>[CH3:45][O:44][C:42](=[O:43])[N:7]([CH2:6][C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:39])[F:40])[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=1)[CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:19])=[O:20])[C:13]2[CH:28]=[CH:29][CH:30]=[CH:31][C:12]1=2
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc21
Reactant: COC(=O)Cl
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc21

Procedure:
The titled compound was prepared following the procedures described for the preparation of (+/−) N-(3,5-Bis-trifluoromethyl-benzyl)-N-[1-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-acetamide (example 191, step 3) by replacing acetic anhydride with methyl chloroformate. MS (ES+): 601(M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[N:15]1[CH:24]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[CH:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:38])(=[O:7])=[O:6].[H-].[Na+].C(OCC)(=O)C.O>C1COCC1>[Cl:32][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=1[CH:24]1[CH:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH2:21]2)[C:16](=[O:38])[N:15]1[CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[N:8]1[CH2:2][CH2:3][CH2:4][S:5]1(=[O:6])=[O:7]
Reactant: CCOC(=O)C1c2ccccc2C(=O)N(C2CCCCC2NS(=O)(=O)CCCCl)C1c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1C2CC=CC=C2C(=O)N(C2CCCCC2N2CCCS2(=O)=O)C1c1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
To a solution of 1.63 g of ethyl(3RS,4RS)-2-[(1SR,2SR)-2-{[(3-chloropropyl)sulfonyl]amino}cyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate in 20 ml of THF was added 142 mg of sodium hydride, followed by stirring at 50° C. overnight. Ethyl acetate and water were added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 466 mg of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-(1,1-dioxidoisothiazolidin-2-yl)cyclohexyl]-1-oxo-tetrahydroisoquinoline-4-carboxylate as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:36])[C:5]2[N:10]=[C:9]([C:11]3[C:12]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])=[N:13][C:14]([CH2:17][N:18]4[N:22]=[N:21][C:20]([C:23]([F:26])([F:25])[F:24])=[N:19]4)=[N:15][CH:16]=3)[O:8][C:7](=[O:34])[C:6]=2[CH:35]=1.[CH3:37][NH2:38].C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:35]=[C:6]([C:7](=[O:34])[NH:38][CH3:37])[C:5]([NH:10][C:9]([C:11]2[C:12]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])=[N:13][C:14]([CH2:17][N:18]3[N:22]=[N:21][C:20]([C:23]([F:26])([F:24])[F:25])=[N:19]3)=[N:15][CH:16]=2)=[O:8])=[C:4]([CH3:36])[CH:3]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cnc(Cn4nnc(C(F)(F)F)n4)nc3-c3ccccc3Cl)nc12
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cnc(Cn2nnc(C(F)(F)F)n2)nc1-c1ccccc1Cl
Temperature: 45 °C
Reaction time: 0.25 h

Procedure:
100 mg (0.18 mmol) of 6-chloro-2-[4-(2-chlorophenyl)-2-{[5-(trifluoromethyl)-2H-tetrazol-2-yl]methyl}pyrimidin-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one were initially charged in 3 ml of THF, and 0.234 ml (0.46 mmol) of a 2 molar methylamine/THF solution was added at RT. The reaction mixture was then stirred at 45° C. for 15 min. After cooling, the mixture was concentrated and purified chromatographically on silice gel using cyclohexane/ethyl acetate. 48 mg (40% of theory; content 89%) of the desired product were isolated.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.O[CH:13]([C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.FC(F)(F)C(O)=O>>[O:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[CH:13]([S:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: OC(Cn1ccnc1)c1ccco1
Reactant: COC(=O)c1ccc(S)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccco2)cc1
Reaction time: 1 h
Yield: 64.2 %

Procedure:
3.5 g of methyl 4-mercaptobenzoate and 2.5 g of 1-[2-hydroxy-2-(2-furyl)ethyl]imidazole were mixed, and 50.7 ml of trifluoroacetic acid were added, whilst ice-cooling, to the resulting mixture. The mixture was stirred at between 0° and 5° C. for 1 hour. At the end of this time, the reaction mixture was treated and purified similarly to the procedure described in Example 13, to yield 2.96 g of the title compound as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[C:29]([CH3:35])=[N:30][N:31]([CH3:34])[C:32]=2[CH3:33])[C:4](=[O:36])[C:3]1=[N:37]NC1C=CC=CC=1>C(O)(=O)C.[Zn]>[NH2:37][CH:3]1[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[C:29]([CH3:35])=[N:30][N:31]([CH3:34])[C:32]=2[CH3:33])[C:4]1=[O:36]
Reactant: COc1ccc(N(C(=O)Cn2c(=O)c(=NNc3ccccc3)c(=O)n(-c3c(C)nn(C)c3C)c3ccccc32)C(C)C)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(N(C(=O)CN2C(=O)C(N)C(=O)N(c3c(C)nn(C)c3C)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 9.9 %

Procedure:
To a solution of 2-[2,4-Dioxo-3-(phenyl-hydrazono)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (4.6 g, 7.74 mmol) in glacial acetic acid (45 mL) was added zinc dust (4.6 g). The heterogenous solution stirred at RT for 15 h and subsequently filtered through a bed of celite, washed with ethyl acetate and concentrated to dryness. The resulting oil was dissolved in ethyl acetate (200 mL) and extracted with saturated sodium bicarbonate (×3), brine, dried MgSO4, and concentrated in vacuo. The resulting oil was purified by silica gel flash chromatography (5% methanol/DCM) to yield the title compound (385 mg): 1HNMR (CDCl3, 300 MHz) δ 7.60-6.80 (m, 10H), 5.05 (m, 1H), 4.4(m, 1H), 3.82 (s, 3H), 3.74 (s, 3H), 3.62 (s, 2H), 2.24 (s, 3H), 1.20 (s, 3H), 1.09 (m, 6H); low resolution MS(FAB) m/z 505 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:14]3[CH:31]=[CH:30][C:17]([O:18][CH2:19][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)=[CH:16][CH:15]=3)=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:32]B1OBOBO1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+].C(O)(=O)CCC(O)=O>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][N:11]1[CH:12]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:32])[CH:7]=2)[C:9]([C:14]2[CH:31]=[CH:30][C:17]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:16][CH:15]=2)=[N:10]1
Reactant: Cn1cc(-c2ccnc(Cl)c2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Reactant: CB1OBOBO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CCC(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(-c2cn(C)nc2-c2ccc(OCc3ccc4ccccc4n3)cc2)ccn1
Temperature: 100 °C

Procedure:
To a solution of 2-{4-[4-(2-Chloro-pyridin-4-yl)-1-methyl-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline (100 mg) in dioxane (1.2 ml) was added methyl boroxine (0.066 ml), palladium tetrakis (41 mg) and 2N sodium carbonate solution (0.234 ml). The reaction mixture was heated at 100° C. for 8 h, poured into 1 N NaOH, extracted with chloroform, dried magnesium sulfate, filtered and concentrated. Prep TLC run with 3% methanol/0.5% saturated ammonium hydroxide/80% ethyl acetate in hexanes provided the free base material. The produce was stirred in ethyl acetate and 2 eq. of succinic acid was added to give a white precipitate which was filtered to provide the title compound as a white solid succinate salt (20 mg). 1H NMR (400 MHz, DMSO) δ 8.40 (d, J=8.3 Hz, 2H), 8.25 (d, J=5.0 Hz, 2H), 8.07 (s, 1H), 8.00 (t, J=7.9 Hz, 2H), 7.77 (t, J=6.6 Hz, 1H), 7.67 (d, J=8.7 Hz, 2H), 7.60 (t, J=6.6 Hz, 1H), 7.29 (d, J=9.1 Hz, 2H), 7.03 (m, 3H), 6.92 (m, 1H), 5.35 (s, 2H), 3.85 (s, 3H), 2.37 (s, 4H) 2.31 (s, 3H); MS: (M+H m/z=407.0).
Reaction SMILES: C([O:3][C:4](=[O:18])[C@H:5]([O:15][CH2:16][CH3:17])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[F:14])C.[OH-].[Na+]>[Na+].[Cl-].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[CH2:16]([O:15][C@H:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[F:14])[C:4]([OH:18])=[O:3])[CH3:17]
Reactant: CCOC(=O)[C@H](OCC)c1ccc(OC)cc1F
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Product: CCO[C@@H](C(=O)O)c1ccc(OC)cc1F
Reaction time: 96 h
Yield: 82.1 %

Procedure:
An emulsion of (R)-ethoxy-(2-fluoro-4-methoxy-phenyl)-acetic acid ethyl ester (416 mg) in 0.1M NaCl, 3 mM Natriumphosphat buffer pH 7.0 (75 ml) was cooled to 4–5° C. was treated with hog liver esterase suspension (0.175 ml). The reaction mixture was stirred for 4 days while maintaining the pH at 7 by gradual addition of 0.1N NaOH (totally 12.8 ml). The reaction mixture was washed with CH2Cl2, then brought to pH 2 by the addition of 2N HCl and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtrated and concentrated to give (R)-ethoxy-(2-fluoro-4-methoxy-phenyl)-acetic acid (304 mg, 97.1% ee) as yellow semisolid.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]=[C:9]=[S:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([NH2:18])=[N:16][CH:17]=1.C(OCC)(=O)C>CN(C=O)C>[Br:11][C:12]1[CH:13]=[C:14]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([NH:18][C:9]2[S:10][C:2]3[C:7]([N:8]=2)=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][CH:17]=1
Reactant: Nc1ncc(Br)cc1Oc1ccccc1
Reactant: S=C=Nc1cccnc1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1cnc(Nc2nc3cccnc3s2)c(Oc2ccccc2)c1
Temperature: 120 °C
Yield: 77.1 %

Procedure:
Heated a mixture of 2-chloro-3-isothiocyanatopyridine (0.257 g, 1.51 mmol) and 5-bromo-3-phenoxypyridin-2-amine (0.400 g, 1.51 mmol) in DMF (4 mL) at 80° C. for 3 hours. Heated at 120° C. overnight. Cooled, partitioned between 2N NaOH and ethyl acetate. Washed the organic layer twice with water, brine, dried, and concentrated. Subjected the residue to Biotage, eluting with 3:1 hexane:ethyl acetate to afford the title compound (0.465 g, 77.2% yield) as a white powder. 1H NMR (d6-DMSO) δ 7.15 (d, 2H), 7.23 (t, 1H), 7.40-7.50 (m, 4H), 7.92 (s, 1H), 8.34 (s, 1H), 8.37 (d, 1H), 11.63 (bs, 1H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:7]=1)C.C([NH2:23])=O.C[O-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C.CO.C(Cl)Cl.O>[Cl:12][C:11]1[C:6]([CH2:5][C:4]([NH2:23])=[O:3])=[CH:7][C:8]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[N:9][CH:10]=1
Reactant: CCOC(=O)Cc1cc(N2CCN(C)CC2)ncc1Cl
Reactant: NC=O
Agent: C[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCN(c2cc(CC(N)=O)c(Cl)cn2)CC1
Temperature: 105 °C
Reaction time: 0.33 h

Procedure:
[5-Chloro-2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-acetic acid ethyl ester (385 mg, 1.29 mmol) is dissolved under an atmosphere of argon in dry DMF (4 ml). Formamide (195 mg, 4.33 mmol) is added, and the mixture is heated to 105° C. At this temperature, sodium methoxide (5.4 M in MeOH, 0.24 ml, 1.29 mmol) is added dropwise. After 20 minutes, TLC analysis indicated incomplete conversion, thus another addition of sodium methoxide (0.08 ml of a 5.4 M solution in MeOH) is done. After a further 10 minutes, the reaction is judged complete according to TLC. The reaction mixture is cooled to RT and diluted with CH2Cl2 (150 ml). Water is added (3 ml) until a clear solution is obtained. Sufficient Na2SO4 is added to absorb the water and the organic solvent is evaporated. The residue is purified by FCC (CH2Cl2/MeOH 95:5 to 80:20) to afford the title compound. 1H NMR (CDCl3, 400 MHz): δ 2.35 (s, 3H), 2.51 (m, 4H), 3.56 (m, 4H), 3.62 (s, 2H), 5.37 (s, broad, 1H), 5.54 (s, broad, 1H), 6.64 (s, 1H), 8.15 (s, 1H). ES+−MS: 269.2, 271.1 (Cl) [M+H]+, ES−−MS: 267.2, 269.3 (Cl) [M−H]−.