Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](Cl)=[CH:3][CH:4]=O.C(O)(=O)C.[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[NH:17])=[CH:14][CH:13]=1.[F:21][C:22]([F:31])([F:30])[C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[F:21][C:22]([F:30])([F:31])[C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][CH:28]=1)[O:29][C:2]1[CH:3]=[CH:4][N:18]=[C:16]([C:15]2[CH:19]=[CH:20][C:12]([F:11])=[CH:13][CH:14]=2)[N:17]=1
Reactant: N=C(N)c1ccc(F)cc1
Reactant: O=CC=C(Cl)Cl
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: COCCOC
Product: Fc1ccc(-c2nccc(Oc3cccc(C(F)(F)F)c3)n2)cc1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
3,3-Dichloroacrolein (10 mmoles) diluted with dimethoxyethane (35 ml), is slowly added to a mixture consisting of a 4-fluorobenzamidine acetate (10 mmoles), 3-trifluoromethylphenol (11 mmoles), potassium carbonate (40 mmoles) and dimethoxyethane (40 ml), which is stirred under reflux. When the addition of 3,3-dichloroacrolein is completed additional 4-fluorobenzamidine acetate (1 mmoles) is added. The reaction mixture is stirred for 3 hours under reflux and subsequently cooled down to ambient temperature over night and filtered through silica. The organic phase is concentrated in vacuo. The residue was purified by chromatography on Al2O3 (petrol ethers/ethyl acetate: 20/1) to yield 2.52 g (75%) of the pure product having a melting point of 52° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][C:26](Br)=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[N:3]3[CH:4]=[CH:5][C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:7][C:2]3=[N:1][CH:26]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)Br)CC1
Reactant: CC(C)(C)c1ccnc(N)c1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cnc3cc(C(C)(C)C)ccn23)CC1

Procedure:
The title compound was prepared from 470 mg of 1-t-butyloxycarbonyl-4-(1-bromo-formylmethyl)piperidine (from Piperidine 1, Step C) and 277 mg of 2-amino-4-tert-butyl pyridine (from Step A) in 12 mL ethanol using a procedure analogous to that described in Piperidine 1, Step D to provide the title compound as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1.[C:27]1([NH2:37])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>>[F:15][C:16]1[CH:17]=[C:18]([S:23]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:37][C:27]2[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=2)=[N:9]3)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: Nc1cccc2ccccc12
Product: O=S(=O)(Nc1cccc2nc(Nc3cccc4ccccc34)ccc12)c1cc(F)cc(F)c1

Procedure:
The title compound, MS: m/e=462.3 (M+H+), was prepared in accordance with the general method of example 89 from 5-nitro-2-chloroquinoline, 3,5-difluorobenzenesulfonylchloride and 1-naphthylamine.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH:3]=[CH2:4].[CH:7](=[O:16])[C:8]1[C:9]([O:14][CH3:15])=[CH:10][CH:11]=[CH:12][CH:13]=1.O>C1COCC1>[OH:16][CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])[CH2:4][CH2:3][CH:2]=[CH2:1]
Reactant: COc1ccccc1C=O
Reactant: C=CCC[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(O)c1ccccc1OC

Procedure:
To a solution of 3-butenylmagnesium bromide in THF (0.50 M, 200 mL) at 0° C. was added o-anisaldehyde (13.62 g, 100 mmol) in THF (20 mL) dropwise and the reaction mixture was heated under reflux for 1 hour. Water was added, the aqueous layer was extracted with ether (x4), and the combined organic layers were washed with brine, dried over MgSO4 and evaporated in vacuo to give the title compound. The crude product was used for Preparation 17 without purification. 1H NMR (CDCl3, 400 MHz) δ: 7.3 (2H), 6.9 (2H), 5.8 (2H), 4.8-5.1 (3H), 3.85 (3H, OMe), 2.5 (1 H), 1.8-2.3 (4H).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:32])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[CH:20][CH:19]=1)=O)C1C=CC=CC=1.[H][H]>C(O)C.O.[Pd]>[OH:24][C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:16]([C@@H:12]2[CH2:13][CH2:14][CH2:15][NH:11]2)=[O:32])=[CH:23][CH:22]=1
Reactant: [H][H]
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc(O)cc1)[C@@H]1CCCN1

Procedure:
A suspension of (S)-2-(4-benzyloxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (7.0 g, 16.3 mmol) in ethanol/water (70 mL/7 mL) was hydrogenated over 10% palladium on carbon (0.41 g) at 55 psi of hydrogen, at 50° C., for 5 hours. The mixture was cooled, and the catalyst was removed by filtration. The solvent was evaporated in vacuo. The residue was dissolved in hot ethanol (30 mL) and treated with a saturated solution of hydrogen chloride in ethanol (3 mL). The product crystallized as the hydrochloride salt, 1.27 g (32%), a colorless solid. MS m/z 207 (MH+). 1H NMR(DMSO-d6) δ 1.92 (m, 3H), 2.43 (m, 1H), 3.28 (m, 2H), 4.31 (m, 1H), 6.77 (d, 2H), 7.47 (d, 2H), 9.44 (br s, 1H) and 10.75 (s, 1H). Anal. calcd for C11H14N2O2: C, 54.44; H, 6.23; N, 11.54. Found: C, 54.28; H, 6.06; N, 11.66.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19].O>CN(C)C=O>[CH2:19]([O:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5])[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: O=Cc1cc(I)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(I)cc1C=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 2-hydroxy-5-iodo-benzaldehyde (16 g, 64.5 mmol) (Aldrich) in N,N-dimethylformamide (100 mL) was added K2CO3 (16 g, 115 mmo) and allyl bromide (20 g, 165 mmol) (Aldrich). The reaction mixture was stirred at 100° C. for 3 h, then cooled to room temperature and poured into water, extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, filtered and concentrated to give 2-allyloxy-5-iodo-benzaldehyde as a white solid (Yield: 18g, 97%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[C:12]([N+:18]([O-])=O)[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl.CO.[Pd].[H][H]>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[C:12]([NH2:18])[CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNc1ccc(S(=O)(=O)c2ccccc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CNc1ccc(S(=O)(=O)c2ccccc2)cc1N

Procedure:
Prepared analogously to Example 1c from (4-benzenesulphonyl-2-nitro-phenyl)-methyl-amine and palladium on activated charcoal/hydrogen in methylene chloride/methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.C([N:25]1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:28]([CH2:35]Br)[NH:27][C:26]1=[O:37])(=O)C.[ClH:38]>C(O)C>[ClH:38].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:35][C:28]2[NH:27][C:26](=[O:37])[NH:25][C:29]=2[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:11][CH2:10]1
Reactant: CCOC(=O)c1c(CBr)[nH]c(=O)n1C(C)=O
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1[nH]c(=O)[nH]c1CN1CCN(c2ccccc2OC)CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a cooled solution (0° C.) of 2 g of 1-(2-methoxyphenyl)piperazine and 2.1 g of triethylamine in 40 ml of ethanol is added 2.9 g of ethyl 3-acetyl-5-(bromomethyl)-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylate. The resulting solution is stirred at 0° C. for 4 hours, 30 ml of ice-water is added and the mixture is filtered. One equivalent of hydrochloric acid is added to the filtrate and it is evaporated to dryness. The residue crystallizes from a mixture of ethanol and ethyl acetate (1:1) and is recrystallized from that solvent mixture to give ethyl 2,3-dihydro-5-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-2-oxo-1H-imidazole-4-carboxylate hydrochloride melting at about 227° C. (dec.). The free base of this compound has the following structural formula: ##STR6##
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].C(N(CC)CC)C.C([O:43][CH:44]=[CH:45][CH3:46])C.O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:8][C:7]1[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)[C:5](=[O:19])[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=2)=[O:21])=[CH:3][C:2]=1[C:44](=[O:43])[CH2:45][CH3:46]
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CC=COCC
Agent: [Pd]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(=O)c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
A solution of 5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (Example 1 (d), 1500 mg, 2.5 mmol), bis[1,2-bis(diphenylphosphino)ethane]palladium(0) (230 mg, 0.25 mmol), triethylamine (7.5 ml, 54 mmol) and ethylpropenyl ether (900 μl, 7.5 mmol) in DMF (45 ml) was heated at 100° C. overnight. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate and the solvent was removed under reduced pressure. The crude product was then dissolved in DMF (25 ml) and 2M HCl (25 ml) and then stirred for 1.5 h. The reaction mixture was then poured into aqueous NaHCO3 and extracted with ethyl acetate. The extracts were separated, evaporated under reduced pressure, and the residue was chromatographed on silica using ethyl acetate/heptane (2/1, 4/1, 10/1) as eluent. Fractions containing the product were combined and evaporated to give the title compound (1.3 g, >99%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[N:21]=[C:22]=S.CC(C)N=C=NC(C)C>C(#N)C>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[NH:12][C:22]([NH:21][C:15]3[C:14]([Cl:13])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:20])=[N:1][C:2]=2[CH:3]=1)=[O:6]
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: COC(=O)c1ccc(N)c(N)c1
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Product: COC(=O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Yield: 56 %

Procedure:
Prepared analogously to example 1c from methyl 3,4-diamino-benzoate and 2,6-dichloro-1-isothiocyanato-benzene with DIC in acetonitrile. Yield: 56%
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Br:5][C:6]1[C:7](=[O:21])[N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:9]=[CH:10][C:11]=1Br>CN(C)C=O>[N:1]([C:11]1[CH:10]=[CH:9][N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:7](=[O:21])[C:6]=1[Br:5])=[N+:2]=[N-:3]
Reactant: O=c1c(Br)c(Br)ccn1Cc1cccc(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccn(Cc2cccc(F)c2)c(=O)c1Br
Temperature: 60 °C
Yield: 98 %

Procedure:
Sodium azide (1.08 g, 16.62 mmol) was suspended in N,N-dimethylformamide (10 mL) and a stock solution of 3,4-dibromo-1-(3-fluorobenzyl)pyridin-2(1H)-one (from step 1) in N,N-dimethylformamide (33.0 mL, 0.33 M) was added and the resulting mixture was heated to 60° C. for 4 hours. Ice water (30 mL) was added and the aqueous layer was extracted with ethyl acetate (4×50 mL). The combined organics were washed with H2O (3×50 mL), brine (2×25 mL), dried over MgSO4, concentrated, and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexane) to afford an off-white solid (3.50 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])=[CH:6][CH:7]=1
Reactant: Fc1ccc([C@@H]2CCCN2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2c2ccc(F)cc2)cc1

Procedure:
The title compound, white solid, m.p. 136° C., [a]D20=172° (c=0.1 in CHCl3) and MS: m/e=319 (M+) was prepared in accordance with the general method of example 1e from (S)-2-(4-fluoro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: [Br:1]Br.[N:3]1[C:8]2[NH:9][CH2:10][CH2:11][CH2:12][O:13][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:1][C:5]1[CH:4]=[N:3][C:8]2[NH:9][CH2:10][CH2:11][CH2:12][O:13][C:7]=2[CH:6]=1
Reactant: c1cnc2c(c1)OCCCN2
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Brc1cnc2c(c1)OCCCN2
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A solution of bromine (960 mg, 6 mmol) in CH2Cl2 (50 mL) was added dropwise at 0° C. to a CH2Cl2 (50 mL) suspension of 6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocycloheptene (750 mg, 5 mmol) and solid K2CO3 (1 g). The mixture was stirred for 30 min at 20° C., then the excess bromine was quenched with a saturated solution of aqueous NaHSO3. The basic aqueous phase was separated, extracted with CH2Cl2, the combined organic layers were dried and evaporated to afford the title compound (1.10 g, 96%). 1H NMR (300 MHz, DMSO-d6, 8): 7.78 (d, J=1.8 Hz, 1H), 7.30 (d, J=1.9 Hz, 1H), 6.35 (s, br, 1H), 4.10 (t, J=5.7 Hz, 2H), 3.24 (m, 2H), 1.92 (m, 2H). MS (ESI): m/e 229 and 231 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C>[C:18]1([C:9]2[CH2:10][C:11]3[C:16]([CH:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Ic1ccccc1
Reactant: C1=Cc2ccccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: C1=C(c2ccccc2)Cc2ccccc21
Temperature: 25 °C
Yield: 41.6 %

Procedure:
20 ml of triethylamine, 2.2 g (20 mmole) of indene, 4.08 g (20 mmole) of iodobenzene and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 10 h. After that the mixture was cooled to room temperature and treated with 100 ml of ethanol. The crystalline precipitate was isolated, washed with ethanol and dried under vacuum to obtain 1.6 g (46%) of 2-phenyl-indene.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[CH3:23][O-:24].[Na+].[CH3:26][OH:27].Cl>O>[CH3:23][O:24][C:26](=[O:27])[C:13]([CH3:8])([CH3:12])[CH2:14][CH2:5][NH:6][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:9]=2)=[O:4]
Reactant: CO
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)C(C)(C)CCNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Yield: 46.7 %

Procedure:
A mixture of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (80 mg, 0.27 mmol) and 4-amino-2,2-dimethyl-butyric acid methyl ester, trifluoroacetic acid salt (210 mg, 0.81 mmol) in 0.5 M NaOMe/MeOH solution (1.62 mL, 0.81 mmol) was microwaved at 130° C. for 3 h. The reaction mixture was diluted with water (50 mL), acidified by 1 N HCl to pH=3-4 and then extracted with EtOAc. Organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated. Residue was purified by silica gel chromatography, eluting with 5-50% EtOAc/hexanes, to provide the title compound 26 mg (0.063 mmol) in 23.6% yield. 1H NMR in CDCl3, δ ppm: 13.23 (s, 1H), 8.40 (s, 1H), 8.32 (d, J=8.8 Hz, 1H), 7.97 (br t, 1H), 7.42 (m, 4H), 7.12 (m, 3H), 3.64 (s, 3H), 3.52 (m, 2H), 1.95 (dd, J=9.1, 5.9 Hz, 2H), 1.27 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])[CH:5]=[O:6].[BH4-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])[CH2:5][OH:6]
Reactant: CN(C)S(=O)(=O)c1ccc(C=O)cc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccc(CO)cc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.7 %

Procedure:
To a solution of OBS02001 (6.0 g, 19.47 mmol) in anhydrous THF (50 mL) was added sodium borohydride (0.81 g, 21.42 mmol). The mixture was stirred at room temperature for 4 h, quenched with water (CARE!!) and filtered through a Celite pad. The filtrate was concentrated in vacuo and re-dissolved in DCM (200 mL). The organic layer was washed with brine (2×200 mL), dried (Na2SO4) and filtered. Concentration in vacuo of the filtrates gave OBS02002 as a pale yellow oil (5.54 g, 92%). TLC [SiO2, EtOAc-n-hexane (1:1)] RF=0.47; 1H-NMR (270 MHz, CDCl3)=2.97 (6H, s), 3.14 (1H, bs, OH), 4.51 (2H, s) 7.19 (1H, dd, J=1.5, 8.1), 7.37 (1H, d, J=8.4), 7.52 (1H, d, J=1.8).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH3:12].[CH:13]1([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14]1>>[CH:13]1([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24]3[CH:31]=[CH:30][C:27]([C:28]4[NH:12][C:4](=[O:6])[C:3]5[C:2](=[C:10]([CH3:11])[CH:9]=[CH:8][CH:7]=5)[N:1]=4)=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14]1
Reactant: N
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: O=Cc1ccc(OC2CCN(C3CCC3)CC2)cc1
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(OC4CCN(C5CCC5)CC4)cc3)nc12

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 2-amino-3-methylbenzoic acid, ammonia and 4-[(1-cyclobutyl-4-piperidinyl)oxy]benzaldehyde.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1)[CH2:24][CH3:25])[CH3:22].Cl>C(O)CC>[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4])[CH2:24][CH3:25])[CH3:22]
Reactant: CCN(CC)CC1CCCCN1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Agent: Cl
Solvent: CCCO
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2ccccc2C(=O)Nc2cccnc21

Procedure:
The title compound is prepared analogously to Example 2 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and (-)-2-[(diethylamino)methyl]piperidine to give colorless crystals, mp. 210°-211.5° C. (n-propanol; [α]D20 =+11.4° (dilute aqueous hydrochloride acid). The dihydrobromide melts at 241°-242° C. (with decomposition; from ethanol).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)O1.Br[C:24]1[CH:25]=[C:26]([NH:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[C:27]([Cl:30])=[N:28][CH:29]=1.O1CCOCC1>C([O-])([O-])=O.[Na+].[Na+].[Pd]>[Cl:30][C:27]1[N:28]=[CH:29][C:24]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)=[CH:25][C:26]=1[NH:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)(=[O:33])=[O:34]
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3ccc4nc(NC(C)=O)sc4c3)cnc2Cl)cc1
Yield: 40.9 %

Procedure:
A mixture of N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.18 g, 0.6 mmol), N-(5-bromo-2-chloropyridin-3-yl)-4-methoxybenzenesulfonamide (0.15 g, 0.4 mmol) and Pd FibreCat® in 1 mL of 10% Na2CO3 and 3 mL of dioxane was heated at 100° C. for 12 minutes. The mixture was then filtered and the filtrate was concentrated in vacuo, washed with small amount of EtOAc, and recrystallized in MeOH to give white solid N-(6-(6-chloro-5-(4-methoxyphenylsulfonamido)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.08 g, 41% yield). MS (ESI pos. ion) m/z: calc'd for C21H17ClN4O4S2: 488.0. found: 489.0 (MH+). 1H NMR (300 MHz, MeOH) δ ppm 2.29 (s, 3H) 3.85 (s, 3H) 6.97-7.07 (m, 2H) 7.66 (dd, J=8.48, 1.90 Hz, 1H) 7.70-7.78 (m, 2H) 7.81-7.90 (m, 2H) 8.11 (d, J=1.61 Hz, 1H) 8.17 (d, J=2.34 Hz, 1H) 8.44 (d, J=2.34 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[C:20]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.Cl.C(=O)([O-])[OH:32].[Na+].[Cl:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][C:45]=1[Cl:46])[C:40](Cl)=[O:41]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:14]1[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=1[N:12]1[C:20]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:21][N:22]=[C:11]1[CH2:10][NH:9][C:40](=[O:41])[C:39]1[CH:43]=[CH:44][C:45]([Cl:46])=[C:37]([Cl:36])[CH:38]=1)=[O:32]
Reactant: CCOC(=O)CCc1nnc2n1-c1sc(CC)cc1C(c1ccccc1Cl)=NC2
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCc1nnc(CNC(=O)c2ccc(Cl)c(Cl)c2)n1-c1sc(CC)cc1C(=O)c1ccccc1Cl
Temperature: 40 °C
Reaction time: 4 h

Procedure:
4-(2-Chlorophenyl)-9-(2-ethoxycarbonylethyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (3.3 g) was added to 5% hydrochloric acid (35 ml), and the mixture was stirred at 40° C. for 4 hours. Then, sodium hydrogencarbonate was added to the reaction mixture to make the mixture alkaline. Chloroform (50 ml) and 3,4-dichlorobenzoyl chloride (1.61 g) were added under ice-cooling, and the mixture was allowed to stand overnight. Then, the organic layer was taken out, washed with an aqueous citric acid solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (developing solvent:ethyl acetate-methanol) and recrystallized from ethyl acetate-hexane to give 1.08 g of ethyl 3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-3-(3,4-dichlorobenzoylaminomethyl) [1,2,4]triazol-5-yl)propionate.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:15])[C:11]=2[C:12]([OH:14])=O)=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:16][C:17]1[N:22]=[CH:21][N:20]2[CH:23]=[C:24]([C:26]3[CH:27]=[C:28]([O:32][C:33](=[O:35])[CH3:34])[CH:29]=[CH:30][CH:31]=3)[N:25]=[C:19]2[CH:18]=1>>[C:33]([O:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([C:24]2[N:25]=[C:21]3[N:22]=[C:17]([NH:16][C:12]([C:11]4[N:10]([CH3:15])[N:9]=[CH:8][C:7]=4[C:5]([N:1]4[CH2:2][CH2:3][CH2:4]4)=[O:6])=[O:14])[CH:18]=[CH:19][N:20]3[CH:23]=2)[CH:27]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Oc1cccc(-c2cn3cnc(N)cc3n2)c1
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)O
Product: CC(=O)Oc1cccc(-c2cn3ccc(NC(=O)c4c(C(=O)N5CCC5)cnn4C)nc3n2)c1

Procedure:
The title compound was prepared in analogy to example 82, step 3, from 4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (156 mg, 746 μmol) and acetic acid 3-(7-amino-imidazo[1,2-c]pyrimidin-2-yl)-phenyl ester (200 mg, 746 μmol). Yield: 158 mg (42%). Yellow foam. MS (m/z)=459.2 [M+H+].