Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH2:17]([O:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[NH:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][C:40]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:34][CH2:33]1)[CH3:18]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[CH:7][C:3]=1[C:4]([N:42]1[CH2:43][CH2:44][C:40]([CH2:39][CH2:38][N:35]2[CH2:36][CH2:37][CH:32]([NH:31][C:23]3[N:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH2:33][CH2:34]2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1)=[O:6]
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: Cc1ccc(-n2cnnn2)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4C)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methyl-5-(1H-tetrazol-1-yl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:19][CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:14][CH:13]=1.C(O)(=O)C>C(O)C.CN(C=O)C>[OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:19][CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)cc1O
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1CCC(c2ccc(N=Cc3ccc(O)cc3O)cc2)=NN1

Procedure:
A solution containing 0.42 g (0.003 mol) of 2,4-dihydroxybenzaldehyde, 0.57 g (0.003 mol) of 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)one and 0.05 ml of acetic acid in a mixture of 40 ml of ethanol and 20 ml of DMF was refluxed for 4 h. After cooling the product was filtered and washed with ethanol. Yield 0.80 g (85%), m.p. 350° C. (decomp).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][C:12]1[C:13]2[C:20]([C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=3)=[O:22])=[CH:19][N:18]([CH:30]([CH3:32])[CH3:31])[C:14]=2[N:15]=[CH:16][N:17]=1>N1C=CC=CC=1>[NH2:11][C:12]1[C:13]2[C:20]([C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[O:10])[CH:24]=3)=[O:22])=[CH:19][N:18]([CH:30]([CH3:32])[CH3:31])[C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: O=C=Nc1ccccc1F
Reactant: CC(C)n1cc(C(=O)c2ccnc(N)c2)c2c(N)ncnc21
Solvent: c1ccncc1
Product: CC(C)n1cc(C(=O)c2ccnc(NC(=O)Nc3ccccc3F)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 55.1 %

Procedure:
1-Fluoro-2-isocyanato-benzene (0.09 mL, 0.81 mmol) was added to a solution of (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(2-amino-pyridin-4-yl)-methanone (0.20 g, 0.67 mmol) in pyridine (2 mL). The mixture was heated to 80° C. in a sealed tube for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with hot EtOAc/MeOH (95:5, 3×10 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash column chromatography (ethyl acetate/MeOH 99:1) afforded the title compound as a yellow solid (160 mg, 55%). MS: 434.2 (MH+); HPLC Rf: 5.83 min. (HPLC method 4); HPLC purity: 98%.
Reaction SMILES: Cl.C[O:3][C:4](=[O:17])[CH2:5][C@@H:6]([NH2:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([NH:28][S:29]([C:32]2[C:33]3[N:34]=[CH:35][CH:36]=[N:37][C:38]=3[CH:39]=[CH:40][CH:41]=2)(=[O:31])=[O:30])[CH:20]=1>>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:16][C@@H:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:5][C:4]([OH:3])=[O:17])=[O:24])=[C:21]([NH:28][S:29]([C:32]2[C:33]3[N:34]=[CH:35][CH:36]=[N:37][C:38]=3[CH:39]=[CH:40][CH:41]=2)(=[O:30])=[O:31])[CH:20]=1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: COC(=O)C[C@@H](N)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: O=C(O)C[C@H](Cc1ccc(Cl)c(Cl)c1)NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
(S)-3-(tert-Butoxycarbonylamino)-4-(3,4-dichloro-phenyl)-butyric acid was treated as in EXAMPLE 2, Part A, to produce (S)-3-amino-4-(3,4-dichloro-phenyl)-butyric acid methyl ester hydrochloride as a white solid. This ester was coupled to 4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E. HPLC: RT=9.78 min. MS (ESI−): mass calcd. for C25H19Cl3N4O5S, 592.01; m/z found; 593/595 [M−H]−. 1H NMR (500 MHz, CD3OD): 8.97 (d, J=1.8, 1H), 8.93 (d, J=1.8, 1H), 8.55 (dd, J=7.4, 1.3, 1H), 8.33 (dd, J=8.5, 1.3, 1H), 7.97-7.94 (m, 1H), 7.69 (d, J=2.0, 1H), 7.42 (d, J=8.2, 1H), 7.38-7.36 (m, 2H), 7.16 (dd, J=8.2, 2.0, 1H), 6.97 (dd, J=8.6, 2.0, 1H), 4.56-4.50 (m, 1H), 2.90 (dd, J=13.7, 6.1, 1H), 2.81 (dd, J=13.7, 7.7, 1H), 2.54 (dd, J=15.9, 6.2, 1H), 2,45 (dd, J=15.9, 7.4, 1H).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([S:9][CH2:10][C:11]3[CH:16]=[C:15]([O:17][CH2:18][CH:19]4[CH2:21][CH2:20]4)[CH:14]=[CH:13][N:12]=3)=[N:8][C:4]=2[CH:3]=1.C([O-])(O)=[O:25].[Na+].ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([S:9]([CH2:10][C:11]3[CH:16]=[C:15]([O:17][CH2:18][CH:19]4[CH2:21][CH2:20]4)[CH:14]=[CH:13][N:12]=3)=[O:25])=[N:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2[nH]c(SCc3cc(OCC4CC4)ccn3)nc2c1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=S(Cc1cc(OCC2CC2)ccn1)c1nc2cc(F)ccc2[nH]1
Reaction time: 0.25 h

Procedure:
5- Fluoro-2-[[(4-cyclopropylmethoxy-2-pyridinyl)methyl]thio]-1H-benz-imidazole (1.25 g, 0.0036 mol) was dissolved in CH2Cl2 (40 ml). NaHCO3 (0.6 g, 0.0072 mol) dissolved in H2O (20 ml) was added and the mixture was cooled to +2° C. m-Chloroperbenzoic acid, 84% (0.73 g, 0.0036 mol) dissolved in CH2Cl2 (5 ml) was added under stirring. Stirring was continued at room temperature for 15 min. The two phases were separated and NaOH (0.29 g, 0.0072 mol) dissolved in H2O (25 ml) was added to the organic phase. The mixture was stirred, the phases were separated and the H2O phase was treated with Norite and filtered. Methylformiate (0.45 ml, 0.0073 mol) dissolved in H2O (5 ml) was added dropwise under stirring. After extraction with CH2Cl2 and drying with Na2SO4 the solvent was evaporated. In this way the title compound was obtained [0.93 g, 69%). NMR data for the final product is given below. NMR data for the intermediates are given below.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.[C:55]([O:59][C:60]([N:62]1[CH2:67][CH2:66][CH:65]([CH2:68][C:69](O)=[O:70])[CH2:64][CH2:63]1)=[O:61])([CH3:58])([CH3:57])[CH3:56]>CN(C=O)C>[N:21]1([C:18]2[N:19]=[CH:20][C:15]([O:14][CH2:13][C:11]3[CH:10]=[N:9][N:8]([CH:5]4[CH2:4][CH2:3][N:2]([C:69](=[O:70])[CH2:68][CH:65]5[CH2:66][CH2:67][N:62]([C:60]([O:59][C:55]([CH3:57])([CH3:56])[CH3:58])=[O:61])[CH2:63][CH2:64]5)[CH2:7][CH2:6]4)[N:12]=3)=[CH:16][CH:17]=2)[CH:25]=[N:24][N:23]=[N:22]1
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)N2CCC(n3ncc(COc4ccc(-n5cnnn5)nc4)n3)CC2)CC1
Reaction time: 0.08 h

Procedure:
To a stirred solution of 5-((2-(Piperidin-4-yl)-2H-1,2,3-triazol-4-yl)methoxy)-2-(1H-tetrazol-1-yl)pyridine (225 mg, 0.688 mmol) (Intermediate 15) dissolved in DMF (10 mL) was added triethylamine (4 eq.) and o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (2 eq.). The solution was stirred for 5 minutes and 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (1.5 eq.) was added and was stirred at room temperature for 3 h. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate and hexanes to afford the desired product. 1H NMR (DMSO-d6): δ 10.07 (1H, s), 8.40 (1H, d), 8.00 (1H, d), 7.93 (1H, s), 7.86 (1H, dd), 5.34 (2H, s), 4.78 (1H, m), 4.35 (1H, m), 3.85-3.94 (3H, m), 3.21 (1H, m), 2.64-2.82 (3H, m), 2.27 (2H, d), 2.10 (2H, m), 1.86 (3H, m), 1.60 (2H, d), 1.35 (9H, s), 1.99 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=S)[CH2:6][CH2:5]2.[C:14]([NH:17][NH2:18])(=O)[CH3:15]>C(O)CCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]1[C:14]([CH3:15])=[N:17][N:18]=[C:7]1[CH2:6][CH2:5]2
Reactant: CC(=O)NN
Reactant: S=C1CCc2cc(Br)c(Cl)cc2N1
Solvent: CCCCO
Product: Cc1nnc2n1-c1cc(Cl)c(Br)cc1CC2

Procedure:
To a stirred solution of 6-bromo-7-chloro-3,4-dihydroquinoline-2(1H)-thione (110-3; 1.8 g, 0.0065 mol) in n-butanol (80 mL) was added acetic hydrazide (1.2 g, 0.0162 mol). Reaction mass was refluxed for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel (60-120 mesh) column chromatography using 0-5% methanol in dichloromethane to afford title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.81 (s, 1H), 2.96 (bs, 4H), 2.66 (s, 3H). MS (M+1): 296.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+].[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:24]=[CH:23]2>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:30]([C:25]2[CH:24]=[CH:23][C:22]3[C:27](=[CH:28][CH:29]=[C:20]([Br:19])[CH:21]=3)[CH:26]=2)(=[O:31])=[O:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc2cc(Br)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a mixture of 1-tert-butoxycarbonylpiperazine (1.25 g), sodium hydrogen carbonate solution (10 ml) and ethyl acetate (10 ml), was added 6-bromonaphthalene-2-sulfonylchloride (2.05 g), and the mixture was stirred at room temperature for 1 hour and extracted with dichloromethane. The extract was washed with water, dried and concentrated. The residue was crystallized with diisopropylether to give 1-(tert-butoxycarbonyl)-4-(6-bromonaphthalene-2-sulfonyl)piperazine as colorless crystals (2.83 g).
Reaction SMILES: C[O:2][C:3]1[C:21]([F:22])=[C:20]([O:23]C)[C:19]([F:25])=[C:18]([F:26])[C:4]=1[C:5]([C:7]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:8]=1[F:17])=[O:6]>C(O)(=O)C.Br>[OH:2][C:3]1[C:21]([F:22])=[C:20]([OH:23])[C:19]([F:25])=[C:18]([F:26])[C:4]=1[C:5]([C:7]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:8]=1[F:17])=[O:6]
Reactant: COc1c(F)c(F)c(C(=O)c2c(F)c(F)c(F)c(F)c2F)c(OC)c1F
Agent: Br
Solvent: CC(=O)O
Product: O=C(c1c(O)c(F)c(O)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F
Yield: 86.4 %

Procedure:
A solution of Compound 45 (450 mg, 1.17 mmol) in 5 mL acetic acid and 5 mL 48% hydrobromic acid is heated for 48 hours at reflux. The reaction mixture is worked up as above, and the crude product is purified by column chromatography to yield 362 mg (87%) of Compound 46 as a colorless solid. 19F NMR (d6-DMSO) 139.80 (m, 1F); 141.69 (dd, J=10.0, 20.1 Hz, 1F); 143.05 (dt, J=5.8, 23.1 Hz, 1F); 155.48 (dd, J=10.2, 22.8 Hz, 1F); 155.67 (s, 1F); 156.27 (dd, J=5.8, 20.5 Hz, 1F); 158.57 (t, J=22.2 Hz, 1F); 162.5 (b, 1F).
Reaction SMILES: Cl.[NH2:2][NH2:3].CCN(C(C)C)C(C)C.C(O/[CH:16]=[C:17](/[C:23](=O)[C:24]([F:27])([F:26])[F:25])\[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C(O)C>[CH2:21]([O:20][C:18]([C:17]1[C:23]([C:24]([F:27])([F:26])[F:25])=[N:2][NH:3][CH:16]=1)=[O:19])[CH3:22]
Reactant: CCO/C=C(\C(=O)OCC)C(=O)C(F)(F)F
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c[nH]nc1C(F)(F)F
Reaction time: 0.17 h
Yield: 46.8 %

Procedure:
To a suspension of hydrazine hydrochloride (10 g, 146.66 mmol) in ethanol (500 mL) at −20° C. was added DIPEA (45.3 mL, 266.66 mmol) followed by stirring at this temperature for 10 minutes. Ethyl (2Z)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (Preparation 113, 32 g, 133.33 mmol) was added and the reaction stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and diluted with EtOAc. The organic solution was washed with water, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 30% EtOAc in hexane to afford the title compound (13 g) that was taken directly on to the next step.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([C:29]5([CH2:35][OH:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1.CCN(C(C)C)C(C)C.[CH:46]([S:48]([CH:51]=C)(=[O:50])=[O:49])=[CH2:47]>>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([C:29]5([CH2:35][OH:36])[CH2:30][CH2:31][N:32]([CH2:47][CH2:46][S:48]([CH3:51])(=[O:50])=[O:49])[CH2:33][CH2:34]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1
Reactant: C=CS(=O)(=O)C=C
Reactant: OCC1(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CCN1CCC(CO)(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1
Yield: 57.5 %

Procedure:
To a stirring mixture of (4-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-piperidin-4-yl)-methanol hydrochloride 75 (97 mg, 0.1873 mmol) in IMS (3 mL) was added DIPEA (165 μL, 0.94 mmol) followed by vinyl sulfone (18 ul, 0.206 mmol) at RT, as illustrated in FIG. 16. After 3 h the solvent was removed in vacuo and the residue was subjected to HPLC (Gemini C6-Phenyl column, gradient 10 to 60%, 20 min ramp) to afford 188 (63 mg, 53%). 1H NMR δ ppm (DMSO-d6): 8.42-8.39 (1H, m), 8.23 (1H, s), 8.19 (1H, s), 7.80 (1H, td, J=8.77, 5.87 Hz), 7.53 (1H, ddd, J=10.34, 8.85, 2.77 Hz), 7.36 (1H, d, J=2.40 Hz), 7.33-7.27 (1H, m), 7.12 (1H, dd, J=8.59, 2.48 Hz), 6.85 (1H, dd, J=8.55, 4.83 Hz), 4.17 (2H, t, J=5.04 Hz), 3.22-3.14 (6H, m), 3.02 (2H, t, J=5.09 Hz), 2.98 (3H, s), 2.02 (2H, s), 1.72 (4H, s). 2 Protons obscured by water peak. LCMS: RT=6.57 min, M+H+=585
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C@@H:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:2].[C:19]([C:27]1[CH:51]=[CH:50][C:30]([O:31][CH2:32][CH2:33][CH2:34]OC2C=CC(C[C@H](OCC)C(O)=O)=CC=2)=[CH:29][CH:28]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4](=[O:18])[C@@H:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:34][CH2:33][CH2:32][O:31][C:30]2[CH:50]=[CH:51][C:27]([C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:28][CH:29]=2)=[C:9]([Cl:14])[CH:8]=1)[CH3:2]
Reactant: CCO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccccc3)cc2)cc1)C(=O)O
Reactant: CCOC(=O)[C@H](Cc1ccc(O)c(Cl)c1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccccc3)cc2)c(Cl)c1)OCC

Procedure:
The title compound was prepared from (S)-2-ethoxy-3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester and [4-(3-bromo-propoxy)-phenyl]-phenyl-methanone (Example 256) using the Standard Procedure I. The product was purified by column chromatography on silica gel using a 4/1 Hexane/Ethyl acetate mixture as eluent to give the title product. MS(ES) for C29H31ClO6 [M+H]+: 511.1
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([NH:34]N)=[CH:33][C:28]=2[O:27][CH2:26]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([N:34]3[C:17]([C:12]4[C:13](=[O:16])[CH:14]=[CH:15][N:10]([C:6]5[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:2]([F:24])[F:1])[CH:5]=5)[N:11]=4)=[CH:18][CH:19]=[N:20]3)=[CH:33][C:28]=2[O:27][CH2:26]1
Reactant: NNc1ccc2c(c1)OCO2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1ccc2c(c1)OCO2
Yield: 16 %

Procedure:
The product was obtained starting from 1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) and benzo[1,3]dioxol-5-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for Example 91 in 16% yield. MS: M=425.2 (M+H)+
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=O)(C)(C)C.S(Cl)(Cl)=O.[CH3:21]O>>[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]1[C:14]([O:16][CH3:21])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCOC[C@@H]1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1COCCN1
Temperature: 25 °C

Procedure:
To a solution of (R)-morpholine-3,4-dicarboxylic acid-4-tert-butyl ester (5.00 g, 21.6 mmol) in MeOH (54 mL) was added thionyl chloride (3.16 mL, 43.2 mmol) dropwise, and the resulting mixture was heated at reflux for 16 h. The solution was cooled to ambient temperature and concentrated in vacuo. The residue was made basic with saturated aqueous NaHCO3 and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to yield the title compound.
Reaction SMILES: I.CS[C:4](=[NH:13])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[NH2:14][NH2:15].[C:16]([C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22])(=O)[CH3:17]>C(O)C.CO>[CH3:17][C:16]([C:19]1[C:20]([C:21]([OH:23])=[O:22])=[CH:24][CH:25]=[CH:26][N:27]=1)=[N:14][NH:15][C:4](=[NH:13])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1
Reactant: CC(=O)c1ncccc1C(=O)O
Reactant: NN
Reactant: CSC(=N)Nc1cccc(F)c1
Agent: I
Solvent: CCO
Solvent: CO
Product: CC(=NNC(=N)Nc1cccc(F)c1)c1ncccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the above isothiourea salt (8.5 g, 27.0 mmol) and hydrazine (1.4 g, 27.0 mmol) in 80 ml of ethanol is heated to reflux for 4 hr. The mixture is cooled and the solvent removed. The residue is diluted with 80 ml of water and filtered. A 20 ml aliquot of the resulting aqueous filtrate (2.0 g, 11.9 mmol) is mixed with 2-acetylnicotinic acid (2.0 g, 11.9 mmol) in 6 ml of methanol and stirred at RT overnight. A bright yellow solid is collected by filtration and dried to give 2-[methyl(3-carboxy-2-pyridyl)methylene]-N-(3-fluorophenyl)hydrazinecarboximidamide, (compound 16).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][CH:9]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CC(=O)C[C@H]1C(O)=O)=O)(C)(C)C.NOC[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[CH2:10][CH:9]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CON)cc1
Reactant: CON=C1CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Product: COc1ccc(CON=C2CC(C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Yield: 85 %

Procedure:
The same method as employed in the preparation of Intermediate 7, but starting from (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (Intermediate 1) and 1[(aminooxy)methyl]-4-methoxy-benzene (Intermediate 10) gave the title compound as a gum in a 85% yield.
Reaction SMILES: [CH:1]1([C:7]([C:10]2[CH:15]=[C:14]([O:16]C)[CH:13]=[C:12]([O:18]C)[CH:11]=2)([CH3:9])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1(C2C=C(O)C=C(O)C=2)SCCS1)CCC>CCCCCC.C(OCC)C>[CH:1]1([C:7]([C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([OH:18])[CH:11]=2)([CH3:9])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(OC)cc(C(C)(C)C2CCCCC2)c1
Agent: CCCCC1(c2cc(O)cc(O)c2)SCCS1
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(c1cc(O)cc(O)c1)C1CCCCC1

Procedure:
Compound 21 was prepared from Compound 14 using the same procedure as described above for Compound 16. Yield 1.11 g (61.9%) as a viscous oil. Rf=0.28 (hexane:diethyl ether 6:4); 1H NMR δ 6.38 (d, J=2 Hz, 2H), 6.17 (t, J=2.25 Hz, 1H), 4.82 (br s, 2H), 1.71–1.68 (m, 2H), 1.63–1.60 (m, 1H), 1.53–1.51 (m, 2H), 1.42–1.36 (m, 1H), 1.17 (s, 6H), 1.16–1.03(m, 3H), 0.94–0.86 (m, 2H); 13C NMR δ 156.32, 154.45, 106.56, 100.02, 49.21, 40.85, 28.12, 27.39, 26.91, 25.39, 14.40; MS: (ESI, Neg.) m/z 233 ([M−H]−).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])#[N:2].C(N(CC)CC)C.ClC(OCC)=O.O.[NH2:26][NH2:27]>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:26][NH2:27])=[O:7])#[N:2]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: NN
Agent: CCOC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cccc(C(=O)NN)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
A solution of 3-cyanobenzoic acid (1.0 g, 6.80 mmol) in tetrahydrofuran (10 mL) at 0° C. was treated with triethylamine (2.84 mL, 20.4 mmol) and ethyl chloroformate (0.78 mL, 8.16 mmol) and stirred at 0° C. for 1 h. The resulting white precipitate was removed by filtration and the filtrate cooled back to 0° C. Hydrazine monohydrate (1.00 mL, 20.4 mmol) was added and the mixture stirred at ambient temperature for 3.5 hours. The reaction mixture was then concentrated to dryness in vacuo and the residue was dissolved in dichloromethane (150 mL). The organic phase was sequentially washed with water (100 mL), 1N sodium hydroxide (100 mL), water (100 mL) and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography using 3% methanol in dichloromethane afforded 0.32 g (30%) of 3-cyanobenzhydrazide.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(N(CC)CC)C>[ClH:31].[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C@H:20]2[C:19]3[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=3[C:17]3[N:16]=[C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][N:36]5[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]5)=[CH:9][CH:10]=4)[N:24]=[CH:23][C:22]=3[CH2:21]2)=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(Cl)cc2)C3)cc1
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Product: Cl
Product: Clc1ccc([C@@H]2Cc3cnc(Nc4ccc(CCN5CCCCC5)cc4)nc3-c3ccccc32)cc1

Procedure:
This was synthesized by using (S)-4-(6-(4-chlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, piperidine and triethylamine as described in general procedure 2 to give a yellow solid. M.p.=261-263° C. 1H NMR 400 MHz (DMSO-d6) δ 9.72 (s, br, 1H), 9.59 (s, 1H), 8.32-8.28 (m, 2H), 7.79 (d, J=8.4 Hz, 2H), 7.50-7.44 (m, 2H), 7.31 (dd, J=1.8, 4.8 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.11-7.08 (m, 3H), 4.42 (t, J=6.2 Hz, 1H), 3.49 (d, J=11.2 Hz, 2H), 3.32-2.84 (m, 8H), 1.79-1.68 (m, 5H), 1.38 (m, 1H). LCMS m/e 495 (M+H).