Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:9]=[CH:8][C:7]=1[NH2:19])[CH3:2].[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)[CH:9]=[CH:8][C:7]=1[NH:19][C:21](=[O:23])[CH3:22])[CH3:2]
Reactant: CCOC(=O)Cc1cc(N2CCN(C)CC2)ccc1N
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1cc(N2CCN(C)CC2)ccc1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [2-Amino-5-(4-methyl-piperazin-1-yl)-phenyl]-acetic acid ethyl ester (438 mg, 1.58 mmol) in CHCl3 (8.0 mL) is added acetic acid anhydride (322 mg, 3.16 mmol) and triethyl amine (240 mg, 2.37 mmol) under argon. The resulting reaction mixture is stirred for 1 h at RT and 1 h at reflux. The reaction mixture is partitioned between CH2Cl2 (25 mL) and water (20 mL) and the layers are separated. The aqueous phase is extracted with CH2Cl2 (2×25 mL) and the combined organic layers are washed with water (2×25 mL), brine (25 mL), dried over Na2SO4 and concentrated at reduced pressure to afford a pale red solid. ES+-MS: 320 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][S-:10].[Na+]>CN(C=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:10][CH3:9])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.1 %

Procedure:
To a solution of 2,5-Dibromo-pyridine (6 g, 25.327 mmol) in DMF (60 mL) is added sodium thiomethoxide (1.95 g, 27.86 mmol) at 0° C. Reaction mixture is allowed to come to room temperature and resulting reaction mixture is stirred at room temperature for 12 h. Reaction mixture is quenched with water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, concentrated and purified by column chromatography using silica (100-200) mesh size and using 4% ethyl acetate in hexane as an eluent to get (4.5 g) of yellow solid title compound. 1H-NMR (400 MHz, DMSO) δ: 2.49 (s, 3H), 7.29 (d, 1H, J=8.76 Hz), 7.85-7.88 (dd, 1H, J1=2.44 Hz, J2=8.48 Hz), 8.55 (d, 1H, J=2.4 Hz). LC-MS (m/z): M+H=206.1.
Reaction SMILES: C(OC(O[CH2:8][CH3:9])CBr)C.COCCOC.C(=O)([O-])O.[Na+].[N:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[N:22]=1>Br.O>[N:21]1[N:22]2[CH:9]=[CH:8][N:27]=[C:23]2[N:24]=[CH:25][CH:26]=1
Reactant: Nc1nccnn1
Reactant: CCOC(CBr)OCC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: c1cnn2ccnc2n1
Temperature: 80 °C
Reaction time: 20 h
Yield: 4.7 %

Procedure:
A stirred mixture of bromoacetaldehyde diethyl acetal (8.88 ml, 57.24 mmol) in concentrated hydrobromic acid (1.7 ml) and water (1.7 ml) was heated at reflux for 20 min, then poured into 1,2-dimethoxyethane (12.5 ml). The solution was neutralised to pH 7 with solid sodium hydrogencarbonate, then filtered. To the filtrate was added [1,2,4]triazin-3-ylamine (5.00 g, 52.03 mmol) and neutralised again with solid sodium hydrogencarbonate. The mixture was stirred at 80° C. for 20 h. After allowing to cool, silica gel was added to the mixture, the solvent was removed in vacuo and the residue was purified by chromatography (silica gel 5% MeOH/CH2Cl2) to give 0.292 g (5%) of the title compound: 1H NMR (360 MHz, DMSO-d6) δ 8.01 (1H, d, J 1.4 Hz), 8.38 (1H, d, J 1.4 Hz), 8.59 (1H, d, J 2.1 Hz), 8.68 (1H, d, J 1.8 Hz); MS (ES+) m/z 121 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10]Cl)=[CH:4][CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: O=C(CCl)Nc1ccc(Br)cc1
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: O=C(CN1CCCC1)Nc1ccc(Br)cc1
Reaction time: 8 h

Procedure:
N-(4-Bromo-phenyl)-2-chloro-acetamide (0.3 g, 1.21 mmol) was dissolved in anhydrous toluene (10 ml). Pyrrolidine (0.3 ml, 3.63 mmol) was added dropwise to the mixture, which was then heated to reflux and stirred overnight. The toluene was removed under reduced pressure and the residue was dissolved in ethyl acetate. Saturated ammonium chloride was added and the aqueous layer was extracted twice with ethyl acetate. The organics were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Yield 0.22 g, 65%. LCMS method: 2, RT: 2.62 min; MI: 283-285 [M+1].
Reaction SMILES: [C:1]1([CH:7]([O:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:8]2[CH2:13][NH:12][C:11](=O)[CH2:10][O:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[C:1]1([C@H:7]([O:15][C:16]2[C:17]([C:26]3[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)[C@H:8]2[O:9][CH2:10][CH2:11][NH:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C1COC(C(Oc2cccnc2)c2ccccc2)CN1
Product: Cc1ccc(-c2ncccc2O[C@@H](c2ccccc2)[C@@H]2CNCCO2)cc1

Procedure:
(S)-2-[(S)-Phenyl-(2-p-tolyl-pyridin-3-yloxy)-methyl]-morpholine was synthesized from the corresponding amide (6-[Phenyl-(pyridin-3-yloxy)-methyl]-morpholin-3-one) using General Procedure B (employing 4-methylphenylboronic acid in the coupling step) and gave 0.20 g of light brown oil. Two chromatographies of the reaction product on silica gel (eluent—3:1 ethyl acetate/methanol) gave 0.080 g (35%) of the desired product. 1H NMR (400 MHz, CDCl3) δ8.24 (m, 1H), 7.96 (d, 2H), 7.27 (m, 7H), 7.07 (m, 1H), 6.98 (m, 1H), 5.13 (d, 1H), 3.96 (m, 1H), 3.87 (m, 1H), 3.64 (m, 1H), 2.80 (m, 2H), 2.53 (m, 2H), 2.44 (s, 3H). (MS) m/z 361.07 [C23H24N2O2+H+].
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:4]=[N:3][CH:2]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[C:5]([C:7]2[CH:14]=[CH:13][C:10](/[CH:11]=[CH:23]/[CH:24]=[O:25])=[CH:9][CH:8]=2)[CH:4]=[N:3][CH:2]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-c2cncnc2)cc1
Product: O=C/C=C/c1ccc(-c2cncnc2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(5-pyrimidinyl)-benzaldehyde (prepared as described in WO 9828264) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 211 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][C:8]2=[O:17])[CH2:3][CH2:2]1.Cl[C:19]1[CH:35]=[CH:34][C:22]([C:23]([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=[O:28])=[O:24])=[CH:21][C:20]=1[N+:36]([O-:38])=[O:37]>>[N+:36]([C:20]1[CH:21]=[C:22]([C:23]([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=[O:28])=[O:24])[CH:34]=[CH:35][C:19]=1[N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][C:8]2=[O:17])[CH2:3][CH2:2]1)([O-:38])=[O:37]
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C1CCc2ccccc2N1C1CCNCC1
Product: O=C(O)c1ccccc1C(=O)c1ccc(N2CCC(N3C(=O)CCc4ccccc43)CC2)c([N+](=O)[O-])c1

Procedure:
The product was prepared from 1-piperidin-4-yl-3,4-dihydroquinolin-2(1H)-one (Chem. Pharm. Bull. (1996), 44(4), 725-33) (0.45 g) and 2-(4-chloro-3-nitrobenzoyl)benzoic acid (0.6 g) using the method of example 1. Used crude.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:22])[C:7]=1[C:8]1[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:10][C:11]([NH2:15])=[C:12]([NH2:14])[CH:13]=1.C(N(CC)CC)C.C1C[O:33][CH2:32]C1>>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:22])[C:7]=1[C:8]1[CH:13]=[C:12]2[NH:14][C:32](=[O:33])[NH:15][C:11]2=[N:10][C:9]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cc(-c2c(F)cncc2F)c(-c2cccnc2)nc1N
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]c2cc(-c3c(F)cncc3F)c(-c3cccnc3)nc2[nH]1
Reaction time: 72 h
Yield: 59 %

Procedure:
A solution of 3″,5″-difluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 14, 0.045 g, 0.15 mmol), N,N′-carbonyldiimidazole (0.1 g, 0.6 mmol) and triethylamine (0.084 mL, 0.6 mmol) in THF (1.5 mL) was heated at 80° C. in a sealed tube. After 72 hours, the mixture was cooled and the solid was separated, washed with THF and dried to give the title compound (0.029 g, 59% of yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10](COC)[C:9]([NH:14][CH2:15][CH3:16])=[N:8][C:5]2=[N:6][CH:7]=1.[CH3:17][C:18]1[N:27]=[C:26]([N:28]2[CH2:34][C:33]3[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:32]=3[O:31][CH2:30][CH2:29]2)[C:25]2[CH2:24][C:23]([CH3:43])([CH3:42])[CH2:22][CH2:21][C:20]=2[N:19]=1>>[CH2:15]([NH:14][C:9]1[NH:10][C:4]2[C:5]([N:8]=1)=[N:6][CH:7]=[C:2]([C:36]1[CH:37]=[CH:38][C:32]3[O:31][CH2:30][CH2:29][N:28]([C:26]4[C:25]5[CH2:24][C:23]([CH3:42])([CH3:43])[CH2:22][CH2:21][C:20]=5[N:19]=[C:18]([CH3:17])[N:27]=4)[CH2:34][C:33]=3[CH:35]=1)[CH:3]=2)[CH3:16]
Reactant: Cc1nc2c(c(N3CCOc4ccc(B(O)O)cc4C3)n1)CC(C)(C)CC2
Reactant: CCNc1nc2ncc(Br)cc2n1COC
Product: CCNc1nc2ncc(-c3ccc4c(c3)CN(c3nc(C)nc5c3CC(C)(C)CC5)CCO4)cc2[nH]1

Procedure:
Prepared according to the method of example 5 by using 6-bromo-N-ethyl-1-[(methyloxy)methyl]-1H-imidazo[4,5-b]pyridin-2-amine (reagent preparation 36) and [4-(2,6,6-trimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1 followed by MOM deprotection. 1H NMR (400 MHz, methanol-d4): 8.15 (d, 1H), 7.64 (d, 1H), 7.55 (d, 1H), 7.43 (dd, 1H), 7.06 (d, 1H), 4.71 (s, 2H), 4.31 (m, 2H), 3.99 (m, 2H), 3.46 (q, 2H), 2.75 (t, 2H), 2.47 (s, 2H), 2.41 (s, 3H), 1.66 (t, 2H), 1.30 (t, 3H), 0.91 (s, 6H); MS (EI) for C27H30N6O: 455 (MH+).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:19][C:20]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:21]=1[CH:22]=O>>[Cl:19][C:20]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:21]=1[CH:22]=[CH:15][C:14]([C:12]1[S:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)=[O:16]
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Product: O=C(C=Cc1ccc(O)cc1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
3-(2-Chloro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl) phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)ethanone and 2-chloro-4-hydroxybenzaldehyde according to general procedure B. The evaporation residue is purified by silica-gel chromatography.
Reaction SMILES: [Na].[C:2]([O:9][CH3:10])(=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Br:11][C:12]([CH2:14]Br)=[CH2:13]>CO>[CH3:7][O:6][C:4](=[O:5])[CH:3]([CH2:14][C:12]([Br:11])=[CH2:13])[C:2]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)CC(=O)OC
Reactant: C=C(Br)CBr
Agent: [Na]
Solvent: CO
Product: C=C(Br)CC(C(=O)OC)C(=O)OC
Reaction time: 0.75 h
Yield: 66.1 %

Procedure:
To a flask under nitrogen was added MeOH (67 mL), and sodium metal (1.15 g, 0.05 g atom) was added in portions over 30 min. To the resulting solution dimethyl malonate (13.2 g, 0.1 mol) in MeOH (10 mL) was added from a dropping funnel over 30 min. The solution was cooled to 0°, and 2,3-dibromopropene (12 g, 0.05 mol) in MeOH (15 mL) was added over 40 min. After a further 45 min at 0°, the pH of the mixture was neutral to litmus paper. The reaction medium was then concentrated under reduced pressure and the residue was dissolved in EtOAc (100 mL) and the resulting solution washed with distilled H2O (100 mL). The aqueous phase was re-extracted with Et2O (100 mL) and the combined organic phases were washed with brine, dried (MgSO4), concentrated under reduced pressure and purified by distillation (82°-84°/1 Torr) to give the title compound as a colorless liquid (8.3 g, 66% yield): 1H NMR (400 MHz, CDCl3) δ5.69 (m, 1H, olefinic), 5.48 (d, J=1.9 Hz, 1H, olefinic), 3.81 (t, J=7.63 Hz, 1H), 3.75 (s, 6H), 3.02 (dd, J=0.95, 7.63 Hz, 2H); 13CNMR (100 MHz, CDCl3) δ8 168.30, 129.18, 119.68, 52.59, 50.28, 40.36.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6](=[O:8])[C:5]2[NH:9][CH:10]=[CH:11][C:4]=2[S:3]1(=[O:13])=[O:12].Br[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][N:9]1[C:5]2[C:6](=[O:8])[CH2:7][N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]=2[CH:11]=[CH:10]1
Reactant: ClCCCCBr
Reactant: CN1CC(=O)c2[nH]ccc2S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN1CC(=O)c2c(ccn2CCCCCl)S1(=O)=O
Yield: 100.1 %

Procedure:
A suspension of 400 mg (2 mmol) of Compound 12, 1.37 g (8 mmol) of 1-bromo-4-chlorobutane and 1.11 g (8 mmol) of potassium carbonate in 20 ml of 2-butanone was refluxed for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: ethyl acetate/hexane=1/2), whereby 582 mg of the title compound were obtained (yield: 100%).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2OC(=O)[S:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:16]>>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[N:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1oc(/C=C/c2ccccc2)ns1
Reactant: CCOC(=O)C#N
Product: CCOC(=O)c1nc(/C=C/c2ccccc2)ns1
Yield: 65.9 %

Procedure:
5-[(E)-2-Phenylethenyl]-1,3,4-oxathiazol-2-one (1.4 g, 7.0 mmol) was mixed with ethyl cyanoformate (2.4 g, 25 mmol) in xylenes, and heated to reflux for 3 h. The reaction mixture was concentrated in vacuo, and the resulting material was recrystallized from ethyl acetate-ethanol (1:1) to give ethyl 3-[(E)-2-phenylethenyl]-1,2,4-thiadiazole-5-carboxylate (1.2 g, 66% yield) as a light yellow solid. M.p. 79–80° C. 1H NMR (CDCl3, 300 MHz) δ 7.98 (d, J=16 Hz, 1H), 7.61 (m, 2H), 7.40 (m, 3H), 7.29 (d, J=11 Hz, 1H), 4.56 (q, J=7 Hz, 2H), 1.50 (t, J=7 Hz, 3H). MS (EI ionization) 259 (M+−H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([NH2:19])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1.C([O:23][C:24](=O)[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:34]Br)C.C(N(CC)CC)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:14])[F:15])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1)[N:19]1[CH2:34][C:26]2[C:25](=[C:30]([N+:31]([O-:33])=[O:32])[CH:29]=[CH:28][CH:27]=2)[C:24]1=[O:23]
Reactant: CCOC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: CCOc1cc(C(N)CC(=O)OC)ccc1OC(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C(CC(=O)OC)N2Cc3cccc([N+](=O)[O-])c3C2=O)ccc1OC(F)F
Yield: 80.8 %

Procedure:
3-(4-Difluoromethoxy-3-ethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester was prepared by the procedure of example 11 from 3-amino-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid methyl ester (7.3 g, 0.025 mol), 2-bromomethyl-6-nitro-benzoic acid ethyl ester (7.6 g, 0.028 mol) and triethyl amine (7 ml, 0.05 mol) in DMF (50 ml) to provide 3-(4-difluoromethoxy-3-ethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester as yellow oil (9.1 g, 81% yield). 1HNMR (CDCl3): δ 1.42 (t, J=7.5 Hz, 3H, OCH2CH3), 3.09 (dd, J=6.8, 15 Hz, 2H, CH2CO), 3.29 (dd, J=6.8, 15 Hz, 1H, CH2CO), 3.65 (s, 3H, OCH3), 4.10 (q, J=7.5 Hz, 2H, OCH2CH3), 4.26 (d, J=17 Hz, 2H, CH2N), 4.46 (d, J=17 Hz, 2H, CH2N), 5.80-5.86 (m, 1H, CHN), 6.55 (t, JH-F=75 Hz, 1H, OCF2H), 6.92 (dd, J=1.8, 8.2 Hz, 1H, Ar), 7.06 (d, J=1.8 Hz, 1H, Ar), 7.14 (d, J=8.25, 1H, Ar), 7.58-7.76 (m, 3H, Ar).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][O:5][CH2:6][C:7](O)=[O:8].C1(N=C=NC2CCCCC2)CCCCC1>CO>[O:8]=[C:7]1[CH2:6][O:5][CH2:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=2[NH:1]1
Reactant: Nc1ccccc1COCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Product: O=C1COCc2ccccc2N1

Procedure:
1 g o-amino-benzyloxy acetic acid and 1.1 g dicyclohexyl carbodiimide were stirred in 15 ml refluxing methanol for 8 hours. The mixture was evaporated, and the residue was stirred with 50 ml acetone and filtered, whereafter the filtrate was evaporated to give the title compound. M.p. 160°-165° C.
Reaction SMILES: C[O-].[Na+].[N:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=O)=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[CH3:27][NH2:28]>CO.C(O)C>[CH3:27][NH:28][C:20]([C:19]1[CH:18]=[CH:17][C:16]([N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:8]=[CH:9][N:4]=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)=[CH:26][CH:25]=1)=[O:22]
Reactant: CCOC(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: CN
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CNC(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A 2M solution of sodium methoxide in methanol (0.89 ml) was added to a suspension of ethyl 4-[4-(4-pyridyl)-1-piperazinyl]benzoate (500 mg) in a 33% solution of monomethylamine in ethanol (15 ml). The mixture was stirred at 40° C. for 18 hours. The mixture was cooled and the solid was collected by filtration. The solid was washed with ethanol and ether to give 1-(4-methylcarbamoylphenyl)-4-(4-pyridyl) piperazine (374 mg) as a cream solid, mp 239-242° C.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([C:13]2([Cl:16])[CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.[H][H]>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([C:13]2([Cl:16])[CH2:15][CH2:14]2)=[O:12])=[CH:7][CH:8]=1
Reactant: O=C(C=Cc1ccc(Cl)cc1)C1(Cl)CC1
Reactant: [H][H]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C(CCc1ccc(Cl)cc1)C1(Cl)CC1
Temperature: 50 °C
Yield: 90.5 %

Procedure:
460 mg (0.5 mmol) of tris-triphenylphosphinerodium chloride (=1 mol %, with respect to the reaction component) are added to a 100 ml autoclave. After purging with nitrogen, an air-free solution of 12 g (0.05 mol) of 1-chlorocyclopropyl 4-chlorophenyl-ethenyl ketone in 40 ml of toluene is added and the mixture is heated to 50° C. under a hydrogen pressure of 30 bar. The hydrogen pressure is held between 40 and 50 bar until gas uptake has ended (after about 1 hour). The mixture is then allowed to react for a further hour. For working up, the solvent is stripped off under reduced pressure and the remaining residue is purified on silica gel using dichloromethane as eluant. 11 g (90% of theory) of 1-chlorocyclopropyl 4-chlorophenylethyl ketone are obtained in the form of an oily product.
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:6]([Cl:29])=[CH:7][C:8]([NH:22][CH2:23][C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)=[C:9]([CH:21]=1)[C:10]([O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[O:11])(=[O:4])=[O:3].[OH-].[Na+]>C(O)C>[NH2:1][S:2]([C:5]1[C:6]([Cl:29])=[CH:7][C:8]([NH:22][CH2:23][C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)=[C:9]([CH:21]=1)[C:10]([O:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:11])(=[O:3])=[O:4]
Reactant: CCOC(=O)CCCOC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NS(=O)(=O)c1cc(C(=O)OCCCC(=O)O)c(NCc2ccco2)cc1Cl

Procedure:
A mixture of ethyl 4-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)butanoate (300) (0.060 mole) in ethanol (100 mL) is cooled in an ice water bath. A solution of 1.0 N sodium hydroxide (60 mL) is added dropwise with stirring, and the reaction is stirred for 12 hours at ambient temperature. The volatiles is removed by spin evaporation in vacuo. The residue is dissolved in cold water, and the solution is washed with diethyl ether. The aqueous solution is cooled in an ice bath and acidified by dropwise addition of 1.0 N hydrochloric acid solution (60 mL). The resulting solid may be collected and recrystallized to give 4-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)butanoic acid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]([CH2:24][OH:25])[CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)(=O)=O)=CC=1.C([Li])CCC>O1CCCC1>[Br:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][CH:13]2[CH2:12][O:25][CH2:24]2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(CO)CCOc2ccc(Br)cc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1ccc(OCCC2COC2)cc1
Yield: 37.4 %

Procedure:
To a solution of 4-(4-bromophenoxy)-2-(hydroxymethyl)butyl 4-methylbenzenesulfonate (0.450 g, 1.04 mmol) in anhydrous tetrahydrofuran (10 mL) was added n-butyl lithium (0.42 mL, 2.5 M, 1.04 mmol) dropwise at 0° C. After complete addition of the n-butyl lithium solution, the resulting mixture was heated at reflux overnight. The reaction was carefully quenched with water and extracted with ethyl acetate (5×20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (0-20% ethyl acetate/petroleum ether) to afford the title compound (0.10 g, 37%) as a white solid. 1H NMR (400 MHz, CDCl3) ppm 7.37 (d, 2 H), 6.74 (d, 2 H), 4.89-4.78 (m, 2 H), 4.56-4.45 (m, 2 H), 3.94-3.87 (m, 2 H), 3.30-3.17 (m, 1 H), 2.23-2.12 (m, 2 H)
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C@:17]([CH3:23])([CH:20]([CH3:22])[CH3:21])[CH2:18][OH:19]>>[OH:19][CH2:18][C@@:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:23])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)[C@@](C)(N)CO
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Product: CC(C)[C@](C)(CO)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and (2R)-2-amino-2,3-dimethyl-1-butanol (CAN 155158-75-1) as starting materials and isolated (19 mg, 19%) as colorless oil; LC-MS (UV peak area, m/z) 98.6%, 327.1464 (MH+).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:20]=[CH:19][C:12]3[C:13](=[O:18])[NH:14][CH2:15][CH2:16][CH2:17][C:11]=3[CH:10]=2)O1.[NH2:22][C:23]1[N:24]=[CH:25][C:26]([C:30]2[CH:35]=[CH:34][C:33]([S:36]([N:39]([CH2:41][CH3:42])[CH3:40])(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[N:27][C:28]=1Br>>[NH2:22][C:23]1[N:24]=[CH:25][C:26]([C:30]2[CH:35]=[CH:34][C:33]([S:36]([N:39]([CH2:41][CH3:42])[CH3:40])(=[O:37])=[O:38])=[CH:32][CH:31]=2)=[N:27][C:28]=1[C:9]1[CH:20]=[CH:19][C:12]2[C:13](=[O:18])[NH:14][CH2:15][CH2:16][CH2:17][C:11]=2[CH:10]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CCCNC3=O)OC1(C)C
Reactant: CCN(C)S(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Product: CCN(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc4c(c3)CCCNC4=O)n2)cc1
Yield: 25.2 %

Procedure:
General method C was applied to 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (95 mg, 0.33 mmol) and 4-(5-amino-6-bromopyrazin-2-yl)-N-ethyl-N-methylbenzenesulfonamide (108 mg, 0.29 mmol) to provide 4-(5-amino-6-(1-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl)pyrazin-2-yl)-N-ethyl-N-methylbenzenesulfonamide (33 mg, 22% yield) after purification by preparatory HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (s, 1H), 8.22 (d, J=8.5 Hz, 2H), 8.12 (t, J=5.8 Hz, 1H), 7.80 (d, J=8.5 Hz, 2H), 7.71 (dd, J=8.0, 1.5 Hz, 1H), 7.62-7.66 (m, 2H), 6.66 (br. s, 2 H), 2.93-3.09 (m, 4H), 2.83 (t, J=1.0 Hz, 2H), 2.67 (s, 3H), 1.94 (dd, J=12.3, 6.0 Hz, 2H), 1.03 (t, J=7.2 Hz, 3H); MS (EI) m/z=452.5 [M+1]+.