Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:6].[N-:12]=[N+:13]=[N-:14].[Na+].[Cl-].[NH4+].Cl>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:14][N:13]=[N:12][N:6]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C#N)cc1Br
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc(-c2nnn[nH]2)cc1Br
Temperature: 90 °C
Yield: 85.9 %

Procedure:
A mixture of 3-bromo-4-methoxybenzonitrile (9 g, 42 mmol), sodium azide (3.03 g, 46.7 mmol) and ammonium chloride (2.5 g, 46.7 mmol) in N,N-dimethylforlmamide (50 ml) was heated at 90° C. for 18 hours. The reaction was cooled, poured onto ice (200 ml) and acidified with 1N HCl to pH1. The resultant solid was filtered, dried and recrystallized from ethanol/water to give 2-bromo-4-(tetrazol-5-yl)anisole (9.2 g). 1H NMR 360 MHz, DMSO-d6) δ 3.95 (3H, s), 7.35 (1H, d, J=8.6 Hz), 8.05 (1H, d, =8.6 Hz), 8.23 (1H, s). To a suspension of sodium hydride (60% dispersed, 1.5 g, 37 mmol) in N,N-dimethylformamide was added the foregoing anisole (5 g, 32.5 mmol) and the reaction stirred at room temperature for 2 hours. The reaction was diluted with water (70 ml) and the resultant solid filtered, dried and chromatographed on silica eluting with 60% ethyl acetate/hexane to give 2-bromo-4-(2-methyltetrazol-5-yl)anisole (3.2 g), 1H NMR (360 MHz, CDCl3) δ 3.97 (3H, s), 4.39 (3H, s), 7.00 (1H, d, J=12.4 Hz), 8.07 (1H, dd, J=12.4 and 3.0 Hz), 8.34 (1H, d, J=3.0 Hz); and 2-bromo-4-(1-methyltetrazol-5-yl)anisole (0.8 g), 1H NMR (360 MHz, CDCl3) δ 3.94 (3H, s), 4.13 (3H, s), 7.01 (1H, d, J=8.6 Hz), 7.66 (1H, dd, J=8.6 and 2.2 Hz), 7.90 (1H, d, J=2.2 Hz).
Reaction SMILES: [C:1]([N:9]1[CH:15]=[CH:14][N:13](C2C=CC=CC=2)[CH:12]=[CH:11][N:10]1[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].O1CCOCC1>[C:1]([N:9]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][N:10]1[C:22](=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)n1ccn(-c2ccccc2)ccn1C(=O)c1ccccc1
Agent: [Pd]
Solvent: C1COCCO1
Product: O=C(c1ccccc1)N1CCNCCN1C(=O)c1ccccc1

Procedure:
A mixture of 1,2-dibenzoyl-5-phenyl-1H-1,2,5-triazepine (25.0 g), dioxane (500 ml), N-hydrochloric acid (250 ml) and 10% Palladium on carbon (1.3 g) was hydrogenated in a Parr apparatus at 16 p.s.i. pressure for 191/2 hours. The catalyst was removed by filtration and washed with water. The filtrate and washings were evaporated to a solid hydrochloride salt which was dried under oil pump vacuum; wt. 22.4 g. The material was assayed by HPLC and shown to be 91% pure. Material prepared in this way was used directly in further syntheses, e.g., in example 8.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([C:15]1[N:16]([CH2:28][CH2:29][CH2:30][CH:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[OH:32])[C:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:27]=1)[CH2:12][CH2:13][CH3:14].C(N(CC)CC)C>ClCCl.C(Cl)(Cl)Cl>[CH2:11]([C:15]1[N:16]([CH2:28][CH2:29][CH2:30][C:31]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:32])[C:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:27]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCC(O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCCc1nc2cnc3ccccc3c2n1CCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.1 %

Procedure:
A solution of DMSO (1.35 g, 17.3 mmol) in dichloromethane (22 mL) was cooled in a dry ice/acetone bath and stirred. Oxalyl chloride (1.61 g, 12.7 mmol) was added dropwise, followed by a solution of 4-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylbutan-1-ol (4.3 g, 11.5 mmol) in dichloromethane (55 mL). After five minutes, triethylamine (3.49 g, 34.5 mmol) was added, and the mixture was allowed to warm to room temperature. After the addition of chloroform (300 mL), the mixture was washed successively with a saturated ammonium chloride solution (100 mL) and a saturated aqueous sodium bicarbonate solution (100 mL), dried over sodium sulfate, filtered, and concentrated to provide 4-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylbutan-1-one (4.15 g) as an off-white solid.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](O)([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=3[OH:25])[C:9]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:28]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=4[O:25][CH2:34]3)[C:9]2=[O:27])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1cc(O)c(C2(O)C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: Cc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4,5-dimethylphenyl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-5,6-dimethylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (54%) as a colorless solid: mp 193-195° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ7.38-7.32 (m, 10H), 7.14-6.92 (m, 4H), 6.75-6.78 (m, 1H), 6.55-6.50 (m, 1H), 6.37-6.31 (m, 1H), 4.99-4.94 (m, 1H), 4.73-4.65 (m, 1H), 2.20 (s, 3H), 2.05 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.9, 159.0, 141.7, 138.4, 137.7, 137.4, 132.8, 129.4, 128.6, 128.4, 128.1, 127.9, 127.8, 126.3, 123.8, 123.0, 112.2, 111.4, 79.7, 58.7, 57.8, 20.3, 19.3; MS (ES+) m/z 432.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:9][CH3:10])[NH:5][C:6]=1[CH2:7][OH:8]>C(Cl)Cl.O1CCOCC1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[N:3]=[C:4]([CH2:9][CH3:10])[NH:5][C:6]=1[CH:7]=[O:8]
Reactant: CCc1nc(Cl)c(CO)[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCc1nc(Cl)c(C=O)[nH]1
Temperature: 25 °C
Yield: 0 %

Procedure:
A solution of (4-chloro-2-ethyl-1H-imidazol-5-yl)methanol (1.60 g, 10.0 mmol) and manganese dioxide (5.5 g, 63.3 mmol) in CH2Cl2 (30 mL) and 1,4-dioxane (15 mL) was heated under reflux for 6.5 h. The reaction mixture was cooled to RT, then filtered through Celite, which was washed thoroughly with CH2Cl2. The filtrate was concentrated and dried to provide the title compound (0.763 mg, 48%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.66 (s, 1H), 2.84 (q, 2H), 1.38 (t, 3 H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][C:8]3[CH:11]4CCN([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)CC4>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[CH2:11][N:9]3[CH2:10][CH2:6][CH:15]([C:7]2=1)[CH2:7][CH2:8]3
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Solvent: CS(C)=O
Product: Brc1cccc2c3c([nH]c12)CN1CCC3CC1

Procedure:
Crude reaction mixture was obtained as described in Example 1B. Analytical HPLC analysis [Phenomenex® Luna® Combi-HTS C8 (2) 5 μm 100 Å (2.1×30 mm), a gradient of 10-100% acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) at a flow rate of 2.0 mL/minute over 3 minutes (0-0.1 minute 10% A, 0.1-2.6 minutes 10-100% A)] identified the product of Example 1B as the major product (retention time 1.77 minutes) and the title compound as the minor product (retention time 1.95 minutes). The crude reaction mixture was dissolved in dimethyl sulfoxide and then was purified by reverse-phase HPLC (Waters XBridge™ C18 5 μm OBD 30×100 mm column, flow rate 40 mL/minute, 20-99% gradient of methanol in water with 0.1% trifluoroacetic acid over 20 minutes) to afford a major fraction containing the product of Example 1B and a minor fraction containing the title compound. The fractions containing the title compound were combined and partitioned between CHCl3/2-propanol (4:1, 2×200 mL) and 1.0 M sodium carbonate (200 mL). The combined organic extracts were dried (sodium sulfate) and concentrated under vacuum to afford the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 1.92-2.13 (m, 4 H), 2.99-3.10 (m, 2 H), 3.19-3.28 (m, 3 H), 4.28 (s, 2 H), 6.88 (t, J=7.8 Hz, 1 H), 7.17 (dd, J=7.6, 0.6 Hz, 1 H), 7.38 (d, J=7.9 Hz, 1 H); MS (APCI) m/z 291/293 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[C:4]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31]C(=O)OC(C)(C)C)[CH2:26]2)=[N:5][C:6]([N:9]2[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[N:22][CH:21]=[C:20]([CH3:24])[N:19]=4)[N:14]=[CH:13][C:12]=3[CH:11]=[N:10]2)=[CH:7][N:8]=1.O1CCOCC1>Cl>[NH2:31][C@H:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:4]2[C:3]([OH:2])=[N:8][CH:7]=[C:6]([N:9]3[C:17]4[CH:16]=[C:15]([C:18]5[CH:23]=[N:22][CH:21]=[C:20]([CH3:24])[N:19]=5)[N:14]=[CH:13][C:12]=4[CH:11]=[N:10]3)[N:5]=2)[CH2:26]1
Reactant: COc1ncc(-n2ncc3cnc(-c4cncc(C)n4)cc32)nc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cnc(O)c(N3CCC[C@H](N)C3)n2)n1
Yield: 27 %

Procedure:
A solution of tert-butyl N-[(3S)-1-[3-methoxy-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-3-piperidyl]carbamate (30 mg, 0.058 mmol) in hydrogen chloride (4 mol/l) in 1,4-dioxane (1.0 ml, 4.0 mmol) and 1,4-dioxane 1.0 mL was stirred at RT 2d. The reaction was concentrated and submitted for reverse phase HPLC to give 223 (7 mg, 27% yield. MS (ESI) m/z: 404.1. 1H NMR (400 MHz, DMSO) δ 9.44 (s, 1H), 9.28 (s, 1H), 9.25 (s, 1H), 8.61 (s, 1H), 8.57 (s, 1H), 7.23 (s, 1H), 4.74 (d, J=11.1 Hz, 1H), 4.44 (d, J=12.8 Hz, 1H), 2.92 (s, 2H), 2.62 (s, 3H), 1.88 (d, J=16.7 Hz, 2H), 1.68 (d, J=11.1 Hz, 1H), 1.39 (d, J=9.5 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29])=[O:24])[C:5]1=[O:32].[N:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][C:27]([CH3:30])([CH3:31])[CH2:28][OH:29])=[O:24])[C:5](=[O:32])[N:4]3[CH2:3][CH2:2][NH:1][C:39]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:40])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: CC(C)(CO)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Reactant: O=C(Cl)N1CCOCC1
Product: CC(C)(CO)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(=O)N2CCOCC2)c1=O

Procedure:
This compound was prepared from 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide and 4-morpholinecarbonyl chloride employing methods similar to those described in Example 450 and was obtained as a white solid: ES+ MS: 556 (M+H+).
Reaction SMILES: [S:1]([CH2:11][N:12]=[C:13]=[O:14])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH:15](=O)[CH2:16][CH3:17].[C-]#N.[Na+].O1CCN=C1>C(O)C>[CH2:16]([CH:17]1[O:14][CH:13]=[N:12][CH:11]1[S:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:3])=[O:2])[CH3:15]
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Reactant: CCC=O
Agent: C1=NCCO1
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: CCC1OC=NC1S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a stirred suspension of tosylmethylisocyanate (TosMIC, 3.90 g, 20 mmol) and propionaldehyde (1.5 mL 20.4 mmol) in 60 mL dry ethanol, finely powdered sodium cyanide (0.098 g, 2 mmol) was added. The reaction mixture became clear and white crystals of oxazoline began to precipitate in 15 min. The reaction was continuously stirred for an additional 30 min, The mixture was filtered and the crystals were washed with ether-hexane (1:1) before drying. Compound 15 was attained in 81% yield (4.1 g). The structure was confirmed by 1H NMR in CDCl3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:19][CH:18]([C:20](OC)=[O:21])[CH2:17]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[BH4-].[Na+].O.[OH-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([S:13]([N:16]2[CH2:19][CH:18]([CH2:20][OH:21])[CH2:17]2)(=[O:14])=[O:15])=[CH:11][CH:12]=1
Reactant: COC(=O)C1CN(S(=O)(=O)c2ccc(-c3ccccn3)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=S(=O)(c1ccc(-c2ccccn2)cc1)N1CC(CO)C1
Yield: 73 %

Procedure:
To a stirred solution of methyl 1-{[4-(pyridin-2-yl)phenyl]sulfonyl}azetidine-3-carboxylate (0.33 g, 0.99 mmol) in anhydrous methanol (20 mL) is added sodium borohydride (0.25 g, 6.58 mmol) portionwise. After 30 mins water (40 mL) is added followed by 5N aqueous NaOH. The aqueous layer is extracted with DCM. The organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure to give 0.22 g (72%) of (1-{[4-(pyridin-2-yl)phenyl]sulfonyl}azetidin-3-yl)methanol. m/z=305 [M++H].
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.CC(C)([O-])C.[K+].[CH:15]1([CH2:18][OH:19])[CH2:17][CH2:16]1.CS(C)=O>O.CCOC(C)=O>[CH:15]1([CH2:18][O:19][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:17][CH2:16]1
Reactant: Nc1cc(Cl)ncn1
Reactant: OCC1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: Nc1cc(OCC2CC2)ncn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
A vial was charged with 6-chloropyrimidin-4-amine (0.200 g, 1.544 mmol), potassium tert-butoxide (0.381 g, 3.40 mmol), cyclopropylmethanol (0.223 g, 3.09 mmol), and dimethyl sulfoxide (3.09 ml). The vial was capped and the reaction was heated to 100° C. After 3 hour, the mixture was diluted with water and EtOAc. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40 g Redi-Sep Gold column, 0-50% of EtOAc/heptane to give 6-(cyclopropylmethoxy)pyrimidin-4-amine (0.189 g, 1.144 mmol, 74.1% yield) as a white solid. In/z (ESI) 166.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[CH3:16][NH2:17]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:17][CH3:16])=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: CN
Product: CNCc1c(C)noc1-c1ccc(Br)cc1

Procedure:
Prepared according to the procedure described in Example 67, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and methylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:11][C:12]1[CH:13]=[C:14]([CH2:20][CH2:21][CH2:22][CH:23]2OCCC[O:24]2)[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)(=[O:10])=[O:9].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:11][C:12]1[CH:13]=[C:14]([CH2:20][CH2:21][CH2:22][CH:23]=[O:24])[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)(=[O:9])=[O:10]
Reactant: COc1cc(CCCC2OCCCO2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CCCC=O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
A solution of 156 mg (0.38 mmol) 2-[3-[3-(2-chlorophenylsulfonyloxy)-5-methoxyphenyl]propyl]-1,3-dioxane, as prepared in the preceding step, in 2 mL of tetrahydrofuran was treated with 4.5 μL of 10% aqueous hydrochloric acid. The reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was diluted with water, extracted into dichloromethane, dried (MgSO4), and purified by flash chromatography (dichloromethane) to give 23.4 mg of the title compound as the minor product of the reaction. 1H-NMR (300 MHz, CDCl3) δ 9.70 (t, 1 H, J=2 Hz), 7.93 (dd, 1 H, J=1.5,8Hz), 7.52-7.9 (m, 2 H), 6.57 (t, 1 H), 6.52 (t, 1 H, J=2 Hz), 6.49 (t, 1 H, J=2 Hz), 3.69 (s, 3 H), 2.52 (t, 2 H, J=7 Hz), 2.33 (dt, 2 H, J=1.5, 7 Hz), 1.80 (pentet, 2 H, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]([CH2:17][O:18][CH3:19])([CH2:14][O:15][CH3:16])[C:11]([OH:13])=O)=[O:8])=[CH:4][CH:3]=1.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C.[CH3:38][N:39]1[CH2:45][CH2:44][C:43]2[CH:46]=[C:47]([NH2:50])[CH:48]=[CH:49][C:42]=2[CH2:41][CH2:40]1>C1COCC1>[CH3:16][O:15][CH2:14][C:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:8])([CH2:17][O:18][CH3:19])[C:11](=[O:13])[NH:50][C:47]1[CH:48]=[CH:49][C:42]2[CH2:41][CH2:40][N:39]([CH3:38])[CH2:45][CH2:44][C:43]=2[CH:46]=1
Reactant: COCC(COC)(NC(=O)c1ccc(Cl)s1)C(=O)O
Reactant: CN1CCc2ccc(N)cc2CC1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: C1CCOC1
Product: COCC(COC)(NC(=O)c1ccc(Cl)s1)C(=O)Nc1ccc2c(c1)CCN(C)CC2
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
0.05 g (0.16 mmol) 2-[(5-chloro-thiophene-2-carbonyl)-amino]-3-methoxy-2-methoxymethyl-propionic acid are dissolved in 1.5 ml THF and at room temperature 0.04 g (0.16 mmol) 2-ethoxy-1-ethoxycarbonyl-1.2-dihydroquinoline (EEDQ) are added. After 30 min, 0.029 g (0.16 mmol) of 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine is added and the mixture is stirred for 12 h at 40° C. Then it is concentrated by evaporation i.vac. And purified by chromatography through RP material (Microsorb C18 Varian; eluant: water/acetonitrile/trifluoroacetic acid=90:10:0.1=>0:100:0.1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH:5]([N+:34]([O-])=O)[CH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[O:14][CH2:15][C:16]([N:18]1[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:20][C@H:19]1[CH3:33])=[O:17])[CH3:2]>C(O)(=O)C.[Zn]>[CH2:1]([O:3][C:4](=[O:37])[CH:5]([NH2:34])[CH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[O:14][CH2:15][C:16]([N:18]1[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:20][C@H:19]1[CH3:33])=[O:17])[CH3:2]
Reactant: CCOC(=O)C(Cc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)C(N)Cc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 60 °C
Yield: 100.3 %

Procedure:
To a solution of 3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-2-nitro-propionic acid ethyl ester (0.035 g, 0.065 mmol) in acetic acid (1 ml) was added zinc dust (0.085 g, 1.3 mmol). After 2 hours of heating at 60° C. the reaction was filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.033 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.[CH3:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[ClH:60]>ClCCl.CO>[ClH:60].[CH3:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]3)=[CH:21][CH:20]=1
Reactant: Cc1ccc(CO)cn1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(O)cc2C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(COc2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)cn1
Temperature: 25 °C

Procedure:
A mixture of N-[(2S)-5-hydroxy-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (700 mg, 2.74 mmol, Description 3) and (6-methyl-3-pyridinyl)methanol (338 mg, 2.74 mmol) in dichloromethane (30 ml) was stirred under argon at room temperature, Triphenylphosphine (719 mg, 2.74 mmol) and diisopropyl azodicarboxylate (0.533 ml, 2.74 mmol) were then successively added. The resulting mixture was stirred at room temperature under argon for 16 hours. The reaction mixture was washed with water, dried over sodium sulphate, filtered and evaporated. The desired product was purified by SCX column eluting with 1 M ammonia in methanol solution and column chromatography on silica using 1 to 99% ethyl acetate in n-pentane to give a white solid. The free base solid was dissolved in methanol and treated with ethereal hydrochloride to give the title compound (554 mg).
Reaction SMILES: [CH2:1]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N12CCN(CC1)CC2.Cl[C:25]1[CH:34]=[C:33]2[C:28]([C:29](=[O:41])[C:30]([C:38]([OH:40])=[O:39])=[CH:31][N:32]2[CH:35]2[CH2:37][CH2:36]2)=[CH:27][C:26]=1[F:42]>CS(C)=O>[CH2:1]([N:10]1[CH2:15][CH2:14][N:13]([C:25]2[CH:34]=[C:33]3[C:28]([C:29](=[O:41])[C:30]([C:38]([OH:40])=[O:39])=[CH:31][N:32]3[CH:35]3[CH2:37][CH2:36]3)=[CH:27][C:26]=2[F:42])[CH2:12][CH2:11]1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: C(=Cc1ccccc1)CN1CCNCC1
Agent: C1CN2CCN1CC2
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCN(CC=Cc4ccccc4)CC3)c(F)cc2c1=O
Yield: 38 %

Procedure:
2.1 g (10 mmol) of 1-cinnamyl-piperazine and 2.2 g of 1,4-diazabicyclo[2.2.2]octane are added to 2.8 g (10 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 35 ml of dimethyl sulphoxide, and the mixture is heated at 140° for 5 hours. It is concentrated under a high vacuum, the residue is stirred with 50 ml of water and the pH is brought to 6 with 2N hydrochloric acid. The precipitate which has separated out is filtered off with suction, washed with water and boiled up with methanol. 1.7 g of 7-(4-cinnamyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 230°-234° (with decomposition) are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1)[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(CC(C)=O)cc1
Temperature: 90 °C
Yield: 100.4 %

Procedure:
1-(4-hydroxyphenyl)propan-2-one (500 mg, 3.33 mmol), ethyl 2-bromoacetate (0.37 mL, 3.34 mmol) and potassium carbonate (575 mg, 4.16 mmol) were dissolved in acetonitrile (7 mL) in a sealed tube under argon atmosphere. The reaction mixture was heated to 90° C. for 3.5 hours. The solids were filtered and washed with additional acetonitrile and the filtrate was concentrated under reduced pressure to give the title compound (790 mg, 100% yield).
Reaction SMILES: B.[CH2:2]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]2[C:20]3[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=3[O:18][CH2:17][C:16]2=O)[CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5].Cl>C1COCC1>[CH2:2]([CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][N:15]2[C:20]3[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=3[O:18][CH2:17][CH2:16]2)[CH2:10][CH2:11]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC1CCN(CCCN2C(=O)COc3ccc(C)cc32)CC1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCCCC1CCN(CCCN2CCOc3ccc(C)cc32)CC1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
A solution of borane in THF (1M, 0.5 mL, 0.5 mmol) was added to a solution of 4-[3-(4-butyl-piperidin-1-yl)-propyl]-6-methyl-4H-benzo[1,4]oxazin-3-one (50 mg, 0.15 mmol) in THF (6 mL). The reaction mixture was stirred at 40° C. for 16 h then aqueous HCl (4M, 10 mL) was added drop wise at room temperature. The reaction mixture was stirred for 16 h then concentrated in vacuo. A solution of K2CO3 (0.5 g) in water (5 mL) was added and the product was extracted with dichloromethane (2×10 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The product was purified on an Isco CombiFlash Sq 16× (4 g silica column, eluting 0-20% ethyl acetate in heptanes+1% Et3N). Yield: 29.2 mg, 56%. HPLC-MS: M+1+=373.5 (UV/MS(%)=95/90). 1H NMR (400 MHz, CDCl3): δ=0.90 (3H, t), 1.18-1.35 (9H, m), 1.68 (2H, broad d), 1.78 (2H, quin.), 1.89 (2H, broad t), 2.24 (3H, s), 2.35 (2H, t), 2.89 (2H, broad d), 3.27 (2H, t), 3.31 (2H, t), 4.19 (2H, t), 6.39 (1H, broad d), 6.52 (1H, broad s), 6.66 (1H, d). 13C NMR (CDCl3): δ 14.3, 21.4, 23.1, 24.2, 29.3, 32.8 (2C), 36.1, 36.6, 47.4, 49.3, 54.5 (2C), 56.5, 64.7, 113.0, 116.2, 117.7, 131.1, 135.3, 142.0.