Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17]I)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C-:19]#[N:20].[Na+].O.Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:19]#[N:20])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: [C-]#N
Reactant: O=c1[nH]c2cc(Br)cc3c2n(c1=O)C(CI)CC3
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Temperature: 40 °C
Yield: 24.4 %

Procedure:
A mixture of 9-bromo-5-iodomethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (Example 36) (632 mg, 1.5 mmol) and sodium cyanide (147 mg, 3 mmol) in DMF (5 mL) was heated at 40° C. for 14.5 h. The mixture was poured into water, acidified by addition of 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with ethyl acetate to 1% acetic acid/ethyl acetate to give 117 mg of the title compound (24%): mp>280° C.; 1H NMR (270 MHz, DMSO-d6) δ12.10 (bs, 1H), 7.23 (s, 1H), 7.16 (s, 1H), 4.97~5.07 (m, 1H), 2.74~3.10 (m, 4H), 2.20 (dm, 1H, J=13.5 Hz), 1.87~2.03 (m, 1H).
Reaction SMILES: C(Cl)(Cl)Cl.[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].C(OC(=O)[NH:18][C:19](=[NH:53])[C:20]1[S:21][C:22]([S:51][CH3:52])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:34]3[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=3[NH:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:24]=1)(C)(C)C>>[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].[C:19]([C:20]1[S:21][C:22]([S:51][CH3:52])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:34]3[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=3[NH:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:24]=1)(=[NH:18])[NH2:53]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCS(C)(=O)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCS(C)(=O)=O)c1
Reaction time: 1 h
Yield: 36 %

Procedure:
A solution of dichloromethane/trifluoroacetic acid (1/1) [1 mL] was added to (imino-{4-[2′-(4-methanesulfonyl-butyrylamino)-6′-methyl-biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester (0.011 g, 0.017 mmol) [example 209, step b] at room temperature and stirred for 1 hour. The reaction mixture was evaporated and purified via reverse-phase HPLC [acetonitrile/water (0.01% TFA)] to give the title compound (0.004 g, 36%) as a solid. 1H-NMR (MeOD): δ 8.29 (s, 1H), 8.04 (md, 1H, J=6.4 Hz), 7.87 (t, 1H, J=2.0 Hz), 7.69 (t, 1H, J=7.6 Hz), 7.54 (md, 1H, J=7.6 Hz), 7.34 (t, 1H, J=7.6 Hz), 7.28 (d, 1H, J=7.2 Hz), 7.18 (d, 1H, J=7.2 Hz), 2.91 (s, 3H), 2.78 (t, 2H, J=7.6 Hz), 2.72 (s, 3H), 2.18 (t, 2H, J=7.6 Hz), 2.07 (s, 3H), 1.74 (m, 2H). ESI-MS (m/z): Calcd. for C24H27N3O5S4: 566.1; found: 566.8.
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[N:46]#[C:47]Br.C(=O)(O)[O-].[Na+]>O>[NH2:46][C:47]1[NH:45][C:44]2[CH:43]=[CH:42][CH:41]=[C:3]([C:4]([NH:6][C:7]3[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=4[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:28])=[O:12])=[CH:9][C:8]=3[O:39][CH3:40])=[O:5])[C:2]=2[N:1]=1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(N)nc12
Reaction time: 2 h
Yield: 26.6 %

Procedure:
To a suspension of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (242 mg) in water (3 ml) was added cyanogen bromide (46 mg) at ambient temperature. The mixture was stirred at the same temperature for 2 hours and then allowed to stand at the same temperature overnight. To the reaction mixture was added saturated aqueous sodium bicarbonate solution and the solution was extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform-methanol=10:1) to give 4-(2-amino-1 H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (67 mg) as a powder.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH2:9][C:10]([NH:12][NH2:13])=[O:11])[S:8][C:4]=2[CH:3]=1.[CH3:16][C:17]1([CH2:24][C:25](O)=O)[C:21](=[O:22])[NH:20][C:19](=[O:23])[NH:18]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>O1CCOCC1.C(Cl)Cl>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH2:9][C:10]3[O:11][C:25]([CH2:24][C:17]4([CH3:16])[NH:18][C:19](=[O:23])[NH:20][C:21]4=[O:22])=[N:13][N:12]=3)[S:8][C:4]=2[CH:3]=1
Reactant: NNC(=O)Cc1nc2ccc(Br)cc2s1
Reactant: CC1(CC(=O)O)NC(=O)NC1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(Cc2nnc(Cc3nc4ccc(Br)cc4s3)o2)NC(=O)NC1=O
Temperature: 90 °C
Reaction time: 6 h
Yield: 54.9 %

Procedure:
To a solution of 2-(6-bromobenzo[d]thiazol-2-yl)acetohydrazide (1.0 g, 3.5 mmol) (prepared as described in WO 2011/074560) in dioxane (10 mL) was added 2-(4-methyl-2,5-dioxoimidazolidin-4-yl)acetic acid (0.80 g, 4.2 mmol), T3P (50% in EtOAc, 5.20 mL, 8.74 mmol) and DIPEA (3.1 mL, 17.5 mmol). The reaction mixture was stirred at 90° C. for 6 h. Additional DIPEA (3.1 mL, 18 mmol) and T3P (50% in EtOAc, 3.1 mL, 1.8 mmol) were added. The reaction mixture was heated at 95° C. for 12 h. The reaction mixture was diluted with DCM, and the organic portion washed with 1.5 M K3PO4, 1.0 M HCl solution and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by ISCO silica gel chromatography eluting with 0-15% MeOH/DCM over 30 min gradient to give racemic material (811 mg, 1.92 mmol, 55.0% yield) as a yellow solid. The enantiomers were separated by preparative chiral SFC (Kromasil 5-Cellucoat 21×250 mm ID, 5 μm, 65 mL/min, 150 bar, 35° C., 25% MeOH/77% CO2) to afford isomer A as Example 23A (Rt=7.8 min, 37% yield), LCMS (method B) Rt=1.6 min, m/z=423.9 (M+H)+; and isomer B as Example 23B (Rt=11.2 min, 35% yield), LCMS (method B) retention time=1.6 min, m/z=423.9 (M+H)+. For Example 23B: 1H NMR (400 MHz, CDCl3) δ 8.26 (br. s., 1H), 8.01 (d, J=1.8 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.60 (dd, J=8.8, 2.0 Hz, 1H), 6.54 (s, 1H), 4.71 (d, J=2.0 Hz, 2H), 3.40-3.21 (m, 2H), 1.59 (s, 3H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[S:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:21][CH:22]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH:29][C@@H:30]([CH2:43][NH2:44])[CH2:31][O:32][C:33]1[C:41]2[NH:40][C:39](=[O:42])[NH:38][C:37]=2[CH:36]=[CH:35][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C)C=O>[OH:29][C@H:30]([CH2:31][O:32][C:33]1[C:41]2[NH:40][C:39](=[O:42])[NH:38][C:37]=2[CH:36]=[CH:35][CH:34]=1)[CH2:43][NH:44][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[S:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:21][CH:22]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(-c4ccccn4)s3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=c1[nH]c2cccc(OC[C@@H](O)CNC3CCN(c4ccc(NS(=O)(=O)c5ccc(-c6ccccn6)s5)cc4)CC3)c2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-Pyridin-2-yl-thiophene-2-sulfonic acid [4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example 227) (0.21 g, 0.5 mmol) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) (0.11 g, 0.5 mmol) were mixed in dimethylformamide (10 mL) and then treated with sodium triacetoxyborohydride, (0.16 g, 0.75 mmol) and acetic acid (0.045 g, 0.75 mmol). After stirring at room temperature under a nitrogen atmosphere for one day the mixture was quenched with 1N NaOH and then poured into a saturated aqueous NaHCO3. The precipitate which formed was collected and purified by preparative thin layer chromatography (16% MeOH/CH2CH2) to give the titled compound as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.25–1.40 (m, 2 H), 1.80–1.90 (m, 2 H), 2.50–2.90 (m, 5 H), 3.53 (brd, J=9.0 Hz, 2 H), 3.85–4.00 (m, 2 H), 4.00–4.10 (m, 1 H), 4.91 (brs, 1 H), 6.56 (d, J=5.7 Hz, 1 H), 6.61 (d, J=5.7 Hz, 1 H), 6.80–6.90 (m, 3 H), 6.96 (d, J=6.6 Hz, 2 H), 7.36 (dd, J=3.3, 1.2 Hz, 1 H), 7.41 (d, J=3.0 Hz, 1 H), 7.75 (d, J=3.0 Hz, 1 H), 7.88 (dd, J=6.0, 1.2 Hz, 1 H), 7.98 (d, J=6.0 Hz, 1 H), 8.54(d, J=3.3 Hz, 1 H), 10.60 (s, 1 H), 10.70 (s, 1 H); MS (ES) m/z: 621.0 (MH+); HRMS Calcd. for C30H33N6O5S2 (MH+): 621.1954. Found: 621.1952.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(Br)c(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-bromo-5-methyl benzoic acid (1.0 g, 0.00465 mole) in dry dichloromethane (10 mL ) was added oxalylchloride (1.22 mL, 0.013 mole) dropwise at 0° C. followed by 1-2 drops of N,N-dimethyl formamide. The reaction mixture was then stirred for 2 hours at room temperature and the solvents were evaporated and the product dried under vacuum to yield 2-bromo-5-methylbenzoyl chloride which was used for the next step. To a precooled solution of 2-bromo-5-methyl benzoyl chloride in toluene (5 mL) was slowly added a pre-cooled solution of triethylphosphite (1.05 mL, 0.00604 mole) in toluene. The reaction was then left at room temperature for overnight. The solvents were then evaporated on a rotovap. The resultant product was diluted with dichloromethane (50 mL), washed with saturated sodium bicarbonate (NaHCO3, 25 mL), and then dried over magnesium sulfate (MgSO4). Filtration and solvent evaporation provided 1.1 g of product. Flash chromatography on silica gel using 0%-5% ethyl acetate/dichloromethane followed by drying of the product under high vacuum afforded 0.900 g of (2-bromo-5-methylbenzoyl)phosphonic acid diethyl ester.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1C=CC=CC=1.C1(C[O:17][C:18]2[CH:19]=[CH:20][C:21]([C@@H:29]([OH:45])[CH2:30][NH:31][CH:32]3[CH2:40][C:39]4[C:34](=[CH:35][C:36]([CH2:43][CH3:44])=[C:37]([CH2:41][CH3:42])[CH:38]=4)[CH2:33]3)=[C:22]3[C:27]=2[NH:26][C:25](=[O:28])[CH:24]=[CH:23]3)C=CC=CC=1.C(C1C=C2C(=CC=1CC)CC(NC[C@@H](C1C=CC(O)=C3C=1C=CC(=O)N3)O)C2)C.[C:75]([OH:78])(=[O:77])[CH3:76]>[Pd]>[C:1]([OH:9])(=[O:8])/[CH:2]=[CH:76]\[C:75]([OH:78])=[O:77].[CH2:41]([C:37]1[CH:38]=[C:39]2[C:34](=[CH:35][C:36]=1[CH2:43][CH3:44])[CH2:33][CH:32]([NH:31][CH2:30][C@@H:29]([C:21]1[CH:20]=[CH:19][C:18]([OH:17])=[C:27]3[C:22]=1[CH:23]=[CH:24][C:25](=[O:28])[NH:26]3)[OH:45])[CH2:40]2)[CH3:42]
Reactant: O=C(O)c1ccccc1
Reactant: CC(=O)O
Reactant: CCc1cc2c(cc1CC)CC(NC[C@H](O)c1ccc(OCc3ccccc3)c3[nH]c(=O)ccc13)C2
Agent: [Pd]
Agent: CCc1cc2c(cc1CC)CC(NC[C@H](O)c1ccc(O)c3[nH]c(=O)ccc13)C2
Product: O=C(O)/C=C\C(=O)O
Temperature: 55 °C

Procedure:
A 1 L hydrogenation vessel is charged with 40 grams of 8-phenylmethloxy-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-1H-quinolin-2-one benzoate and 400 mL of acetic acid. Palladium on charcoal 5% (5.44 g) is added and the reaction mass is hydrogenated for 2-8 hours until complete conversion to 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one. The mixture is filtered over a pad of filter-aid. The filtrate is concentrated at 50-60° C. under vacuum (100 mbar) to a volume of 70-90 mL. This residue is dissolved in 400 mL of ethanol and heated to 50-60° C. A solution of 11.6 g maleic acid in 24 mL ethanol is added and the resulting clear solution is seeded at an internal temperature of 50° C. with a suspension of 350 mg micronised 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one in 20 mL isopropanol. The product is crystallized by slow cooling to 0-5° C. Filtration and washing with 50 mL of ethanol followed by 25 mL of isopropanol provides 65 g crude 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one maleate which is further purified by crystallization from 1.36 L of ethanol. This gives 24.3 g pure 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one maleate as a white crystalline powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].FC(F)(F)S([O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])(=O)=O>>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:16][S:17]([C:20]([F:21])([F:22])[F:23])(=[O:18])=[O:19]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: COc1ccc(O)c(F)c1
Product: COc1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1

Procedure:
The title compound was prepared by reacting 2-fluoro-4-methoxy-phenol (2.8 g, 19.7 mmol) with trifluoromethanesulfonic anhydride (4.31 mL, 7.23 g, 25.6 mmol) according to method B to yield 3.86 g (68%) of a clear yellow oil. 1H NMR (DMSO-d6): δ 3.82 (3H, s), 6.89-6.94 (1H, m), 7.24 (1H, dd, J=12.49 Hz, J=2.98 Hz), 7.61 (1H, t, J=9.09 Hz).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[N:6]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:5]=1)(O)=[O:2].S(Cl)([Cl:26])=O>CN(C)C=O>[Cl:26][C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[N:6]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:5]=1)=[O:2]
Reactant: O=C(O)c1cn(-c2ccnc3ccccc23)c2cc(F)ccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cn(-c2ccnc3ccccc23)c2cc(F)ccc12

Procedure:
20 cm3 of sulphinyl chloride and one drop of dimethylformamide are added at a temperature in the region of 20° C. under an argon atmosphere to 1.39 g (4.53 mmol) of 3-carboxy-6-fluoro-1-(quinol-4-yl)-1H-indole. After stirring at reflux for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give 1.7 g of 3-chlorocarbonyl-6-fluoro-1-(quinol-4-yl)-1H-indole in the form of a cream solid which is used directly in the following step.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2([CH3:16])[CH2:15][O:14][CH2:13]2)[CH:7]=[C:6]([CH3:17])[C:5]=1[C:18]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]2[C:19]=1[CH2:20][CH2:21][C@H:22]2[O:28][C:29]1[CH:42]=[CH:41][C:32]2[C@H:33]([CH2:36][C:37]([O:39]C)=[O:38])[CH2:34][O:35][C:31]=2[CH:30]=1>CO.O.Cl.C(#N)C.O>[CH3:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2([CH3:16])[CH2:13][O:14][CH2:15]2)[CH:7]=[C:6]([CH3:17])[C:5]=1[C:18]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]2[C:19]=1[CH2:20][CH2:21][C@H:22]2[O:28][C:29]1[CH:42]=[CH:41][C:32]2[C@H:33]([CH2:36][C:37]([OH:39])=[O:38])[CH2:34][O:35][C:31]=2[CH:30]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC6(C)COC6)cc5C)ccc(F)c43)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: Cc1cc(OCC2(C)COC2)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1 M aqueous NaOH solution (1.15 mL) is added to a solution of methyl 2-((S)-6-((R)-4-(2,6-dimethyl-4-((3-methyloxetan-3-yl)methoxy)phenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (420 mg) in methanol (12 mL) at room temperature. The mixture is stirred at room temperature for 48 hours. The mixture is diluted with water and neutralized with 1 M aqueous HCl solution (1.15 mL). The resulting mixture is extracted with ethyl acetate, and the combined extract is washed with brine and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 70:30→20:80). The product thus obtained is dissolved in acetonitrile/water (1:1) and lyophilized to give the title compound. Yield: 265 mg; LC (method 4): tR=1.87 min; Mass spectrum (ESI+): m/z=533 [M+H]+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[S:27][C:11]3[N:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:13]=[C:14]([C:17]([O:19]C)=O)[C:15](=[O:16])[C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][C:17]([C:14]2[C:15](=[O:16])[C:10]3[CH:9]=[C:8]([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[S:27][C:11]=3[N:12]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:13]=2)=[O:19])=[CH:31][CH:30]=1
Reactant: COC(=O)c1nn(-c2ccccc2)c2sc(CN3CCOCC3)cc2c1=O
Reactant: NCc1ccc(Cl)cc1
Product: O=C(NCc1ccc(Cl)cc1)c1nn(-c2ccccc2)c2sc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Yield: 65 %

Procedure:
A solution of methyl 6-(4-morpholinylmethyl)-4-oxo-1-phenyl-1,4-dihydrothieno[2,3-c]pyridazine-3-carboxylate (0.29 g) in 4-chlorobenzylamine (2 mL) is heated to 190 ° C. for 30 min. The reaction mixture is cooled to ambient temperature, the solvent is removed in vacuo and Et2O (15 mL) is added to the residue. The resulting precipitate is filtered and rinsed with Et2O to afford 0.24 g (65%) of the title compound as a tan solid. Physical characteristics: m.p. 182-184° C.; 1H NMR (400 MHz, CDCl3) δ 10.56, 7.71, 7.58, 7.42, 7.32, 4.69, 3.71, 3.65, 2.51; IR (diffuse reflectance) 1677, 1587, 1549, 1532, 1508, 1493, 1347, 1297, 1278, 1261, 1115, 1112, 799, 777, 701 cm−1; MS (EI) m/z 494 (M+); HRMS (FAB) m/z 495.1265 (C25H23ClN4O3S+H). Anal. Found: C, 60.18; H, 4.79; N, 11.04.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2(O)[C:13]3([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[NH:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1>S(=O)(=O)(O)O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[NH:12][CH2:11][CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2cccc(Cl)c2)CCCNC12CCCCC2
Agent: O=S(=O)(O)O
Product: Cl
Product: Clc1cccc(C2=CCCNC23CCCCC3)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(3-Chlorophenyl)-5-hydroxy-1-azaspiro[5.5]undecane (2.5 g, prepared as described in Example D) was dissolved in concentrated sulphuric acid (35 ml) and stirred at ambient temperature for 2 hours. The mixture was then poured cautiously onto ice (100 ml) and the resulting white precipitate was collected by filtration and suspended in ethyl acetate (300 ml). 5M Aqueous sodium hydroxide solution (250 ml) was added and the mixture was stirred at ambient temperature for 15 minutes. The aqueous layer was separated and extracted with ethyl acetate (2×200 ml), then the combined organic solutions were washed with water, dried over magnesium sulphate and the solvent removed in vacuo. The resulting oil was dissolved in ether (100 ml), charcoal (1 g) was added, and the mixture was heated under reflux for 5 minutes and hot-filtered. The cooled filtrate was saturated with hydrogen chloride and the resulting solid collected, washed with ether and dried in vacuo at ambient temperature to give 5-(3-chlorophenyl)-1-azaspiro[5.5]undec-4-ene hydrochloride as a white solid. Yield 2.1 g, mp 281°-282° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1C#N.[OH:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([NH:25][NH2:26])=[O:24].ClC1C(C)=C(N[C@H]([C@@H](O)C)C(NNC(=O)C2C=CC=CC=2)=O)C=CC=1[C:37]#[N:38]>CO.CCOC(C)=O>[Cl:1][C:2]1[CH:3]([CH3:18])[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([NH:26][NH:25][C:23](=[O:24])[C:22]2[CH:27]=[CH:28][CH:29]=[C:20]([OH:19])[CH:21]=2)=[O:14])([C:37]#[N:38])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: NNC(=O)c1cccc(O)c1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1C(Cl)=CC=CC1(C#N)N[C@@H](C(=O)NNC(=O)c1cccc(O)c1)[C@@H](C)O

Procedure:
(2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (663 mg, 2.5 mmol) (intermediate 3a) and 3-hydroxy-benzohydrazide (376 mg, 2.5 mmol) were coupled similarly to the procedure used for intermediate 1b. After column chromatography (5% methanol/EtOAc) the title compound was isolated as a white solid (615 mg, 62%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.79 (br s, 1H), 8.81 (br s, 1H), 7.45 (ad, J=8.7 Hz, 1H), 7.38 (m, 2H), 7.27 (t, J=7.87 Hz, 1H), 7.02 (m, 1H), 6.71 (d, J=8.7 Hz, 1H), 5.61 (m, 1H), 4.23 (m, 1H), 4.14 (m, 1H), 2.29 (s, 3H), 1.37 (d, J=6.5 Hz, 3H).
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13]([F:19])=[C:12]([CH2:20][OH:21])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[NH:1]([C:8]1[N:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:10]2[N:11]=[C:12]([CH:20]=[O:21])[C:13]([F:19])=[CH:14][C:15]=2[C:16](=[O:18])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(CO)c(F)cc12
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=Cc1nc2c(cc1F)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 70 °C
Yield: 15.1 %

Procedure:
2-anilino-6-fluoro-7-(hydroxymethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.277 mmol) was dissolved in 4.5 mL CHCl3. MnO2 (311 mg, 3.05 mmol) was added and the reaction was heated to 70° C. under argon for 3 d. The reaction mixture was filtered through celite and concentrated in vacuo. Purification by silica gel flash chromatography eluting with 3:1 to 100:0 EtOAc:Hex provided 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carbaldehyde (15 mg, 15%) as a white solid: LCMS RT: 2.18 min, MH+: 360.2.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[CH:8][CH:9]=2)[N:4]([Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:3]=1.[C:26]([Li])(C)([CH3:28])[CH3:27].C(I)CC>>[C:22]([Si:19]([CH3:21])([CH3:20])[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:6]=2)[C:2]([CH2:27][CH2:26][CH3:28])=[CH:3]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(Br)cn([Si](C)(C)C(C)(C)C)c2c1
Solvent: CCCI
Product: CCCc1cn([Si](C)(C)C(C)(C)C)c2cc(O[Si](C)(C)C(C)(C)C)ccc12

Procedure:
In analogy to the procedure described in example 21 b], 3-bromo-1-(tert-butyl-dimethyl-silanyl)-6-(tert-butyl-dimethyl-silanyloxy)-1H-indole (example 21 a]) was treated with tert-butyllithium and propyl iodide to yield 1-(tert-butyl-dimethyl-silanyl)-6-(tert-butyl-dimethyl-silanyloxy)-3-propyl-1H-indole as red liquid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[F:17][C:18]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:19]=1[CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[CH2:15][CH2:14][C@H:13]([N:24]4[CH2:23][CH2:22][CH:21]([CH2:20][C:19]5[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:18]=5[F:17])[CH2:26][CH2:25]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Fc1ccc(F)c(CC2CCNCC2)c1
Reactant: O=C1CCC(c2ccc3c(c2)OCO3)CC1
Product: Fc1ccc(F)c(CC2CCN([C@H]3CC[C@H](c4ccc5c(c4)OCO5)CC3)CC2)c1

Procedure:
4-(1,3-Benzodioxol-5-yl)cyclohexanone and 4-(2,5-difluorobenzyl)piperidine were reacted as described in example 9 to give the product (31%, mp: 96°-97° C.). Calc'd for C25H29F2NO2 : C, 72.61%; H, 7.07%; N, 3.39%. Found: C, 72.66%; H, 7.07%; N, 3.30%.