Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[Na+].[F:6][C:7]([F:32])([F:31])[CH2:8][O:9][C:10]1[C:11]([OH:30])=[CH:12][C:13]2[C:14](=O)[CH2:15][C@@H:16]3[C@@H:25]([C:26]=2[CH:27]=1)[CH2:24][CH2:23][C@@:21]1([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]1[OH:28].Cl.[NH2:34][OH:35]>CO.O>[F:6][C:7]([F:32])([F:31])[CH2:8][O:9][C:10]1[C:11]([OH:30])=[CH:12][C:13]2[C:14](=[N:34][OH:35])[CH2:15][C@@H:16]3[C@@H:25]([C:26]=2[CH:27]=1)[CH2:24][CH2:23][C@@:21]1([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]1[OH:28]
Reactant: NO
Reactant: C[C@]12CC[C@@H]3c4cc(OCC(F)(F)F)c(O)cc4C(=O)C[C@H]3[C@@H]1CC[C@@H]2O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@@H]3c4cc(OCC(F)(F)F)c(O)cc4C(=NO)C[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 90 °C
Reaction time: 6 h
Yield: 62.6 %

Procedure:
Sodium acetate (2.86 g, 35 mmol) was added to a stirred solution of 6-oxo derivative (9) (0.45 g, 1.2 mmol) in methanol (55 mL). Hydroxylamine hydrochloride salt (2.2 g, 32 mmol) in water (3 mL) was then added at room temperature. The resulting mixture was stirred at 90° C. for 6 h. Then solvent was removed under reduced pressure, the resulting residue was diluted with water (60 mL), and product was extracted into ethyl acetate (3×120 mL). The combined organic layer was washed with water (70 mL), brine (70 mL), and dried over anhydrous sodium sulfate. The organic layer on evaporation under reduced pressure provided the crude product, which on crystallization from ethyl acetate-hexane mixture gave oxime (12) (0.3 g, 65%): mp 187-191° C.; IR (KBr) 3330, 2960-2860, 1500, 880, 750 cm-1 ; 1H NMR (CDCl3 +DMSO-d6 +D2O) δ 0.77 (s, 3 H), 1.10-2.38 (m, 11 H), 2.67 (s, 2 H), 3.05-3.27 (m, 2 H), 3.72 (t, J=8.5 Hz, 1 H), 4.50 (q, J=8.5 Hz, 2 H), 6.88 (s, 1 H), 7.57 (s, 1 H) 10.20 (s, 1 H). Anal. (C20H24NF3O4) C, H.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=2)[N:5]2[CH:21]=[CH:22][N:23]=[C:4]2[CH:3]=1.[CH3:24][C:25]1[S:26][C:27]([Sn](C)(C)C)=[CH:28][N:29]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:24][C:25]1[S:26][C:27]([C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[N:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=3)[N:5]3[CH:21]=[CH:22][N:23]=[C:4]3[CH:3]=2)=[CH:28][N:29]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2nc(Cl)cc3nccn23)cn1
Reactant: Cc1ncc([Sn](C)(C)C)s1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ncc(-c2cc3nccn3c(-c3cnn(COCC[Si](C)(C)C)c3)n2)s1
Temperature: 100 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A flask charged with 7-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation G; 0.200 g, 0.572 mmol) and 2-methyl-5-(trimethylstannyl)thiazole (0.165 g, 0.629 mmol) was evacuated and backfilled with argon before 4 mL of dioxane were added and argon was bubbled through for 5 minutes. Tris(dibenzylideneacetone)dipalladium (0.0523 g, 0.0572 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.0545 g, 0.114 mmol) were added, argon was bubbled through the reaction for 10 minutes. The reaction flask was sealed and heated to 100° C. with stirring for 2 hours. The reaction mixture was loaded directly onto a silica gel column pre-wetted and eluted with a gradient of 25-100% ethyl acetate with 1% ammonium hydroxide to afford 2-methyl-5-(5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-7-yl)thiazole (0.196 g, 0.475 mmol, 83.1% yield). MS (apci) m/z=413.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C:14]3[CH:22]=[C:21]4[C:17]([C:18]([C:23]5[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=5)=[CH:19][NH:20]4)=[CH:16][CH:15]=3)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:18]2[C:17]3[C:21](=[CH:22][C:14]([NH:13][C:11]([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:2]([CH3:1])[CH:3]=[CH:4]5)=[O:12])=[CH:15][CH:16]=3)[NH:20][CH:19]=2)=[CH:28][CH:27]=1
Reactant: Cn1ccc2cc(C(=O)Nc3ccc4c(-c5ccc([N+](=O)[O-])cc5)c[nH]c4c3)ccc21
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cn1ccc2cc(C(=O)Nc3ccc4c(-c5ccc(N)cc5)c[nH]c4c3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a slurry of 1-methyl-N-(3-(4-nitrophenyl)-1H-indol-6-yl)-1H-indole-5-carboxamide (59.0 mg, 0.14 mmol) in ethanol (1.50 mL) under an atmosphere of nitrogen was added 20 wt % palladium hydroxide on carbon (5.9 mg, 10 wt %), followed by a balloon of hydrogen. The reaction was stirred overnight at room temperature and was then filtered through a pad of Celite, rinsing with excess methanol and methylene chloride. The filtrate was concentrated to give a grey-pink solid for N-(3-(4-aminophenyl)-1H-indol-6-yl)-1-methyl-1H-indole-5-carboxamide (56.9 mg, 0.14 mmol, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[N+:18]([O-])([OH:20])=[O:19]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[C:5]([OH:17])=[C:6]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc(-c2cc(Cl)ccc2O)n1
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cccc(-c2cc(Cl)cc([N+](=O)[O-])c2O)n1

Procedure:
To the solution of 6-(5-chloro-2-hydroxyphenyl)-pyridine-2-carboxylic acid; (2.3 g, 10.1 mmol) in 100 ml acetic acid; was added 1 ml fuming nitric acid; and stirred at 35° C. to 40° C. for half an hour. The reaction mixture was diluted with water and adjusted pH to 2.5. The resulting precipitation was collected, washed and dried to give solid (2.74 g; 78%, three steps). MS (ES) m/z 295 [M+H].
Reaction SMILES: C(OP([CH:9]([F:11])[F:10])(=O)OCC)C.C([N-]C(C)C)(C)C.[Li+].[CH3:20][O:21][C:22]1[CH:40]=[CH:39][C:38]2[C@@H:37]3[C@H:27]([C@H:28]4[C@@:32]([CH2:35][CH2:36]3)([CH2:33][CH3:34])[C:31](=O)[CH2:30][CH2:29]4)[CH2:26][CH2:25][C:24]=2[CH:23]=1>O1CCCC1.C(OCC)(=O)C>[F:11][C:9]([F:10])=[C:31]1[CH2:30][CH2:29][C@H:28]2[C@H:27]3[C@H:37]([CH2:36][CH2:35][C@:32]12[CH2:33][CH3:34])[C:38]1[CH:39]=[CH:40][C:22]([O:21][CH3:20])=[CH:23][C:24]=1[CH2:25][CH2:26]3
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: CCOP(=O)(OCC)C(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CCC2=C(F)F
Reaction time: 1 h
Yield: 80.8 %

Procedure:
A solution of 9.4 g of diethyl-(difluoromethyl)-phosphonate in 150 ml of tetrahydrofuran is slowly mixed with 25 ml of 2 M lithium diisopropylamide solution at a bath temperature of -50° C., and it is stirred for 1 hour. Then, a solution of 6 g of 3-methoxy-18-methyl-estra-1,3,5(10)-trien-17-one in 173 ml of tetrahydrofuran is slowly added, stirred for 15 minutes, slowly heated at a bath temperature of from -50° C. to 100° C. and refluxed for 6 hours. For working-up, it is diluted with ethyl acetate, washed with water as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 5.4 g of 17-difluoromethylene-3-methoxy-18-methyl-estra -1,3,5(10)-triene is obtained as colorless crystals with a melting point of 145-146° C., [α]D22 =+40.2° (c=0.515% in pyridine).
Reaction SMILES: C([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][CH2:14][CH2:15][N:16]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])(=[O:29])=[O:28])[CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[CH:11][CH:12]=1)=[O:7])(C)(C)C>Cl.O1CCOCC1>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[S:27]([N:16]([CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[CH2:15][CH2:14][CH2:13][C:10]1[S:9][C:8]([C:6]([OH:7])=[O:5])=[CH:12][CH:11]=1)(=[O:28])=[O:29]
Reactant: CC(C)(C)OC(=O)c1ccc(CCCN(CCCc2cccc(Cl)c2)S(=O)(=O)c2ccccc2Cl)s1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1ccc(CCCN(CCCc2cccc(Cl)c2)S(=O)(=O)c2ccccc2Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(3-((2-chloro-benzenesulfonyl)-(3-(3-chloro-phenyl)-propyl)-amino)-propyl)-thiophene-2-carboxylic acid tert-butyl ester prepared of Example 6, Step A (0.010 g, 0.010 mmol) in 4N HCl in 1,4 dioxane (3 mL) and the reaction was stirred overnight at room temperature. HCl (g) was bubbled in until reaction was determined to be complete by thin layer chromatography. The reaction mixture was concentrated in vacuo. The resulting organic residue was azeotroped with CCl4 to produce a powder (5 mg). 1H NMR (400 MHz, CDCl3) δ 8.00 (d, 1H, J=4), 7.00-7.72 (m, 8H,), 6.75 (d, 1H, J=4), 3.20-3.40 (m, 4H), 2.81 (m, 2H), 2.52 (m, 2H), 1.90 (m, 2H), 1.80 (m, 2H), 1.20 (m, 2H); MS 509.9 (M−1).
Reaction SMILES: C(C1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]NC(NS(C3C=CC(C)=CC=3)(=O)=O)=O)=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)C.C(OCC)(=[O:38])C>[Pd]>[NH2:4][C:5]1[C:6]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][OH:38])=[CH:18][CH:19]=2)=[N:7][C:8]([CH3:12])=[CH:9][C:10]=1[CH3:11]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CCOC(C)=O
Agent: [Pd]
Product: Cc1cc(C)c(N)c(Nc2ccc(CCO)cc2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
To a stirred solution of 2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 3, 1.6 g, 5.6 mmol) in ethyl acetate (15 mL) was added 10% Pd—C (160 mg). The mixture was stirred at room temperature for 6 h under hydrogen atmosphere. The palladium catalyst was removed by filtration and washed with ethanol (100 mL). The filtrate was concentrated under reduced pressure to afford 1.3 g (92%) of the title compound as pale yellow solids: 1H-NMR (CDCl3) δ 7.10 (4H, s), 6.61 (1H, s), 3.81 (2H, t, J=6.4 Hz), 2.80 (2H, t, J=6.4 Hz), 2.36 (3H, s), 2.19 (3H, s).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][O:12][C:11]2[CH:15]=[C:16]([S:19]([N:22](CC3C=CC(OC)=CC=3)[C:23]3[S:24][CH:25]=[CH:26][N:27]=3)(=[O:21])=[O:20])[CH:17]=[CH:18][C:10]1=2)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][O:12][C:11]2[CH:15]=[C:16]([S:19]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)(=[O:21])=[O:20])[CH:17]=[CH:18][C:10]1=2)[CH3:2]
Reactant: CCc1ccccc1N1CCOc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
To a solution of 4-(2-ethylphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (400 mg, 0.77 mmol) in DCM (50 mL) was added TFA (2.0 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product which was purified by prep HPLC purification to obtain 4-(2-ethylphenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (176 mg, 56.9%) as a white solid. MS (ESI, positive ion) m/z; 402.3 (M+1). 1H NMR (400 MHz, DMSO) δ 12.51 (s, 1H), 7.42-7.38 (m, 1H), 7.33 (dt, J=4.4, 2.0 Hz, 2H), 7.29-7.24 (m, 1H), 7.21 (d, J=4.6 Hz, 1H), 7.12 (d, J=2.0 Hz, 1H), 7.08 (dd, J=8.5, 2.0 Hz, 1H), 6.77 (d, J=4.4 Hz, 1H), 6.00 (d, J=8.5 Hz, 1H), 4.34 (dd, J=10.2, 3.1 Hz, 2H), 3.74 (dt, J=7.3, 3.8 Hz, 1H), 3.51 (d, J=12.5 Hz, 1H), 2.47-2.44 (m, 2H), 1.11 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[C:2]([O:4]C)=O.[CH2:12]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Li+].CC([N-]C(C)C)C.Cl>O1CCCC1>[CH2:12]([O:19][CH:20]([C:2](=[O:4])[C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[C:21]([O:23][CH3:24])=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)COCc1ccccc1
Reactant: COC(=O)C(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(OCc1ccccc1)C(=O)C(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 3 h
Yield: 105.8 %

Procedure:
tert-Butyl methyl oxalate (34 g, 210 mmol) and methyl (benzyloxy)acetate (35 g, 190 mmol) were dissolved in tetrahydrofuran (250 mL) and a solution of LDA in tetrahydrofuran prepared at −78° C. was added dropwise under a nitrogen atmosphere, followed by stirring at the same temperature for 3 hours. The temperature of the reaction solution was gradually raised to −40° C., and subsequently hydrochloric acid (2 M, 210 mL) was added, followed by extraction with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution, followed by drying over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to afford 4-tert-butyl 1-methyl 2-(benzyloxy)-3-oxosuccinate (62 g) as a yellow oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[CH:8][CH:7]=1)[OH:5].C(=O)([O-])[O-].[K+].[K+].[C:24](Cl)(=[O:26])[CH3:25]>O.C(OCC)(=O)C>[OH:5][CH:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[CH:8][CH:7]=1)[CH2:3][NH:2][C:24](=[O:26])[CH3:25]
Reactant: COc1ccc2cccc(C(O)CN)c2c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2cccc(C(O)CNC(C)=O)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The compound obtained in Step E (20 mmol) is dissolved in a mixture of water/ethyl acetate (25 ml/75 ml) cooled to 0° C. Potassium carbonate (60 mmol) is added, and then acetyl chloride (26 mmol) is added dropwise to the reaction mixture. The mixture is stirred vigorously for 30 minutes at ambient temperature. The two phases are separated and the organic phase is washed with 0.1M aqueous hydrochloric acid solution and then with water. After drying over magnesium sulphate, the organic phase is evaporated under reduced pressure. The residue obtained is recrystallised from acetonitrile to yield the title product in the form of a white solid.
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(C)=O.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[C:19](=[C:20]([CH2:25]Cl)[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][N:16]=2)=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:25][C:1]#[N:2])[C:19]=3[CH:18]=[CH:17][N:16]=2)=[CH:11][CH:10]=1
Reactant: [C-]#N
Reactant: ClCc1cccc2c(-c3ccc(Br)cc3)nccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CCc1cccc2c(-c3ccc(Br)cc3)nccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a mixture of 2.5 g of sodium cyanide and 150 ml of dimethylsulfoxide was added 14 g of 1-(4-bromophenyl)-5-chloromethylisoquinoline little by little. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a mixture of ethyl acetate and a dilute aqueous solution of sodium bicarbonate. The organic layer was separated, dried, and recrystallized from dichloromethane-hexane to afford 8.5 g of 1-(4-bromophenyl)isoquinoline-5-acetonitrile as colorless prisms having a melting point of 121.5° to 122.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH:29]=O)=[CH:28][C:23]=2[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:29][C:27]2[CH:26]=[CH:25][C:24]3[O:20][CH2:21][CH2:22][C:23]=3[CH:28]=2)[CH2:16][CH2:15]1
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: O=c1cc(NC2CCNCC2)c2cc(Cl)ccc2o1
Product: O=c1cc(NC2CCN(Cc3ccc4c(c3)CCO4)CC2)c2cc(Cl)ccc2o1

Procedure:
Prepared from 6-Chloro-4-(piperidin-4-ylamino)-chromen-2-one and 2,3-dihydro-benzofuran-5-carbaldehyde in a manner analogous to that described above. 1H NMR (500 MHz, MeOD-d4) δ ppm 8.13 (s, 1H), 7.61 (d, 1H), 7.33-7.36 (m, 2H), 7.84 (d, 1H), 7.24 (s, 1H), 5.45 (s, 1H), 4.61 (t, 2H), 4.26 (s, 2H), 3.85 (br t, 1H), 3.58 (br d, 2H), 3.26 (t, 2H), 3.16(br t, 2H), 3.35 (br d, 2H), 1.93 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N+:11]([O-])=O)=[CH:5][N:4]=1>[Pd].CCOC(C)=O>[CH3:10][O:9][C:8]1[CH:7]=[C:6]([NH2:11])[CH:5]=[N:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc([N+](=O)[O-])cnc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(N)cnc1OC
Temperature: 50 °C

Procedure:
A stainless steel bomb was charged with 2,3-dimethoxy-5-nitropyridine (430 mg, 2335 μmol), 10% Pd/C (124 mg, 1168 μmol) and 4.7 mL EtOAc. The vessel was sealed and was purged with hydrogen once, before filling with hydrogen at a pressure of 2 attn. The reaction mixture was heated at 50° C. for 3 h. Upon cooling, the mixture was filtered through a pad of Celite, rinsing with EtOAc. The filtrate was concentrated and passed through a silica plug using 5% MeOH/DCM. The filtrate was concentrated to provide 5,6-dimethoxypyridin-3-amine as a peach colored oil that crystallized upon standing. GC/MS confirmed the correct mass to be [M+H]=155.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.S(Cl)([Cl:17])=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([Cl:17])=[O:14])[CH:6]=[CH:5]2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2cc(F)ccc2c1
Product: O=C(Cl)c1ccc2cc(F)ccc2c1

Procedure:
6-fluoro-2-naphthoic acid (2 g, 10.52 mmol) was stirred in thionyl chloride (21.03 ml) at 80° C. for 4 h in pressure vessel. The mixture was cooled and concentrated. The acid chloride was dried and used as is for next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:29](Cl)(=[O:31])[CH3:30].Cl>O.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:16]([C:29](=[O:31])[CH3:30])=[CH:15][C:14]2[CH2:13][CH:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:11]3[CH:6]([C:5]=2[CH:4]=1)[CH2:7][CH2:8][CH2:9][CH2:10]3
Reactant: CC(=O)Cl
Reactant: COc1ccc(C2Cc3ccc(OC)cc3C3CCCCC23)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C2Cc3cc(C(C)=O)c(OC)cc3C3CCCCC23)cc1
Temperature: -5 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
Combine 6-Methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthrene (0.13 g, 0.4 mmol) and methylene chloride (6 ml). Cool to −5° C. and add aluminum chloride (0.11, 0.81 mmol) followed by acetyl chloride (0.032 g, 0.4 mmol). After 2 hours, add ice, water and 1N HCl. Filter precipitate and rinse filtrate with sodium bicarbonate solution solution followed by brine. Remove solvent in vacuo, and chromatograph on silica gel with 17% ethyl acetate/hexanes to yield the titled compound (0.081 g, 55%). 1H NMR (CDCl3). MS m/z 365, (M+1).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.Cl.[NH2:17][OH:18].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[OH:18][N:17]=[CH:1][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C=NO)CC1
Temperature: 14 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A solution of tert-butyl 4-formylpiperidine-1-carboxylate (50.0 g, 234 mmol) in MeOH (200 mL) and water (200 mL) was cooled in an ice-bath and then hydroxylamine hydrochloride (19.5 g, 272 mmol) and sodium carbonate (12.4 g, 117 mmol) were added. The resulting mixture was stirred at 13-15° C. overnight. The solution was concentrated in vacuo to an aqueous suspension, which was extracted with EtOAc. The organic extract was washed with 100 mL brine, dried (MgSO4), filtered, concentrated to provide tert-butyl 4-((hydroxyimino)methyl)piperidine-1-carboxylate (53.1 g, 99.2% yield) as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([Cl:1])[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:5]=2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cc(Cl)c(C(F)(F)F)cc2[nH]1
Product: FC(F)(F)c1cc2nc(Cl)[nH]c2cc1Cl

Procedure:
The benzoimidazol-2-one from step (b) above (1.43 g, 6.0 mmol) reacted with POCl3 under the conditions of Example 1c to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 254.9 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][N:6]([C:13](=[O:26])[C:14]([CH3:25])([CH3:24])[CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>C1COCC1>[CH2:17]([O:16][CH2:15][C:14]([CH3:25])([CH3:24])[C:13]([N:6]([CH2:5][C:4]([OH:27])=[O:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CN(C(=O)C(C)(C)COCc1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(COCc1ccccc1)C(=O)N(CC(=O)O)c1ccccc1
Temperature: 50 °C

Procedure:
To a stirred solution of ethyl[[3-(benzyloxy)-2,2-dimethylpropanoyl](phenyl)amino]acetate from Step C (530. mg, 1.44 mmol) in THF (10 mL), at ambient temperature, was added aqueous 1M NaOH (2.40 mL, 2.40 mmol). The stirred reaction was then heated to 50° C. for 19 hours, before being allowed to cool to ambient temperature. The bulk of the THF was then removed in vacuo, and aqueous 1M HCl (2.4 mL, 2.4 mmol) was then added resulting in an oily biphasic mixture. The mixture was extracted with ethyl acetate (twice) and the combined organics were washed with water and lastly saturated brine. The organics were then dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound which was used without further purification. MS: m/z=342 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:31]([CH:32]=C)=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[F:34].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.C[OH:58]>>[NH2:1][C:2]1[C:3]([F:34])=[CH:4][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:26])([CH3:25])[CH3:27])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:30][C:31]=1[CH:32]=[O:58]
Reactant: C=Cc1cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc(F)c1N
Reactant: CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4cc(F)c(N)c(C=O)c4)CS(=O)(=O)C[C@@H]32)c1
Temperature: 25 °C

Procedure:
A solution of (3aR*,7S*,7aS*)-7-(4-amino-3-fluoro-5-vinyl-benzyl)-3-(3-tert-butyl-benzyl)-5,5-dioxo-hexahydro-1-oxa-5lambda*6*-thia-3-aza-inden-2-one (0.215 g, 0.44 mmol) in CH2Cl2-MeOH 4:1 (10 mL) was ozonized at −78° C. until the educt disappeared. After addition of PPh3 (0.139 g, 0.53 mmol) the reaction mixture was allowed to warm to 25° C. and the solvents were removed under reduced pressure. The title compound was obtained after flash-chromatography on silica gel (hexane-EtOAc 2:1) as white solid: ESIMS [M−H]−=487.