Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:20]=[CH:19][C:18]3[O:17][C:16]4[CH:15]=[CH:14][NH:13][C:12](=[O:21])[C:11]=4[C:10](=O)[C:9]=3[CH:8]=2)[CH:2]=1.[CH3:23][Mg]Br.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1.ClCCCl>[CH2:23]=[C:10]1[C:11]2[C:12](=[O:21])[NH:13][CH:14]=[CH:15][C:16]=2[O:17][C:18]2[CH:19]=[CH:20][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:8][C:9]1=2
Reactant: O=c1[nH]ccc2oc3ccc(-c4cccnc4)cc3c(=O)c12
Reactant: C[Mg]Br
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCCl
Solvent: C1CCOC1
Product: C=C1c2cc(-c3cccnc3)ccc2Oc2cc[nH]c(=O)c21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 8-(pyridin-3-yl)-1H-chromeno[3,2-c]pyridine-1,10(2H)-dione (0.100 g, 0.345 mmol) in THF (3.00 mL) was cooled to 0° C. and methylmagnesium bromide (3.0 M in diethyl ether) (0.345 mL, 1.034 mmol) was added dropwise. The mixture stirred at 0° C. for 1 h. The mixture was quenched at 0° C. with saturated aqueous ammonium chloride solution and diluted with ethyl acetate. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a tan solid. The material was dissolved in 1,2-dichloroethane (3.00 mL), pyridinium p-toluenesulfonate (8.66 mg, 0.034 mmol) was added, and the mixture was heated at reflux for 2 h to afford a tan suspension. This mixture was filtered, and the solids were washed with 1,2 dichloroethane and dried to afford 10-methylene-8-(pyridin-3-yl)-2,10-dihydro-1H-chromeno[3,2-c]pyridin-1-one as a tan solid. MS m/z=289.0 [M+H]+. Calcd for C18H12N2O2: 288.1.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([S:35][C:36]1[C:44]([Br:45])=[CH:43][C:39]3[O:40][CH2:41][O:42][C:38]=3[CH:37]=1)[N:6]2[C:11]1[CH:34]=[CH:33][C:14]([CH2:15][C@@H:16]([C:25]([O:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:26])[NH:17]C(OC(C)(C)C)=O)=[CH:13][CH:12]=1.C(O)(C(F)(F)F)=O.CO.C(Cl)Cl>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([S:35][C:36]1[C:44]([Br:45])=[CH:43][C:39]3[O:40][CH2:41][O:42][C:38]=3[CH:37]=1)[N:6]2[C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C@@H:16]([C:25]([O:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:26])[NH2:17])=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-n2c(Sc3cc4c(cc3Br)OCO4)nc3c(N)ncnc32)cc1)C(=O)OC1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Nc1ncnc2c1nc(Sc1cc3c(cc1Br)OCO3)n2-c1ccc(C[C@H](N)C(=O)OC2CCCC2)cc1
Yield: 53.1 %

Procedure:
A solution of cyclopentyl 4-{6-amino-8-[(6-bromo-1,3-benzodioxol-5-yl)thio]-9H-purin-9-yl}-N-(tert-butoxycarbonyl)-L-phenylalaninate (44 mg, 0.063 mmol) in TFA (250 μl, 3.24 mmol) and DCM (1 ml) was stirred at room temp for 2 h. Chromatography (silica gel, 2-5% MeOH/DCM) afforded the title compound (20 mg) as a pale yellow solid. m/z 597 (M+H)+. 1H NMR (400 MHz, CHCl3-d) d: 8.28 (1H, s), 7.32-7.40 (4H, m), 7.03 (1H, s), 6.93 (1H, s), 6.00 (1H, s), 5.53 (2H, s), 5.20 (1H, m), 3.71 (1H, dd, J=7.8, 5.4 Hz), 3.13 (1H, dd, J=13.7, 5.4 Hz), 2.90 (1H, dd, J=13.7, 7.8 Hz), 1.86 (2H, m), 1.75-1.55 (10H, br m).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.O>CS(C)=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]3[CH2:14][CH2:15][C:16](=[O:19])[CH2:17][CH2:18]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O[C@H]1CC[C@H](Nc2ccnc3cc(Cl)ccc23)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCC(Nc2ccnc3cc(Cl)ccc23)CC1
Reaction time: 1.5 h

Procedure:
13.6 g of trans-4-(7-chloro-quinolin-4-ylamino)-cyclohexanol (Example 123, step 1) were dissolved in 100 ml of dimethyl sulphoxide and 68 ml of triethylamine and cooled to +10° C. under argon. A solution of 25.5 g of sulphur trioxide-pyridine complex in 100 ml of dimethyl sulphoxide was added dropwise in such a manner that the internal temperature did not exceed +15° C. After stirring for an additional 90 minutes, 800 ml of water were rapidly added dropwise. The emulsion obtained became a filterable suspension after vigourous stirring at +10° C. The filter material was recrystallized from ethanol-ether. Yield: 10.1 g (75%) of beige crystals; dec. 195° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10](F)=[CH:9][CH:8]=3.[Li]CCCC.[CH:28](N1CCOCC1)=[O:29]>C1COCC1>[Br:1][C:2]1[CH:14]=[C:13]2[C:5](=[CH:4][CH:3]=1)[N:6]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[C:7]1[CH:8]=[CH:9][C:10]([CH:28]=[O:29])=[CH:11][C:12]2=1
Reactant: COCCOCCn1c2ccc(F)cc2c2cc(Br)ccc21
Reactant: O=CN1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCCn1c2ccc(Br)cc2c2cc(C=O)ccc21
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 65 %

Procedure:
To a solution of 3-bromo-6-fluoro-9-(2-(2-methoxyethoxy)ethyl)-9H-carbazole (3.4 g, 9.3 mmol) in dry THF (50 ml) was added n-BuLi (1.6 M, 8.7 ml, 13.9 mmol) at −78° C. The resulting mixture was stirred for 50 min at −78° C. and then added with N-formylmorpholine (1.86 ml, 18.6 mmol). The reaction mixture was allowed to warm to rt and stirred for 2 h before quenched with ammonia chloride solution. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by silica gel column chromatography eluting with 2:1 petroleum ether/ethyl acetate to give compound 7 in 65% yield. 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.53 (s, 1H), 8.02-8.00 (m, 1H), 7.80-7.77 (m, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.45 (dd, J=4.0 Hz, J=9.2 Hz 1H), 7.28-7.23 (m, 1H), 4.52 (t, J=5.6 Hz, 2H), 3.88 (t, J=5.6 Hz, 2H), 3.52-3.50 (m, 2H), 3.40 (d, J=2.8 Hz, 2H), 3.28 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 191.8, 159.3, 156.9, 145.2, 137.8, 128.8, 127.5, 124.4, 123.7, 123.7, 123.7, 122.8, 114.8, 114.5, 110.6, 110.5, 109.8, 106.7, 106.4, 72.1, 71.0, 69.5, 59.2, 43.9. HRMS (MALDI-TOF) m/z Calcd for C18H18FNO3 316.1343 Found 316.1340[M]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])=[C:17]([C:30]2[C:35]([O:36][CH2:37][CH3:38])=[CH:34][C:33](=[O:39])[N:32]([CH3:40])[CH:31]=2)[CH:16]=1)=[O:13].I[CH3:42]>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH:11]([CH3:42])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])=[C:17]([C:30]2[C:35]([O:36][CH2:37][CH3:38])=[CH:34][C:33](=[O:39])[N:32]([CH3:40])[CH:31]=2)[CH:16]=1)=[O:13]
Reactant: CI
Reactant: CCOc1cc(=O)n(C)cc1-c1cc(NC(=O)Cc2cc(F)ccc2Cl)ccc1Oc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(=O)n(C)cc1-c1cc(NC(=O)C(C)c2cc(F)ccc2Cl)ccc1Oc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A 4 mL vial with stirbar was charged with sodium hydride, dry 95% (2.9 mg, 0.115 mmol), placed in an ice bath and charged with a solution of Example 1H (0.0527 g, 0.097 mmol) in DMF (1 mL). After stirring 10 min at 0° C., iodomethane (8 μL, 0.128 mmol) was added by syringe. After 1 hour, the mixture was partitioned between 25 mL each of ethyl acetate and aqueous ammonium chloride. The organics were dried over anhydrous sodium sulfate. After filtration and solvent removal, the material was purified by reverse phase HPLC (C18, CH3CN/water (0.1% TFA), 0-100%) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.60 (d, J=2.6 Hz, 1H), 7.58 (s, 1H), 7.54-7.49 (m, 2H), 7.46-7.25 (m, 2H), 7.22-6.92 (m, 3H), 6.87 (d, J=8.8 Hz, 1H), 5.79 (s, 1H), 4.15 (q, J=7.1 Hz, 1H), 3.93 (d, J=7.0 Hz, 2H), 3.34 (s, 3H), 1.47 (d, J=7.1 Hz, 3H), 1.14 (t, J=6.9 Hz, 3H). MS (ESI) 557.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:35][CH2:36][O:37][C:38]([F:41])([F:40])[F:39])(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:35][CH2:36][O:37][C:38]([F:41])([F:40])[F:39])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: O=S(=O)(OCCOC(F)(F)F)C(F)(F)F
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Product: COc1cn(C(CCOC(F)(F)F)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
416 mg (1.00 mmol) of tert-butyl {4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}acetate in the presence of 1.20 ml (1.20 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 393 mg (1.50 mmol, 1.5 eq.) of 2-(trifluoromethoxy)ethyl trifluoromethanesulphonate were reacted according to General Method 7B. Yield: 327 mg (62% of theory)
Reaction SMILES: [C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[C:21]([P:26](=[O:29])([OH:28])[OH:27])[P:22](=[O:25])([OH:24])[OH:23])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[O-]CC.[Na+:33].C(O)C>O1CCCC1>[C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[C:21]([P:26](=[O:27])([O-:28])[O-:29])[P:22](=[O:23])([OH:24])[OH:25])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Na+:33].[Na+:33]
Reactant: CCCCCCCCCCCC#Cc1ccccc1C=C(P(=O)(O)O)P(=O)(O)O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCCCCCC#Cc1ccccc1C=C(P(=O)([O-])[O-])P(=O)(O)O
Reaction time: 0.33 h
Yield: 94 %

Procedure:
[2-[2-(1-Tridecynyl)phenyl]ethenylidene]bisphosphonic acid (0.101 g, 0.228 mmol) prepared according to Example 10 was dissolved in dry tetrahydrofuran (10 ml) and stirred while sodium ethoxide in ethanol (0.177M, 2.58 ml, 0.457 mmol) was added. After 20 minutes, the solvent was removed under reduced pressure to give a yellowish solid. This solid was pulverized and washed successively with dry ether, tetrahydrofuran, acetone, acetonitrile, and ethanol, then dried on the vacuum line, 0.104 g, 0.214 mmol, 94% yield. 1H NMR (D2O) ∂ 0.74 (m, 3H), 1.17 (m, 14H), 1.35 (m, 2H), 1.52 (m, 2H), 2.39 (t, J=7.1 H, 2H), 7.24 (m, 2H), 7.37 (m, 1H), 7.92 (dd+m, J=43.8, 27.0 Hz, 2H); FAB mass spectrum m/z 443 (M-2Na+3H)+, 465 (M-Na+2H)+, 487 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([N:5]1[C:13]2[N:12]=[C:11]([CH2:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=4)[CH:18]=[N:17][CH:16]=3)[NH:10][C:9]=2[C:8](=[O:29])[N:7]([CH3:30])[C:6]1=[O:31])[CH:3]=[CH2:4].C(N(C(C)C)CC)(C)C.[OH-:41].[Na+].OO>C1COCC1>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[CH:18]=[N:17][CH:16]=[C:15]2[CH2:14][C:11]1[NH:10][C:9]2[C:8](=[O:29])[N:7]([CH3:30])[C:6](=[O:31])[N:5]([CH2:2][CH2:3][CH2:4][OH:41])[C:13]=2[N:12]=1
Reactant: C=CCn1c(=O)n(C)c(=O)c2[nH]c(Cc3cncc4cc(OC)c(OC)cc34)nc21
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CCCO)c2cc1OC
Temperature: 50 °C

Procedure:
A suspension of the product of Example 13, 3-allyl-8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-1-methyl-3,7-dihydro-purine-2,6dione -hydrochloride salt (0.760 g, 1.87 mmol), 9-borabicyclo[2.2.0]nonane (0.5M THF solution, 18.7 ml, 9.35 mmol) and diisopropylethylamine (0.33 ml, 1.89 mmol) in THF (9 ml) is heated to reflux for 2.5 hours. Sodium hydroxide (4M aqueous solution, 6 ml) and hydrogen peroxide (27.5%, 3 ml) are added sequentially and the reaction heated at 50° C. for 1.5 hours. After evaporation, the crude product is purified by flash chromatography (19:1 CH2Cl2:methanol elution) and triturated with water to afford 8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-3-(3-hydroxy-propyl)-1-methyl-3,7-dihydro-purine-2,6-dione, [MH]+ 426.
Reaction SMILES: [N:1]1([CH2:10][C@@H:11](O)[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:55]=[N+:56]=[N-:57])(C2C=CC=CC=2)=O)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:55]([C@H:11]([CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)=[N+:56]=[N-:57]
Reactant: O[C@@H](COCc1ccccc1)Cn1cnc2ccccc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@H](COCc1ccccc1)Cn1cnc2ccccc21
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To a solution of Example 441A (1.0 g, 3.54 mmol) and triphenylphosphine (1.39 g, 5.31 mmol) in anhydrous THF (30 mL) was added diphenylphosphoryl azide (1.14 mL, 5,31 mmol) at 0° C. followed by the addition of DEAD (836 μL). The reaction mixture was stirred at 0° C. for 30 mins and at room temperature for 15 hrs. The concentrated residue was then purified by flash column chromatography on silica gel eluting with 60%-80% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[I:22]N1C(=O)CCC1=O>CN(C=O)C>[OH:1][CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([I:22])[CH:9]=2)[N:4]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(OCc1ccccc1)N1c2ccccc2CC1CO
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1c2ccc(I)cc2CC1CO
Temperature: 60 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution containing benzyl 2-(hydroxymethyl)-1-indolinecarboxylate (Preparation 6, 1.78 g), N-iodosuccinimide (2.83 g), and anhydrous DMF (12 mL) is stirred overnight at 60° C. in a foil-covered flask. This solution is cooled and concentrated to half volume with a stream of nitrogen. The resulting brown solution is partitioned between water (50 mL) and CH2Cl2 (150 mL). The organic phase is washed with brine, dried (Na2SO4), filtered, and concentrated to give a brown oil. The crude product is chromatographed eluting with 0-40% EtOAc in heptane (300 mL each 10%) to give 2.03 g (79%) of the title compound as a peach solid. Physical characteristics: M.p. 110-111° C.; HRMS (FAB) m/z 410.0270 (C17H16INO3+H). Anal. Found: C, 49.83; H, 3.95; N, 3.37.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[C:12](=[O:15])[CH:11]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[NH:9][C:8]=3[C:7](=[O:20])[C:6]=2[CH:21]=1.[CH2:22](I)[CH2:23][CH3:24]>>[CH2:22]([N:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:12](=[O:15])[C:13]2[O:14][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][C:6]=3[C:7](=[O:20])[C:8]1=2)[CH2:23][CH3:24]
Reactant: COC(=O)c1cc(=O)c2oc3ccc(Cl)cc3c(=O)c2[nH]1
Reactant: CCCI
Product: CCCn1c(C(=O)OC)cc(=O)c2oc3ccc(Cl)cc3c(=O)c21
Yield: 33.9 %

Procedure:
Prepared from methyl 8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano-[3,2-b]pyridine-2-carboxylate (4.5 g, 0.015 mole) and n-propyl iodide (9.1 g, 0.054 mole) by the method described for Ex. 7. Recrystallization from methanol gave white crystals (1.77 g, 35%), m.p. 240°-244°.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]2[O:22][C:21]3[CH:23]=[C:24]([Br:27])[CH:25]=[CH:26][C:20]=3[O:19][CH2:18]2)[CH2:12][CH2:11]1.[Cl:28][C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[S:36](Cl)(=[O:38])=[O:37]>ClCCl>[Br:27][C:24]1[CH:25]=[CH:26][C:20]2[O:19][CH2:18][C@H:17]([CH2:16][N:13]3[CH2:14][CH2:15][CH:10]([CH2:9][NH:8][S:36]([C:30]4[CH:31]=[CH:32][CH:33]=[C:34]([Cl:35])[C:29]=4[Cl:28])(=[O:38])=[O:37])[CH2:11][CH2:12]3)[O:22][C:21]=2[CH:23]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: NCC1CCN(C[C@H]2COc3ccc(Br)cc3O2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCC1CCN(C[C@H]2COc3ccc(Br)cc3O2)CC1)c1cccc(Cl)c1Cl
Reaction time: 24 h
Yield: 99.2 %

Procedure:
Triethylamine (0.63 ml) was added to a solution of (S)-4-(aminomethyl)-1-(7-bromo-1,4-benzodioxan-2-ylmethyl)piperidine (0.5 g) and 2,3-dichlorobenzenesulphonyl chloride (0.74 g) in dichloromethane (15 ml) and stirred under nitrogen for 24 hours. The reaction was diluted with dichloromethane (100 ml), washed with water (100 ml) and brine (100 ml), dried over anhydrous magnesium sulphate and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with a 9:1 mixture of dichloromethane and methanol gave (S)-(-)-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,3-dichlorobenzensulphonamide as a cream solid (0.8 g) m.p. 93-95° C., [α]D22 -37.1°(c=0.93, MeOH).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([CH3:9])[C:6]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)[CH:12]=2)=[CH:5][CH:4]=1)[NH2:2].[CH3:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26].C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:24]([C:25]1[O:26][C:38](=[O:40])[N:1]([C:3]2[CH:4]=[CH:5][C:6]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:12]=3)=[C:7]([CH3:9])[N:8]=2)[N:2]=1)([CH3:29])([CH3:28])[CH3:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1nc(NN)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-n2nc(C(C)(C)C)oc2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.9 %

Procedure:
A mixture of Example A4 (0.20 g, 0.67 mmol) in DCM (4 mL) was cooled in an ice-water bath and treated with trimethylacetyl chloride (0.16 g, 1.35 mmol). The mixture was allowed to warm up to RT and stirred for 30 min. The reaction mixture was cooled to 0° C. and then diluted with DCM (4 mL). Triethylamine (0.5 mL, 3.61 mmol) was added and then a solution of triphosgene (80 mg, 0.26 mmol) in DCM (4 mL) was added drop-by-drop under the same conditions. The reaction mixture was allowed to warm to RT and stirred at RT overnight. The mixture was quenched with NaHCO3 solution and extracted with DCM (2×). The organic was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified via silica gel chromatography (EtOAc) to obtain 5-(tert-butyl)-3-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1,3,4-oxadiazol-2(3H)-one (114 mg, 37.8%). 1H NMR (400 MHz, DMSO-d6): δ 8.39 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 7.97 (s, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 6.67 (dd, J=5.7, 2.4 Hz, 1H), 3.85 (s, 3H), 2.37 (s, 3H), 1.33 (s, 9H); MS (ESI) m/z: 407.2 (M+H+).
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20].Cl>C(=S)=S>[C:19]([C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:13][CH2:12][C:11]=2[CH:10]=1)(=[O:21])[CH3:20]
Reactant: c1ccc2c(c1)CCc1ccccc1-2
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c(c1)CCc1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of 3.00 g (16.6 mM) of 9,10-dihydrophenanthrene in 40 ml of dry carbon disulfide, 2.73 g (20.5 mM) of anhydrous aluminum chloride was added while being cooled on an ice-common salt bath. Under cooling on the bath, 1.27 ml (17.9 mM) of acetylchloride was gradually added dropwise to the mixture at -4° to -2° C., followed by stirring for 1 hour and 30 minutes at room temperature without cooling on the bath. After the reaction, the reaction mixture was poured into a mixture of 50 g of ice and 15 ml of hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water, dried with anhydrous sodium sulfate, and distilled-off the solvent under reduced pressure to obtain 3.57 g of oily 2-acetyl-9,10-dihydrophenanthrene (Yield: 96.5%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([F:29])[CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:32]1([CH2:37][CH2:38][C:39](Cl)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][N:18]([C:39](=[O:40])[CH2:38][CH2:37][CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([F:29])[CH:20]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(C(=O)OC)c(F)c3)cc2)cc1
Reactant: O=C(Cl)CCC1CCCC1
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)c3ccc(C(=O)OC)c(F)c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure B using methyl 4-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate and 3-cyclopentylpropionyl chloride as a pale yellow oil (54%). M+ (ESI): 540.1. HPLC, Rt: 6.35 min (Purity: 98.2%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:4][CH2:3][CH2:2][Br:1])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: BrCCCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(CCCBr)CC1
Yield: 70.4 %

Procedure:
1,3-Dibromopropane (6.78 mL, 66.8 mmol) is added to a stirred solution of piperazine-1-carboxylic acid tert-butyl ester (4.15 g, 22.2 mmol) and diisopropylethylamine (7.73 mL, 44.4 mmol) in anhydrous 1,4-dioxane (40 mL). The resultant mixture is heated in an oil bath at 90° C. for 20 hours. At ambient temperature ethyl acetate (160 mL) and half-saturated aqueous sodium bicarbonate (NaHCO3) (120 mL) are added to the mixture. The organic layer is separated, dried over magnesium sulfate, filtered, and concentrated. The crude oil is subjected to chromatography on silica gel and eluted with 2 M NH3/MeOH in dichloromethane 0-3% to provide the title compound as a dark oil (4.80 g, 70% yield).
Reaction SMILES: B(Br)(Br)[Br:2].Cl.Cl.Cl.[F:8][C:9]1[C:10]([O:38]C)=[CH:11][C:12]([CH2:33][C:34]([F:37])([F:36])[F:35])=[C:13]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([C:24]4[NH:32][C:27]5[CH2:28][NH:29][CH2:30][CH2:31][C:26]=5[N:25]=4)=[N:20][NH:21]3)=[CH:17][CH:16]=2)[CH:14]=1>C(Cl)Cl>[BrH:2].[BrH:2].[F:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([C:24]4[NH:25][C:26]5[CH2:31][CH2:30][NH:29][CH2:28][C:27]=5[N:32]=4)=[N:20][NH:21]3)=[CH:17][CH:16]=2)[C:12]([CH2:33][C:34]([F:35])([F:36])[F:37])=[CH:11][C:10]=1[OH:38]
Reactant: BrB(Br)Br
Reactant: COc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CNCC5)n[nH]c3c2)cc1F
Agent: Cl
Solvent: ClCCl
Product: Br
Product: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCNC5)n[nH]c3c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
Boron tribromide (750 μL, 7.83 mmol) was added driowuse to a solution of 2-{6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoro-ethyl)-phenyl]-1H-indazol-3-yl}-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine trihydrochloride salt (Preparation 38, 2.03 g, 3.66 mmol) in DCM (25 mL) at 0° C. The resulting solution was stirred at room temperature for 18 hours. Further boron tribromide (2 mL, 20.7 mmol) was added dropwise and the reaction mixture was allowed to stir at room temperature for 18 hours. The precipitated solid was collected by filtration, washed with DCM and triturated with EtOAc to yield the title compound as the dihydrobromide salt (1.56 g) in a 67% yield.