Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH:20]=O)[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].CC(C)C(=O)C(P(=O)([O-])[O-])=[N+]=[N-]>CO>[CH2:1]([O:8][CH2:9][C:10]1([C:20]#[CH:22])[CH2:11][CH2:12][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:18][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1(COCc2ccccc2)CCC2(CC1)OCCO2
Reactant: O=C([O-])[O-]
Agent: CC(C)C(=O)C(=[N+]=[N-])P(=O)([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC1(COCc2ccccc2)CCC2(CC1)OCCO2
Yield: 90.1 %

Procedure:
To a solution of 8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decane-8-carbaldehyde (Reference Example 86) (100 mg, 0.344 mmol) in methanol (5.2 mL), potassium carbonate (143 mg, 1.03 mmol) and dimethyl-1-diazo-2-oxopropylphosphonate (165 mg, 0.861 mmol) were added with stirring under ice-cooling, and the obtained solution was stirred at room temperature for 1 hour. The reaction was quenched by adding water to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (88.9 mg, 0.310 mmol, 90%) as a colorless oily compound.
Reaction SMILES: [CH3:1][C@H:2]([CH:26]([CH3:28])[CH3:27])[CH2:3][C:4]1[CH:9]=[C:8]([S:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH2:19][C@H:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])[CH:13]=2)=[O:11])[CH:7]=[CH:6][C:5]=1[CH3:25].ClC1C=C(C=CC=1)C(OO)=[O:34]>ClCCl>[CH3:1][C@H:2]([CH:26]([CH3:28])[CH3:27])[CH2:3][C:4]1[CH:9]=[C:8]([S:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH2:19][C@H:20]([CH3:24])[CH:21]([CH3:22])[CH3:23])[CH:13]=2)(=[O:34])=[O:11])[CH:7]=[CH:6][C:5]=1[CH3:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)c2ccc(C)c(C[C@H](C)C(C)C)c2)cc1C[C@H](C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)c2ccc(C)c(C[C@H](C)C(C)C)c2)cc1C[C@H](C)C(C)C

Procedure:
(2S)-2,3-Dimethylbutyl-p-tolylsulfoxide (4) (52 mg, 0.2 mmol) was dissolved in 1.0 mL of anhydrous dichloromethane and 60 mg (0.3 mmol) of 3-chloroperoxybenzoic acid (80-85%, Sigma) added with stirring. The reaction mixture was stirred for 2 h and quenched with 10% sodium bicarbonate. More dichloromethane was added and the combined organic extracts were washed with aqueous sodium sulfite and brine and dried with MgSO4. The solvent was removed in vacuo and the crude sulfone was purified by silica gel flash chromatography using hexane ethyl acetate mixtures to afford sulfone (6) as a colorless oil. For analytical purposes this was also purified by HPLC (Zorbax Sil 9.4×25 cm column) using 10% ethyl acetate in hexane to give 42 mg of pure (2S)-sulfone (6): [α]D20 =+17 (c=3.5 in CHCl3); MS m/z (relative intensity) 240 (M+, 3), 197 (5), 157 (100), 92 (19), 91 (27), 85 (25), 84 (31), 43 (72); 1H NMR δ 0.77 (3H, d, J=7 Hz), 0.82 (3H, d, J=7.0 Hz), 1.00 (3H, d, J=7.0 Hz), 1.66-1.98 (2H, m), 2.45 (3H, s, CH3 -Aryl), 2.86 (1H, dd, J=8, 11 Hz), 3.06 (1H, dd, j=4, 12 Hz), 7.35 (2H, d, J=7.0 Hz, H-aryl ortho), 7.75 (2H, d, J=8, H-aryl ortho).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.[C:16](Cl)(=[O:18])[CH3:17].C(=O)([O-])O.[Na+]>O1CCCC1>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.3 %

Procedure:
Triethylamine (0.65 ml, 4.65 mmol) was added to a solution of 200 mg (1.16 mmol) of 4-bromoaniline in tetrahydrofuran (2 ml), and the mixture was stirred at room temperature for 5 min. Acetyl chloride (0.165 ml, 2.33 mmol) was added thereto, and the mixture was stirred at room temperature for 17 hr. The reaction was stopped by adding a saturated aqueous sodium hydrogencarbonate solution, and the reaction solution Was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, was dried over anhydrous sodium sulfate and was filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform:methanol=20:1) to give 249 mg (yield 99%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.CO>C1C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:23][CH2:24][N:25]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]3[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=3[O:13][CH3:14])[CH2:26][CH2:27]2)=[CH:18][CH:17]=1
Reactant: COc1cc(F)ccc1C(=O)N1CC1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Solvent: c1ccccc1
Solvent: CO
Product: COc1cc(F)ccc1C(=O)NCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 8 parts of 1-(4-fluoro-2-methoxybenzoyl)-aziridine, 3.7 parts of 4-(4-chlorophenyl)-4-piperidinol, 54 parts of benzene and 8 parts of methanol is stirred and refluxed for 1.50 hours. The reaction mixture is cooled to room temperature and 90 parts of benzene are added. The whole is washed with water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from 2-propanone. The product is filtered off and dried, yielding 3.5 parts of N-{2-[4-(4-chlorophenyl)-4- hydroxy-1-piperidinyl]ethyl}-4-fluoro-2-methoxybenzamide; mp. 156.7° C.
Reaction SMILES: [S-2:1].[K+].[K+].CN(C=O)C.Cl[C:10]1[CH:29]=[CH:28][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1.Cl>CC1C=CC=CC=1>[C:22]1([C:19]2[CH:20]=[CH:21][C:16]([C:14](=[O:15])[C:13]3[CH:28]=[CH:29][C:10]([SH:1])=[CH:11][CH:12]=3)=[CH:17][CH:18]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: [S-2]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(c1ccc(S)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
15 g anhydrous potassium sulfide and 100 ml DMF are added into a 250 ml three-neck flask. The solution is heated to 50° C. under stirring, and then 8 g 4-chloro-4′-phenyl benzophenone is added into the solution; the solution is heated to reflux (about 110° C.), and is cooled after 7 h; adding 100 ml methylbenzene, regulating the pH value to 5-6 with diluted hydrochloric acid, and separating the solution; the organic phase is extracted twice with 50 ml NaOH solution having a content of 5%, and the aqueous phases are mixed; the obtained aqueous phase is put into a 250 ml three-neck flask, and nitrogen is supplied to blow for 30 min, then 15% hydrochloric acid is dropped into the aqueous solution while agitating to regulate the pH value to 5-6, and light yellow solid precipitate; filtering to obtain a light yellow solid, and the weight after drying at a reduced pressure is 5.0 g, the purity is 99.11%, the yield is 63%, the melting point is 173˜176.7° C., and 1H-NMR data (solvent CDCl3): δ3.654 ppm, s, 1H, δ7.432, 7.370 ppm, d, 2H, δ7.413, 7.436 ppm, d, 1H, δ7.466, 7.491, 7.515 ppm, t, 2H, δ7.641, 7.665 ppm, d, 2H, δ7.695, 7.719 ppm, 7.743, t, 4H, δ7.850, 7.874 ppm, d, 2H.
Reaction SMILES: [CH2:1]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:20])=O>>[CH2:1]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([Cl:20])=[O:17])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=S(Cl)Cl
Product: CCCCCCCC[C@H]1CC[C@H](C(=O)Cl)CC1
Temperature: 60 °C

Procedure:
1.16 g (4.82 mM) of trans-4-n-octylcyclohexane-carboxylic acid was added to thionyl chloride, and the mixture was heated at 60° C. for 3 hours, followed by distilling-off of an excess of the thionyl chloride, to obtain 1.00 g (3.86 mM) of trans-4-n-octylcyclohexane-carboxylic acid chloride.
Reaction SMILES: [N:1]([C:4]1[CH2:5][C@@H:6]2[CH2:23][C:22](=[O:24])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10])=[N+]=[N-].[C:25]([O:28][CH:29]=[CH2:30])(=[O:27])[CH3:26].C(=O)(O)[O-].[Na+]>ClCCl>[C:25]([O:28][CH:29]1[CH2:30][N:1]1[C:4]1[CH2:5][C@@H:6]2[CH2:23][C:22](=[O:24])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10])(=[O:27])[CH3:26]
Reactant: [N-]=[N+]=NC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C[C@H]2C1
Reactant: C=COC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC1CN1C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C[C@H]2C1
Reaction time: 48 h
Yield: 41 %

Procedure:
A mixture of p-nitrobenzyl 2-azido-carbapen-2-em-3-carboxylate (11.3 mg, 34 micromol), vinyl acetate (0.1 ml), and solid sodium bicarbonate in dry dichloromethane was kept 2 days at ambient temperature, filtered through florisil, and evaporated under vacuum. The residue was chromatographed on one 15 cm×20 cm 250 micron silica gel preparative thin layer chromatography plate developed with 5:1 (v/v) diethyl ether-ethyl acetate. The band centered at Rf 0.20 was eluted with ethyl acetate and the eluate was evaporated under vacuum to provide 5.5 mg (41%) p-nitrobenzyl 2-(2-acetoxyaziridin-1-yl)-carbapen-2-em-3-carboxylate; IR (CH2Cl2): 1770, 1735 cm-1 ; NMR (CDCl3): δ 1.90 dd (J1 =6 Hz, J2 =7 Hz, 1H), 2.10 t (J=7 Hz, 1H), 2.13 s (3H), 2.76 bd (J=5 Hz, 2H), 2.85 dd (J 1 =2.5 Hz, J2 =15 Hz, 1H), 3.25 dd (J1 =5 Hz, J2 =15 Hz, 1H), 4.12 m (1H), 4.87 dd (J1 =6 Hz, J2 =7 Hz, 1H), 5.27 s (2H), 7.49 d (J=9 Hz, 2H), 8.25 d (J=9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:41]1([CH2:47][CH2:48][NH:49][C:50](=[O:52])[CH3:51])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:38])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:44]3[CH2:45][CH2:46][N:41]([CH2:47][CH2:48][NH:49][C:50](=[O:52])[CH3:51])[CH2:42][CH2:43]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(=O)NCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNC(C)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with N-(2-piperazin-1-yl-ethyl)-acetamide dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). LR-MS: 703.3 [(M+H)+]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([C:26]4[CH:34]=[CH:33][C:29]([C:30]([O-:32])=O)=[CH:28][CH:27]=4)=[CH:14][N:15]3[C:18]3[CH:23]=[C:22]([NH:24][CH3:25])[N:21]=[CH:20][N:19]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[O:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][NH2:43])[CH2:37][CH2:36]1.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([C:26]4[CH:34]=[CH:33][C:29]([C:30]([NH:43][CH2:42][CH2:41][N:38]5[CH2:39][CH2:40][O:35][CH2:36][CH2:37]5)=[O:32])=[CH:28][CH:27]=4)=[CH:14][N:15]3[C:18]3[CH:23]=[C:22]([NH:24][CH3:25])[N:21]=[CH:20][N:19]=3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CNc1cc(-n2cc(-c3ccc(C(=O)[O-])cc3)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Reactant: NCCN1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(-n2cc(-c3ccc(C(=O)NCCN4CCOCC4)cc3)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Yield: 24 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU; 63 mg, 0.167 mmol) was added to a mixture solution of 4-(6-(4-methoxyphenyl)-1-(6-(methylamino)pyrimidin-4-yl)-1H-indol-3-yl)benzoate (50 mg, 0.111 mmol), 2-morpholinoethanamine (14.6 μL, 0.111 mmol) and diisopropylethylamine (DIPEA; 29 μL, 0.167 mmol) in THF (2 mL) at room temperature. 2 hours later, the mixture was added to saturated sodium bicarbonate aqueous solution and then extracted with methylene chloride. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The residue was purified by chromatography (preparative HPLC). The target compound (15 mg) was obtained as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=1)[C:23](Cl)=[O:24]>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=1)[C:23]([NH:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[NH:12][C:13](=[O:15])[NH:14][C:7]=23)[CH:3]=1)=[O:24]
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1ccnc(Cl)c1
Yield: 49 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 2-chloroisonicotinoyl chloride to afford the title compound (39 mg, 49%). 1H-NMR (δ, ppm, DMSO-d6): 6.50 (d, 1H, HPy,5, J=6.0 Hz), 6.96 (d, 1H, Harom, J=8.0 Hz), 7.45 (t, 1H, Harom, J=8.0 Hz), 7.59 (t, 1H, Harom, J=2.0 Hz), 7.64 (d, 1H, Harom, J=8.0 Hz), 7.82 (d, 1H, HPy,6, J=6.0 Hz), 7.85 (d, 1H, Harom, J=5.0 Hz), 7.97 (s, 1H, Harom), 7.61 (d, 1H, Harom, J=5.0 Hz), 10.66 (s, 1H, NHamide), 11.21 (s, 1H, NHPy3), 11.42 (s, 1H, NHPy2). HRMS (EI): m/z [M+H] calcd for C18H13N5O3Cl: 382.0707; found: 382.0702.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.Cl[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:24][C:25]1[CH:30]=[N:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: COc1ccc(CCl)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c3c(c(=O)n2-c2ccc(F)cc2F)[C@@H]2CC[C@@]3(C)C2(C)C)cn1
Temperature: 100 °C
Yield: 8.7 %

Procedure:
A mixture of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 480 mg, 1.6 mmol), 5-chloromethyl-2-methoxy-pyridine (Intermediate 50; 995 mg, 6.3 mmol) and tetrabutylammonium iodide (583 mg, 1.6 mmol) in dimethylformamide (63 mL) was heated at 100° C. for 48 h. The solvent was evaporated and dichloromethane (150 mL) was added. The solution was washed with saturated aqueous sodium thiosulfate (200 mL), saturated aqueous sodium hydrogen carbonate (200 mL) and brine (200 mL), dried (sodium sulfate), filtered, evaporated and purified using a Biotage 40M system, eluting with 20-50% ethyl acetate/hexanes and then 2% methanol/dichloromethane, to give a crude product that contains some tetrabutylammonium iodide. This material was taken up in dichloromethane (50 mL) and washed with 5% dimethylformamide in water (2×100 mL) and water (5×100 mL). The organic phase was dried (sodium sulfate), filtered and evaporated to give (4R,7S)-2-(2,4-difluoro-phenyl)-1-(6-methoxy-pyridin-3-ylmethyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (59 mg, 9%). APCI(+)-MS (M+H) 426.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@@H:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1>ClCCl>[C:1]([O:5][C:6](=[O:13])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C2CCOCC2)C1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
(R)-Pyrrolidin-3-yl carbamic acid tert-butyl ester (200 mg; 1.074 mmol) was suspended in 7 ml of dichloromethane and sodium triacetoxyborohydride (455 mg; 2.15 mmol) was added. A solution of tetrahydro-4H-pyran-4-one (0.297 ml; 3.22 mmol) in 3 ml of dichloromethane was added drop-wise to the reaction mixture. The reaction mixture was maintained at room temperature overnight, it was then diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was dried with MgSO4 and concentrated in vacuo. The product was obtained after loading the crude on a SCX-cartridge and recovering with MeOH/ammonia solution. 220 mg (0.641 mmol; 60% yield) of (R)-[1-(tetrahydro-pyran-4-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester were obtained as colourless oil.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][CH:8]=1.Cl.Cl.[NH2:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:33][CH:34]1[CH2:37][N:36]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][CH:8]=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:35]1
Reactant: Nc1ccc(F)c(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)n1
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1ccc(F)c(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)n1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
To 190 mg of N,N-dimethylformamide were added 57 mg of 1-(6-amino-3-fluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 37 mg of 3-aminoazetidine dihydrochloride, and 100 mg of N-methyl-pyrrolidine, and the mixture was stirred at 90° C. for 30 minutes. After adding 0.2 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 40 mg of the title compound as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: Cc1cc(CCl)ccn1
Product: Cc1cc(Cn2cc(C(=O)N3CCC4(CC3)OCc3ccccc34)c3ccc(Cl)cc32)ccn1
Yield: 56 %

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with 4-chloromethyl-2-methyl-pyridine (described in WO 2006023707) gave the title compound in 56% yield. ES-MS m/e (%): 472.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:5]2[C:20](I)=[N:21][N:22]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:4]=2[CH:3]=1.CC([O-])(C)C.[Na+].C1COCC1>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:22]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:21]=[C:20]3[C:5]2=[C:6]([CH2:8][CH2:9][N:10]3[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[N:7]=1
Reactant: COc1ccc(CNCCc2nc(Cl)cc3c2c(I)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN2CCc3nc(Cl)cc4c3c2nn4C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 55 °C

Procedure:
2-(6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N-(4-methoxybenzyl)ethanamine (268 mg, 0.391 mmol) and RuPhos pre-catalyst (16 mg, 0.02 mmol) were charged in a 1 dram vial, evacuated and backfilled with nitrogen and taken in 1,4-dioxane (2 mL). Added a solution of 2M NaOtBu in THF (0.5 ml, 0.978 mmol) and reaction heated to 55° C. for 1 hour. The reaction mixture was diluted with EtOAc and washed with water, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-25% EtOAc-hexanes) gave 7-chloro-3-(4-methoxybenzyl)-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridine. MS ESI calc'd. for C35H29 ClN4O [M+H]+ 558. found 558.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.CCN(CC)CC.[CH:34]([NH2:37])([CH3:36])[CH3:35]>C(Cl)Cl>[CH:34]([NH:37][S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13])([CH3:36])[CH3:35]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Reactant: CC(C)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 15.9 %

Procedure:
A mixture of 74 mg (0.18 mmol) 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride, 73 mg (0.72 mmol) NEt3 and 14.8 mg (0.252 mmol) isopropylamine in 2 mL CH2Cl2 was stirred for 16 h at 50° C. The mixture was evaporated to dryness and the residue was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 12.5 mg (16%) of the title compound. MS (ESI): 436.4 (MH+).
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.[C@@H:19]12[NH:26][CH2:25][C@@H:24]1[CH2:23][CH2:22][N:21]([C:27]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[N:36]1[N:40]=[CH:39][CH:38]=[N:37]1)=[O:28])[CH2:20]2.Cl[C:42]1[CH:47]=[C:46]([CH3:48])[N:45]=[C:44]([NH:49][CH3:50])[N:43]=1>>[F:35][C:33]1[CH:32]=[CH:31][C:30]([N:36]2[N:40]=[CH:39][CH:38]=[N:37]2)=[C:29]([C:27]([N:21]2[CH2:22][CH2:23][C@@H:24]3[C@@H:19]([N:26]([C:42]4[CH:47]=[C:46]([CH3:48])[N:45]=[C:44]([NH:49][CH3:50])[N:43]=4)[CH2:25]3)[CH2:20]2)=[O:28])[CH:34]=1
Reactant: CNc1nc(C)cc(Cl)n1
Reactant: O=C(c1cc(F)ccc1-n1nccn1)N1CC[C@H]2CN[C@H]2C1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: CNc1nc(C)cc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using (1R,6S)-3,8-diazabicyclo[4.2.0]octan-3-yl(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 4-chloro-N,6-dimethyl-2-pyrimidinamine. MS (ESI) mass calcd. for O21H23FN8O, 422.5; m/z found, 423.2 [M+H]+.