Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[CH:50]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=1)=[CH2:51]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[N:53]1[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=1[CH:50]=[CH:51][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1
Reactant: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccc1
Reactant: C=Cc1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1c(C=Cc2ccccn2)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
23 mg of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one was dissolved in 20 ml of acetonitrile. To the mixture were added 0.2 mg of palladium acetate, 4.3 mg of tri-o-tolylphosphine and 0.04 ml of triethylamine, followed by stirring at 110° C. in nitrogen atmosphere overnight. To the mixture was added 9.2 mg of 2-vinylpyridine, followed by stirring at 110° C. in nitrogen atmosphere for 5 hours. After cooling to room temperature, the reaction mixture was poured into water, followed by extracting with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 2 mg of the title compound.
Reaction SMILES: O1CCOCC1.[Cl:7][C:8]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]([Cl:24])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:25]([C:27]3[C:28]([CH3:33])=[N:29][O:30][C:31]=3[CH3:32])[OH:26])[CH:14]=2)[N:9]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:7][C:8]1[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:16]([Cl:24])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:25]([C:27]3[C:28]([CH3:33])=[N:29][O:30][C:31]=3[CH3:32])=[O:26])[CH:14]=2)[N:9]=1
Reactant: Cc1noc(C)c1C(O)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1noc(C)c1C(=O)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Temperature: 100 °C

Procedure:
THF (5 mL) was added to a mixture of 6-bromo-2,4-dichloro-3-phenylquinoline (363 mg, 1.03 mmol, Intermediate 1, step c) and 3,5-dimethylisoxazole-4-carbaldehyde (180 mg, 1.44 mmol) under a nitrogen atmosphere. The resulting colorless solution was cooled in a dry ice/acetone bath. n-BuLi (1.6 M in hexane, 0.771 mL, 1.23 mmol) was added dropwise and the mixture was stirred at −78° C. for 30 min, then moved to an ice bath and stirred for 30 min. The reaction was quenched by addition of saturated aqueous NH4Cl and was diluted with water. The mixture was extracted three times with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated to afford crude (2,4-dichloro-3-phenylquinolin-6-yl)(3,5-dimethylisoxazol-4-yl)methanol which was used without further purification in the next step. 1,4-dioxane (7.5 mL) and manganese (IV) dioxide (447 mg, 5.14 mmol) were added to the crude alcohol from the prior step. The resulting black suspension was heated in a 100° C. oil bath in a sealed tube overnight. The mixture was allowed to cool, was diluted with DCM, and was filtered through Celite®. The filtrate was concentrated and the residue was purified by flash column chromatography—(silica gel, 3-15% EtOAc-heptane) to isolate the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[N:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH2:29][CH2:30][CH3:31].[C:32](OC(=O)C)(=[O:34])[CH3:33]>ClCCl.C(=O)(O)[O-].[Na+].C(#N)C>[NH2:28][C:19]1[C:18]2[N:17]=[C:16]([CH2:29][CH2:30][CH3:31])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:10]([O:9][CH3:8])[C:32](=[O:34])[CH3:33])[C:27]=2[C:26]2[N:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: CCCc1nc2c(N)nc3cccnc3c2n1CCCCNOC
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: CCCc1nc2c(N)nc3cccnc3c2n1CCCCN(OC)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
Triethylamine (0.24 mL, 1.69 mmol, 1.2 eq) was added to 1-[4-(methoxyamino)butyl]-2-propyl-1H-imidazo[4,5-c]-1,5-naphthyridin-4-amine (0.46 g, 1.41 mmol, 1.0 eq) in dichloromethane (6 mL) and cooled to 0° C. Acetic anhydride (0.13 mL, 1.41 mmol, 1.0 eq) was added dropwise and the reaction mixture was stirred for 1 hour. The reaction was then diluted with dichloromethane (40 mL) and saturated aqueous sodium bicarbonate (30 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (20 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated to afford a yellow solid, which was purified by HPFC (silica gel eluting with 0-25% CMA in chloroform) to afford 0.49 g of a pale yellow substance. The material was dissolved in acetonitrile (10 mL), sonicated for 2 minutes, filtered, and dried under vacuum at 100° C. for 24 hours to afford 0.278 g of N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N-methoxyacetamide as off-white needles, mp 155-156° C. Anal. calcd for C19H26N6O2: C, 61.60; H, 7.07; N, 22.69. Found: C, 61.58; H, 7.31; N, 22.64.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Li]C(C)(C)C.[CH3:16][S:17]SC>C1COCC1>[CH3:16][S:17][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CSSC
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CSc1ccc2cc[nH]c2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a solution of 6-bromo-1H-indole (5 g, 25.50 mmol) in anhydrous THF (60 mL) at 0° C. was added KH (6.80 g, 51.00 mmol, 30% wt in mineral oil). After stirring for 30 min, the mixture was cooled to −78° C. and t-BuLi (39.23 mL, 51.0 mmol, 1.3 M) was added under nitrogen. After 30 min, 1,2-dimethyldisulfane (4.80 g, 51.0 mmol) was added to the mixture. The reaction mixture was stirred at −78° C. for 1 h and quenched with sat. aq NH4Cl (30 mL) at −78° C. slowly (Caution: flame), adjusted pH=7 with 1 N aqueous phosphoric acid and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography on silica gel eluted with (petroleum ether/EtOAc 10:1) to give 6-(methylthio)-1H-indole (3.9 g, 93.67% yield) as a grey solid. LC-MS MS (ESI) m/z 164.1 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 8.14 (brs, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.37 (s, 1H), 7.18-7.11 (m, 1H), 6.56-6.51 (m, 1H), 2.52 (s, 3H).
Reaction SMILES: [NH:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:14][C:15]([F:50])([F:49])[C:16]1[CH:17]=[C:18]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:19][N:20]1[CH2:25][C:24]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=2)([CH2:26][CH2:27]OS(C)(=O)=O)[CH2:23][O:22][C:21]1=[O:41].C(=O)([O-])[O-].[K+].[K+].[ClH:57]>C(#N)C.CCOCC.O>[OH2:22].[ClH:39].[ClH:57].[NH:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:27][CH2:26][C:24]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=3)[CH2:23][O:22][C:21](=[O:41])[N:20]([CH2:19][C:18]3[CH:17]=[C:16]([C:15]([F:49])([F:50])[F:14])[CH:44]=[C:43]([C:45]([F:47])([F:46])[F:48])[CH:42]=3)[CH2:25]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(NC2CCNCC2)cc1
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)COC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: O=C1OCC(CCN2CCC(Nc3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A mixture of 0.3 g of 4-anilinopiperidine, 0.8 g of the compound obtained in step C of EXAMPLE 4 and 0.69 g of potassium carbonate in 5 ml of acetonitrile is heated at 50°-60° C. for 5 hours. The reaction mixture is poured into water and extracted with AcOEt, the organic phase is washed twice with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (96/4; v/v) as the eluent. The product obtained is taken up with a saturated solution of gaseous HCl in ether and the precipitate formed is wrung to give 0.12 g of the expected product. M.p.=158° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:19][CH:20]=O)[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[NH:22]1[CH2:25][CH:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:23]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH2:19][CH2:20][N:22]2[CH2:25][CH:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH2:23]2)[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:6][CH:7]=1
Reactant: C1CN(C2CNC2)CCO1
Reactant: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C[C@@H](CCN1CC(N2CCOCC2)C1)c1ccc(F)cc1)C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 19.7 %

Procedure:
tert-Butyl [(2S)-2-(4-fluorophenyl)-4-oxobutyl]methylcarbamate (1.57 g, 5.3 mmol) and 4-azetidin-3-ylmorpholine (0.83 g, 5.8 mmol) were dissolved in CH2Cl2 (60 mL) together with DIPEA (1.4 g, 10.6 mmol). The mixture was stirred for 20 min and then sodium triacetoxyborohydride (1.6 g, 7.4 mmol) was added. The mixture was stirred at room temperature for 6 h and then the solvent was removed by evaporation. The residue was partitioned between an aqueous solution of NaHCO3 and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the organic solution was dried over MgSO4 and then removed by evaporation. The product was chromatographed on a silica gel using a mixture of methanol and CH2Cl2 (5%-20% methanol) and there was obtained 440 mg (20%) tert-butyl [(2S)-2-(4-fluorophenyl)-4-(3-morpholin-4ylazetidin-1-yl)butyl]methylcarbamate as an oil. 1H NMR (400 MHz, CDCl3): 1.3 (s, 9H), 1.4-1.6 (m, 2H), 2.1-2.3 (b, 5H), 2.5-3.8 (cm, 16H), 6.9 (t, 2H), 7.0-7.1 (b, 2H); LCMS: m/z 422 (M+1)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:8][CH2:9][C:10](=[O:11])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:31][CH2:30]2)[CH:24]=1)=[O:21]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(=O)c3ccccc3)CC2)c1

Procedure:
Procedure K (KI) and Scheme E (K2CO3) using 3-chloro-1-phenyl-1-propanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 379.2 (M+H)+.
Reaction SMILES: [I-].[NH:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([CH2:15][N+:16]([CH3:19])([CH3:18])C)=[N:3]1.C1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]CN1.C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[CH2:19]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:18][N:16]1[CH2:15][C:4]1[C:5]2[CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[C:10]=2[NH:2][N:3]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: C[N+](C)(C)Cc1n[nH]c2c1CCc1ccccc1-2
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(c1)CCN(Cc1n[nH]c3c1CCc1ccccc1-3)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 33 %

Procedure:
A solution of (4,5-dihydro-1H-benzo[g]indazol-3-ylmethyl)-trimethylammonium iodide (0.40 g), 1,2,3,4-tetrahydroisoquinoline (0.20 cm3) and diisopropylethylamine (0.28 cm3) in DMF (10 cm3) was heated under argon at 80° C. for 24 hours, then stirred at room temperature for 48 hours. The mixture was poured into water (30 cm3) and extracted with ethyl acetate (2×20 cm3). The organic extracts were dried (MgSO4), filtered and concentrated. Flash column chromatography on silica gel, eluting with 5% ethanol-ethyl acetate, gave a yellow oil that crystallised on standing. The material was recystallised from ethyl acetate-hexane to give the title compound (0.111 g; 33%) as white needles, m.p. 180°-182° C. (from EtOAc-hexane); Found: C, 79.7; H, 6.7; N, 13.1. C21H21N3 requires C, 80.0; H, 6.7; N, 13.3%. δH (360 MHz; CDCl3) 2.72-2.80 (4H, m, 2 x --CH2 --), 2.90-2.98 (4H, m, 2 x --CH2 --), 3.70 (2H, s, --CH2N), 3.73 (2H, s, --CH2N), 6.99 (1H, d, J5.8, 1 of ArH), 7.10-7.28 (6H, m, 6 of ArH) and 7.79 (1H, d, J 7.3, 1 of ArH); m/z (CI+ ; NH3) 316 (MH+ ; 100%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].CCCCCC.CC(O)C.C(O)C>C(#N)C>[CH3:1][C:2]1[C:3]([CH2:14][S@:15]([C:17]2[NH:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:11])[F:12]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Solvent: CC(C)O
Solvent: CCO
Solvent: CCCCCC
Product: Cc1c(OCC(F)(F)F)ccnc1C[S@@](=O)c1nc2ccccc2[nH]1
Yield: 40.2 %

Procedure:
2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole (lansoprazole) (racemate) (3.98 g) was dissolved in the following mobile phase (330 ml) and acetonitrile (37 ml) and fractionated by HPLC (column: CHIRALCEL OD 20 mm dia.×250 mm, temperature: 30° C., mobile phase: hexane/2-propanol/ethanol=255/35/10, flowrate: 16 ml/min, detection wavelength: 285 nm, 1 shot: 20-25 mg). Fractions of optical isomers of shorter retention time were combined and concentrated; the individual lots were combined and dissolved in ethanol and filtered through a 0.45 μm filter; after hexane was added, the filtrate was again evaporated to dryness to yield R(+)-lansoprazole (1.6 g, optical purity>97.6% ee) as an amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[C:5]([C:15]#[N:16])=[C:4]([SH:17])[N:3]=1.Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[S:23][CH:24]=1.C(=O)(O)[O-].[Na+].O>CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1cc[nH]n1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cc[nH]n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
50 mg (0.21 mmol) of the compound from Example 6A and 156 mg (0.64 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole were dissolved in 1 ml of dimethylformamide, 52 mg (0.62 mmol) of sodium bicarbonate were added and the mixture was stirred at RT for 2.5 h. About 10 ml of water were added to the mixture, and the solid formed was purified by preparative HPLC (acetonitrile/water 10:90→95:5, 0.1% TFA added).
Reaction SMILES: C1(N)CCCCCCC1.CCC(C(Cl)=O)=O.[CH:17]1([NH:25][C:26](=[O:32])[C:27]([O:29]CC)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[Na]>C(Cl)(Cl)Cl.C(O)C>[CH:17]1([NH:25][C:26](=[O:32])[C:27]([OH:29])=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)C(=O)NC1CCCCCCC1
Agent: CCC(=O)C(=O)Cl
Agent: NC1CCCCCCC1
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=C(O)C(=O)NC1CCCCCCC1
Temperature: 10 °C

Procedure:
To a solution of cyclooctylamine (12.7 g., 0.10 mole) in chloroform (50 ml.) at 10°-20° C. is added dropwise ethyloxalyl chloride (6.83 g., 0.05 mole) in chloroform (50 ml.) over a period of 30 minutes. After stirring for 2 additional hours at 10° C., the mixture is washed with H2O (4×50 ml.), and the organic layer dried over Na2SO4. After filtration and evaporation an oil is obtained (11.3 g.). To the crude ethyl N-cyclooctyloxamate dissolved in ethanol (27 ml.) is added sodium (1.15 g., 0.05 mole) dissolved in absolute ethanol (35 ml.) and the mixture is stirred overnight. Following evaporation, the residue is dissolved in H2O (41 ml.) with heating, and the solution filtered while hot. The filtrate is acidified with 6 N HCl, and the resulting slurry cooled at ice temperature. The solid obtained by filtration is recrystallized from boiling H2O (100 ml.) to give N-cyclooctyloxamic acid, m.p. 115°-116° C.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[Si:20]([O:19][CH2:18][CH2:17][N:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: C1CCCNCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCN1CCCCCCC1
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of azocane (5.59 g, 49.4 mmol) and triethylamine (6.53 g, 64.7 mmol) in DCM (50 mL) at room temperature was added (2-bromoethoxy)(tert-butyl)dimethylsilane (13.0 g, 54.4 mmol). The mixture was stirred overnight, and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed (brine (2×)), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure, and the residue was purified on a silica gel column (eluting with PE/EA=10/1) to afford 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)azocane (11.8 g, 88%). LCMS: 272 (M+H)+.
Reaction SMILES: [F:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7](=[O:41])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:3]1.FC(F)(F)C(O)=O.C(N)CN.O>ClCCl.C(OCC)(=O)C>[F:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7](=[O:41])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:3]1
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC[C@H](F)C1
Solvent: NCCN
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 56.7 %

Procedure:
2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-((S)-3-fluoro-pyrrolidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (54 mg, 0.09 mmol) was dissolved in dichloromethane (0.9 ml) and cooled in ice bath. Trifluoroacetic acid (0.45 ml) was slowly added and the reaction was stirred at room temperature for 2.5 h. The reaction was evaporated and the residue was suspended in dichloromethane (0.9 ml). Ethylenediamine (0.36 ml, 5.4 mmol) was added and the mixture was stirred for 18 h. Water and then ethyl acetate were added to the mixture. The resulting precipitate was filtered off, rinsed with water and dried under high vacuum to give 24 mg (58%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-((S)-3-fluoro-pyrrolidin-1-yl)-1-methyl-2-oxo-ethyl]-amide. MS: (M+H)+=470; mp=269-271° C. 1H NMR (300 MHz, DMSO-d6) δ: 9.16 (s, 1H), 8.81-8.91 (m, 1H), 8.53-8.62 (m, 1H), 8.47 (d, J=2.0 Hz, 1H), 7.97 (s, 1H), 7.25-7.33 (m, 1H), 5.27-5.52 (m, 1H), 4.95-5.11 (m, 1H), 4.18 (s, 3H), 3.96-4.12 (m, 1H), 3.73-3.92 (m, 1H), 3.61-3.72 (m, 1H), 2.08-2.35 (m, 1H), 1.38-1.48 (m, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH2:3][CH2:2]1.Cl.[NH2:21][C:22]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:23]([O:25][CH3:26])=[O:24]>>[CH3:26][O:25][C:23](=[O:24])[C:22]([NH:21][C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:8]=1)=[O:19])([CH2:29][CH3:30])[CH2:27][CH3:28]
Reactant: CCC(N)(CC)C(=O)OC
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Agent: Cl
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CCCO2)n1)C(=O)OC

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 b) and methyl 2-amino-2-ethylbutanoate hydrochloride (CAN 92398-54-4) as starting materials, MS (EI): m/e=391.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2NN=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:9][CH:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(C2CC(c3ccccc3)=NN2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1cccc(C2CC2c2ccccc2)c1
Temperature: 250 °C
Yield: 58.2 %

Procedure:
To a 250 ml round bottom flask equipped with nitrogen inlet, thermometer, and reflux condenser was charged 3.5 g (0.0147 moles) of 5-(3-hydroxyphenyl)-3-phenyl-2-pyrazoline, and 4.2 g (0.1 moles) of powdered sodium hydroxide. The two solids were mixed thoroughly, then heated slowly to 250° C., under a rapid stream of nitrogen. The reaction mixture was heated continuously at 250° C. for a total of 2 hours, then cooled to ambient temperature. The resulting residue was the dissolved in 200 mls of water, then acidified to pH 2 with 1 N aqueous hydrochloric acid. The acidic solution was extracted with 3×100 mls of ethyl ether, and the ether extract was washed with 2×100 mls of water, and 100 mls of saturated aqueous sodium chloride solution. The ether extract was the dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure with a rotary evaporator at 45° C. The resulting crude product was chromatographed on silica gel with a 15% ethyl acetate, 85% hexane mobile phase. The pure fractions were combined and concentrated under reduced pressure on a rotary evaporator to afford 1.8 g of the title compound 1-(3-hydroxyphenyl)-2-phenyl-cyclopropane as a pale yellow liquid. 58% yield.
Reaction SMILES: C(NC1C(=CC=CC=1)C(O)=O)C.[NH2:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:19]([O:18][C:16](=[O:17])[C:15]1[CH:21]=[CH:22][CH:23]=[CH:24][C:14]=1[NH:13][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1ccccc1N
Agent: CCNc1ccccc1C(=O)O
Product: CCOC(=O)Nc1ccccc1C(=O)OCC
Yield: 95.5 %

Procedure:
A mixture of ethyl 2-aminobenzoate (ethyl anthranilate) (50.0 g, 0.30 mole) and ethyl chloroformate (32.8 g, 0.30 mole) in 400 mL of xylenes was heated at reflux for 8 hours. The xylene was removed and the residue was dissolved in chloroform. The chloroform layer was extracted with 5% sodium hydroxide, dried (Na2SO4), filtered, and the chloroform removed to give an oil which crystallized. The solid was triturated with isopropyl ether and placed in the freezer. Two crops of white solid were obtained and dried in vacuo overnight at room temperature. This provided 67.95 g (97.6% yield) of white crystalline solid, mp 41°-42° C.