Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Br)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>C1COCC1>[CH:14]1([N:17]2[CH2:2][CH2:3][N:4]3[N:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[C:8]3[CH2:9]2)[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc2n(n1)CCN(C1CC1)C2
Temperature: 30 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
A mixture of 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole 113c (4 g, 12.9 mmol) and cyclopropanamine (7.35 g, 129 mmol) in THF (40 mL) was stirred at 30° C. overnight. After the completion of the reaction, the mixture was filtered and the solid was washed with THF (100 mL). The filtrate was concentrated under reduced pressure to give 128a (2.68 g, 99%). MS: [M+H]+ 209.
Reaction SMILES: O1CCCC1.C([N-]C(C)C)(C)C.[Li+].[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.CON(C)[C:24]([C:26]1[CH:34]=[C:33]2[C:29]([C:30]([CH:36]([C:50]3[CH:58]=[CH:57][C:53]4[O:54][CH2:55][O:56][C:52]=4[CH:51]=3)[C:37]([NH:39][S:40]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=3)(=[O:42])=[O:41])=[O:38])=[CH:31][N:32]2[CH3:35])=[CH:28][CH:27]=1)=[O:25]>O1CCCC1>[O:54]1[C:53]2[CH:57]=[CH:58][C:50]([CH:36]([C:30]3[C:29]4[C:33](=[CH:34][C:26]([C:24](=[O:25])[CH2:14][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=5)=[CH:27][CH:28]=4)[N:32]([CH3:35])[CH:31]=3)[C:37]([NH:39][S:40]([C:43]3[CH:44]=[CH:45][C:46]([CH3:49])=[CH:47][CH:48]=3)(=[O:42])=[O:41])=[O:38])=[CH:51][C:52]=2[O:56][CH2:55]1
Reactant: Cc1ccccn1
Reactant: CON(C)C(=O)c1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C)cc3)c3ccc4c(c3)OCO4)cn(C)c2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(C(=O)Cc4ccccn4)ccc23)cc1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
Lithium diisopropylamide mono(tetrahydrofuran) (0.53 ml of 1.5M solution in cyclohexane) was added to a stirred solution of 2-methylpyridine (0.08 ml, 0.8 mmol) in anhydrous tetrahydrofuran (3 ml) at -70° C. under a nitrogen atmosphere. After 20 minutes a solution of N6-methoxy-N6,1-dimethyl-3-{1-(1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-1H-6-indolecarboxamide (the compound of Example 103, 200 mg, 0.36 mmol) in anhydrous tetrahydrofuran (2 ml) was added to the mixture at -70° C. The mixture was stirred at -70° C. for an additional 2 hours before being warmed to 0° C. and then quenched with the addition of water (5 ml). The mixture was acidified with acetic acid, and extracted with ethyl acetate (100 ml). The organic phase was separated and washed with brine, dried (magnesium sulphate) and the solvent was removed in vacuo. The residue was flash chromatographed using a gradient elution of a mixture of 90% hexane and 10% ethyl acetate, through to 100% ethyl acetate, to give the title compound (95 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C@:6]12[CH2:14][C@H:13]1[C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)=[N:20][NH:21]2)=[CH:17][CH:16]=1.[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>C(Cl)Cl>[F:46][C:45]([F:48])([F:47])[C:43]([OH:49])=[O:44].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C@:6]12[CH2:14][C@H:13]1[C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[CH:26][CH:25]=3)=[N:20][NH:21]2)=[CH:17][CH:16]=1
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)n[nH]c3c1)C(=O)N2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(C5CCNCC5)cc4)n[nH]c3c1)C(=O)N2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 19.1 %

Procedure:
To a solution of tert-butyl 4-(4-(6-((1R,2S)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-2-yl)-1H-indazol-3-yl)phenyl)piperidine-1-carboxylate (102 mg, 0.181 mmol) in CH2Cl2 (5 mL) was added TFA (0.4 mL, 5.4 mmol). The resulting reaction mixture was stirred at rt for 2.5 h. The crude reaction mixture was concentrated under reduced pressure to dryness, and purified by preparative HPLC to give the title compound as a yellow solid (20 mg, 72%). 1H NMR (400 MHz, MeOD) δ 7.89 (d, J=8.2 Hz, 3H), 7.47 (s, 1H), 7.41 (d, J=8.2 Hz, 2H), 7.01 (d, J=8.6 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.91 (dd, J=8.4, 2.4 Hz, 1H), 5.60 (d, J=2.3 Hz, 1H), 3.56-3.50 (m, 2H), ), 3.39-3.32 (m, 1H), 3.25 (s, 3H), 3.17 (t, J=11.9 Hz, 2H), 3.02-2.92 (m, 1H), 2.25-2.22 (m, 1H), 2.19-2.01 (m, 3H), 2.02-1.91 (m, 2H); MS ESI 465.3 [M+H]+, calcd for [C29H28N4O2+H]+ 465.22.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11]3[C:14]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[CH:15][C:16]4[NH:17][C:18]([CH3:21])=[N:19][C:20]=4[C:10]=3[O:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:30][C:31]1[CH:35]=[CH:34][O:33][N:32]=1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11]3[C:14]([C:22]([N:24]([CH3:25])[CH3:26])=[O:23])=[CH:15][C:16]4[N:17]=[C:18]([CH3:21])[N:19]([CH2:30][C:31]5[CH:35]=[CH:34][O:33][N:32]=5)[C:20]=4[C:10]=3[O:9]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccon1
Reactant: Cc1nc2c3c(c(C(=O)N(C)C)cc2[nH]1)CCC(c1ccc(F)cc1)O3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(C(=O)N(C)C)c3c(c2n1Cc1ccon1)OC(c1ccc(F)cc1)CC3
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a solution of 8-(4-fluorophenyl)-N,N,2-trimethyl-3,6,7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide (50.0 mg, 0.141 mmol, Step 8 of Example 8) in N,N-dimethylformamide (1.4 mL), was added sodium hydride (6.7 mg, 0.17 mmol) at 0° C. and the mixture was stirred at 0° C. for 30 minutes. Then a solution of 3-(bromomethyl)isoxazole in N,N-dimethylformamide (1.0 mL, Step 1) was added to the mixture at 0° C. The mixture was allowed to warm to room temperature, stirred for 4 hours and left at the same temperature overnight. The reaction was quenched by saturated ammonium chloride aqueous solution. The mixture was extracted twice with ethyl acetate. The combined organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative TLC eluting with hexane/ethyl acetate (1:1, twice), then dichloromethane/methanol (20:1, twice) to afford the title compound as a pale yellow solid (23.5 mg, 38%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=1)[CH2:9][CH3:10].S(=O)(=O)(O)O.[CH2:27](O)[CH3:28]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([CH2:17][O:19][CH2:27][CH3:28])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)O)nn1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOCc1ccc(N(CC)Cc2cc(Br)ccc2O)nn1

Procedure:
The 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridazine-3-carboxylic acid (example 8) (6.5 g) was suspended in ethanol (30 ml) and treated cautiously with concentrated sulphuric acid (1.5 ml). The reaction was heated to reflux overnight, then the organic solvent was evaporated. The residue was partitioned between ethyl acetate/water and the organic phase was dried over (MgSO4) and evaporated to give the title compound as a brown solid (5.86 g).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.[C:16]([O:19][CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:24]=[C:23]([CH3:35])[C:22]=1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42]O)[CH:37]=1)(=[O:18])[CH3:17].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[C:16]([O:19][CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:24]=[C:23]([CH3:35])[C:22]=1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][O:1][C:2]2[CH:15]=[CH:14][C:5]3[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=3[CH:3]=2)[CH:37]=1)(=[O:18])[CH3:17]
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: CC(=O)OCc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OCCCS(C)(=O)=O)cc4COC(C)=O)c3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
A solution of methyl [(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (0.208 g, 1.00 mmol), {3′-(hydroxymethyl)-6-methyl-4-[3-(methylsulfonyl)propoxy]biphenyl-2-yl}methyl acetate (0.360 g, 1.00 mmol) and tributylphosphine (0.324 g, 1.60 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.404 g, 1.60 mmol) was added, and the mixture was stirred at room temperature for 3 hr under nitrogen atmosphere. Hexane (8 mL) was added to the reaction mixture, the precipitated insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30) to give the title compound (0.432 g, yield 79%) as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([C:36]1([O:39]C(=O)C)[CH2:38][CH2:37]1)=[O:35]>>[OH:39][C:36]1([C:34]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=5[O:28][CH2:29][CH:30]5[CH2:31][CH2:32]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:35])[CH2:38][CH2:37]1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)C5(O)CC5)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A150) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[N:21]=[C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][N:32](C(OCC5C=CC=CC=5)=O)[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[C:19]([C:45](=[O:47])[NH2:46])=[CH:18][CH:17]=2)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CCO.[Pd]>[C:1]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[CH:18][C:19]([C:45]([NH2:46])=[O:47])=[C:20]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]4)=[CH:27][CH:28]=3)[N:21]=2)[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)c3ccccc3)C2)nc1Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)c3ccccc3)C2)nc1Nc1ccc(N2CCNCC2)cc1
Yield: 98.5 %

Procedure:
To a suspension of (R)-benzyl 4-(4-(6-(3-benzamidopiperidin-1-yl)-3-carbamoylpyridin-2-ylamino)phenyl)piperazine-1-carboxylate (1.12 g, 1.767 mmol) in EtOAc (10 mL) and EtOH (10.00 mL) was added Pd/C (0.188 g, 0.177 mmol) under nitrogen. The resulting mixture was hydrogenated at 50 psi in a parr shaker overnight. The reaction mixture was filtered and the filtrate was concentrated to give 870 mg of (R)-6-(3-benzamidopiperidin-1-yl)-2-(4-(piperazin-1-yl)phenylamino)nicotinamide. LCMS: (M+H)+=500.14. 1H NMR (400 MHz, CDCl3-MIX) δ ppm 10.64 (1H, s), 7.51-7.59 (3H, m), 7.35-7.44 (3H, m), 7.28-7.34 (2H, m), 6.96 (1H, d, J=7.03 Hz), 6.75 (2H, d, J=9.23 Hz), 6.01 (1H, d, J=8.79 Hz), 4.10 (1H, br. s.), 3.75-3.83 (1H, m), 3.66-3.73 (1H, m), 3.58-3.66 (1H, m), 3.47-3.57 (1H, m), 3.15-3.20 (4H, m), 2.88-2.95 (4H, m), 1.82-1.96 (2H, m), 1.65-1.76 (1H, m), 1.54-1.65 (1H, m).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12](=O)[CH2:13][CH2:14][C:15]([OH:17])=O)[CH:8]=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2].S(Cl)(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>[N+](C)([O-])=O>[CH3:11][C:10]1[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][C:7]2[CH2:12][CH2:13][CH2:14][C:15](=[O:17])[C:8]=2[CH:9]=1
Reactant: CC(=O)Nc1cc(C(=O)CCC(=O)O)ccc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: CC(=O)Nc1cc2c(cc1C)C(=O)CCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.9 %

Procedure:
In a mechanically stirred 50 L vessel, 4-(3-acetamido-4-methylphenyl)-4-oxobutanoic acid (74) (675 g, 2.87 mol) was dissolved in nitromethane (13.75 L). Thionyl chloride (255 mL, 3.49 mol) was added. The resulting mixture was stirred for about 1.5 h at rt. AlCl3 (973 g, 7.30 mol) was added maintaining a temperature of about 25° C. The resulting mixture was stirred for another about 30 min and then poured onto ice water (30 L). The resulting mixture was extracted with EtOAc (1×60 L then 2×20 L). The organic layers were combined and washed with sat. aq. NaCl (1×10 L), 1 M aq. NaOH (15 L) and sat. aq. NaCl (1×10 L). The organic layer was dried over Na2SO4, filtered, and concentrated to afford N-(3-Methyl-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide (380 g, 65% yield). 1H NMR (300 MHz, DMSO): δ 9.36 (s, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 2.86 (m, 2H), 2.55 (m, 2H), 2.23 (s, 3H), 2.06 (s, 3H), 2.00 (m, 2H).
Reaction SMILES: FC1C=C(C=C(C(F)(F)F)C=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])C)=O.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:41]=1)[C:36]([OH:38])=O>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:7]([CH3:5])[C:36](=[O:38])[C:35]2[CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:41]=[C:33]([O:32][CH3:31])[CH:34]=2)=[C:16]([O:22][CH3:23])[CH:17]=1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Reactant: COc1cc(C(=O)O)cc(C(F)(F)F)n1
Product: COc1cc(C(=O)N(C)c2cnccc2-c2ccc(F)cc2OC)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-methyl-amine (example 129, intermediate) and 2-methoxy-6-trifluoromethyl-isonicotinic acid after a reaction time of 64 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100), followed by a second chromatography using preparative HPLC (Gemini NX column) and a gradient of methanol:water (containing 0.1% formic acid) (20:80 to 98:2) as eluant. Colorless solid (33%). MS (ESI): m/z=436.13 [M+H]+.
Reaction SMILES: CO.[NH3:3].[Si:4]([O:21][CH2:22][C@@H:23]1[CH2:27][C@H:26]([N:28]2[C:32]3[N:33]=[CH:34][N:35]=[C:36](Cl)[C:31]=3[C:30]([I:38])=[CH:29]2)[CH2:25][N:24]1[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])([C:17]([CH3:20])([CH3:19])[CH3:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1COCC1>[NH2:3][C:36]1[C:31]2[C:30]([I:38])=[CH:29][N:28]([C@@H:26]3[CH2:25][N:24]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:23]([CH2:22][O:21][Si:4]([C:17]([CH3:20])([CH3:19])[CH3:18])([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:27]3)[C:32]=2[N:33]=[CH:34][N:35]=1
Reactant: N
Reactant: CC(C)(C)OC(=O)N1C[C@@H](n2cc(I)c3c(Cl)ncnc32)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](n2cc(I)c3c(N)ncnc32)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 120 °C
Reaction time: 2 h

Procedure:
THF (10 ml) and an 8N ammonia methanol solution (5 ml) were added to the (2S,4S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (400 mg) obtained in Step 1. The mixture was stirred at 120° C. for 2 hours under microwave irradiation, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: chloroform/ethanol) to obtain the title compound as a light-yellow solid (293 mg). Physical properties: m/z [M+H]+ 698.5
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[O:23][C:24](=[O:29])[NH:25][CH2:26][CH2:27]Br)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:51]([NH:53][CH3:54])[CH3:52]>C(Cl)(Cl)Cl>[CH2:51]([N:53]([CH2:27][CH2:26][NH:25][C:24]([O:23][CH:22]([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:21][O:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:29])[CH3:54])[CH3:52]
Reactant: CCNC
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)OC(=O)NCCBr
Solvent: ClC(Cl)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)OC(=O)NCCN(C)CC
Reaction time: 8 h
Yield: 81.7 %

Procedure:
In 3 ml of chloroform was dissolved 131 mg (0.170 mmol) of 1,3-O-dioleoyl-2-O-(2-bromoethyl) carbamoylglycerol followed by addition of 470 mg (7.951 mmol) of N-ethylmethylamine and the reaction was conducted in a sealed tube at 80° C. overnight. This reaction mixture was then washed with 5% sodium dihydrogen phosphate-H2O, dried and concentrated. The residue was subjected to column chromatography (silica gel/methylene chloride-methanol) to provide 104 mg (81.5%) of the title compound.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10](OCC)(=[O:14])[CH:11]([CH3:13])[OH:12]>>[CH2:1]([NH:9][C:10](=[O:14])[CH:11]([CH3:13])[OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN
Reactant: CCOC(=O)C(C)O
Product: CCCCCCCCNC(=O)C(C)O
Temperature: 90 °C

Procedure:
388 g (3 mol) of n-octylamine were added to 473 g (4 mol) of ethyl lactate in a round-bottomed flask with a distillation apparatus over the course of two hours with stirring and a nitrogen purge. When the addition was complete, the temperature was increased to 90° C. and the ethanol which formed was distilled. The temperature was then increased to 140° C. and maintained for one hour. The pressure was then reduced to 50 mbar and unreacted ethyl lactate was distilled. 585 g of octllactamide were obtained as a clear, pale pink-colored liquid. 1H-NMR (400 MHz, CDCl3): 0.8 ppm (3H), 1.2 ppm (10H), 1.4 ppm (3H), 1.5 ppm (2H), 3.2 ppm (2H), 4.0 ppm (0.8H, br), 4.2 ppm (1H), 6.8 ppm (1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][N:3]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(Cn2ccnc2)cn1
Temperature: 80 °C
Yield: 68.7 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (500 mg, 3.08 mmole) in 4 mL of dry acetonitrile is added 420 mL (6.17 mmol) of imidazole followed by 852 mg (6.17 mmol) of potassium carbonate. The reaction is heated at 80° C. for 20 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 410 mg (69% yield) of 2-Chloro-5-imidazol-1-ylmethyl-pyridine. Diagnostic C13 NMR (100 MHz, CDCl3) 47.7, 119.2, 124.9, 130.6, 131.1, 137.5, 137.8, 148.6, 151.8; MS 194.2 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:24][C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)[CH:14]=[C:15]([O:16]CC3C=CC=CC=3)[C:7]1=2)[CH3:2]>C1COCC1.CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:24][C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)[CH:14]=[C:15]([OH:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(OCc3ccccc3)c21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(O)c21
Yield: 62.1 %

Procedure:
A solution of [4-benzyloxy-1-hydroxy-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (410 mg, 0.976 mmol) in THF/EtOH (20 mL, 1:1) was degassed 3 times and Pd/C (40 mg) was added. The suspension was degassed 3 times and charged with H2 at room temperature overnight. The reaction was filtered through a pad of Celite and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC to give the title compound (200 mg, 62%). MS calcd for (C15H15BN2O6+H)+: 331.1. MS found: (M+H)+=331.1.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[OH:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[S:22][C:21]3[C:16](=[N:17][CH:18]=[CH:19][C:20]=3[Cl:23])[CH:15]=2)=[O:13])[CH2:8]1>>[Cl:23][C:20]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:15]=[C:14]([C:12]([N:9]3[CH2:10][CH2:11][C@H:7]([O:6][CH2:2][CH:3]4[CH2:5][CH2:4]4)[CH2:8]3)=[O:13])[S:22][C:21]=12
Reactant: BrCC1CC1
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@H](O)C1
Product: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@H](OCC2CC2)C1

Procedure:
The title compound was prepared from bromomethyl-cyclopropane and (3S)-(3-hydroxy-pyrrolidin-1-yl)-[7-chloro-thieno[3,2-b]pyridin-2-yl]-methanone by a procedure analogous to Example 67B. MS: 337.2/339.2 (MH+); HPLC Rf: 5.232 min.; 85%.
Reaction SMILES: [H-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][SH:9].Cl[C:11]1[CH:16]=[CH:15][N+:14]([O-:17])=[C:13]([CH3:18])[C:12]=1[CH3:19]>O1CCOCC1.O>[CH3:18][C:13]1[C:12]([CH3:19])=[C:11]([S:9][CH2:8][C:4]2[O:3][CH:7]=[CH:6][CH:5]=2)[CH:16]=[CH:15][N+:14]=1[O-:17]
Reactant: SCc1ccco1
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(SCc2ccco2)cc[n+]([O-])c1C
Reaction time: 0.25 h
Yield: 79.9 %

Procedure:
6 g (60% strength) of NaH are added in portions to 50 ml of dry dioxane, the mixture is stirred for 15 minutes, 11.7 g (0.11 mol) of 2-furylmethylmercaptan are metered in over a period of 20 minutes and the mixture is stirred again for 30 minutes until the evolution of gas has ended. A solution of 14.4 g (0.1 mol) of 4-chloro-2,3-dimethylpyridine N-oxide in 100 ml of dioxane is then added dropwise in the course of 20 minutes, and the reaction mixture is stirred at RT for 1 h, subsequently at 70° C. for 1 h and then at 100° C. for another 1 h. When the reaction has ended, the mixture is allowed to cool and is diluted with 500 ml of water and extracted 4 times with 300 ml of ethyl acetate each time. The combined organic phases are washed with water, dried over magnesium sulfate and concentrated and the residue is crystallized by addition of diisopropyl ether. 18.8 g (80% of theory) of 2,3-dimethyl-4-(2-furylmethylthio)-pyridine N-oxide of m.p. 111-112° C. are obtained.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1([O:33][CH3:34])[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@@H:22]([CH2:24]CS([O-])(=O)=O)[O:21][C:20]3=[O:30])=[CH:15][C:14]=2[F:31])[CH2:9][CH:8]1[F:32]>CN(C)C=O>[CH3:34][O:33][C:7]1([O:6][CH3:5])[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@@H:22]([CH2:24][N:1]=[N+:2]=[N-:3])[O:21][C:20]3=[O:30])=[CH:15][C:14]=2[F:31])[CH2:9][CH:8]1[F:32]
Reactant: [N-]=[N+]=[N-]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@@H](CCS(=O)(=O)[O-])OC3=O)cc2F)CC1F
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(OC)CCN(c2ccc(N3C[C@@H](CN=[N+]=[N-])OC3=O)cc2F)CC1F
Temperature: 70 °C
Yield: 78 %

Procedure:
The mixture of sodium azide (67.0 mmol) and (R)-{3-[4-(4,4-dimethoxy-3-fluoropiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-methanesulfonate (27.0 mmol) in dimethylformamide was heated at 70° C. for 14 hours. The reaction mixture was poured on ice cold water, and the solid was filtered to afford title compound in 78% yield.