Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8]C(=O)OC(C)(C)C)[C:3]1=[O:16].FC(F)(F)CO>>[NH2:8][C@@H:4]1[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[C:3]1=[O:16]
Reactant: CN1CCC[C@@H](NC(=O)OC(C)(C)C)C1=O
Solvent: OCC(F)(F)F
Product: CN1CCC[C@@H](N)C1=O
Yield: 68.8 %

Procedure:
A solution of (R)-tert-butyl 1-methyl-2-oxopiperidin-3-ylcarbamate (310 mg, 1.36 mmol) in 2,2,2-trifluoroethanol (4.95 mL, 67.9 mmol) was heated at 150° C. for 3 h under microwave assisted conditions. The solvent was evaporated to dryness and the crude residue was purified by SiO2 chromatography (11 g, CH2Cl2/MeOH/NH4OH, 100:0:0 to 94:5.7:0.3) to give 120 mg (69%) of (R)-3-amino-1-methyl-piperidin-2-one as a light yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:35]=[CH:34][C:29]3[O:30][CH2:31][CH2:32][NH:33][C:28]=3[CH:27]=2)[CH2:22][CH2:21]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:33]3[C:28]4[CH:27]=[C:26]([N:23]5[CH2:24][CH2:25][O:20][CH2:21][CH2:22]5)[CH:35]=[CH:34][C:29]=4[O:30][CH2:31][CH2:32]3)=[C:3]([CH3:19])[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: c1cc2c(cc1N1CCOCC1)NCCO2
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CCOc2ccc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y by stirring 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (50 mg, 0.183 mmol), 6-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazine (40.4 mg, 0.183 mmol), Pd2dba3 (16.8 mg, 0.018 mmol), XPhos (17.5 mg, 0.037 mmol) and sodium tert-butoxide (35.2 mg, 0.367 mmol) in toluene (2.0 mL) for 1 h at 120° C. in the microwave. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 4-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6-(4-morpholinyl)-3,4-dihydro-2H-1,4-benzoxazine). 1H NMR (400 MHz, chloroform-d) δ ppm 8.72-8.79 (1H, m), 7.81-7.96 (4H, m), 7.40 (1H, ddd, J=7.0, 5.0, 1.7 Hz), 7.28 (1H, ddd, J=9.2, 8.1, 2.6 Hz), 6.89 (1H, d, J=8.6 Hz), 6.29 (1H, dd, J=8.8, 2.7 Hz), 5.63 (1H, d, J=2.7 Hz), 4.40-4.51 (2H, m), 3.57-3.82 (6H, m), 2.71-2.82 (4H, m), 2.40 (3H, s). Mass Spectrum (ESI) m/e=457.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]([N:24](C)[C:25](=O)C(F)(F)F)=[C:22]([I:32])[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=1.[BH4-].[Na+].C(OCC)(=O)C>C(O)(C)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]([NH:24][CH3:25])=[C:22]([I:32])[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15]#[N:16]
Reactant: CN(C(=O)C(F)(F)F)c1c(I)ncnc1Nc1ccc(Oc2cccc(C#N)c2)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNc1c(I)ncnc1Nc1ccc(Oc2cccc(C#N)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.7 %

Procedure:
To a solution of N-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-6-iodopyrimidin-5-yl)-2,2,2-trifluoro-N-methylacetamide (1.0 g) in isopropanol-tetrahydrofuran (5.0 mL-10 mL) was added sodium borohydride (70 mg) at room temperature. The mixture was stirred at room temperature for 1.5 hrs, and ethyl acetate was added. The mixture washed with water and saturated brine and the organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=4:1→3:2) to give the title compound (755 mg) as a white amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:14])[C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:19]O>>[F:1][C:2]1[CH:3]=[C:4]([OH:14])[C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:19])=[O:8]
Reactant: O=C(O)c1cc(F)cc(O)c1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(F)cc(O)c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 41 %

Procedure:
Crude 5-fluoro-3-hydroxy-2-nitrobenzoic acid (2.60 g, 12.92 mmol), was suspended in CH3OH (50 mL) and cooled to 0° C. Thionyl chloride (9.4 ml, 129.26 mmol) was added drop wise at 0° C. The mixture was allowed to warm to ambient temperature then heated to reflux for 17 h. The reaction mixture was allowed to cool to ambient temperature, and the solvent removed under reduced pressure. The crude material was purified by column chromatography (silica gel, 0 to 20% CH3OH in CH2Cl2) to afford methyl 5-fluoro-3-hydroxy-2-nitrobenzoate (1.15 g, 41%) as a white solid. 1H NMR and MS consistent.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([NH:25][C:26]([NH:28][C:29]3[CH:39]=[CH:38][C:32]([C:33]([O:35]CC)=[O:34])=[CH:31][CH:30]=3)=[O:27])[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:40]([F:43])([F:42])[F:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([NH:25][C:26]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:38][CH:39]=3)=[O:27])[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:40]([F:43])([F:41])[F:42])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(NC(=O)Nc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(Nc1ccc(C(=O)O)cc1)Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from ethyl 4-{[({3-[3-benzoyl-8-(trifluoromethyl) quinolin-4-yl]phenyl}amino)carbonyl]amino}benzoate by hydrolysis with LiOH. HRMS: calcd for C31H20F3N3O4, 555.1406; found (ESI, [M+H]+), 556.1495.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[O:7][C@@H:6]([N:18]2[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:5]1)=[N+]=[N-].C(N(CC)CC)C.[C:33](Cl)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl.N1C=CC=CC=1>[C:33]([NH:1][C@@H:4]1[C@@H:8]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[O:7][C@@H:6]([N:18]2[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:5]1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
3'-(Trityl)amino-5'-O-(tert-butyldimethylsilyl)-2',3'-dideoxyuridine, 2du. Crude 1du (33.2 g, 90.3 mmol) was dissolved in 2:1 EtOH/CH2Cl2 (300 mL) and reduced via hydrogenation (60 psi H2) in the presence of 10% Pd/C (3.0 g) for 18 h. Subsequent removal of the catalyst via filtration and evaporation of solvent in vacuo, afforded quantitative yield (30.4 g, 89.8 mmol) of the corresponding 3'-amine which was taken on directly to the next reaction. The 5'-O-(tert-butyldimethylsilyl)-3'-amino-2',3'-dideoxyuridine (30.4 g, 89.8 mmol) was azeotroped from pyridine (2×300 mL), and dissolved in a mixture of CH2Cl2 (600 mL) and anhydrous pyridine (70 mL). To this solution was added triethylamine (25.0 mL, 179.6 mmol) and trityl chloride (35.0 g, 125.7 mmol), and the reaction mixture was stirred for 2 h at ambient temperature. Solvents were removed in vacuo, and the crude product was purified on silica (1-5% MeOH/CH2Cl2) to afford 85% yield (44.3 g, 75.9 mmol) of 3'-(Trityl)amino-5'-O-(tert-butyldimethylsilyl)-2',3'-dideoxyuridine, 2du.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([N:15]([CH2:24][CH:25](OCC)[O:26]CC)[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])=[CH:4][CH:3]=1.Cl.ClCCl>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([N:15]([CH2:24][CH:25]=[O:26])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])=[CH:6][CH:7]=1
Reactant: CCOC(CN(CCc1ccccc1)C(=O)CCOCCc1ccc(Br)cc1)OCC
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=CCN(CCc1ccccc1)C(=O)CCOCCc1ccc(Br)cc1
Reaction time: 1 h
Yield: 88.3 %

Procedure:
3-[2-(4-Bromophenyl)ethoxy]-N-(2,2-diethoxyethyl)-N-phenethyl-propanamide (Example 10c) 0.72 g) was dissolved in anhydrous dioxane (15 mL) and treated with concentrated hydrochloric acid (10 mL) and stirred for 1 hour. The reaction mixture was then poured into dichloromethane (15 mL), washed with water (2×30 mL) and brine (30 mL). The organic layer was separated, dried over anhydrous magnesium sulphate, filtered and concentrated to give the sub-titled compound (0.54 g) as a viscous oil.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([O:15][C:16]3[N:17]([CH3:27])[C:18]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)=[N:19][N:20]=3)[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:28][N:29](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH3:27][N:17]1[C:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[N:19][N:20]=[C:16]1[O:15][CH:13]([C:10]1[N:11]=[N:12][N:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:28]#[N:29])[N:9]=1)[CH3:14]
Reactant: CC(Oc1nnc(-c2ccncc2)n1C)c1nnn(-c2cccc(I)c2)n1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(Oc1nnc(-c2ccncc2)n1C)c1nnn(-c2cccc(C#N)c2)n1

Procedure:
The title compound is prepared from 4-(5-{1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine (1 mmol), zinc cyanide (1.1 mmol), palladium (0) tetrakis-triphenylphosphine (0.05 mmol) in DMF (5 mL) at 80° C. overnight.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[CH2:19]([O:21][C:22](=[O:25])[CH2:23]Br)[CH3:20].C(O)C>CC(C)=O>[Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:25]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C=O)cc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Product: CCOC(=O)COc1c(Cl)cc(C=O)cc1OC
Yield: 44.8 %

Procedure:
The compound was prepared according to general procedure E with 5-chlorovanillin (2.7 mmol) in dry acetone (25 ml), anhydrous K2CO3 (3.5 mmol), and ethylbromoacetate (4.05 mmol) at reflux for 1 h30. Ethanol was added and evaporated by azeotropic distillation with ethylbromoacetate. 957 mg of crude product were obtained and purified by silica gel chromatography (eluent dichloromethane). 330 mg of purified compound were obtained (45% yield). 1H NMR (250 MHz, CD3COCD3): δ 1.27 (t, J=7.2 Hz, 3H), 3.98 (s, 3H), 4.22 (q, J=7.2 Hz, 2H), 4.87 (s, 2H), 7.50 (s, 1H), 7.58 (s, 1H), 9.90 (s, 1H) 13C NMR (126 MHz, CD3COCD3): δ 15.1, 57.5, 62.1, 70.5, 112.3, 125.8, 128.9, 134.0, 149.7, 154.5, 169.5, 191.2. MS (ESI): m/z 272.9 and 274.9 [M+H]+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:20][N:21]1[C:27](=[O:28])[N:26]2[CH2:29][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:30]([OH:32])=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:33]([NH:35][NH2:36])=[O:34]>C1COCC1.[Cl-].[Na+]>[CH2:13]([O:20][N:21]1[C:27](=[O:28])[N:26]2[CH2:29][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:30]([NH:36][NH:35][CH:33]=[O:34])=[O:32])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NNC=O
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CNNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 190.9 %

Procedure:
1,1′-Carbonyldiimidazole (5.8 g, 36.2 mmol) was added to a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (5.0 g, 18.1 mmol) in dry THF (200 mL). The reaction mixture was allowed to warm to rt then was stirred at rt for 3 hrs. Formohydrazide (5.4 g, 90.5 mmol) was added in one portion, and the reaction mixture was stirred for additional 3 hrs. The mixture was then diluted with saturated sodium chloride and extracted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated to afford crude (2S,5R)-6-(benzyloxy)-N′-formyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (˜11 g), which was directly used in the next step. ESI-MS (EI+, m/z): 319.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][CH2:5][CH2:6][S:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12][OH:13].OO.ClCCl.C(OCC)(=[O:35])C>C(O)(=O)C>[OH:1][CH2:2][C:3]([CH3:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][CH2:5][CH2:6][S:7]([CH2:8][CH2:9][CH2:10][C:11]([CH3:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12][OH:13])=[O:35]
Reactant: CC(CO)(CCCSCCCC(C)(CO)c1ccccc1)c1ccccc1
Reactant: CCOC(C)=O
Agent: OO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(CO)(CCCS(=O)CCCC(C)(CO)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a solution of 5-(5-hydroxy-4-methyl-4-phenylpentylsulfanyl)-2-methyl-2-phenylpentan-1-ol (3.37 g, 8.14 mmol) in glacial acetic acid (100 mL) was added 50% aqueous hydrogen peroxide solution (0.55 g, 8.14 mmol) drop-wise at rt over 5 min. The reaction mixture was stirred at rt for 3 h, while the reaction progress was monitored by TLC (dichloromethane/ethyl acetate=2/1). The reaction mixture was concentrated to yield a crude product (3.5 g) that was purified by column chromatography on silica gel (dichloromethane, then dichloromethane/ethyl acetate=1/1, followed by dichloromethane/ethanol=1/1). The product-containing fractions were concentrated and dried at 120° C. under high vacuo for 2.5 h to give 5-(5-hydroxy-4-methyl-4-phenylpentylsulfinyl)-2-methyl-2-phenylpentan-1-ol (2.55 g, 71%) as colorless, viscous oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 7.30 (m, 8 H), 7.20 (m, 2 H), 3.66-3.56 (m, 4 H), 2.54-2.38 (m, 4 H), 2.13 (br., 2 H), 1.90-1.43 (m, 8 H), 1.33 (s, 6 H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 144.56, 128.68, 126.66, 126.62, 126.62, 71.82, 71.57, 52.92, 43.38, 43.35, 37.56, 37.43, 22.14, 21.77, 17.87, 17.71. HRMS (LSIMS, gly): Calcd. for C24H35O3S1 (MH+): 403.2307, found: 403.2295.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10]C)=[O:9])[CH:3]=1.O.S.[Na].Br[C:16]1[S:20][C:19]([NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]=2)=[N:18][CH:17]=1.SC1C=CC=CN=1.C[O-].[Na+].[OH-].[Na+].Cl>CO.O.CN(C=O)C>[CH3:28][C:26]1[CH:25]=[CH:24][N:23]=[C:22]([NH:21][C:19]2[S:20][C:16]([S:1][C:2]3[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=3)=[CH:17][N:18]=2)[CH:27]=1
Reactant: Cc1ccnc(Nc2ncc(Br)s2)c1
Reactant: COC(=O)c1cc(S)ccn1
Agent: C[O-]
Agent: Cl
Agent: S
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3)s2)c1
Temperature: 35 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A DMF (8 mL) suspension of methyl 4-mercaptopicolinate (1.40 g, 8.16 mmol, prepared as described in Org. Prep. and Proc. Int. vol. 29 no 1, p. 117 (1997)) and sodium hydrogensulfide hydrate (0.685 g, 12.24 mmol, 1.5 eq) was bubbled with argon and heated to 35° C. 5-bromo-N-(4-methylpyridin-2-yl)thiazol-2-amine (1.103 g, 4.08 mmol, 1 eq, described in the synthesis of bromides, Example A) was diluted in methanol (15 mL) and this was treated by the DMF suspension of mercaptopyridine followed by a solution of sodium methoxide (4.6M in methanol, 2.7 mL, 12.24 mmol). The reaction was purged with argon and stirred at 65° C. for 1 hour. The reaction was then concentrated to remove most of the methanol, diluted in ethyl acetate/THF and acidified with 1N HCl. The aqueous phase was extracted with ethyl acetate (3×) but part of the compound remained in the aqueous phase. The two phases were combined and evaporated. The residue was then mixed with aqueous sodium hydroxide (5N, 8 mL, 40.8 mmol) and methanol followed by water were added. The reaction was stirred at 23° C. overnight, then acidified with 1N HCl. Methanol was evaporated and the solid was collected by filtration to give the crude title material (0.812 g, 58%) as a solid which was used as such in the next reaction. LC/MS (M+H)+: 345. HPLC ret. time (Condition B): 1.187 min.
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]12[CH2:14][CH:13]1[NH:12][CH2:11][CH2:10][N:9]2[CH2:15][C@@H:16]([C:18]1[CH:27]=[CH:26][C:21]2[C:22](=[O:25])[O:23][CH2:24][C:20]=2[C:19]=1[CH3:28])[OH:17].CCN(C(C)C)C(C)C.[N:38]1([C:43]2[N:48]=[CH:47][C:46]([CH2:49][C:50](O)=[O:51])=[CH:45][CH:44]=2)[CH:42]=[N:41][N:40]=[N:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[OH:17][C@H:16]([C:18]1[CH:27]=[CH:26][C:21]2[C:22](=[O:25])[O:23][CH2:24][C:20]=2[C:19]=1[CH3:28])[CH2:15][N:9]1[CH2:10][CH2:11][N:12]([C:50](=[O:51])[CH2:49][C:46]2[CH:47]=[N:48][C:43]([N:38]3[CH:42]=[N:41][N:40]=[N:39]3)=[CH:44][CH:45]=2)[CH:13]2[CH:8]1[CH2:14]2
Reactant: Cc1c([C@@H](O)CN2CCNC3CC32)ccc2c1COC2=O
Reactant: O=C(O)Cc1ccc(-n2cnnn2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c([C@@H](O)CN2CCN(C(=O)Cc3ccc(-n4cnnn4)nc3)C3CC32)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a round bottom flask, 5-{(1R)-2-[(±)-2,5-diazabicyclo[4.1.0]hept-2-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one TFA salt (66 mg, 0.126 mmol) was dissolved in DMF (2 mL). DIEA (66 mg, 0.511 mmol) was added, followed by [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetic acid (32 mg, 0.153 mmol). HATU (73 mg, 0.192 mmol) was added and let reaction stir at room temperature for 6 hours. Then reaction was diluted by adding small amount of water and was put on prep-HPLC for purification (Sunfire-C18 column, eluted by 10-75% AcCN/H2O+0.1% formic acid). Lyophilization gave the title compound. 1H NMR (ppm) (500 MHz, CD3OD): δ 9.90 (1H, s), 8.50 (1H, s), 8.07-8.00 (2H, m), 7.80 (1H, m), 7.72 (1H, d, J=8.0 Hz), 5.36 (2H, d, J=3.10 Hz), 5.40-5.31 (1H, m), 4.10 (2H, s), 4.08-3.95 (1H, m), 3.20-3.07 (1H, in), 3.06-2.83 (3H, m), 2.80 (2H, s), 2.78-2.68 (2H, m), 2.54-2.39 (1H, m), 2.36 (3H, s), 0.95 (1H, t, J=6.39 Hz), 0.81 (1H, t, J=4.98 Hz); LC/MS: (M+23)+ =498.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1>C(#N)C>[Cl:1][CH2:2][C:3]1[N:7]=[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]2[CH:5]=1
Reactant: Nc1ccccn1
Reactant: O=C(CCl)CCl
Solvent: CC#N
Product: ClCc1cn2ccccc2n1
Yield: 45.2 %

Procedure:
1,3-Dichloroacetone (22.9 g, 180.3 mmol) was added to a solution of 2-amino pyridine (10 g, 106.3 mmol) in acetonitrile (200 ml). The mixture was heated at reflux for 14 h (the reaction was monitored by TLC). Upon completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water and adjusted the pH to 7.5 with sodium bicarbonate solution which was extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 12% ethyl acetate in n-hexanes and silica gel (230-400 mesh) to afford 2-(chloromethyl) imidazo[1,2-a]pyridine (8.0 g, 47.9%) as pale yellow solid. 1H NMR: 200 MHz, CDCl3: δ 8.15 (d, 1H), 7.6 (dd, 2H), 7.1 (t, 1H), 6.8 (t, 1H), 4.75 (s, 2H). MS: [M+H]+: m/z=167.2.
Reaction SMILES: CN(C1C=C(C=C(CBr)C=1)C(N[C@@H](C1C=CC(F)=CC=1)C)=O)S(C)(=O)=O.NC(CC1C=CC=CC=1)(CC)CO.[NH2:40][C:41]([CH2:73][C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)([CH2:69][CH2:70]CC)[CH2:42][O:43][CH2:44][C:45]1[CH:46]=[C:47]([CH:60]=[C:61]([N:63]([CH3:68])[S:64]([CH3:67])(=[O:66])=[O:65])[CH:62]=1)[C:48]([NH:50][C@@H:51]([C:53]1[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=1)[CH3:52])=[O:49]>>[NH2:40][C:41]([CH2:69][CH3:70])([CH2:73][C:74]1[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1)[CH2:42][O:43][CH2:44][C:45]1[CH:46]=[C:47]([CH:60]=[C:61]([N:63]([CH3:68])[S:64]([CH3:67])(=[O:65])=[O:66])[CH:62]=1)[C:48]([NH:50][C@@H:51]([C:53]1[CH:54]=[CH:55][C:56]([F:59])=[CH:57][CH:58]=1)[CH3:52])=[O:49]
Reactant: CCCCC(N)(COCc1cc(C(=O)N[C@H](C)c2ccc(F)cc2)cc(N(C)S(C)(=O)=O)c1)Cc1ccccc1
Agent: CCC(N)(CO)Cc1ccccc1
Agent: C[C@@H](NC(=O)c1cc(CBr)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Product: CCC(N)(COCc1cc(C(=O)N[C@H](C)c2ccc(F)cc2)cc(N(C)S(C)(=O)=O)c1)Cc1ccccc1

Procedure:
Prepared from 3-(N-methyl-N-(methylsulfonyl)amino)-5-(bromomethyl)-N-((R)-1-(4-fluorophenyl)ethyl)benzamide and 2-amino-2-benzylbutan-1-ol using a similar procedure as described for the preparation of 3-{[(2-amino-2-benzylhexyl)oxy]methyl}-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methyl sulfonyl)amino]benzamide (Example 4). HRMS ES calculated for C29H36FN3O4S: 542.2484, found: 542.2484.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]#[N:12])[CH:8]=2)[NH:3]1.[H-].[Na+].Cl[C:16]1[CH:27]=[CH:26][C:19]([C:20]([N:22]([O:24][CH3:25])[CH3:23])=[O:21])=[CH:18][N:17]=1>CN(C=O)C>[C:11]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([OH:1])=[C:10]2[C:16]1[CH:27]=[CH:26][C:19]([C:20]([N:22]([O:24][CH3:25])[CH3:23])=[O:21])=[CH:18][N:17]=1)#[N:12]
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(-c2c(O)[nH]c3ccc(C#N)cc23)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a solution of 473 mg (2.99 mmol) of 2-oxoindoline-5-carbonitrile in DMF (10 mL) were added 229 mg (5.73 mmol) of sodium hydride (60% on mineral oil) as a solid. After stirring the resulting suspension for 60 min at RT, a solution of 500 mg (2.49 mmol) of 6-chloro-N-methoxy-N-methylnicotinamide from example 1.1 in DMF (10 mL) was added slowly and the mixture was stirred for 80 min at 120° C. The reaction was cooled down to RT and a saturated solution of NH4CL (40 mL) was added and the resulting precipitate was collected by filtration. The precipitate was washed with water and hexane and afterwards dried in a vacuum oven. Yellow solid. Amount 265 mg. Yield 33%.