Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:31][CH3:32])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:9]([C:27]([O:29]C)=[O:28])[CH2:8]2)=[CH:3][CH:2]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[C:1]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:31][CH3:32])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([CH3:15])([CH3:16])[CH3:17])[C@H:9]([C:27]([OH:29])=[O:28])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: COC(=O)[C@@H]1C[C@@](SC)(c2ccc(-c3ccccc3)cc2)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of (2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(methylthio)pyrrolidine-2-carboxylate (164 mg, 0.303 mmol) in THF (2 mL) and MeOH (2.000 mL) was added pre-made solution of Lithium hydroxide monohydrate (25.5 mg, 0.607 mmol) in water (2 mL). The resulting cloudy solution was stirred at room temperature overnight. Quenched with 5% citric acid, extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, evaporated, to afford the desired product (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(methylthio)pyrrolidine-2-carboxylic acid (136 mg, 0.232 mmol, 77% yield) as a white foam. LC-MS (retention time: 3.25 min, method B), MS m/z 527 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([C:34]([CH3:39])([CH3:38])[C:35]([NH2:37])=[O:36])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([C:34]([CH3:39])([CH3:38])[C:35]([NH2:37])=[O:36])(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC(C)(C(N)=O)S(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: CC(C)(C(N)=O)S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 2-((2-bromophenyl)sulfonyl)-2-methylpropanamide. MS (ESI): mass calcd. for C20H19FN4O3S, 414.12; m/z found, 415.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 2H), 7.97 (d, J=7.9, 1H), 7.79 (m, 1H), 7.68 (m, 1H), 7.58 (m, 1H), 7.41 (s, 1H), 7.36 (d, J=7.5, 1H), 7.32-7.29 (m, 2H), 7.26 (d, J=7.9, 1H), 1.32 (s, 6H).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].[Br:11][C:12]1[CH:13]=[C:14](I)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:11][C:12]1[CH:17]=[C:16]([C:6]2[O:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: Brc1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1ccc(-c2cccc(Br)c2)o1
Yield: 25.9 %

Procedure:
5-Formyl-2-furanboronic acid (676 mg, 4.8 mmol) and 3-bromoiodobenzene (1132 mg, 4 mmol) were dissolved in 1,2-dimethoxyethane (30 mL), tetrakis(triphenylphosphine)palladium (228 mg, 0.2 mmol) was added thereto, 2 mol/L sodium carbonate (9.6 mL) was further added thereto, and the mixture was heated to reflux for 2 hours while stirring. After the reaction was completed water (20 mL) was added thereto, and extraction with ethyl acetate (20 mL×2) was carried out. The organic layer was washed with saturated brine, water was removed using anhydrous sodium sulfate, the solvent was then removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate/hexane (3/7 (volume ratio)) as an eluent, to give 5-(3-bromophenyl)furan-2-carbaldehyde in a yield of 306 mg (yield 25.9%).
Reaction SMILES: CS[CH2:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:5]=1[NH2:6]>[Ni].C(O)C>[CH3:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[C:5]=1[NH2:6]
Reactant: CSCc1cccc(C(F)(F)F)c1N
Agent: [Ni]
Solvent: CCO
Product: Cc1cccc(C(F)(F)F)c1N
Temperature: 25 °C
Yield: 27.4 %

Procedure:
Several scoops of Raney nickel were added to 28.6 g of 2-{(methylthio)methyl}-6-(trifluoromethyl)aniline (Example 1A) in 50 ml of absolute ethanol. The reaction slurry was stirred at room temperature and the progress of the reaction was followed by gas-liquid chromatography (GLC). Periodically, additional Raney nickel was added to the reaction slurry. The reaction was allowed to stir overnight. Most but not all of the starting material had reacted. The Raney nickel was removed by filtration, the filter cake rinsed with 1200 ml of absolute ethanol and the filtrate concentrated. The concentrate was dissolved in 100 ml of ethyl acetate, washed with 70 ml of water, dried with magnesium sulfate, filtered, and concentrated to yield 19.2 g of the crude product as a yellow oil which was distilled at 30-40 torr, to give 6.2 g of the desired product at 93°-108° C. in 80% purity.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[C:18]([C:22]([CH3:25])=[CH:23][N:24]=3)[C:19](O)=[O:20])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:32]([NH:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[CH:33]=[CH2:34]>>[CH2:32]([N:35]([CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C:19](=[O:20])[C:18]1[C:22]([CH3:25])=[CH:23][N:24]=[C:16]([N:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:11][CH2:12]2)[CH:17]=1)[CH:33]=[CH2:34]
Reactant: Cc1cnc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)cc1C(=O)O
Reactant: C=CCNC1CCCCC1
Product: C=CCN(C(=O)c1cc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)ncc1C)C1CCCCC1
Yield: 72.8 %

Procedure:
Step (d) of Example 107 was repeated, except that the compound (50 mg) prepared in step (d) of Example 108 and allylcyclohexylamine (34 mg) were used as the starting compounds. Thus, the title compound (47 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]3[N:15]([C:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)=[CH:18][N:19]=3)[N:16]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.[N:38]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)[C:42]2C=CC=CC=2N=N1.CN.C1COCC1.C(N(CC)CC)C>CN(C)C=O.O>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]3[N:15]([C:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)=[CH:18][N:19]=3)[N:16]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:38][CH3:42])=[O:5]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)c1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1F
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
A suspension of 2-fluoro-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzoic acid (14, 431.4 g, 0.914 mol, 1.0 equiv) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP, 570 g, 1.1 mol, 1.2 equiv) in N,N-dimethylformamide (DMF, 3700 mL) was treated with a solution of 2 M methylamine in THF (1830 mL, 3.656 mol, 4.0 equiv) over 15 min at room temperature. The reaction temperature increased to 30° C. during the addition of methylamine and the reaction mixture became homogeneous once the addition of methylamine was complete. Triethylamine (TEA, 382 mL, 2.742 mol, 3.0 equiv) was then added to the reaction mixture and the resulting reaction mixture was stirred at room temperature for 2-4 h. When LC/MS showed the coupling reaction was deemed complete, the reaction mixture was treated with water (950 mL). The resulting suspension was cooled down to 0-5° C. in an ice-bath and stirred at 0-5° C. for 30 min. The solids were collected by filtration and washed with water (200 mL). The wet solid cake was then suspended in a mixture of water and acetonitrile (1/1 by volume, 2000 mL) and the resulted suspension was stirred at room temperature for 1 h. The solids were collected by filtration, washed with water and acetonitrile, and dried in a vacuum oven at 40-45° C. to constant weight to afford 2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide (15, 322 g, 377 g theoretical, 85.4% yield) as yellow to bright-yellow powders. For 15: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.20 (s, 1H), 8.82 (dd, 1H, J=4.05, 1.56 Hz), 8.38 (br m, 1H), 8.27 (dd, 1H, J=8.50 Hz, 1.25 Hz), 8.06-7.93 (m, 5H), 7.81-7.74 (m, 2H), 7.49 (dd, 1H, J=8.40 Hz, 4.35 Hz), 4.62 (s, 2H), 2.78 (d, 3H, J=4.36 Hz); C23H17FN6O (MW 412.42), LCMS (EI) m/e 413.1 (M++H).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(N(CC)CC)C.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[S:24](Cl)(=[O:26])=[O:25]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[S:24]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])(=[O:25])=[O:26]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: OCC(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=S(=O)(OCC(F)(F)F)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a stirred solution of 25.0 parts of 2,2,2-trifluoroethanol in 175 parts of N,N-diethylethanamine were added portionwise 62.2 parts of 2-naphthalenesulfonyl chloride and then a mixture of 1.5 parts of N,N-dimethyl-4-pyridinamine and 25 parts of ethyl acetate. After stirring overnight at room temperature, the reaction mixture was filtered and the filtrate was evaporated. The residue was stirred in water. The solid was filtered off and dissolved in dichloromethane. This solution was dried, filtered and evaporated. The residue was successively triturated with petroleumether and crystallized from 2-propanol. The product was filtered off and dried, yielding 65.3 parts (89%) of 2,2,2-trifluoroethyl 2-naphthalenesulfonate; mp. 72.7° C. (interm. 12).
Reaction SMILES: [CH2:1]([N:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH:2]([CH3:4])[CH3:3].[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([S:6]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:27])([F:25])[F:26])(=[O:8])=[O:7])=[CH:10][CH:11]=1
Reactant: CC(C)CN(c1ccccc1C(F)(F)F)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)CN(c1ccccc1C(F)(F)F)S(=O)(=O)c1ccc(N)cc1
Yield: 98.1 %

Procedure:
A partial solution of N-isobutyl-4-nitro-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (1.68 g, 4.19 mmol), in EtOH (IMS grade, 50 mL) and water (15 mL) was treated with iron powder (˜325 mesh, 936 mg, 16.76 mmol) and ammonium chloride (896 mg, 16.76 mmol) and heated at reflux for 1 hour. The cooled mixture was filtered through diatomaceous earth washing the filter cake with EtOH and the filtrate concentrated to low volume under vacuum. The residue obtained was diluted with water and extracted into DCM. The combined extracts were dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-75% EtOAc in cyclohexane) gave 4-amino-N-isobutyl-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (1.53 g, 98%). 1H NMR (300 MHz, CDCl3) δ 7.72 (dd, J=7.5, 2.1 Hz, 1H), 7.54-7.39 (m, 4H), 7.14 (d, J=7.7 Hz, 1H), 6.70-6.63 (m, 2H), 3.35 (dd, J=13.5, 8.3 Hz, 1H), 3.15 (dd, J=13.5, 5.3 Hz, 1H), 1.71-1.55 (m, 1H), 0.88 (d, J=6.5 Hz, 3H), 0.77 (d, J=6.7 Hz, 3H). LCMS (m/z, Method A) ES+ 373.1 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.Br.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]3)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=2)[CH2:22][C:21]1=[O:26]
Reactant: CN1CCNCC1=O
Reactant: CC1CCN(c2nc(Cl)ccc2[N+](=O)[O-])CC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CCN(c2nc(N3CCN(C)C(=O)C3)ccc2[N+](=O)[O-])CC1
Temperature: 100 °C
Yield: 81 %

Procedure:
To a solution of 6′-chloro-4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (as prepared in Example 55, step (a)) (510 mg, 2.00 mmol) in DMF (10 mL) was added 1-methyl piperazinone hydrobromide (390 mg, 2.00 mmol) and K2CO3 (691 mg, 5.00 mmol). The resulting mixture was heated at 100° C. overnight. DMF was removed in vacuo and the residue obtained was purified on silica (20-100% EtOAc:hexane) to obtain the title compound (540 mg, 81%). 1H-NMR (CDCl3; 400 MHz): δ 8.15 (d, 1H, J=9.1 Hz), 5.94 (d, 1H, J=9.1 Hz), 4.22 (s, 2H), 3.88 (m, 2H), 3.76 (m, 2H), 3.46 (m, 2H), 3.01-2.92 (m, 5H), 1.68 (m, 3H), 1.25 (m, 2H), 0.93 (d, 3H, J=6.3 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][NH:6][CH:7]([CH3:17])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=O)[CH3:2].[CH:19]1([N:22]=[C:23]=[O:24])[CH2:21][CH2:20]1>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:7]([CH3:17])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:22]([CH:19]2[CH2:21][CH2:20]2)[C:23]1=[O:24])[CH3:2]
Reactant: CCOC(=O)CNC(C)C(=O)c1ccc(Cl)cc1
Reactant: O=C=NC1CC1
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(C)c(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
355 mg (1.32 mmol) of N-[2-(4-chlorophenyl)-1-methyl-2-oxoethyl]-glycine ethyl ester from Example 117A are placed in 5 ml tetrahydrofuran, treated with 109 mg (1.32 mmol) of cyclopropyl isocyanate and stirred overnight at room temperature. The reaction mixture is evaporated and the residue purified by flash chromatography on silica gel (eluent: first dichloromethane, then dichloromethane/methanol 200:1→100:1). 425 mg (91% of theory) of the target compound are thus obtained.
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][CH:16]([N:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:21][C:20]4=[O:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].C(OC([N:38]1[CH2:42][CH2:41]OS1(=O)=O)=O)(C)(C)C.C(N(CC)CC)C.Cl.O1CCOCC1>CN(C=O)C>[NH2:38][CH2:42][CH2:41][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][C:20]3=[O:28])[CH2:15][CH2:14]2)=[O:12])=[CH:7]1
Reactant: CC(C)(C)OC(=O)N1CCOS1(=O)=O
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(N2C(=O)Cc3ccccc32)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: NCCn1cc(C(=O)N2CCC(N3C(=O)Cc4ccccc43)CC2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-indol-2-one (1 eq) in dry DMF was treated with NaH (1.1 eq) at 0° C. for 60 min. and then a solution of 2,2-dioxo-2λ6-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (1.1 eq) and triethylamine (1.1 eq) in dry DMF was added and the mixture stirred at RT for 2 h. After concentration the mixture was treated with 4 M HCl in dioxan (5 eq) at 50° C. for 1 h, evaporated to dryness and partitioned between ethyl acetate and 1 N NaHCO3. The organic layer was washed with brine, separated, evaporated and the crude product chromatographed on silica gel (CH2Cl2-MeOH) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4](Cl)[N:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH3:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[N:3]=1
Reactant: C1CCNCC1
Reactant: Cc1nc(Cl)cc(N)[n+]1[O-]
Product: Cc1nc(N2CCCCC2)cc(N)[n+]1[O-]
Yield: 69.6 %

Procedure:
A solution of 44 g (0.261 mol) of 2-methyl4-amino-6-chloropyrimidine 3-oxide in 352 ml of piperidine is refluxed gently for 4 hours 30 minutes, with stirring and under nitrogen. A yellow suspension is obtained. The suspension is cooled in a salt ice bath and the precipitate is drained and washed on the filter with 30 ml of piperidine and then with ethyl ether. It is then taken up, with stirring, twice ill 150 ml of ice-water. The solid is drained and dried under vacuum at ambient temperature. 42 g of product in the form of the monohydrate are obtained. The product is recrystallized from acetonitrile with 3% of water, After drying at 80° C., 37.8 g (0.181 mol) of anhydrous pure product having a melting point of 200°-200.5° C. are recovered. The yield is 69.6%.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[N:13]1([C:19](=[O:21])[CH3:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.N1C=CC=CC=1>C(Cl)Cl>[C:19]([N:13]1[CH2:18][CH2:17][N:16]([C:7]([Cl:10])=[O:6])[CH2:15][CH2:14]1)(=[O:21])[CH3:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(=O)N1CCNCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)Cl)CC1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (2.31 g, 7.80 mmol) in CH2Cl2 (30 ml) at 0° C., was added a solution of 1-piperazin-1-yl-ethanone (2.0 g, 15.6 mmol) and pyridine (1.38 ml, 17.2 mmol) in CH2Cl2 (5 ml) over 30 minutes. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Purification by flash chromatography (SiO2, EtOAc) yielded 1.12 g (38%) of the title compound as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(S[C:15](=[O:28])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:17](=[O:19])[CH3:18])(C)(C)C>>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][CH:16]([C:17](=[O:19])[CH3:18])[C:15]([NH:1][C:2]2[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=2[F:8])=[O:28])=[CH:26][CH:25]=1
Reactant: CC(=O)C(Cc1ccc(F)cc1)C(=O)SC(C)(C)C
Reactant: Nc1cc(O)ccc1F
Product: CC(=O)C(Cc1ccc(F)cc1)C(=O)Nc1cc(O)ccc1F

Procedure:
The title compound was prepared by the method of Preparation 34b using 3-amino-4-fluorophenol and 2-(4-fluorobenzyl)-3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[C:12](=[O:16])C(O)=O)=[CH:9][C:4]=2[O:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:55]([CH3:57])[CH3:56])C2C=CC=CC=2N=N1.C(N(CC)CC)C.CNC.C1COCC1>CN(C=O)C.O>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([C:11]([C:12](=[O:16])[N:55]([CH3:57])[CH3:56])=[CH:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[CH:18][CH:19]=2)=[CH:25][CH:26]=1)[CH3:36]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(C(=Cc3ccc4c(c3)OCO4)C(=O)C(=O)O)cc2)cc1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1ccc(Oc2ccc(C(=Cc3ccc4c(c3)OCO4)C(=O)N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-benzo[1,3]dioxol-5-yl-3-{4-[4-(2-ethoxycarbonylethyl)-phenoxy]-phenyl}-2-oxobut-3-enoic acid, 68, (0.08 g, 0.17 mmol), benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (BOP, 0.09 g, 0.21 mmol), triethylamine (36 μL, 0.25 mmol), dimethylamine in THF (2M, 0.25 mL, 0.5 mmol) in DMF (2.0 mL) was stirred for 10 min at room temperature. Reaction mixture was poured in water (20 mL). Solid separated was filtered and boiled in toluene, cooled and filtered. Crude solid was purified by silica gel chromatography to yield 69.
Reaction SMILES: [CH3:1][C:2]([C:9]([CH3:20])=[CH:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:21][OH:22]>>[CH3:21][O:22][C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][CH2:13][CH:12]([CH3:19])[CH2:11][CH:10]=[C:9]([CH3:20])[C:2]([CH3:1])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CO
Reactant: CCOC(=O)C=C(C)C(C)=CCC(C)CCC=C(C)C
Product: CCOC(=O)C=C(C)C(C)=CCC(C)CCCC(C)(C)OC

Procedure:
Methanol is added to the terminal bond of ethyl 3,4,7,11-tetramethyldodeca-2,4,10-trienoate using the process of Example 23 or 29 to give ethyl 11-methoxy-3,4,7,11 -tetramethyldodeca- 2,4 -dienoate. In the same manner, water is added to give ethyl 11-hydroxy-3,4,7,11-tetramethyldodeca-2,4-dienoate. Similarly, there is prepared ethyl 11-methoxy-3,5,7,11-tetramethyldodeca-2,4-dienoate and ethyl 11-hydroxy-3,5,7,11-tetramethyldodeca-2,4-dienoate from ethyl 3,5,7,11-tetramethyldodeca-2,4,10-trienoate. The hydrochloride, ethyl 11-chloro-3,4,7,11-tetramethyldodeca-2,4-dienoate and ethyl 11-chloro-3,5,7,11-tetramethyldodeca-2,4-dienoate are prepared from the trienoate using the process of Example 39.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:28])[N:13]([CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1.Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:28])[N:13]([CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:24][CH2:23]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1
Reactant: Brc1ccccn1
Reactant: O=C(Nc1cccc2c1C(=O)N(CCC1CCNCC1)C2=O)c1ccc(Cl)s1
Product: O=C(Nc1cccc2c1C(=O)N(CCC1CCN(c3ccccn3)CC1)C2=O)c1ccc(Cl)s1

Procedure:
can be prepared from 5-chloro-N-{1,3-dioxo-2-[2-(4-piperidinyl)ethyl]-2,3-dihydro-1H-isoindol-4-yl}-2-thiophenecarboxamide and 2-bromopyridine
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH:11]3[O:15][C:16](=[O:18])[CH:17]=[C:10]23)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:26]N1C(=O)CCC1=O>C(#N)C>[Cl:26][C:17]1[C:16](=[O:18])[O:15][CH:11]2[CH2:12][CH2:13][CH2:14][N:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:10]=12
Reactant: O=C1C=C2C(CCCN2Cc2ccc(Cl)nc2)O1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1OC2CCCN(Cc3ccc(Cl)nc3)C2=C1Cl
Reaction time: 1 h
Yield: 72.6 %

Procedure:
524 mg (1.98 mmol) of 4-[(6-chloropyridin-3-yl)methyl]-5,6,7,7a-tetrahydrofuro[3,2-b]pyridin-2(4H)-one (1-2) are dissolved in 20 ml of acetonitrile, then 414 μl (2.97 mmol) of triethylamine and 317 mg (2.37 mmol) of N-chlorosuccinimide are added at room temperature. After one hour of stirring, a 159 mg (1.19 mmol) of N-chlorosuccinimide are added. After a further hour of stirring, the entire reaction mixture is concentrated under reduced pressure. The residue is taken up in dichloromethane, washed successively twice with 1N aqueous hydrochloric acid, twice with 1N aqueous sodium hydroxide solution and saturated sodium chloride solution and dried over sodium sulphate. Concentration of the organic phase under reduced pressure and purification of the residue column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (2:1) gives 430 mg (72% of theory) of 3-chloro-4-[(6-chloropyridin-3-yl)methyl]-5,6,7,7a-tetrahydrofuro[3,2-b]pyridin-2(4H)-one.