Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.C([O:6][C@@H:7]1[C@@H:12]([O:13]C(=O)C)[C@H:11]([O:17]C(=O)C)[C@@H:10]([CH2:21][O:22]C(=O)C)[O:9][C@H:8]1[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([CH2:33][C:34]2[S:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[CH:38]=2)[CH:27]=1)(=O)C.[OH-].[Na+].Cl>O>[S:35]1[C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[CH:38]=[C:34]1[CH2:33][C:28]1[CH:27]=[C:26]([C@@H:8]2[O:9][C@H:10]([CH2:21][OH:22])[C@@H:11]([OH:17])[C@H:12]([OH:13])[C@H:7]2[OH:6])[CH:31]=[CH:30][C:29]=1[F:32]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(F)c(Cc3cc4ccccc4s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC[C@H]1O[C@@H](c2ccc(F)c(Cc3cc4ccccc4s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 44.54999923706055 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a methanol (427.4 kg) solution of (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]glucitol (76.9 kg) was added a water (230 liters) solution of sodium hydroxide (26.9 kg) at a temperature of 25° C. or lower, followed by stirring at 40.0 to 49.1° C. for 4 hours. Water (850 liters) was added to the reaction mixture, and 12.9 kg of 38% hydrochloric acid was added thereto at a temperature of 25° C. or lower. The mixture was heated to 60° C., followed by stirring at 20.2 to 25.0° C. for 9.5 hours. The separated-out crystals were collected by filtration, washed with tap water (80 liters), and vacuum-dried to obtain, as white crystals, (1S)-1,5-anhydro-1-C-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl]-D-glucitol [52.7 kg, yield: 97.0%, purity: 99% (HPLC)].
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH2:14][CH3:15])[C:11]=1I)[CH:7]=[O:8])[CH3:2].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[O:8])[CH:9]=[C:10]([O:13][CH2:14][CH3:15])[C:11]=1[C:21]1[CH:22]=[CH:23][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:19][CH:20]=1)[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOc1cc(C=O)cc(OCC)c1I
Product: CCOc1cc(C=O)cc(OCC)c1-c1ccc(C(F)(F)F)cc1

Procedure:
The necessary intermediate 2,6-Diethoxy-4′-trifluoromethyl-biphenyl-4-carbaldehyde was prepared as described in example 94, but coupling in the Suzuki reaction 3,5-diethoxy-4-iodo-benzaldehyde instead of 3-benzyloxy-5-ethoxy-4-iodo-benzaldehyde with 4-trifluoromethyl-phenyl boronic acid instead of 4-fluorophenyl boronic acid, as white crystals.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].O[CH:9]1[C:16](=C)C[C@H:14]2[C@@H:10]1[CH2:11][C@@H:12]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C@H:13]2/[CH:18]=[CH:19]/[C@@H:20]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>N1C=CC=CC=1>[C:5]([O:4][CH:1]1[C:9](=[CH2:16])[CH2:10][C@H:14]2[C@@H:2]1[CH2:11][C@@H:12]([O:34][Si:35]([C:38]([CH3:40])([CH3:39])[CH3:41])([CH3:36])[CH3:37])[C@H:13]2/[CH:18]=[CH:19]/[C@@H:20]([O:26][Si:27]([C:30]([CH3:32])([CH3:31])[CH3:33])([CH3:28])[CH3:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: C=C1C[C@@H]2[C@H](/C=C/[C@H](CCCCC)O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]2C1O
Solvent: c1ccncc1
Product: C=C1C[C@@H]2[C@H](/C=C/[C@H](CCCCC)O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]2C1OC(C)=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 98 %

Procedure:
Acetic anhydride (0.5 ml) and pyridine (0.5 ml) were added to 95 mg (0.187 mmole) of (1S,2RS,5S,6S,7R)-2-hydroxy-3-methylene-6-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-7-t-butyldimethylsilyloxybicyclo[3.3.0]octane obtained in Example 3, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure, and then subjected to column chromatography (silica gel 20 g, hexane/ethyl acetate=19/1) to give (1S,2RS,5S,6S,7R)-2-acetoxy-3-methylene-6-[(E,3S)-3-t-butyldimethylsilyloxy-l-octenyl]-7-t-butyldimethylsilyloxybicyclo[3.3.0]octane (101 mg, 0.184 mmole, 98%).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]2[N:12]=[C:13]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=3)=[C:10]2[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:38])C=1>C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH2:1]([NH:5][C:6]1[N:11]2[N:12]=[C:13]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([S:21]([CH3:22])=[O:38])[N:16]=3)=[C:10]2[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCNc1cccc2c(-c3ccnc(SC)n3)c(-c3ccc(F)cc3)nn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCNc1cccc2c(-c3ccnc(S(C)=O)n3)c(-c3ccc(F)cc3)nn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.6 %

Procedure:
To a cold (0° C.) solution of N-butyl-2-(4-fluorophenyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-α]pyridin-7-amine (1.51 g, 3.7 mmol) in 50 mL chloroform was added m-chloroperbenzoic acid (0.87 g, 70–75%, 3.7 mmol). The reaction was allowed to warm to rt. After stirring for 5 h, another 0.2 g m-chloroperbenzoic acid was added and the reaction was stirred for 15 min. The reaction was diluted with aqueous sodium bicarbonate and extracted with dichloromethane. The organic extracts were washed with brine, dried over magnesium sulfate and concentrated. The crude product was recrystallized from ethyl acetate-hexanes to afford N-butyl-2-(4-fluorophenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1,5-α]pyridin-7-amine (0.95 g, 60%) as an orange solid. 1H NMR (CDCl3): δ 8.40 (broad, 1H), 7.99 (d, 1H), 7.58 (m, 2H), 7.45 (t, 1H), 7.20 (t, 2H), 6.94 (d, 1H), 6.13 (d, 1H), 6.10 (broad, 1H), 3.38 (m, 2H), 2.98 (s, 3H), 1.79–1.42 (m, 4H), 0.97 (t, 3H); MS m/z 422 (M−1).
Reaction SMILES: [F:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][CH2:11][CH2:12][NH:13][CH3:14])[CH:6]=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:13]([CH2:12][CH2:11][C:10]#[C:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][F:1])[N:8]=1)[CH3:14])(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CNCCC#Cc1cccc(CF)n1
Product: CN(CCC#Cc1cccc(CF)n1)S(=O)(=O)c1ccccc1Cl
Yield: 31 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from 4-(6-(fluoromethyl)pyridin-2-yl)-N-methylbut-3-yn-1-amine (70 mg, 0.36 mmol) and 2-chlorobenzene-1-sulfonyl chloride (92 mg, 0.44 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, Cyclohexane/AcOEt:70/30 as eluent) to afford 41 mg of 2-chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzenesulfonamide as a yellow oil (Yield: 31%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]([O:14][C:15]1[CH:25]=[CH:24][C:18]([CH:19]=[CH:20][C:21](Cl)=[O:22])=[CH:17][CH:16]=1)(=[O:13])[CH3:12]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:11]([O:14][C:15]1[CH:25]=[CH:24][C:18]([CH:19]=[CH:20][C:21]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:22])=[CH:17][CH:16]=1)(=[O:13])[CH3:12]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)Oc1ccc(C=CC(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1ccc(C=CC(=O)Nc2ccc(C(=O)O)cc2)cc1

Procedure:
In a mixture of 20 ml of dry chloroform and 10 ml of dry pyridine were dissolved 2.6 g of 4-aminobenzoic acid. To this mixture were added dropwise under cooling 20 ml of dry chloroform containing 3.2 g of 4-acetoxycinnamoyl chloride. The mixture was heated under reflux for 2 hours and the reaction mixture was concentrated under reduced pressure. The residue was poured into water and hydrochloric acid was then added to make the liquid weakly acidic. The precipitated crystals were collected by filtration and recrystallized from alcohol to yield 2.9 g of 4-(4'-acetoxycinnamoylamino)-benzoic acid. M.P.=305°-307° C. (with decomposition).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([Cl:12])=[C:4]([NH2:13])[N:3]=1.Cl[CH2:15][C:16](=O)[CH2:17][CH2:18][CH3:19].[I-].[Na+]>>[NH2:13][C:4]1[N:3]2[CH:15]=[C:16]([CH2:17][CH2:18][CH3:19])[N:1]=[C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[Cl:12]
Reactant: COC(=O)c1cc(Cl)c(N)nc1N
Reactant: CCCC(=O)CCl
Agent: [I-]
Agent: [Na+]
Product: CCCc1cn2c(N)c(Cl)cc(C(=O)OC)c2n1

Procedure:
The title compounds were prepared according to the procedure described in the step 2 EXAMPLE 1 (METHOD B) using methyl 2,6-diamino-5-chloro-3-pyridinecarboxylate (EXAMPLE 1, METHOD B, Step 1), 1-chloropentane-2-one (Synthesis, 1987, 2, 188-190) and sodium iodide.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>>[Si:20]([O:19][CH2:18][CH2:17][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH2:15])(=[O:13])=[O:14])=[CH:9]2)=[CH:4][CH:3]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: NS(=O)(=O)c1ccc2ccc(O)cc2c1
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc2ccc(S(N)(=O)=O)cc2c1
Yield: 48 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 17, 7-hydroxynaphthalene-2-sulfonamide (40 mg, 0.18 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (43 mg, 0.18 mmol) were converted to the title compound (33 mg, 48%) after purification using flash column chromatography (gradient from 0% to 2% MeOH/CH2Cl2). 1H NMR (CDCl3) δ 8.31 (s, 1H), 7.84-7.82 (m, 1H), 7.77-7.73 (m, 2H), 7.26 (dd, J=8.9, 2.5 Hz, 1H), 7.19 (d, J=2.2 Hz, 1H), 4.13 (t, J=4.9 Hz, 2H), 4.02 (t, J=4.9 Hz, 2H), 0.90 (s, 9H), 0.10 (s, 6H); MS(ESI−) m/z 380.4 (M−H)−.
Reaction SMILES: C([N:4]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][CH:9]=1)[C:5](=[O:7])[CH3:6])(=O)C.[CH3:16][C:17]1[N:22]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:21](=[O:28])[C:20]([N+:29]([O-:31])=[O:30])=[C:19](OS(C(F)(F)F)(=O)=O)[CH:18]=1.N>>[C:5]([NH:4][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:19]2[CH:18]=[C:17]([CH3:16])[N:22]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:21](=[O:28])[C:20]=2[N+:29]([O-:31])=[O:30])=[CH:12][CH:13]=1)(=[O:7])[CH3:6]
Reactant: COC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1=O
Reactant: CC(=O)N(C(C)=O)c1ccc(CBr)cc1
Agent: N
Product: COC(=O)Cn1c(C)cc(Cc2ccc(NC(C)=O)cc2)c([N+](=O)[O-])c1=O

Procedure:
It is prepared from 7.3 g (27 mmol) of N-acetyl-N-[4-(bromomethyl)phenyl]acetamide and 4 g (13.4 mmol) of methyl 6-methyl-3-nitro-2-oxo-4-[[(trifluoromethyl)sulphonyl]oxy]-1,2-dihydropyridine-1-acetate. The crude product is treated with ammonia.
Reaction SMILES: Cl.[CH2:2]([C:5]1[S:6][C:7]([C:10]([OH:12])=[O:11])=[CH:8][N:9]=1)[CH2:3][CH3:4].[CH2:13](O)[CH3:14]>>[CH2:2]([C:5]1[S:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:9]=1)[CH2:3][CH3:4]
Reactant: CCO
Reactant: CCCc1ncc(C(=O)O)s1
Agent: Cl
Product: CCCc1ncc(C(=O)OCC)s1

Procedure:
A current of hydrochloric acid gas was passed with stirring through a solution of 30 g of 2-propyl-thiazole-5-carboxylic acid in 400 ml of absolute ethanol overnight and the ethanol was then evaporated off. The oily residue was taken up in ether containing 10% of potassium carbonate and the mixture was extracted with ether. The ether extracts were washed with water until a pH of 6 was obtained and the resulting yellow oil was purified by distillation to obtain 31.2 g of ethyl 2-propyl-thiazole-5-carboxylate with a boiling point of 139°-140° C. at 16 mmHg.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH2:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(O)(=O)C>C(Cl)Cl>[CH:13]([C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Yield: 68.7 %

Procedure:
Following the procedure of Example 2, 16.0 g of pyridinium chlorochromate, 10.0 g of (S)-2-(hydroxymethyl)-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester, 36.0 g of crushed 4 Å molecular sieves and 4.5 ml of glacial acetic acid in 250 ml of methylene chloride gives 6.8 g of the product as a yellow oil.
Reaction SMILES: [Li][CH3:2].[CH2:3]([O:5][C:6]([C:8]1[C:9]2[C:24](=[O:25])[CH:23]=[CH:22][CH2:21][CH2:20][C:10]=2[N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:12]=1)=[O:7])[CH3:4]>CCOCC.C1COCC1.[Cu]I>[CH2:3]([O:5][C:6]([C:8]1[C:9]2[C:24](=[O:25])[CH2:23][CH:22]([CH3:2])[CH2:21][CH2:20][C:10]=2[N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH:12]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C=CCC2
Reactant: [Li]C
Agent: [Cu]I
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)CC(C)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
MeLi (1.4M in ether, 2 ml) is added dropwise to a stirred suspension of CuI (268 mg, 1.40 mmol) in Et2O at 0° C. The reaction mixture is kept at 0° C. for 15 min. 4-oxo-7,8-dihydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (300 mg, 0.94 mmol) in THF is added slowly to the solution at 0° C., the reaction mixture is allowed to warm up to room temperature over a period of 30 min and then quenched with saturated NH4Cl(aq., 30 ml). 50 ml Et2O is added and stirring is continued for 5 min. The layers are separated; the organic layer is washed with water (20 ml), dried (Na2SO4), and evaporated. Flash chromatography (30% EtOAc/hexanes) provides the title compound as white powder. 1H NMR (400 MHz, CDCl3) δ 1.02 (3H, d), 1.28 (3H, t), 1.56 (9H+1H, s+m), 1.92 (1H, m), 2.15 (1H, m), 2.48 (1H, q), 2.80 (1H, q), 3.15-3.25 (2H, m), 4.24 (2H, q), 7.57 (1H, s). MS (ES+) 336 (M+1) Step 2: 6-Methyl-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylic acid ethyl ester
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.Cl.[OH:18][NH3+:19].O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:19][OH:18])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: [NH3+]O
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: ON=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Yield: 42.8 %

Procedure:
106.8 g (0.44 mole) of 1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-1-ethanone are dissolved in 780 ml of ethanol, 48 g of hydroxylammonium hydrochloride are added and the mixture is heated under reflux for 5 hours. 1,000 ml of water are then added to the reaction mixture, and the mixture is filtered. 51 g (45% of theory) of 1-(2,4-dichlorophenyl)-1-oximino-2-(1,2,4-triazol-1-yl)-ethane of melting point 165°-170° C. are obtained. ##STR8##
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[Cl:25])[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11]Br)=[O:4].[F:26][CH:27]1[CH2:33][CH:32]2[NH:34][CH:28]1[CH2:29][O:30][CH2:31]2>>[Cl:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C@H:6]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:10]([CH2:11][N:34]2[CH:28]3[CH:27]([F:26])[CH2:33][CH:32]2[CH2:31][O:30][CH2:29]3)[NH:9][C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:7]1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: FC1CC2COCC1N2
Product: COC(=O)C1=C(CN2C3COCC2C(F)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl

Procedure:
The title compound was prepared in analogy to compound 1a in Example 1 starting from compound C and compound 6-fluoro-3-oxa-8-azabicyclo[3.2.1]octane 51a. Preparation of 6-fluoro-3-oxa-8-azabicyclo[3.2.1]octane 51a:
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18](=[O:28])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1)[CH3:16]>CCOC(C)=O>[CH2:15]([O:17][C:18](=[O:28])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:12]([C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:14])[CH:22]=1)[CH3:16]
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Reactant: CCOC(=O)COc1cccc(N)c1
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccc(NC(=O)c2ccc(-c3ccccc3)o2)c1

Procedure:
Carboxylic acid (56)(50 mg, 0.27 mmol) was coupled to aniline (64)(52 mg, 0.27 mmol) using Method C. During this reaction, partial hydrolysis occurred. The residue was re-dissolved in EtOAc (2 ml) and the organic layer was washed with 1M HCl (2×1 ml), dried (Na2SO4), filtered and the solvent removed in vacuo to give a mixture of acid and ester, which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:8]#[N:9])[CH2:6][C:5](=[CH2:7])[CH2:4]1.C(Cl)Cl.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>>[CH3:20][S:21]([O:1][CH2:2][C:3]1([C:8]#[N:9])[CH2:6][C:5](=[CH2:7])[CH2:4]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: C=C1CC(C#N)(CO)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C1CC(C#N)(COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-(hydroxymethyl)-3-methylenecyclobutanecarbonitrile (0.756 g, 0.00614 mol) in methylene chloride (20 mL, 0.3 mol) was added triethylamine (1.28 mL, 0.00921 mol) followed by methanesulfonyl chloride (0.594 mL, 0.00767 mol) at 0° C. The reaction was stirred at rt for 1 h, quenched with water, and extracted with dichloromethane. The combined organic layers were washed with water, brine, and then dried over magnesium sulfate and evaporated to dryness. The residue was used directly in next step.
Reaction SMILES: [CH:1]1([CH2:7][C:8](O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClS([N:15]=C=O)(=O)=O.CN(C=O)C>C(Cl)Cl>[CH:1]1([CH2:7][C:8]#[N:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C(O)CC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCC1CCCCC1
Temperature: 0 °C

Procedure:
A solution of the cyclohexylacetic acid (20.0 g, 141 mmol) in CH2Cl2 (80 mL) was heated to reflux and a solution of chlorosulfonyl isocyanate (20.9 g, 148 mmol) in CH2Cl2 (18 mL) was added dropwise over 40 minutes. After the addition was complete, stirring was continued at reflux for 65 minutes. The mixture was cooled to 0° C., and DMF (21.1 g, 288 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred 18 hours. The mixture was poured over ice, the organic layer separated, and the aqueous layer extracted with CH2Cl2 (50 mL). The combined organic layers were washed with water (3×50 mL), brine, dried (Na2SO4), filtered through a plug of Florosil and concentrated. The nitrile was obtained as 14.6 g (85%) of an oil of sufficient purity for use in the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][CH2:16][C:17]([OH:19])=O)([CH3:14])[CH2:6][CH2:5]2.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.C1COCC1>[CH3:14][C:7]1([CH2:15][CH2:16][CH2:17][OH:19])[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([O:1][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][O:20]3)[CH:3]=2)[O:8]1
Reactant: Cc1c(O)cc2c(c1C)OC(C)(CCC(=O)O)CC2
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(OC2CCCCO2)cc2c(c1C)OC(C)(CCCO)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(6-hydroxy-2,7,8-trimethyl-chroman-2-yl)-propionic acid (500 mg), 3,4-dihydro-2-H-pyran (2 mL) and pyridinium p-toluenesulfonate (PPTS) (50 mg) in dichloromethane (20 mL) was stirred at RT for overnight. The mixture was washed with water, dried over MgSO4, and concentrated to give an oily residue. The oil was dissolved in THF, then LiAIH4 (85 mg) was added and the mixture was stirred at RT for 2 h. The excess LiAIH4 was destroyed by adding ethyl acetate, and the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography eluting with 30% EtOAc in hexane to give 732 mg of 3-[2,7,8-trimethyl-6-(tetrahydro-pyran-2-yloxy)-chroman-2-yl]-propan-1-ol as an oily product. 1H-NMR (300 MHz, CDCl3) δ (ppm): 6.67 (s, 1H), 5.32 (t, J=3.2 MHz, 1H), 4.0-3.9 (m, 1H), 3.70-3.55 (m, 3H), 2.75-2.70 (m, 2H), 2.15, 2.09 (2s, 6H), 2.10-1.60 (m, 12H), 1.25 (s, 3H). 13C-NMR (75 MHz, CDCl3) δ (ppm): 148.08, 146.23, 125.51, 125.25, 117.66, 112.99, 112.96, 97.36, 75.17, 63.25, 62.09, 60.41, 36.26, 36.03, 31.51, 31.47, 30.78, 26.97, 25.41, 24.01, 23.81, 22.48, 21.05, 19.11, 14.19, 12.18, 11.94.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10](=[NH:14])OCC)=[C:6]([CH2:17][CH2:18][CH3:19])[C:5]=1[OH:20])(=[O:3])[CH3:2].[NH3:21]>C(O)C>[C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([NH2:14])=[NH:21])=[C:6]([CH2:17][CH2:18][CH3:19])[C:5]=1[OH:20])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC(=N)OCC)ccc(C(C)=O)c1O
Reactant: N
Solvent: CCO
Product: CCCc1c(OCC(=N)N)ccc(C(C)=O)c1O

Procedure:
Obtained using the procedure described in section b of Example 17, starting with 25.0 g (0.0895 mole) of ethyl 2-(4-acetyl-3-hydroxy-2-propylphenoxy)acetimidate and 7.6 g (0.45 mole) of ammonia in 300 ml of absolute ethanol.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:8]=1.Br[C:24]1[CH:25]=[C:26]([CH2:30][OH:31])[CH:27]=[N:28][CH:29]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[OH:31][CH2:30][C:26]1[CH:25]=[C:24]([C:3]2[CH:4]=[CH:5][C:6]3[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[O:13])[N:11]=3)[CH:8]=2)[CH:29]=[N:28][CH:27]=1
Reactant: C[Sn](C)(C)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Reactant: OCc1cncc(Br)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cn2cc(-c3cncc(CO)c3)ccc2n1
Yield: 43.5 %

Procedure:
163 mg of 6-trimethylstannyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 4), 310 mg of (5-bromopyrid-3-yl)methanol, 66 mg of tetrakis(triphenylphosphine)-palladium and 4 mL of N,N-dimethylformamide are placed in a microwave tube. The reaction mixture is heated for 20 minutes in a microwave machine set at 150° C. and concentrated to dryness. The residue is chromatographed on a silica cartridge, eluting with dichloromethane. The fractions containing the expected product are combined and evaporated to dryness under reduced pressure to give 61 mg of 6-[5-(hydroxymethyl)pyrid-3-yl]-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>CN(C=O)C>[CH:25]([NH:28][C:7]1[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:20])([F:21])[F:22])[N:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH3:27])[CH3:26]
Reactant: CC(C)N
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1NC(C)C
Yield: 83.8 %

Procedure:
This compound was prepared as described in Example 37: 7.0 g (0.018 mol) of product of Example 27, 3.2 ml (0.037 mol) of isopropylamine in 30 ml of DMF were reacted at room temperature for 1/2 hour affording a brown oil which was kugelrohr distilled at 78 Pa, pot temperature 95° C., to give 6.07 g (83.8%) of product as a yellow oil, nD25 1.4560.