Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([O:24][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Reactant: OC1CCCC1
Product: O=C(NC(=O)C(c1ccccc1)c1ccccc1)OC1CCCC1

Procedure:
The title compound, white solid, m.p. 120-123° C. and MS: m/e=323.4 (MH+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and cyclopentanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[C:13]([O:17][C:18]([N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Na+].[Na+]>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.O.COCCOC>[NH2:5][C:4]1[CH:3]=[C:2]([C:21]2[N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH:24]=[CH:23][CH:22]=2)[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
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: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1cccc1-c1cc(N)cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 74.6 %

Procedure:
A mixture of 3-bromo-5-(trifluoromethyl)aniline (1.50 mL, 10.6 mmol), water (15.0 mL), 1,2 dimethoxyethane (75 mL), [1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]boronic acid (3.36 g, 15.9 mmol) and sodium carbonate (4.50 g, 42.4 mmol) was degassed with nitrogen for 5 min. Tetrakis(triphenylphosphine)palladium(0) (0.74 mg, 0.64 mmol) was added to the mixture and the slurry was heated at 80° C. for 3 h. Water was added and the mixture was extracted with EtOAc. The organic solutions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on basic alumina to give tert-butyl 2-[3-amino-5-(trifluoromethyl)phenyl]-1H-pyrrole-1-carboxylate (2.58 g, 74%). LCMS: (FA) ES+ 327.3.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([C:22]([O:24]CC)=[O:23])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=1)/[CH:9]=[CH:10]/[C:11]1[S:12][CH:13]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=1.[OH-].[K+]>C(O)C.CO.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>[C:22]([C:2]([CH3:27])([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=1)/[CH:9]=[CH:10]/[C:11]1[S:12][CH:13]=[C:14]([CH:16]([CH3:17])[CH3:18])[N:15]=1)([OH:24])=[O:23]
Reactant: CCOC(=O)C(C)(C)CCOc1cccc(/C=C/c2nc(C(C)C)cs2)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CC(C)c1csc(/C=C/c2cccc(OCCC(C)(C)C(=O)O)c2)n1
Yield: 66.3 %

Procedure:
To a solution of 200 mg of 2-[trans-3-(3,3-dimethyl-3-ethoxycarbonylpropyloxy)styryl]-4-isopropylthiazole dissolved in 5 ml of ethanol were added 2 ml of 10% aqueous potassium hydroxide solution and three drops of 40% benzyltrimethylammonium hydroxide methanol solution, and the mixture was refluxed for 1 hour to effect hydrolysis of the ester. After completion of the reaction, ethanol was evaporated under reduced pressure and the residue was adjusted to pH 1-2 with addition of 10% hydrochloric acid and then extracted with ethyl ether. After drying of anhydrous magnesium sulfate, the solvent was evaporated and the solid formed was recrystallized from methanol to give 123 mg (yield 66%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.O>COC(C)(C)C>[CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:9]
Reactant: Cc1ccccc1OCc1ccccc1C(=O)Cl
Reactant: C1COCCN1
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1ccccc1OCc1ccccc1C(=O)N1CCOCC1
Yield: 51.4 %

Procedure:
At 20 to 30° C., 2.6 g (0.01 mol) of 2-(2-methylphenoxymethyl)benzoyl chloride (EP-A 493 711, page 22) are added dropwise to a solution of 1.8 g (0.02 mol) of morpholine in 40 ml of tert-butyl methyl ether. The mixture is admixed with water and the organic phase is separated off, dried over sodium sulphate and concentrated under reduced pressure. The residue is recrystallized from 5 ml of methanol. 1.6 g (51.4% of theory) of N-[2-(2-methylphenoxymethyl)-benzoyl]-morpholine are obtained.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH2:6][N:7]1[CH2:12][CH2:11][C@@H:10]([CH2:13][CH2:14][O:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:9]([OH:29])[CH2:8]1)(=[O:3])[CH3:2]>C(Cl)(Cl)Cl>[C:1]([O:4][C@@H:5]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][O:15][CH:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]([OH:29])[CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](CN1CC[C@@H](CCOC(c2ccccc2)c2ccccc2)[C@H](O)C1)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@H](CN1CCC(CCOC(c2ccccc2)c2ccccc2)C(O)C1)c1ccc(F)cc1

Procedure:
(S)-2-((3S,4S)-4-(2-(benzhydryloxy)ethyl)-3-hydroxypiperidin-1-yl)-1-(4-fluorophen-yl)ethyl acetate (8d′). 1H-NMR (CDCl3; 400 MHz): 1.28-1.38 (m, 2H, H-4, H-5ax), 1.54-1.65 (2H, m, H-5eq, CH2CH2O), 1.83-1.92 (m, 1H, H-6ax), 1.97-1.99 (t, 1H, J=13.2 Hz, H-2ax), 2.07 (s, 3H, OCOCH3), 2.11-2.14 (t, 1H, J=8.8 Hz, CHHCH2O), 2.54-2.58 (dd, J=13.6, 4.8 Hz, 1H, NCHHCHAr), 2.70-2.73 (brd, 1H, J=11.2 Hz, H-6eq), 2.79-2.85 (m, 1H, NCHHCHAr), 3.01-3.05 (dd, 1H, J=10.4, 2.8 Hz, H-2eq), 3.31-3.36 (m, 1H, H-3ax), 3.48-3.53 (m, 1H, CH2CHHO), 3.55-3.60 (m, 1H, CH2CHHO), 5.36 (s, 1H, PhCH(O)Ph), 5.87-5.90 (dd, 1H, J=8.4, 4.8 Hz, CHOCOCH3), 6.99-7.04 (t, 2H, ArH), 7.22-7.33 (m, 12H, ArH). [a]25D=+13.30° (c=1.0, CHCl3).
Reaction SMILES: Br[C@H:2]1[C@H:7]([OH:8])[C:6]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:5]=2[O:4][C:3]1([CH2:17][CH3:18])[CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:8]1[CH:7]2[CH:2]1[C:3]([CH2:17][CH3:18])([CH2:15][CH3:16])[O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:6]=12
Reactant: CCC1(CC)Oc2ccc(C#N)cc2[C@@H](O)[C@@H]1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC1(CC)Oc2ccc(C#N)cc2C2OC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
A mixture of trans-3-bromo-2,2-diethyl-3,4-dihydro-4-hydroxy-2H-1-benzopyran-6-carbonitrile (1.95 g) and potassium carbonate (1.74 g) in N,N-dimethylformamide (8 ml) was stirred overnight at ambient temperature. The reaction mixture was poured into water, extracted with ethyl acetate, and then washed with water and brine successively. The extract was dried over anhydrous magnesium sulfate, treated with active charcoal, and evaporated in vacuo. The residue was purified with silica gel column chromatography using a mixture of methylene chloride and n-hexane (1:2) as an eluent to give 3,4-epoxy-2,2-diethyl-3,4-dihydro-2H-1-benzopyran-6-carbonitrile (1.17 g).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].CS(C)=O.[CH3:10][N:11]([O:16][CH3:17])[C:12](=[O:15])[CH2:13]Cl>C(Cl)Cl>[CH3:10][N:11]([O:16][CH3:17])[C:12](=[O:15])[CH2:13][O:3][C:1](=[O:4])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CON(C)C(=O)CCl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CON(C)C(=O)COC(C)=O
Temperature: 70 °C
Reaction time: 7 h
Yield: 75.2 %

Procedure:
A mixture of 23 g (0.28 mole) of sodium acetate, 200 ml of dimethylsulphoxide and 34.4 g (0.25 mole) of chloroacetic acid N-methyl-N-methoxy-amide (for its preparation, see DE-OS (German Published Specification) No. 2,753,182) was stirred at 70° C. for 7 hours. The mixture was then cooled to room temperature, 500 ml of methylene chloride were added and the inorganic salt was filtered off. The filtrate was evaporated in vacuo and the residue was distilled. 30.3 g (75% of theory) of acetoxyacetic acid N-methyl-N-methoxy-amide were thus obtained as a colourless liquid with a boiling point of 70° C./0.3 mm Hg.
Reaction SMILES: C[Si](C)(C)[O:3][C:4](=[CH2:19])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C(=O)(O)[O-].[Na+].[Br:27]N1C(=O)CCC1=O>C1COCC1>[Br:27][CH2:3][C:4](=[O:19])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1
Reactant: C=C(CC1CCN(C(=O)OC(C)(C)C)CC1)O[Si](C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)CBr)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 109.7 %

Procedure:
To a solution of tert-butyl 4-(2-(trimethylsilyloxy)allyl)piperidine-1-carboxylate (6.43 g, 20.5 mmol) in THF (100 mL) at 0° C. was added sodium bicarbonate (2.58 g, 30.7 mmol) followed by 1-bromopyrrolidine-2,5-dione (3.65 g, 20.5 mmol). Warmed to ambient temperature and stirred 90 minutes. Partitioned between ether (150 mL) and saturated sodium bicarbonate. The aqueous layer was reextracted with ether (100 mL). The combined organic layers were washed with saturated bicarbonate, brine, dried, and concentrated to afford the title compound (7.2 g, 110% yield) as a yellow oil. Purity was 85% with the major impurity being succinimide. The crude material was used in the next step.
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])=[N:4][C:5]2[N:6]([N:17]=[C:18]([CH3:20])[CH:19]=2)[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].[CH3:22][N:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[C:26]2[CH:38]=[CH:39][N:40]([S:41]([C:44]3[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[C:25]=2[C:24]1=[O:51]>>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:7]1[N:6]2[N:17]=[C:18]([CH3:20])[CH:19]=[C:5]2[N:4]=[C:3]([CH3:21])[C:2]=1[C:27]1[C:26]2[CH:38]=[CH:39][N:40]([S:41]([C:44]3[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[C:25]=2[C:24](=[O:51])[N:23]([CH3:22])[CH:28]=1
Reactant: Cc1cc2nc(C)c(Br)c(Oc3ccc(F)cc3F)n2n1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(C)nc5cc(C)nn5c4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 6-bromo-7-(2,4-difluorophenoxy)-2,5-dimethylpyrazolo[1,5-a]pyrimidine and 6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting materials. LCMS calculated for C29H24F2N5O4S (M+H)+: m/z=576.1. found: 576.1.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[CH:22][CH:21]=2)[C:7]2[N:8]([C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:38]=[N+:39]=[N-:40])(C)C>>[CH2:1]([C:5]1[N:6]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:40][N:39]=[N:38][N:33]=3)=[CH:24][CH:25]=2)[C:7]2[N:8]([C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nn2c(-c3ccccc3)cnc2n1Cc1ccc(-c2ccccc2C#N)cc1
Product: CCCCc1nn2c(-c3ccccc3)cnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 46 %

Procedure:
Reaction of 2-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-6-phenyl-3H-imidazo[1,2-b][1,2,4]triazole (from Step A) with trimethyltin azide according to the procedure of Example 1, Step G, gave a 46% yield of the title compound as a light brown solid, mp>70° C. (gradual): homogeneous by TLC in 90:10:0.1 CH2Cl2 -MeOH-AcOH.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14](Br)[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[C:22]([Cu])#[N:23]>CN(C)C=O.O>[F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([C:22]#[N:23])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: N#C[Cu]
Reactant: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1C#N)C(C)CN(C(=O)C(F)(F)F)CC2
Yield: 64 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (18 mg, 0.05 mmol) in dimethylformamide (1 mL) was treated with CuCN (20 mg, 0.24 mmol) and the mixture was microwaved at 200 C for 0.5. hours. The product mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4 and concentrated. Flash chromatography (35% EtOAc in hexane, silica) resulted in 10 mg of a clear oil. MS calculated for C15H15F3N2O2+H: 313, observed: 313.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:18]([N:25]1[C:29]([CH:30]=[O:31])=[CH:28][N:27]=[CH:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>O1CCCC1>[CH2:18]([N:25]1[C:29]([CH:30]([OH:31])[CH2:3][CH2:4][CH:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:28][N:27]=[CH:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: BrCCC(c1ccccc1)c1ccccc1
Reactant: O=Cc1cncn1Cc1ccccc1
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: OC(CCC(c1ccccc1)c1ccccc1)c1cncn1Cc1ccccc1
Temperature: 25 °C

Procedure:
2,0 g of magnesium turnings are covered with 60 ml of dry tetrahydrofuran. To the mixture is then added dropwise a solution of 1-bromo-3,3-diphenylpropane (22,9 g) in 20 ml of dry tetrahydrofuran at such a rate that a smooth reaction is maintained. After the addition is complete, the reaction mixture is refluxed for one additional hour and cooled to room temperature. The reaction mixture is then added dropwise to a solution of 1-benzyl-5-imidazolecarbaldehyde (7,35 g) in 80 ml of tetrahydrofuran at 60° C. After the addition is complete, the reaction mixture is refluxed for 2 hours, cooled and poured into cold water. Tetrahydrofuran is evaporated and to the solution is added conc. hydrochloric acid. The solution is cooled and the precipitate which contains the product as hydrochloride salt is removed by filtration, washed with water and dried. Yield 14,1 g. M.p. 160°-168° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2].[BH4-].[Na+].C([OH:35])C>>[CH2:29]([O:28][C:26]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][CH2:9][C:8](=[O:35])[N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:27])[CH3:30]
Reactant: CCO
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Product: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1c1ccc(Oc2ccc(CO)cc2)nc1
Reaction time: 3 h
Yield: 80 %

Procedure:
To a solution of 1-[6-(4-formyl-phenoxy)-pyridin-3-yl]-pyrolidine-2,2-dicarboxylic acid diethyl ester (1.0 g, 2.3 mmol) in 30 mL of ethanol was added sodium borohydride (0.090 g, 2.3 mmol) at 0° C. After stirring for 3 hours, the mixture was concentrated in vacuo, diluted with ethyl acetate and water, and the aqueous layer was cautiously acidified with 1M hydrochloric acid, then neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted three times with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo, affording 0.80 g (80%) of 1-[6-(4-hydroxymethyl-phenoxy)-pyridin-3-yl]-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester as a colorless syrup. 1H NMR (CDCl3, 400 MHz): 8.04 (d, 1H, J=2.4 Hz), 7.72 (dd, 1H, J=2.4, 8.8 Hz), 7.40 (d, 2H, J=8.8 Hz), 7.12 (d, 2H, J=8.4 Hz), 6.91 (d, 1H, J=8.8 Hz), 4.70 (s, 2H), 4.19 (q, 4H, J=7.6 Hz), 2.75 (m, 2H), 2.65 (m, 2H), 1.18 (t, 6H, J=7.2 Hz) ppm. MS (APCl, m/z): 429.1 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10]CC)=[O:9])[N:7]=1.[OH-].[Li+]>C1COCC1.O>[CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[N:7]=1
Reactant: CCOC(=O)c1csc(NC)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CNc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 2-methylamino-1,3-thiazole-4-carboxylate (300 mg, 1.611 mmol) was dissolved in THF/water mixture and 1M litium hydroxide (3.22 ml, 3.22 mmol) was added. The reaction mixture was stirred at RT for 3 hours, pH was adjusted to acidic and the mixture was evaporated to dryness to yield the title compound. 1H-NMR (400 MHz; DMSO-d6): δ 2.84 (s, 3H), 7.46 (s, 1H), 7.90 (bs, 1H).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29]C)=[O:28])C(=O)C2=CC=CC=C12.O.NN.Cl>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28]
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCCCCCCCCCCCCCCCCCCC(=O)O
Yield: 77.5 %

Procedure:
A mixture of methyl 22-phthalimidodocosanoate (1.5 g, 3.0 mmoles), 40 ml of ethanol and 80% hydrazine hydrate was refluxed for 10 hours. To the reaction mixture was added 11.3 ml of 6N aqueous hydrochloric acid solution, and further refluxed for 1 hour. After removal by filtration of the insoluble matter that formed, the reaction mixture was concentrated under reduced pressure. To the residue were added 30 ml of ethanol and 15 ml of 1N aqueous sodium hydroxide solution, and the resulting mixture was refluxed for 19 hours. After neutralization of the reaction mixture with 6N aqueous hydrochloric acid solution, the precipitates that formed were collected by filtration and recrystallized from ethanol-acetic acid-water to give 22-aminodocosanoic acid (827 mg, 77%) having the following properties.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][O:11][CH2:12][CH3:13])=[CH:4][C:3]=1[N+:14]([O-])=O.CO.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][O:11][CH2:12][CH3:13])=[CH:4][C:3]=1[NH2:14]
Reactant: CCOCCSc1ccc(N)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOCCSc1ccc(N)c(N)c1

Procedure:
6.4 G. of 1-amino-2-nitro-4-(2-ethoxyethylthio) benzene in 100 ml. of methanol and 50 ml. of water is treated with 16 ml. of sodium dithionite and 14 g. sodium carbonate at reflux under nitrogen. Heating is continued for one-half hour, then the methanol is evaporated from the mixture. The mixtue is diluted with 100 ml. of water and is extracted with chloroform. The chloroform solution is dried over sodium sulfate and 1,2-diamino-4-(2-ethoxyethylthio) benzene is obtained by evaporation of the solution.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:15])[C:4](=[O:14])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[N:7]=1.Cl.[CH3:17][CH:18]1[CH2:24][NH:23][CH2:22][CH2:21][CH2:20][O:19]1.C(N(CC)CC)C>>[CH3:15][N:3]1[C:4](=[O:14])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[N:7]=[C:2]1[N:23]1[CH2:22][CH2:21][CH2:20][O:19][CH:18]([CH3:17])[CH2:24]1
Reactant: CC1CNCCCO1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: Cl
Solvent: CCN(CC)CC
Product: CC1CN(c2nc(-c3ccncn3)cc(=O)n2C)CCCO1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a slurry of 2-Chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (126 mg, 0.565 mmol) and 2-methyl-[1,4]oxazepane hydrochloride (100 mg, 0.660 mmol) was added triethylamine (172 mg, 1.70 mmol) at room temperature. The resulting mixture was stirred at room temperature for 10 hours and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant; ethyl acetate) to afford 1-methyl-2-(2-methyl-[1,4]oxazepan-4-yl)-1H-[4,4′]bipyrimidinyl-6-one as white solid (A051) (103 mg, 61%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]([CH2:19]Cl)=[CH2:18].O>CN(C)C=O>[Cl:16][C:17](=[CH2:18])[CH2:19][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: C=C(Cl)CCl
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(Cl)COc1ccc(C#N)cc1
Reaction time: 3 h
Yield: 93.5 %

Procedure:
10.0 g of 4-cyanophenol and 11.6 g of potassium carbonate were suspended in 100 ml of dimethylformamide, and 9.4 g of 2,3-dichloropropene was added dropwise. The reaction solution was stirred at 80 oC for 3 hours, allowed to cool, and poured into 200 ml of water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried. Ethyl acetate was evaporated under reduced pressure. The resulting oily product was purified by column chromatography (silica gel; developing solvent hexane/ethyl acetate (9:1)) to give 15.2 g of the desired 4-(2-chloro-2-propeneoxy)benzonitrile as an oil.
Reaction SMILES: [N:1]1[C:5]2[C:6]3[CH:12]=[CH:11][S:10][C:7]=3[CH2:8][CH2:9][C:4]=2[S:3][C:2]=1[NH2:13].[Cl:14][C:15]1[CH:16]=[C:17]([S:22](Cl)(=[O:24])=[O:23])[CH:18]=[CH:19][C:20]=1[Cl:21]>>[Cl:14][C:15]1[CH:16]=[C:17]([S:22]([NH:13][C:2]2[S:3][C:4]3[CH2:9][CH2:8][C:7]4[S:10][CH:11]=[CH:12][C:6]=4[C:5]=3[N:1]=2)(=[O:23])=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nc2c(s1)CCc1sccc1-2
Product: O=S(=O)(Nc1nc2c(s1)CCc1sccc1-2)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from 4,5-dihyrothieno[3,2-e][1,3]benzothiazol-2-amine (107 mg, synthesized according to METHOD I from 4-keto-4,5,6,7-tetrahydrothianaphthene) and 3,4-dichlorobenzenesulfonyl chloride (127 mg) as described in the synthetic METHOD A to give a white powder (62 mg) with a purity >90%: MS-ES (neg) m/z 417.2.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[C:16]([CH3:40])=[C:17]([N:21]([CH2:25][C:26]2[CH:38]=[CH:37][C:29]([O:30][CH2:31][C:32]([O:34]CC)=[O:33])=[C:28]([CH3:39])[CH:27]=2)[CH2:22][CH2:23][CH3:24])[CH:18]=[CH:19][CH:20]=1>>[CH3:39][C:28]1[CH:27]=[C:26]([CH2:25][N:21]([C:17]2[C:16]([CH3:40])=[C:15]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:22][CH2:23][CH3:24])[CH:38]=[CH:37][C:29]=1[O:30][CH2:31][C:32]([OH:34])=[O:33]
Reactant: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1C

Procedure:
Prepared from 4-(trifluoromethyl)phenylboronic acid and ethyl (4-{[(3-bromo-2-methylphenyl)(propyl)amino]methyl}-2-methylphenoxy)acetate using the procedure described for Example 25 (Method A).