Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[CH3:28][N:29]([CH3:37])[C:30]1[C:31]([NH2:36])=[CH:32][CH:33]=[CH:34][CH:35]=1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:6]([C:11]([NH:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]([CH3:37])[CH3:28])=[O:12])=[CH:7][N:8]=[CH:9][CH:10]=1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Reactant: CN(C)c1ccccc1N
Product: CN(C)c1ccccc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and N,N-dimethylbenzene-1,2-diamine (commercially available, CAS RN 2836-03-5). The compound was purified by preparative HPLC (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2). Light brown foam (71%). MS (ESI): m/z=402.078 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:4]1[S:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][N:5]=1)[CH3:3].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:1][CH:2]([C:4]1[S:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][N:5]=1)[CH3:3])(=[O:25])=[O:24]
Reactant: CC(O)c1nnc(-c2ccccn2)s1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)c1nnc(-c2ccccn2)s1
Reaction time: 1 h

Procedure:
To a mixture of (RS)-2-(5-(1-hydroxy-ethyl)-1,3,4-thiadiazol-2-yl)-pyridine (1.0 gm), and triethylamine (2 ml) in dichloromethane (50 ml) was added methanesulfonyl chloride (0.9 gm) at −10° C. The reaction mixture was stirred over a period of 1 h. The reaction was quenched by addition of water and layers were separated. Aqueous layer was extracted with dichloromethane. Combined organic layer was washed with aqueous sodium bicarbonate followed by water and evaporated under vacuum to provide the title compound in 1.0 gm quantity (73%) as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10](/[CH:11]=[CH:12]/[C:13]2[N:21]([CH3:22])[C:20]3[C:19](=[O:23])[N:18]([CH2:24][CH3:25])[C:17](=[O:26])[N:16]([CH2:27][CH3:28])[C:15]=3[N:14]=2)=[CH:9][CH:8]=1.[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C)C=O>[N:31]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10](/[CH:11]=[CH:12]/[C:13]2[N:21]([CH3:22])[C:20]3[C:19](=[O:23])[N:18]([CH2:24][CH3:25])[C:17](=[O:26])[N:16]([CH2:27][CH3:28])[C:15]=3[N:14]=2)=[CH:9][CH:8]=1)=[N+:32]=[N-:33]
Reactant: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCCCCBr)cc3)n2C)n(CC)c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCCCCN=[N+]=[N-])cc3)n2C)n(CC)c1=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Compound 177 (235 mg, 0.49 mmol) obtained in Reference Example 116 was dissolved in 10 ml of dimethylformamide. To the solution was added 161 mg (2.48 mmol) of sodium azide, and the mixture was stirred at 80° C. for 3 hours. Water was added thereto under ice cooling and the deposited crystals were collected by filtration. The collected crude crystals were dissolved in chloroform, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform), followed by recrystallization from hexane/ethyl acetate to give 216 mg (yield quant.) of Compound 178 as pale yellow grains.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:6][N:5]=[C:4]([CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)[CH:3]=1.CCCCCCCCCCCCN>>[CH3:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][C:11]([F:14])([F:12])[F:13])=[CH:6][N:5]=[C:4]([CH2:15][NH2:16])[CH:3]=1
Reactant: Cc1cc(CN2C(=O)c3ccccc3C2=O)ncc1OCCC(F)(F)F
Agent: CCCCCCCCCCCCN
Product: Cc1cc(CN)ncc1OCCC(F)(F)F
Yield: 69 %

Procedure:
The title compound is prepared in 69% yield (133 mg, a pale brown oil) from 2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)isoindoline-1,3-dione (300 mg, 0.82 mmol, Step-4) in a similar manner to Step-5 of Amine-12.
Reaction SMILES: C([N:5]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]2[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])=[N:6]1)(C)(C)C>C(O)=O.Cl>[CH3:22][C:16]1[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:15]=1[C:7]1[C:8]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH2:14])[NH:5][N:6]=1
Reactant: Cc1cccc(-c2nn(C(C)(C)C)c3ncnc(N)c23)c1C
Agent: Cl
Solvent: O=CO
Product: Cc1cccc(-c2n[nH]c3ncnc(N)c23)c1C

Procedure:
1-tert-butyl-3-(2,3-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (34 mg, 0.14 mmol) was dissolved in a solution of formic acid (2 mL) and conc. HCl (0.2 mL) and heated to reflux for 30 min. Reaction was concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA). ESI-MS (M+H)+ m/z calcd 240.1, found 240.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]#[N:10])[CH:2]=1>C(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]#[N:10])[CH:2]=1
Reactant: N#CC=Cc1cccnc1
Agent: [Pd]
Solvent: CCO
Product: N#CCCc1cccnc1
Yield: 76.3 %

Procedure:
49.5 g (0.38 mol) of 3-(3-pyridyl)-acrylonitrile is dissolved in 428 ml of ethanol, 9.5 g of 10% Pd/C is added and hydrogenated under normal pressure. After the requisite hydrogen absorption, it is filtered off, and the filtrate is concentrated by evaporation in a vacuum. Chromatography (CH2Cl2→CH2Cl2/acetone 1:4) yields 38.3 g (76%) of 3-(3-pyridyl)propionitrile.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.C([N-]C(C)C)(C)C.[Li+].CON(C)[C:20](=[O:24])[CH:21]([CH3:23])[CH3:22]>C1COCC1>[CH3:22][CH:21]([CH3:23])[C:20]([C:2]1[S:1][CH:5]=[CH:4][C:3]=1[C:6]([OH:8])=[O:7])=[O:24]
Reactant: CON(C)C(=O)C(C)C
Reactant: O=C(O)c1ccsc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C(=O)c1sccc1C(=O)O
Temperature: 25 °C
Yield: 94.4 %

Procedure:
To a solution of thiophene-3-carboxylic acid (26.65 g) in THF (300 ml) was added 2M lithium diisopropylamide (229 ml) dropwise at 0–5° C. with stirring under nitrogen, and the resulting mixture stirred for 15 min. A solution of N-methoxy-N,2-dimethylpropanamide (30 g) in THF (150 ml) was added dropwise over a period of 1 hr. When the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 2 hr. It was poured onto water, the layers separated and the aqueous washed with ether. The aqueous was acidified with conc. hydrochloric acid and extracted with ethyl acetate, the organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the sub-title compound as a solid (38.91 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C@@:9]([OH:19])([C:14]#[C:15][CH:16]2[CH2:18][CH2:17]2)[C:10]([F:13])([F:12])[F:11])[CH:3]=1.[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]2[NH:6][C:20](=[O:21])[O:19][C@:9]([C:14]#[C:15][CH:16]3[CH2:18][CH2:17]3)([C:10]([F:12])([F:13])[F:11])[C:4]=2[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C1Nc2ccc(Cl)cc2[C@@](C#CC2CC2)(C(F)(F)F)O1

Procedure:
A solution of (S)-4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)aniline (4.42 g, 15.3 mmol), 1,1′-carbonyl diimidazole and toluene (50 mL) was stirred at room temperature for 10 minutes. The reaction was quenched with ice-water (10 mL). The two layers were separated, ethyl acetate (10 mL) was added to the toluene layer and the mixture was washed with brine (2×30 mL) and the two layers were separated. The organic layer was evaporated to dryness to give an orange oil and further crystallized with hexanes to give (S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white or off-white solid. 1H NMR (CDCl3) δ 9.64 (s, 1H), 7.49 (a, s, 1H), 7.36 (dd, J=8.4, 1.8 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 1.43-1.36 (m, 1H), 0.97-0.91 (m, 2H), 0.88-0.86 (m, 2H).
Reaction SMILES: C(O)(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-].[C:13]([C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][C:24]([C:30]([OH:32])=[O:31])=[CH:23][C:22]=1[N+]#N)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.O.O.C([O-])(=O)C.[Na+].C(OCC)C>C(#N)C.O>[C:13]([C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][C:24]([C:30]([OH:32])=[O:31])=[CH:23][C:22]=1[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: N#[N+]c1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cc(C=Cc2ccccc2)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of cinnamic acid (3.1 g) in acetonitrile (200 ml), moist 2-benzoyl-5-carboxy-3-nitrobenzenediazonium chloride (corresponding to about 8 g dry material) is added. To the vigorously stirred suspension, a solution of sodium acetate trihydrate (9.4 g) in water (160 ml) is added, followed immediately by a solution of cupric chloride dihydrate (1 g) in water (10 ml). After stirring at room temperature for a further 2 hours, the vigorous nitrogen-evolution has subsided and the mixture is diluted with water (180 ml) followed by diethyl ether (130 ml). The mixture is filtered, and the organic layer is separated. The aqueous layer is extracted with five portions of diethyl ether, and the combined ether extracts are washed with water and evaporated in vacuo. The residue is crystallized by trituration with aqueous ethanol (50-100 ml). The crude 4-benzoyl-5-nitro-3-styrylbenzoic acid obtained is collected by filtration, washed with aqueous ethanol and dried. The crude acid is dissolved in hot 1 N sodium hydrogen carbonate, and after cooling, the precipitated sodium 4-benzoyl-5-nitro-3-styrylbenzoate is collected by filtration and washed with a small amount of icecold water. After drying, the salt is dissolved in hot water (100 ml) and the solution is clairied by filtration hot in the presence of decolorizing carbon. 4-Benzoyl-5-nitro-3-styrylbenzoic acid is precipitated by acidification with acetic acid. It is collected by filtration and is, after drying, obtained with a melting point of 288°-289° C. (dec.).
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[N:9][C:8]=2[C:12]([O:14]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>C(O)C>[C:1]1([C:7]2[S:11][CH:10]=[N:9][C:8]=2[C:12]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCOC(=O)c1ncsc1-c1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ncsc1-c1ccccc1
Yield: 60.1 %

Procedure:
4.8 g (20.58 mmol) of ethyl 5-phenyl-4-thiazolecarboxylate and 4.0 g (25.0 mmol) of t-butyl (2-aminoethyl)carbamate were heated under reduced pressure for 21 hours at a bath temperature of 100°, whereby the ethanol formed was distilled off continuously. Subsequently the mixture was cooled, dissolved in 50 ml of methylene chloride and chromatographed on 150 g of silica gel. Elution was first carried out with methylene chloride, then with a 9:1, 8:2 and finally 7:3 mixture of methylene chloride and ethyl acetate. The fractions which were pure according to the thin-layer chromatogram were combined and recrystallized from ethyl acetate/hexane. In this manner there were obtained 4.3 g (60.1%) of t-butyl [2-(5-phenyl-4-thiazolecarboxamido)ethyl]carbamate as white crystals, melting point 139-140°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[N:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1>C(Cl)Cl.CO>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[N:39]=[CH:38][C:37]([NH:40][C:23]([C:20]3[CH:21]=[CH:22][C:13]([C:3]4[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[Cl:1])=[C:14]4[C:19]=3[N:18]=[CH:17][CH:16]=[CH:15]4)=[O:24])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1
Reactant: CN1CCN(Cc2ccc(N)cn2)CC1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncccc23)c1Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)nc3)c3ncccc23)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.1), 6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-ylamine (Step 39.1), and stirring the reaction mixture for 3 h at rt. Title compound: ESI-MS: 566.0 [M+H]+; tR=3.64 min (System 1); TLC: Rf=0.24 (DCM/MeOH, 9:1).
Reaction SMILES: [C:1]([C:3](=[CH:12][NH:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])[C:4]([NH:6][C:7](OCC)=[O:8])=[O:5])#[N:2]>CC1C=CC(C(C)C)=CC=1>[C:1]([C:3]1[C:4](=[O:5])[NH:6][C:7](=[O:8])[N:13]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])[CH:12]=1)#[N:2]
Reactant: CCOC(=O)NC(=O)C(C#N)=CNc1c(C)cccc1C
Solvent: Cc1ccc(C(C)C)cc1
Product: Cc1cccc(C)c1-n1cc(C#N)c(=O)[nH]c1=O

Procedure:
A mixture of α-cyano-β-(2,6-dimethylanilino)-N-ethoxycarbonylacrylamide (1.2 g) and about 10 ml of p-cymene is heated at reflux for about 1.5 hour. After cooling on standing, the crystalline product is collected by filtering and washing with ether to yield 5-cyano-1-(2,6-dimethylphenyl)uracil, m.p. 267°-269°.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][CH:9]=[C:8]2[O:17][CH2:18][CH2:19][N:20]1[C:25](=[O:26])[CH:24]=[CH:23][C:22]([C:27]2[CH:28]=[C:29]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:30]=[CH:31][CH:32]=2)=[N:21]1)CO.C1COCC1.CO>CS(C)=O.O.[O-]S([O-])=O.[Na+].[Na+].C(Cl)Cl>[CH:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][CH:9]=[C:8]2[O:17][CH2:18][CH2:19][N:20]1[C:25](=[O:26])[CH:24]=[CH:23][C:22]([C:27]2[CH:28]=[C:29]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH:30]=[CH:31][CH:32]=2)=[N:21]1)=[O:1]
Reactant: COc1cc2nccc(OCCn3nc(-c4cccc(CNC(=O)OC(C)(C)C)c4)ccc3=O)c2cc1C(O)CO
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1cc2nccc(OCCn3nc(-c4cccc(CNC(=O)OC(C)(C)C)c4)ccc3=O)c2cc1C=O
Reaction time: 5 h

Procedure:
To a solution of tert-butyl (3-(1-(2-(6-(1,2-dihydroxyethyl)-7-methoxyquinolin-4-yloxy)ethyl)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)methylcarbamate (30 mg, 53 μmol) in DMSO (0.5 mL)-THF (1 mL)-MeOH (1 mL) was added a solution of NaIO4 (80 mg, 374 μmol) in H2O (0.5 mL). After 5 h, the mixture was diluted with aqueous Na2SO3 (2 mL) and CH2Cl2 (5 mL). The organic layer was separated, the aqueous was extracted with CH2Cl2 (3×5 mL). The combined organic phase was dried over MgSO4, concentrated, and purified on silica (1-6% MeOH in CH2Cl2) to give the product as a film (24 mg). LCMS (ESI pos. ion): calc'd for C29H30N4O6: 530.1; found 531.3 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.46 (s, 9 H), 4.02 (s, 3 H), 4.36 (d, J=5.52 Hz, 2 H), 4.70 (t, J=5.52 Hz, 2 H), 4.81 (t, J=5.27 Hz, 2 H), 5.38 (none, 1H), 5.38 (m, 1 H), 6.73 (d, J=5.02 Hz, 1 H), 7.04 (d, J=9.54 Hz, 1 H), 7.35-7.47 (m, 3 H), 7.60 (d, J=7.53 Hz, 1 H), 7.65-7.73 (m, 2 H), 8.60 (s, 1 H), 8.72 (d, J=5.02 Hz, 1 H), 10.36 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]1([CH3:20])[CH2:19][O:18]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:17]2([CH3:20])[CH2:19][O:18]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC1(CCl)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(COc2ccc(Br)cc2)CO1

Procedure:
4-Bromophenol (80 g, 462 mmol), 2-(chloromethyl)-2-methyloxirane (400 ml) and potassium carbonate (95.86 g, 693 mmol) were mixed and allowed to react at 100° C. for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. Ethyl acetate (200 ml) and water (400 ml) were added thereto, followed by extraction. The water layer was extracted with ethyl acetate (200 ml). The organic layer was washed with water (200 ml) twice. The organic layer was then concentrated under reduced pressure to remove the ethyl acetate. Thereafter, toluene was added and the resulting mixture was concentrated under reduced pressure, obtaining 120 g of crude product.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[N:11][OH:12])[CH2:8]2.[CH:13]1([N:19]=[C:20]=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>ClCCl>[CH:13]1([NH:19][C:20]([O:12][N:11]=[C:2]2[CH:1]3[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]2[CH2:4]4)[CH2:8]3)=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: ON=C1C2CC3CC(C2)CC1C3
Reactant: O=C=NC1CCCCC1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)ON=C1C2CC3CC(C2)CC1C3
Temperature: 10 °C
Reaction time: 3.5 h

Procedure:
To a cooled solution (ice-water at 10° C.) of 2-adamantanone oxime (5.0 g, 0.03 mol) in 300 ml dichloromethane was added dropwise cyclohexyl isocyanate (3.77 g, 0.03 mol) in dichloromethane (25 ml). The resulting solution was stirred at 10° C. for 3-4 h, then the solvent was evaporated under reduced pressure to yield the title compound, tricyclo[3.3.1.13,7 ]decane-2-one O-[(cyclohexyl)aminocarbonyl]oxime. After repeated crystallization from ether-hexane, 6.2 g of the title compound were obtained as white crystals (m.p., 110°-112° C.).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:8][CH2:9][CH2:10]CCC.CCOCC>C[O-].[Na+].C(O)CCC.CO>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCCCCC
Reactant: C=C(C)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CO
Solvent: CCOCC
Product: C=C(C)C(=O)OCCCC
Yield: 95.1 %

Procedure:
A 74.1g (0.1 mole) amount of n-butyl alcohol, 200.2g (2.0 mols) of methyl methacrylate, 187g (2.18 mols) of n-hexane and 0.17 g of hydroquinonemonomethyl ether were added to the apparatus described in Example 1 and were heated and agitated under full reflux to remove water from the reaction system. The amount of water obtained in the reaction solution was 0.001 mol. To the reaction solution was added 0.0035 mol of sodium methylate as a catalyst and the solution was heated and agitated. An azeotropic mixture was n-hexane and methanol fom the upper part (top) of the fractionating tower was obtained and was kept stationary in a decanter. The n-hexane layer which separated was returned to the tower and the methanol layer was removed continuously to advance the reaction. Meanwhile, the temperature at the top of the tower was 56° to 59.8° C and the flask temperature was 83° to 90° C. The results of the experiment were a 98.8% conversion of n-butyl alcohol and a 95.1% yield of n-butyl methacrylate. However, it was found bu gas chromatography that an additive of methylmethacrylate was produced as a by-product as well as a polymer. As soon as this reaction solution was distilled, it polymerized.
Reaction SMILES: C(OC([N:11]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][C:32]([OH:34])=[O:33])[CH:26]=1)[CH2:12][CH3:13])=O)C1C=CC=CC=1>CCO.[Pd]>[CH2:12]([NH:11][CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:18]=[CH:17][C:16]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][C:32]([OH:34])=[O:33])[CH:26]=1)[CH3:13]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cccc(CC(=O)O)c1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cccc(CC(=O)O)c1
Reaction time: 3 h

Procedure:
{2′-[(Benzyloxycarbonyl-ethyl-amino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (0.16 g, 0.34 mmol) in EtOH (7 mL) was treated with 10% palladium on carbon (0.072 g), and the reaction was stirred under a balloon of H2 for 3 hours to give the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([O:12][CH3:13])[CH:6]=[N:7]2.C(OC(=O)[NH:23][CH:24]1[CH2:27][NH:26][CH2:25]1)C1C=CC=CC=1>>[CH3:13][O:12][C:5]1[CH:6]=[N:7][C:8]2[C:3]([CH:4]=1)=[C:2]([N:26]1[CH2:27][CH:24]([NH2:23])[CH2:25]1)[CH:11]=[CH:10][CH:9]=2
Reactant: O=C(NC1CNC1)OCc1ccccc1
Reactant: COc1cnc2cccc(Br)c2c1
Product: COc1cnc2cccc(N3CC(N)C3)c2c1

Procedure:
Starting from 5-bromo-3-methoxyquinoline (WO 2007/107965) and azetidin-3-yl-carbamic acid benzyl ester (commercial) the title compound was prepared according to procedure L followed by procedure G and was isolated as a pale yellow solid (122 mg, 63% over two steps).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[N:9][CH:10]=1)=[O:4].[Li+].[OH-]>CO>[F:17][C:13]1[CH:12]=[C:11]([C:8]2[N:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][N:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cnc(-c2cccc(F)c2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid methyl ester (1.76 g, 7.58 mmol) in anhydrous MeOH (35 mL) is added LiOH (0.38 g, 15.9 mmol) and the reaction mixture is stirred at rt overnight. The mixture is concentrated in vacuo and the residue is partitioned between EtOAc and 3 N aqueous HCl (7.6 mL). The mixture is extracted with EtOAc and the organic layer is washed with brine, dried (MgSO4), filtered and concentrated in vacuo to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (1.62 g, 98%) as a solid. MS: 219 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][C:33](B(O)O)=[CH:34][CH:35]=2)[CH:30]=[CH:29]1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:33]5[CH:32]=[C:31]6[C:36](=[CH:35][CH:34]=5)[N:28]([CH3:27])[CH:29]=[CH:30]6)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cn1ccc2cc(B(O)O)ccc21
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc6c(ccn6C)c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and N-methyl-indole-5-boronic acid following a procedure analogous to that described for Intermediate 6. LC (method 4): tR=0.87 min; Mass spectrum (ESI+): m/z=488 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:13])=[C:7]([NH:9][C:10](=[O:12])[CH3:11])[CH:8]=1.[H-].[Na+].Cl[CH2:17][CH2:18][CH2:19][O:20][CH3:21].[I-].[Na+]>CN(C)C=O>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:13])=[C:7]([N:9]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:10](=[O:12])[CH3:11])[CH:8]=1
Reactant: CC(=O)Nc1cc(CO)ccc1C
Reactant: COCCCCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCN(C(C)=O)c1cc(CO)ccc1C

Procedure:
The solution of 0.892 g of N-(5-hydroxymethyl-2-methylphenyl)acetamide in 8 ml of N,N-dimethylformamide is cooled to 0° C. with stirring and admixed with 0.16 g of sodium hydride dispersion (60%). The mixture is stirred at 0° C. over 30 minutes and subsequently admixed with 0.489 ml of 1-chloro-3-methoxypropane and 60 mg of sodium iodide. The reaction mixture is stirred at 80° C. over 48 hours and poured onto water (50 ml). The mixture is extracted with ethyl acetate (2×50 ml). The organic phases are washed successively with water (2×50 ml) and brine (1×50 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as an orange oil from the residue by means of flash chromatography (SiO2 60F). Rt=2.73.