Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][CH2:9][CH:10]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].Br[CH2:26][F:27].O>CN(C=O)C>[NH2:2][C@@H:3]([CH2:8][CH2:9][CH:10]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:26][F:27])=[CH:20][CH:21]=1)[C:11]([O:13][CH3:14])=[O:12])[C:4]([O:6][CH3:7])=[O:5]
Reactant: FCBr
Reactant: COC(=O)C(CC[C@H](N)C(=O)OC)Cc1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(CC[C@H](N)C(=O)OC)Cc1ccc(OCF)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
Dimethyl (2S)-2-amino-5-(4-hydroxybenzyl)hexanedioate hydrochloride (200 mg, 0.54 mmol) were solved in DMF (5 ml) and at 0° C. sodium hydride (34 mg, 1.14 mmol) were added. After 30 min, bromofluoromethane (1.35 mmol) were added and the resulting mixture was stirred at 0° C. for one hour. The mixture was then poured into water and extracted three times with methylene chloride. The organic phase was dried with sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography to yield 37 mg (20.8%) of the product.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[C:17](=[O:18])[CH2:16][C:15](=[O:19])[N:14]=[C:13]1[CH3:20].C([O-])([O-])=O.[K+].[K+].[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30]Br>CN(C=O)C.C1OCCOCCOCCOCCOCCOC1>[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30][O:19][C:15]1[N:14]=[C:13]([CH3:20])[N:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[CH3:1])[C:6]([O:8][CH3:9])=[O:7])[C:17](=[O:18])[CH:16]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COC(=O)c1ccc(C)c(N2C(=O)CC(=O)N=C2C)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)cc2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
A mixture of methyl 4-methyl-3-(2-methyl-4,6-dioxo-5,6-dihydropyrimidin-1(4H)-yl)benzoate (0.1 g, 0.00036 mol, from Step 2), K2CO3 (0.075 g, 0.00054 mol) and 2,4 difluorobenzylbromide (0.075 g, 0.00036 mol) in DMF (2.0 mL) containing 18-crown-6 (0.005 g) is stirred at room temperature for 1 h under argon atmosphere. DMF is distilled in vacuo and the residue is purified by reverse-phase HPLC using 10-90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=401) are combined and concentrated to a small volume (˜20 mL). After cooling, 5% NaHCO3 solution (10 mL) is added and the solution is extracted with dichloromethane (3×20 mL). The combined organic extracts are dried (Na2SO4), filtered, and concentrated to dryness to afford the title compound (0.12 g, 82%) as a white amorphous substance: 1H NMR (CD3OD/400 MHz) δ 8.04 (d, 1H, J=1.6 Hz), 7.87 (d, 1H, J=1.16 Hz), 7.55 (m, 2H), 7.00 (m, 2H), 5.79 (s, 1H), 5.38 (s, 2H), 3.89 (s, 3H), 2.14 (s, 3H), and 2.12 (s, 3H); ES-HRMS m/z 401.1346 (M+H calcd for C21H19N2O4F2 requires 401.1307).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][C:13]([OH:15])=[O:14].[C:16]1([C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N+]=[N-])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>C(Cl)Cl>[C:16]1([CH:22]([O:14][C:13](=[O:15])[CH2:12][C:4]2[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc([N+](=O)[O-])cc1CC(=O)O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])cc1CC(=O)OC(c1ccccc1)c1ccccc1
Yield: 21 %

Procedure:
Using 2-methoxyphenylacetic acid (5.00 g) as a starting material, the same procedure of Example 188 gave 2-methoxy-5-nitrophenylacetic acid. To a solution of the resulting nitro compound in methylene chloride (140 ml), a solution of diphenyldiazomethane in methylene chloride was added at room temperature until the reaction mixture turned purple and then acetic acid was added until the purple color of the reaction mixture disappeared. The reaction mixture was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 2.34 g of the titled compound (yield, 21%).
Reaction SMILES: [O:1]([CH2:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]=[O:16].[OH-].[Na+]>C(O)C>[OH:16][CH2:15][CH:8]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C(=O)COc1ccccc1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)C(=O)C(CO)Oc1ccccc1
Yield: 65.2 %

Procedure:
1Phenoxy-3,3-dimethyl-butan-2-one (192.2 g, 1.0 mol) prepared according to German Offenlegungsschrift, i.e., (German Published Specification No. 2,105,490; Example 3) and having a boiling point of 75°-83°C at 0.08 atmospheres is dissolved in ethanol (800 ml) and a 30% formaldehyde solution (240 ml, 2.4 mols) is added. A 10% sodium hydroxide solution (5 ml) is then added until the pH is 9. The reaction mixture is heated for 4 hours reflux and the solvent is distilled off in vacuo. The resulting precipitate is filtered off, well rinsed with petroleum ether and discarded. The filtrate is freed from the solvent in vacuo and the resulting oil is taken up in ether and extracted by shaking with water. The organic phase is dried over sodium sulphate and freed from the solvent and the residue is purified by vaccum distillation to afford 145 g (65% of theory) of 1 -hydroxy-2-phenoxy-4,4-dimethyl-pentan-3-one, boiling point 95°-100°C (0.1 mm Hg).
Reaction SMILES: CN.[CH2:3]([N:5](CC)CC)C.[S:10](F)(=[O:19])([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)=[O:11]>C(O)C>[CH3:3][NH:5][S:10]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)(=[O:19])=[O:11]
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Reactant: CCN(CC)CC
Agent: CN
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(N)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 78.1 %

Procedure:
Methylamine (3 ml of a 33% solution in ethanol) and then triethylamine (0.159 ml, 1.1 mmol) was added to sulphanilyl fluoride (200 mg, 1.1 mmol), and the mixture heated at 80° C. for 6 hours then at ambient temperature for 18 hours. The volatiles were removed by evaporation and the residue azeotroped with toluene to give the title compound (160 mg, 76%). NMR: 2.30 (s, 3H), 5.85 (s, 2H), 6.60 (d, 2H), 7.39 (d, 2H); m/z: 187 [MH]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:32]([O:34]CC)=O)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].O.[NH2:38][NH2:39]>CO>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:38][NH:39][C:32](=[O:34])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C(F)(F)F)cc1)C(c1ccc(CN(C)C)cc1)N2
Solvent: O
Solvent: CO
Product: CN(C)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(F)(F)F)cc2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
A mixture of ethyl 2-(4-((dimethylamino)methyl)phenyl)-4-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (150 mg, 0.30 mmol) and hydrazine monohydrate (0.5 mL) in methanol (10 mL) was stirred at 30° C. overnight. The mixture was concentrated under reduced pressure to give crude product, which was purified by flash chromatography to give the title compound (60 mg, yield 34.5%) as a white solid. LC-MS (ESI) m/z: 465 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.64 (s, 3H), 2.65 (s, 3H), 4.19-4.20 (d, J=4.0 Hz, 2H), 4.53-4.55 (d, J=9.2 Hz, 1H), 4.88-4.90 (d, J=9.2 Hz, 1H), 7.20-7.22 (d, J=7.6 Hz, 1H), 7.35-7.46 (m, 7H), 7.50 (s, 1H), 7.56-7.63 (m, 3H), 9.69-9.71 (br s, 1H), 12.20 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](Br)[CH:9]=2)[NH:4][N:3]=1.[CH2:12]([O:14][C:15](=[O:35])[CH:16]=[C:17](C1C=CC=C2C=1C(C#N)=CN2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:35])[CH:16]=[C:17]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[CH3:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Reactant: Cc1n[nH]c2ccc(Br)cc12
Product: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]nc(C)c2c1

Procedure:
3-(3-Methyl-1H-indazol-5-yl)-3-phenyl-acrylic acid ethyl ester CCXIX) was prepared from 3-methyl-5-bromo-1H-indazole using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH:21]([CH3:23])[CH3:22])[N:15]=2)[CH:3]=1.[NH3:24].CO>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:24])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH:21]([CH3:23])[CH3:22])[N:15]=2)[CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(OC(C)C)n1
Solvent: CO
Product: CC(C)Oc1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Temperature: 40 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
To a solution of give ethyl 6-chloro-4-(6-isopropoxypyridin-2-ylamino)pyridazine-3-carboxylate (530 mg, 1.57 mmol) was added 7N ammonia in MeOH (16.9 mL, 118 mmol). The mixture was stirred at 40° C. for 18 h, after which the solvent was removed to give 6-chloro-4-(6-isopropoxypyridin-2-ylamino)pyridazine-3-carboxamide (470 mg, 97%) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 11.57 (s, 1H), 9.08 (s, 1H), 8.17 (s, 1H), 7.58 (t, J=7.8 Hz, 1H), 6.50 (d, J=7.3 Hz, 1H), 6.44 (d, J=8.0 Hz, 1H), 5.69 (s, 1H), 5.23 (m, 1H), 1.47 (d, J=6.3 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=O)[CH2:10][O:11][CH2:12][CH3:13])=[C:6]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH:5]=[C:4]([CH3:20])[N:3]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:10][O:11][CH2:12][CH3:13])[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]=2[CH:5]=[C:4]([CH3:20])[N:3]=1
Reactant: CCOCC(=O)Nc1c(NCC(C)C)cc(C)nc1Cl
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOCc1nc2c(Cl)nc(C)cc2n1CC(C)C
Temperature: 135 °C
Reaction time: 48 h

Procedure:
N-[2-Chloro-4-(2-methylpropylamino)-6-methylpyridin-3-yl]-2-ethoxyacetamide (3.64 g), anhydrous toluene (100 ml), and phosphorus oxychloride (10.2 ml) were combined in a sealed glass tube and heated to 135° C. for 16 hours. The resulting reaction mixture was cooled, and the phosphorus oxychloride and toluene were removed under reduced pressure. The resulting black oil was dissolved in ethyl acetate, and the resulting solution was washed with saturated aqueous sodium bicarbonate. The basic aqueous layer was then washed with ethyl acetate. The organic layers were combined and concentrated to a black oil under reduced pressure. The oil was put through a column of silica gel using 60/40 ethyl acetate/hexane. The resulting eluted solution was dried under reduced pressure to a brown oil, which solidified after sitting for 48 hours. NMR analysis of the resulting product (2.59 g) indicated only minor impurities, and the product was carried on to the next step.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]1=[O:23]>>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][N:19]3[CH2:20][CH2:21][CH2:22][O:17][C:18]3=[O:23])=[N:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1ccc(C#Cc2ccccc2)cn1
Reactant: O=C1NCCCO1
Product: O=C1OCCCN1Cc1ccc(C#Cc2ccccc2)cn1

Procedure:
The title compound, light brown solid, MS: m/e=293.1 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from (5-phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) and 1,3-oxazinan-2-one.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[N:10]1.O.[OH-].[Na+]>C(Cl)Cl>[CH3:15][C:11]1[CH:12]=[C:13]([CH3:14])[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[OH:2])[N:10]=1
Reactant: COc1ccccc1-n1nc(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)n(-c2ccccc2O)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
3.88 g of 1-(2-methoxyphenyl)-3,5-dimethyl-1H-pyrazol was dissolved in 40 ml of methylene chloride, and 32 ml of 1 M solution of borontribromide in methylene chloride was added and stirred at room temperature for 1.5 hours. The reaction mixture was added to 150 ml of water, neutralized with 1N-sodium hydroxide and extracted with 150 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure, and purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to yield 2.83 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[CH:11]=[CH:10][C:9]=2[F:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[CH:11]=[CH:10][C:9]=2[F:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(C)ccc(F)c2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Product: CCOC(=O)c1cc2c(C)ccc(F)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound was prepared in accordance with the general method of example 12b) from 7-fluoro-4-methyl-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].Cl[CH2:7][C:8]1[CH:30]=[CH:29][C:11]([CH2:12][O:13][C:14]2[CH:15]=[C:16]([C:21]3([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:17]=[C:18]([F:20])[CH:19]=2)=[CH:10][CH:9]=1>>[F:20][C:18]1[CH:17]=[C:16]([C:21]2([O:27][CH3:28])[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH:15]=[C:14]([CH:19]=1)[O:13][CH2:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][O:5][N:4]=[C:2]([CH3:3])[CH3:1])=[CH:30][CH:29]=1
Reactant: COC1(c2cc(F)cc(OCc3ccc(CCl)cc3)c2)CCOCC1
Reactant: CC(C)=NO
Product: COC1(c2cc(F)cc(OCc3ccc(CON=C(C)C)cc3)c2)CCOCC1
Yield: 72 %

Procedure:
Using an analogous procedure to that described in Example 1, acetone oxime was reacted with 4-[3-(4-chloromethylbenzyloxy)-5-fluorophenyl]-4-methoxytetrahydropyran to give acetone O-{4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenoxymethyl]benzyl}oxime as a gum in 72% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=O)[CH3:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[C:26]([CH:27]=O)=[CH:25][CH:24]=[CH:23][N:22]=1.N1CCC[C@H]1C(O)=O>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[CH:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncccc1C=O
Reactant: CC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC(c2ccc3cccnc3n2)CC1

Procedure:
100 mg (0.383 mmol) ketone (21), 47 mg (0.383 mmol) 2-aminopyridine-3-carbaldehyde and 22 mg (0.192 mmol) proline were refluxed in ethanol for 3 days. The solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel (ethyl acetate/hexane) to yield 4-[1,8]naphthyridin-2-yl-piperidine-1-carboxylic acid benzyl ester as an oil. 210 mg (0,605 mmol) of this intermediate were dissolved together with 50 mg 10% Pd/C in 50 ml methanol and stirred under an atmosphere of hydrogen for 18 h. Removal of the catalyst by filtration through a pad of Celite followed by evaporation of the solvent under reduced pressure gave the desired amine (22).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@@H:37]1[C@@H:42]([OH:43])[CH2:41][CH2:40][N:39]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][C@@H:37]4[C@@H:42]([OH:43])[CH2:41][CH2:40][N:39]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:38]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: COc1cc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@@H](N)C1
Product: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CN(C(=O)OC(C)(C)C)CC[C@@H]4O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c10) and tert-butyl (3S*,4S*)-3-amino-4-hydroxy-piperidine-1-carboxylate (Example C3) the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH3:22])[CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>ClCCl>[CH3:24][N:2]([CH3:1])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=3[CH3:32])=[CH:17][C:16]=2[CH3:22])[CH2:6][CH2:5][CH2:4]1
Reactant: Cc1cc(N)ccc1C(=O)N1CCCC(N(C)C)c2ccccc21
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)C)c3ccccc32)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Dimethylamino-1-(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (H) (1.00 g) is dissolved in dichloromethane (30 ml), and thereto is added triethylamine (0.48 ml) under ice-cooling, and further added dropwise 2-methylbenzoyl chloride (0.44 ml). The mixture is stirred at room temperature for 1 hour. The reaction solution is washed with water, and dried over magnesium sulfate. The solvent is distilled off, and the resulting residue is crystallized by adding thereto ethyl acetate. The precipitated crystal is recrystallized from dichloromethane/ethyl acetate to give 5-dimethylamino-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.92 g) as white powder, m.p. 191°-192° C. HPLC retention time: 7.5 minutes
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH3:23][CH:24]([C:26]1[O:30][N:29]=[C:28]([CH2:31][NH2:32])[CH:27]=1)[CH3:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:20])([F:22])[F:21])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:32][CH2:31][C:28]2[CH:27]=[C:26]([CH:24]([CH3:25])[CH3:23])[O:30][N:29]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: CC(C)c1cc(CN)no1
Product: CC(C)c1cc(CNC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CAS Registry No. 1018782-82-5) and 5-(1-methylethyl)-3-isoxazolemethanamine (CAS Registry No. 154016-49-6) as starting materials, 454.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[N:13]=2)=[N:6][CH:7]=1.O.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[N:13]=2)=[N:6][CH:7]=1
Reactant: COC(=O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Reaction time: 8 h
Yield: 51.7 %

Procedure:
To a mixture of methyl 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoate (0.100 g, 0.230 mmol) in 10 mL THF, and 5 mL water was added sodium hydroxide (0.0368 g, 0.921 mmol) and the reaction was stirred overnight. The mixture was concentrated to dryness. Water was added and washed with Et2O and EtOAc. The aqueous was acidified with a saturated NH4Cl solution, extracted with 3:1 CH2Cl2-THF. The organics were dried over Na2SO4 and concentrated to a residue. The crude solids were recrystallized from EtOAc/Hexanes to give the title compound (0.050 g, 51.7% yield). 1H NMR (d6DMSO) δ 2.58 (t, J=7.5 Hz, 2H), 2.81 (t, J=7.5 Hz, 2H), 6.66 (s, 1H), 7.10 (d, J=7.8 Hz, 2H), 7.21 (t, J=7.4 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 2H), 8.21 (d, J=2.0 Hz, 1H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[C:8]([O:12][C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19](OS(C)(=O)=O)[CH2:18][CH2:17]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>CN(C=O)C>[C:8]([O:12][C:13](=[O:14])[NH:15][C@H:16]1[CH2:17][CH2:18][C@@H:19]([N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)[CH2:20][CH2:21]1)([CH3:11])([CH3:9])[CH3:10]
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](n2cncn2)CC1
Temperature: 65 °C
Yield: 48.8 %

Procedure:
Sodium hydride (104 mg of a 60% dispersion in mineral oil, 2.60 mmol) was added portionwise to a solution of 1,2,4-triazole (194 mg, 2.80 mmol) in DMF (5 mL). After 5 minutes trans methanesulfonic acid 4-tert-butoxycarbonylamino-cyclohexyl ester (587 mg, 2.00 mmol) was added. The reaction mixture was then heated at 65° C. for 3 days. The cooled mix was poured into ice-cold water (75 mL) which was then extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (75 mL), dried over sodium sulfate and concentrated under vacuum to give the crude product. This was purified by chromatography on silica gel (eluting with 0-5% methanol in ethyl acetate) to afford 260 mg (49%) of cis (4-[1,2,4]triazol-1-yl-cyclohexyl)-carbamic acid tert-butyl ester a white solid. LCMS (Method H, ESI): RT=2.60 min M+H=267.0; 1H NMR (400 MHz, DMSO): δ 8.55 (s, 1H), 7.95 (s, 1H), 6.89 (br s, 1H), 4.32-4.22 (m, 1H), 3.58 (br s, 1H), 2.20-2.07 (m, 2H), 1.88-1.77 (m, 2H), 1.69-1.56 (m, 4H), 1.39 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].[CH3:10][C:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][C:27]#[CH:28])=[CH:19][C:18]=1[CH3:29])([CH3:15])[C:12]([OH:14])=[O:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:28]#[C:27][CH2:26][CH2:25][CH2:24][O:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:11]([CH3:15])([CH3:10])[C:12]([OH:14])=[O:13])=[C:18]([CH3:29])[CH:19]=2)=[CH:4][C:3]=1[F:9]
Reactant: Fc1cc(I)ccc1Cl
Reactant: C#CCCCOc1ccc(OC(C)(C)C(=O)O)c(C)c1
Product: Cc1cc(OCCCC#Cc2ccc(Cl)c(F)c2)ccc1OC(C)(C)C(=O)O

Procedure:
In analogy to the procedure described in example 24E], 1-chloro-2-fluoro-4-iodobenzene and 2-methyl-2-(2-methyl-4-pent-4-ynyloxy-phenoxy)-propionic acid (example 26B]), followed by purification described in example 26A] yielded the title compound as off-white powder, mp. 106-107° C., dec.