Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:14]1=2)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].I.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32](SC)=[NH:33]>CCO.[Pd]>[CH2:1]([N:3]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([NH:23][C:32]([C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)=[NH:33])[CH:21]=[CH:22][C:14]1=2)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2]
Reactant: CSC(=N)c1cccs1
Reactant: CCN(CCN1CCOc2cc([N+](=O)[O-])ccc21)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: I
Solvent: CCO
Product: CCN(CCN1CCOc2cc(NC(=N)c3cccs3)ccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.6 %

Procedure:
A suspension of tert-butyl ethyl(2-(7-nitro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethyl)carbamate (7 g, 19.92 mmol) and Pd—C (2.11 g, 1.992 mmol, 10% wt) in anhydrous EtOH (100 mL) was purged with hydrogen gas. The reaction was stirred at room temperature for 16 hours under a hydrogen atmosphere (balloon pressure). The reaction mixture was filtered through a Celite pad and washed with EtOH (50 mL). The filtrate containing tert-butyl 2-(7-amino-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethyl(ethyl)carbamate was treated with methyl thiophene-2-carbimidothioate hydroiodide (11.36 g, 39.8 mmol) and stirred overnight at room temperature. The reaction was concentrated and then partitioned between saturated NaHCO3 solution (150 mL) and CH2Cl2 (75 mL). The mixture was transferred to a separatory funnel, and the product was extracted into CH2Cl2 (2×100 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was subjected to flash chromatography on silica gel using a sequence of eluents (CH2Cl2; 1:99 (2M NH3 in MeOH):CH2Cl2; 1.75:98.25 (2M NH3 in MeOH):CH2Cl2; and 2.5:97.5 (2M NH3 in MeOH):CH2Cl2) to give a brown solid (4 g, 46.7%). 1H-NMR (CDCl3) δ 7.43-7.41 (m, 2H), 7.11-7.05 (m, 1H), 6.72-6.69 (m, 1H), 6.54-6.51 (m, 2H), 4.23-4.20 (m, 2H), 3.39-3.25 (m, 8H), 1.47 (s, 9H), 1.11-1.10 (m, 3H); ESI-MS (m/z, %): 431 (MH+, 100).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]#[N:7])=[N:2]1.[CH2:8]1[O:13][C@:12](O)([CH2:14][NH2:15])[C@@H:11]([OH:17])[C@H:10]([OH:18])[C@@H:9]1[OH:19]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[NH:7][C:12]([C@@H:11]([OH:17])[C@H:10]([OH:18])[C@H:9]([OH:19])[CH2:8][OH:13])=[CH:14][N:15]=2)=[N:2]1
Reactant: N#Cc1ccon1
Reactant: NC[C@@]1(O)OC[C@@H](O)[C@@H](O)[C@@H]1O
Product: OC[C@@H](O)[C@@H](O)[C@H](O)c1cnc(-c2ccon2)[nH]1

Procedure:
which comprises: combining isoxazole-3-carbonitrile with a solvent and a first base to provide a first reaction mixture; combining the first reaction mixture with fructosamine to provide a second reaction mixture; and isolating (1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-5-yl)butane-1,2,3,4-tetraol from the second reaction mixture.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20](F)=[C:21]([NH:23][C:24](=[O:31])[CH2:25][C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.N1([CH2:38][C:39]2[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=2)[NH2:42])CCCC1>>[NH2:3][CH:4]1[CH2:38][C:39]2[CH:40]=[C:41]([NH:42][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:22]=[C:21]([NH:23][C:24](=[O:31])[CH2:25][C:26]6[S:27][CH:28]=[CH:29][CH:30]=6)[CH:20]=[CH:19][CH:18]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:43]=[CH:44][C:45]=2[CH2:6][CH2:5]1
Reactant: O=C(Cc1cccs1)Nc1cc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)ccc1F
Reactant: Nc1cccc(CN2CCCC2)c1
Product: NC1CCc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)Cc6cccs6)c5)nn5ccccc45)n3)cc2C1
Yield: 55.7 %

Procedure:
N-{5-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorophenyl}-2-(2-thienyl)acetamide (100 mg, 0.22 mmol) and 3-(1-pyrrolidinylmethyl)aniline (78 mg, 0.44 mmol) were coupled according to the procedure of Example 56, Step H to give of the title compound (35 mg, 26%). 1H NMR (400 MHz, d6-DMSO) δ 10.11 (s, 1H), 9.49 (s, 1H), 8.80 (d, J=6.8 Hz, 1H), 8.44 (d, J=8.8 Hz, 1H), 8.26-8.22 (m, 2H), 7.64 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.37-7.32 (m, 3H), 7.16-7.07 (m, 2H), 6.95-6.93 (m, 2H), 6.85 (d, J=7.2 Hz, 1H), 6.49 (d, J=4.8 Hz, 1H), 3.96 (s, 2H), 3.48 (br s, 2H), 2.38 (m, 4H), 1.64 (m, 4H) ppm. ES-LC/MS m/z=604 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].O[CH2:26][CH2:27][CH2:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH3:34]>>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:26][CH2:27][CH2:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH3:34])[N:9]=[CH:8][N:7]=[C:6]2[NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2
Reactant: COc1cc2c(Nc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Reactant: Cc1nccn1CCCO
Product: COc1cc2c(Nc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCn1ccnc1C
Yield: 37.4 %

Procedure:
Using an analogous procedure to that described in Example 224, 7-hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline (102 mg, 0.32 mmol), (prepared as described for the starting material in Example 205), was reacted with 1-(3-hydroxypropyl)-2-methylimidazole (67 mg, 0.48 mmol), (EP 0060696 A1), to give 6-methoxy-7-(3-(2-methylimidazol-1-yl)propoxy)-4-(2-methylindol-5-ylamino)quinazoline (53 mg, 37%).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH2:5]([O: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][CH3:25])[CH:6]1[O:8][CH2:7]1>>[OH:8][CH:6]([CH2:5][O: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][CH3:25])[CH2:7][NH:4][CH2:3][CH2:1][OH:2]
Reactant: NCCO
Reactant: CCCCCCCCCCCCCCCCOCC1CO1
Product: CCCCCCCCCCCCCCCCOCC(O)CNCCO
Reaction time: 0.75 h
Yield: 62.4 %

Procedure:
61.1 g (1.0 mol) of ethanolamine was introduced into a 200-ml four-necked flask equipped with a stirrer, a dropping funnel, a thermometer and a reflux condenser and heated to 60° to 70° C. under stirring. 24.3 g (0.082 mol) of hexadecyl glycidyl ether was added dropwise thereto over a period of 45 minutes. After the completion of the addition, the resulting mixture was stirred by heating under the same conditions as those described above for additional two hours. Then unreacted ethanolamine was distilled off under reduced pressure (79° to 81° C./20 Torr). The residue was purified by silica gel flash column chromatography to thereby give 18.4 g of the compound (IVa) at a yield of 63%. The 1H-NMR data of the obtained compound are as follows:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[H-].[Na+].I[CH3:27]>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH3:27]
Reactant: CI
Reactant: COC(=O)c1cccc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cccc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a solution of 1.0 g (2.985 mmol) of the product of Example 3 in 10 mL of DMF was added 0.149 g (3.731 mmol) of 60% sodium hydride. The resulting mixture was stirred for 30 minutes at room temperature and then 0.28 mL (4.478 mmol) of iodomethane was added. The reaction was then stirred for 18 h, and next diluted with ether. The organics were washed with water, dried over MgSO4, filtered and concentrated in vacuo to provide a white solid. The solid was washed with ether/hexanes (1:1) to give 0.788 g (76%) of the desired product as a white solid. Electrospray Mass Spec: 350.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([S:13](Cl)(=[O:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][S:13]([C:7]1[C:6](=[O:17])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]([CH3:12])[CH:8]=1)(=[O:15])=[O:14])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cn1cc(S(=O)(=O)Cl)c(=O)c2ccc(Cl)cc21
Reactant: NCc1ccccc1
Product: Cn1cc(S(=O)(=O)NCc2ccccc2)c(=O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7-Chloro-1-methyl-4-oxo-1,4-dihydroquinoline-3-sulphonyl chloride (9.2 g) was added portionwise to a stirred solution of benzylamine (10.5 ml) in absolute alcohol (300 ml). The mixture was stirred at ambient temperature for 24 hours, then evaporated to dryness. The residue was crystallised from industrial methylated spirit to give the novel compound N-benzyl-7-chloro-1-methyl-4-oxo-1,4-dihydroquinoline-3-sulphonamide, m.p. 208°-210°.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@@H:9]1[C:10](O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16]O>>[C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@@H:9]1[C:10]#[CH:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Product: C#C[C@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from N-BOC-(R)-proline according to the procedures of Examples 1a-c above. [α]D≤ +113.0 (c 0.94, MeOH).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:18]1([CH2:24][CH2:25]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.O>[C:18]1([CH2:24][CH2:25][C:4]2([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2][NH:1][CH2:11][CH2:10]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(CCc2ccccc2)CCNCC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
A mixture of ethyl isonipecotate (64 mmol; 10.0 g), anhydrous potassium carbonate (192 mmol; 26.5 g) and phenylethyl bromide (77 mmol, 14.25 g) in anhydrous N,N-dimethylformamide (100 ml) was stirred at 70° C. for 5 hours 30 minutes. After cooling, the reaction mixture was diluted with water (300 ml) and extracted with ethyl acetate (3×200 ml). The combined organic phases were washed with saturated NaCl solution (3×100 ml), dried over sodium sulfate and evaporated under reduced pressure. A crude product was obtained, which was purified on a column of alumina (eluting with 2/1 n-hexane/ethyl acetate) to give 14.0 g (84%) of pure product as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16]([CH2:20][OH:21])=[C:17]([CH3:19])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:22]1([C:27]2[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=2)[CH:26]=[N:25][N:24]=[N:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC1C(Cl)=CN=C(N2CCC(C3SC=C(COC4C=CC(N5C=NN=N5)=CC=4)N=3)CC2)N=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][C:16]([CH2:20][O:21][C:30]3[CH:31]=[CH:32][C:27]([N:22]4[CH:26]=[N:25][N:24]=[N:23]4)=[CH:28][CH:29]=3)=[C:17]([CH3:19])[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)sc1CO
Reactant: Oc1ccc(-n2cnnn2)cc1
Agent: Clc1cnc(N2CCC(c3nc(COc4ccc(-n5cnnn5)cc4)cs3)CC2)nc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)sc1COc1ccc(-n2cnnn2)cc1
Reaction time: 4 h

Procedure:
To a solution of 4-(5-Hydroxymethyl-4-methyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 3.2 mmol) in THF (6.4 mL) was added, 4-tetrazol-1-yl-phenol (0.52 g, 3.2 mmol), polymer bound triphenylphosphine (3 mmol/g, 1.6 g). To this solution was added ditertierybutylazodicarboxylate (1.1 g, 4 8 mmol), stirred for 4 hours and filtered through a pad of celite. The filtrate was concentrated and purified by silica gel chromatography to provide the desired product. 1H NMR (CDCl3): δ 9.01 (1H, s), 7.66 (2H, d), 7.15 (2H, d), 5.21 (2H, s), 4.19 (2H, m), 3.10 (1H, m), 2.86 (2H, m), 2.45 (3H, s), 2.08 (2H, m), 1.72 (2H, m), 1.47 (9H, s).
Reaction SMILES: [OH:1][C@:2]12[C@@H:15]3[NH:16][CH2:17][CH2:18][C@:7]1([C:8]1[CH:9]=[C:10]([O:19][CH3:20])[CH:11]=[CH:12][C:13]=1[CH2:14]3)[CH2:6][CH2:5][CH2:4][CH2:3]2.N1C=CC=CC=1.[CH:27]1([C:31](O)=[O:32])[CH2:30][CH2:29][CH2:28]1>C(Cl)Cl>[CH:27]1([C:31]([N:16]2[CH2:17][CH2:18][C@@:7]34[C:8]5[CH:9]=[C:10]([O:19][CH3:20])[CH:11]=[CH:12][C:13]=5[CH2:14][C@@H:15]2[C@:2]3([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6]4)=[O:32])[CH2:30][CH2:29][CH2:28]1
Reactant: O=C(O)C1CCC1
Reactant: COc1ccc2c(c1)[C@@]13CCCC[C@@]1(O)[C@@H](C2)NCC3
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2c(c1)[C@@]13CCCC[C@@]1(O)[C@@H](C2)N(C(=O)C1CCC1)CC3

Procedure:
To a stirred and cooled solution of 400 mg. (0.00146 mole) of the amino alcohol XXI in 0.16 g. (0.002 mole) of dry pyridine and 5 ml. of methylene chloride, there was added, dropwise, a solution of 0.19 g. (0.0016 mole) of the acid chloride of cyclobutylcarboxylic acid in 5 ml. of methylene chloride. After stirring for ten minutes, the reaction mixture was washed successively with cold dilute aqueous hydrochlorid acid, dilute aqueous sodium hydroxide, water and finally with a saturated aqueous sodium chloride solution. After drying over Na2SO4 and evaporation of the solvent, there was obtained 400 mg. of an oil which crystallized on standing. The oil was treated with a small amount of cold ether and filtered to yield 320 mg. (61.6 %) of crystals which after recrystallization from methanol melted at 183°-85° C. The IR and NMR spectra were consistent with the structure.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:17].[C:18]1([CH2:24][C:25](=[NH:29])OCC)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[ClH:17].[C:11]1([CH:9]([O:8][C:7]2[C:2]([NH:1][C:25](=[NH:29])[CH2:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH3:10])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(Oc1cccnc1N)c1ccccc1
Reactant: CCOC(=N)Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(Oc1cccnc1NC(=N)Cc1ccccc1)c1ccccc1
Yield: 14.3 %

Procedure:
A mixture of 2-amino-3-(1-phenylethoxy)pyridine (4.28 g, 20 mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave a residue which was purified by chromatography (silica, chloroform/methanol) to obtain the product (1.05 g), m.p. 75°-80° C.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:9])[CH2:7][NH2:8])[CH2:2]1.C(N(CC)CC)C.S=[C:18]1[CH2:22][S:21][C:20](=[O:23])[NH:19]1>C(O)C>[O:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:9])[CH2:7][NH:8][C:18]2[CH2:22][S:21][C:20](=[O:23])[N:19]=2)[CH2:2]1
Reactant: NCC(=O)NC1COC1
Reactant: O=C1NC(=S)CS1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(CNC1=NC(=O)SC1)NC1COC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the crude product (5.7 g) containing N-oxetan-3-ylglycinamide obtained in B) and triethylamine (13.3 g) in ethanol (100 mL) was added 4-thioxo-1,3-thiazolidin-2-one (5.8 g), and the mixture was stirred at room temperature is for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/methanol/dichloromethane) to give the title compound (2.03 g).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:21](O)=[O:22])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].[Al].O>COCCOCCOC>[CH:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([CH2:21][OH:22])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1CCCCC1
Agent: [Al]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: O=C(N[C@H](CO)Cc1ccc(O)cc1)OCC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 15 ml of diglyme (bis (2-methoxy) ether) was dissolved 1.0 g of N-(cyclohexylmethoxycarbonyl)-tyrosine. To the solution were added 570 mg of sodium borohydride and 50 ml of diglyme solution containing 7 g of anhydrous aluminium chyloride. The mixture was stirred at room temperature for 2 hours. After addition of 150 ml of water, the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was crystallized from ethyl acetate-petroleum ether to give N-(cyclohexylmethoxycarbonyl)-tyrosinol.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]([Si](C)(C)C)([F:13])[F:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[C:11]([F:13])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)C(F)(F)F
Yield: 121.2 %

Procedure:
According to Reference Example 8-12, by use of 4-fluorobenzaldehyde (500 mg, 4.03 mmol), (trifluoromethyl)trimethylsilane (715 μL, 4.83 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 403 μL, 0.403 mmol) and tetrahydrofuran (10 mL), the mixture was stirred and reacted at room temperature for 30 minutes. Thus, 1-fluoro-4-(2,2,2-trifluoro-1-hydroxyethyl)benzene (Compound CS) (948 mg, yield: quantitative) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH2:20]([CH:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH2:25])[CH3:21].[BH4-].[Na+]>CO>[CH2:20]([CH:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH:25][CH2:18][C:16]1[CH:15]=[CH:14][C:3]([O:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=2)=[C:2]([F:1])[CH:17]=1)[CH3:21]
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Reactant: CCC(CC)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)CCNCc1ccc(Oc2ccc(C(N)=O)nc2)c(F)c1
Reaction time: 8 h
Yield: 57.4 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.650 g, 2.50 mmol), 3-ethylpentylamine (Example 733, Part B) (0.317 g, 2.75 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (12 mL), cap and stir overnight. Add NaBH4 (slight excess) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 10% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound (0.516 g, 58%): TOF MS ES+ 360.2 (M+H)+, HRMS calcd for C20H27N3O2F 360.2087 (M+H)+, found 360.2086, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=12.3 min, 100% purity.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](Cl)[N:10]=2)[CH2:5][C:4]([CH3:19])([CH3:18])[NH:3]1.[CH:21]1([C:24]2[C:29]([N:30]3[CH:34]=[N:33][N:32]=[N:31]3)=[CH:28][C:27]([NH2:35])=[C:26]([F:36])[CH:25]=2)[CH2:23][CH2:22]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.FC1C(NC2CC(C)(C)NC(C)(C)C2)=NC(OC(C)C)=NC=1>CC(O)C>[CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([NH:35][C:27]3[CH:28]=[C:29]([N:30]4[CH:34]=[N:33][N:32]=[N:31]4)[C:24]([CH:21]4[CH2:22][CH2:23]4)=[CH:25][C:26]=3[F:36])[N:10]=2)[CH2:5][C:4]([CH3:19])([CH3:18])[NH:3]1
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2C#N)CC(C)(C)N1
Reactant: Nc1cc(-n2cnnn2)c(C2CC2)cc1F
Agent: CC(C)Oc1ncc(F)c(NC2CC(C)(C)NC(C)(C)C2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CC1(C)CC(Nc2nc(Nc3cc(-n4cnnn4)c(C4CC4)cc3F)ncc2C#N)CC(C)(C)N1
Temperature: 80 °C

Procedure:
A mixture of 4-(2,2,6,6-tetramethylpiperidin-4-ylamino)-2-chloropyrimidine-5-carbonitrile (112 mg, 0.380 mmol, 1 equiv), 4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)benzenamine (100 mg, 0.456 mmol, 1.2 equiv), and para-toluenesulfonic acid monohydrate (58 mg, 0.304 mmol, 0.8 equiv) in IPA (4 mL) were heated to 80° C. overnight. LCMS indicated desired product plus approximately 18% of 5-fluoro-2-isopropoxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine byproduct. After cooling to ambient temperature, the crude mixture was quenched with 2M NH3/MeOH followed by concentrating to dryness and repeating once. The crude product was purified by flash chromatography and eluted with DCM:2M NH3/MeOH (100:0 to 95:5 using 1% 2M NH3/MeOH increments) to provide the desired product which was recrystallized with DCM/IPA to give the title compound (88 mg, 49%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH:25]([CH:27](OS(C)(=O)=O)[CH3:28])[CH3:26])(=O)=O>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]3[O:13][CH:25]([CH3:26])[CH:27]([CH3:28])[N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(OS(C)(=O)=O)C(C)OS(C)(=O)=O
Reactant: Oc1cc(-c2ccc(F)cc2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1Oc2cc(-c3ccc(F)cc3)nn2C1C
Temperature: 60 °C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1H-pyrazol-5-ol (3 g, 16.8 mmol) in DMF (15 mL) was added K2CO3 (9.3 g, 67.4 mmol) and butane-2,3-diyl dimethanesulfonate (4.8 g, 18.5 mmol) (prepared as described in US2010/41748) at room temperature and then stirred for 16 h at 60° C. Thereafter, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to get the crude product. Purification by column chromatography over silica gel (eluent 5-10% ethyl acetate in petrol ether) yielded 6-(4-fluorophenyl)-2,3-dimethyl-2,3-dihydropyrazolo[5,1-b][1,3]oxazole (2.8 g, 71%) as yellow oil and a mixture of diastereoisomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](Cl)=[O:9].[C:18]([NH:22][C:23]([CH:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:26])=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([N:30]1[CH2:29][CH2:28][N:27]([CH:25]([C:23]([NH:22][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:24])[CH3:26])[CH2:32][CH2:31]1)=[O:9]
Reactant: CC(C(=O)NC(C)(C)C)N1CCNCC1
Reactant: COc1cc(C=CC(=O)Cl)cc(OC)c1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(C=CC(=O)N2CCN(C(C)C(=O)NC(C)(C)C)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.78 g of 3,4,5-trimethoxycinnamoyl chloride is added to a solution of 0.50 g of 1-[1-(tert-butylaminocarbonyl)ethyl]piperazine and 0.31 g of triethylamine in 15 ml of chloroform, and the resulting solution is stirred at room temperature for 1 hour.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH:10]([CH2:14][CH2:15][CH2:16][OH:17])[C:11](O)=[O:12].O>CN(C)C=O>[OH:17][CH2:16][CH2:15][CH2:14][CH:10]1[C:11](=[O:12])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]1
Reactant: Nc1ccccc1S
Reactant: O=C(O)C(Br)CCCO
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2SC1CCCO
Temperature: 100 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
To a solution of 6.26 g of 2-aminothiophenol in 50 ml of dimethylformamide was added 9.85 g of 2-bromo 5-hydroxyvaleric acid. The mixture was stirred at room temperature for 2 hours and at 100° C. for 1 hour. The reaction solution was cooled, poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then concentrated under reduced pressure. The concentrate was subjected to a column chromatography on silica-gel (200 g). From the eluate with hexane-acetone (2:1, v/v) was obtained 3.7 g (31.6%) of 2-(3-hydroxypropyl)-2H-1,4-benzothiazin-3(4H)-one as crystals. Recrystallization from ethyl acetate-hexane gave prisms, m.p. 59°-60° C.