Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=[O:13])[C:8]([O:10]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1>C(O)C>[CH2:21]([N:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:8](=[O:10])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:13])[CH2:16][CH2:17]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)C(=O)c1ccccc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CCO
Product: O=C(NC1CCN(Cc2ccccc2)CC1)C(=O)c1ccccc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
Added to 4.28 g of ethyl phenylglyoxylate were 9.12 g of 4-amino-1-benzylpiperidine. The mixture was heated and stirred at 120° C. for 3 hours on an oil bath. Thereafter, ethanol formed was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel, thereby obtaining 6.3 g (yield: 81.4%) of N-(1-benzyl-4-piperidinyl)phenyl-glyoxylic acid amide.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.[Br:11]Br.O>C(OCC)C.ClC(Cl)(Cl)Cl>[Br:11][CH:7]1[CH2:8][CH2:9][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]1=[O:10]
Reactant: O=C1CCCc2sccc21
Reactant: BrBr
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C1c2ccsc2CCC1Br
Temperature: -10 °C
Reaction time: 18 h

Procedure:
6,7-Dihydro-5H-benzo[b]thiophen-4-one (198, 5.8 g, 38.3 mmol) is dissolved in 200 ml of dry diethyl ether and cooled down to −10° C. A solution of bromine (6.1 g, 38.3 mmol) in 30 ml of tetrachloromethane and 2-3 drops of diethyl ether is slowly added. The mixture is stirred for 15 min at −10° C., 15 min at 0° C. and 18 h at room temperature. Then water and diethyl ether is added slowly. The organic layers are washed with water, dried over Na2SO4 and evaporated.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[OH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[OH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:23][CH:22]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2ccc(CO)cc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, light yellow solid (75 mg, 91%), MS (ISP) m/z=332.5 [(M+H)+], mp 256.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-hydroxymethyl-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:12]=[CH:13][S:14][C:15]=1/[CH:16]=[CH:17]/[CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([O:3]C)=[O:2].P([O-])([O-])([O-])=O.[Na].C[C@@H]([C@@H]1[C@@]2(C)[C@@H](O)C[C@@H]3[C@@]4(C)CC[C@@H](O)C[C@H]4C[C@@H](O)[C@H]3[C@@H]2CC1)CCC(NCCS([O-])(=O)=O)=O.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C(OCC)(=O)C.CCCCCCC>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:12]=[CH:13][S:14][C:15]=1/[CH:16]=[CH:17]/[CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([OH:3])=[O:2]
Reactant: CCCCCC(O)/C=C/c1scnc1CCCCCCC(=O)OC
Agent: C[C@H](CCC(=O)NCCS(=O)(=O)[O-])[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCCC(O)/C=C/c1scnc1CCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.4 %

Procedure:
To the suspension of 1.75 g of 4-(6-carbomethoxyhexyl)-5-(3-hydroxy-1-trans-octenyl)-thiazole (Ic, R1 = H) in 35 ml of a 0.2 M phosphate buffer of pH 7.5, 175 mg of the lipase enzyme specified in Example 5, 17.5 mg of the sodium salt of taurocholic acid and 1.75 ml of a 10 % solution of gum arabic were added. The mixture was then shaken at 25° C in a screening shaker desk at 260 revolutions/minute and an amplitude of 2 cm for 24 hours, whereafter the reaction mixture was diluted with 100 ml of water, acidified with citric acid and extracted with 3 × 70 ml of ethyl acetate. The ethyl acetate extract was dried over sodium sulphate and evaporated in vacuo. The obtained 1.95 g of evaporation residue was purified by chromatography on a column prepared with 50 g of silicic acid, using mixtures of n-heptane and ethyl acetate whose ethyl acetate content was gradually increased, as the eluting solvent. 4-(6-Carboxyhexyl)-5-(3-hydroxy-1-trans-octenyl)-thiazole (ID, R1 = H) was eluted from the column by a mixture consisting of 70 % ethyl acetate and 30 % n-heptane. Thus, 1.25 g of a product of chromatographic purity was obtained which was recrystallized from a mixture of diethyl ether and n-hexane. 30
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[OH-].[K+].[CH3:12]I>CS(C)=O>[Br:1][C:2]1[C:7]([O:8][CH3:12])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CI
Reactant: Oc1cc(Cl)cnc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(Cl)cnc1Br

Procedure:
To a stirred mixture of 2-bromo-5-chloro-3-pyridinol (15.66 g) and pulverized KOH (16.79 g) in DMSO (100 mL) at 55-60° C. was added dropwise a solution of CH3I (13.27 g) in DMSO (35 mL) while under nitrogen atmosphere. After the addition was complete, the reaction was maintained at 55°-60° C. for 1 h. The reaction was extracted with Et2O (3×150 mL) and the combined Et2O extracts were treated in turn with 1N NaOH (150 mL), water (150 mL), 1N HCl (150 mL), water (150 mL), and a saturated NaCl solution (150 mL). The organic phase was dried with MgSO4, filtered, and concentrated under reduced pressure to yield a solid material. Recrystallization of the solid from hexane afforded b) (3.52 g, 21%).
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]#[C:19][C:20]([OH:22])=O)[CH2:13][CH2:12]1)[CH3:10].CN1CCOCC1.N#N.[NH2:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[N:39]=[CH:38][C:37]([C:43]#[N:44])=[C:36]2[NH:45][C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([Br:52])[CH:47]=1>N1C=CC=CC=1>[Br:52][C:48]1[CH:47]=[C:46]([NH:45][C:36]2[C:35]3[C:40](=[CH:41][CH:42]=[C:33]([NH:32][C:20](=[O:22])[C:19]#[C:18][CH2:17][N:14]4[CH2:13][CH2:12][N:11]([CH2:9][CH3:10])[CH2:16][CH2:15]4)[CH:34]=3)[N:39]=[CH:38][C:37]=2[C:43]#[N:44])[CH:51]=[CH:50][CH:49]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: CCN1CCN(CC#CC(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Agent: N#N
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Product: CCN1CCN(CC#CC(=O)Nc2ccc3ncc(C#N)c(Nc4cccc(Br)c4)c3c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Isobutyl chloroformate (0.785 g, 5.75 mmol) was dropwise added into an ice cold solution of 4-(N-ethylpiperazino)-2-butynoic acid (1.75 g, 8.85 mmol) and N-methylmorpholine (1.3453 g, 13.3 mmol) in 50 mL of tetrahydrofuan under N2. After stirring for 30 min, a solution of 1.5 g (4.42 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 10 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by flash column chromatography. The product fractions were collected, and dried in vacuo to give 1.07 g (46%) of light brown solid; ESMS m/z 517.1, 519.1 (M+H+); mp 161° C. (dec).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]([CH3:18])[CH3:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:21]1([C:27]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:28]2[C:32]([C:33]3[C:38]([C:39]4[CH:44]=[CH:43][C:42]([CH2:45]Br)=[CH:41][CH:40]=4)=[CH:37][CH:36]=[C:35]([F:47])[CH:34]=3)=[N:31][N:30]=[N:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:1]([C:5]1[N:14]([CH2:45][C:42]2[CH:41]=[CH:40][C:39]([C:38]3[CH:37]=[CH:36][C:35]([F:47])=[CH:34][C:33]=3[C:32]3[N:28]([C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[N:29]=[N:30][N:31]=3)=[CH:44][CH:43]=2)[C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:16]([CH3:17])[CH3:18])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Fc1ccc(-c2ccc(CBr)cc2)c(-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CCCCc1nc(=O)c2cc(C(C)C)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2ccc(C(C)C)cc2c(=O)n1Cc1ccc(-c2ccc(F)cc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of 2-butyl-6-isopropylquinazolinone (55.6 mg; 0.228 mmol) (Example 8) in dry DMF (1.5 mL) was added NaH, 80% oil dispersion, (11.8 mg; 1.5 eq). The reaction mixture was allowed to stir for 30 min. under N2. To this was added a solution of N-triphenylmethyl-5-(4-fluoro-4'-bromomethyl-biphen-2-yl)tetrazole (crude) in dry DMF (1.5 mL). The reaction was stirred under N2 for 3 hrs. then quenched with saturated NH4Cl solution. The solvent was removed at high vacuum, replaced by EtOAc, and the insoluable salts filtered off. The product was purified by flash chromatography on a silica column eluting with Hex/EtOAc (35:1) to afford 94.5 mg (56%) of the titled compound. Characteristic peaks 1H-NMR (300 MHz, CDCl3) δ 0.87 (t, 3H), 1.30 (d, 6H), 1.68 (m, 2H), 2.63 (t, 2H), 3.05 (q, 1H), 5.28 (s, 2H), 8.13 (s, 1H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24].S(Cl)(Cl)=O>>[C:1]([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][CH:23]([CH3:24])[CH3:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: CC(C)CCCCCCCCCCCCCO
Reactant: O=C(O)c1cccnc1
Solvent: O=S(Cl)Cl
Product: CC(C)CCCCCCCCCCCCCOC(=O)c1cccnc1
Temperature: 80 °C

Procedure:
Iso-hexadecyl nicotinate was prepared from nicotinic acid and a commercial material, iso-hexadecyl alcohol, obtained from Farbwerke Hoechst AG. The general method of Example 1 was used except that the temperature after thionyl chloride addition was maintained at 80° C. for 2 hours, and after the esterification reaction the solution was cooled and washed with 0.5M sodium hydroxide, 0.5M hydrochloric acid and water. The solution was treated with activated carbon (2.5% on the expected weight of product) at 50° C. for 1 hour, filtered and the solvent removed under reduced pressure. The light brown oil had an estimated purity of 93.4% and was distilled (boiling range 141°-146° C. at 0.03 mm mercury pressure) to provide a product of 99.8% estimated purity.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:53])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[C:44]([CH2:45][O:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)=[CH:43][N:42]=[N:41]2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:53])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[C:44]([CH2:45][O:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)=[CH:43][N:42]=[N:41]2)[CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1

Procedure:
The title compound was prepared from (2-amino-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J1) (181 mg, 0.5 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (201 mg, 0.5 mmol) according to the general procedure M. Obtained as an amorphous off-white substance (223 mg).
Reaction SMILES: [CH:1]([C@H:14]1[NH:19][CH2:18][C@@H:17]([NH2:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]1[CH2:30][CH:22]1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:1]([C@H:14]1[NH:19][CH2:18][C@@H:17]([NH:20][CH2:30][C@@H:22]([OH:21])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)NC1
Reactant: c1ccc(CC2CO2)cc1
Product: O[C@H](CN[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)NC1)Cc1ccccc1
Yield: 32.9 %

Procedure:
Compound 3 (0.075 g, 0.281 mmol) was reacted with S-(−)-2,3-epoxypropyl benzene (0.056 g, 0.422 mmol) (Procedure A) and was purified by flash column chromatography over silica gel using diethyl ether/MeOH/Et3N (90:10:0.2) to yield 4d (0.037 g, 33%). 1H NMR (400 MHz, CDCl3): δ 1.23-1.35 (2H, m, H-5), 1.41-1.49 (1H, m, H-4ax), 1.75-1.78 (1H, m, H-4eq), 2.36-2.41 (1H, dd, J=3.2 Hz, J=8.8 Hz, NHCH2), 2.66-2.84 (5H, m, H-2, NHCH2, Ph-CH2), 2.89-2.92 (1H, m, H-3eq), 3.23 (1H, dt, J=2.4 Hz, J=10.0 Hz, H-6ax), 3.75 (1H, d, J=10.0 Hz, (Ph)2CH) 3.78-3.85 (1H, m, and CH—OH), 7.12-7.31 (13H, m, ArH), 7.35-7.36 (2H, m, ArH). Optical rotation, [α]25D=(−) 49.3° (c 0.96, MeOH). Free base was converted into oxalate salt 206-209° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=2)[CH2:10][CH2:9]1)(C)(C)C>C(O)C.Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]2)=[CH:16][C:17]=1[O:22][CH2:23][CH3:24]
Reactant: CCOc1cc(CN2CCC(NC(=O)OC(C)(C)C)CC2)ccc1Cl
Agent: Cl
Solvent: CCO
Product: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Yield: 56.2 %

Procedure:
A solution of [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.78 g, 2.12 mmol) in ethanol (10 mL) and 4 M HCl (15 mL) was stirred at rt for 2 h. The hydrochloric acid was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (50 mL) with ethyl acetate (3×50 mL). The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure yielding 0.32 g (57%) of a white solid. The crude material was directly used in the following reaction step. MS (ISP): 269.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8](O)=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[Al].[Li]>O1CCCC1>[OH:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)c1nccnc1O
Agent: [Al]
Agent: [Li]
Solvent: C1CCOC1
Product: OCc1nccnc1O

Procedure:
3-Hydroxypyrazine-2-carboxylic acid is converted to the methyl ester and the ester is reduced with lithium aluminium hyride in tetrahydrofuran to give 3-hydroxy-2-hydroxymethylpyrazine. Treatment of 3-hydroxy-2-hydroxymethylpyrazine at room temperature with thionyl chloride gives 3-hydroxy-2-chloromethylpyrazine and reacting this intermediate with cysteamine by the procedure of Example 62 gives 2-[(2-aminoethyl)thiomethyl]-3-hydroxypyrazine.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][O:8][N:9]([C:18](=[O:28])[CH:19]=[C:20]1[C:24](=[O:25])[O:23][C:22]([CH3:27])([CH3:26])[O:21]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:26][C:22]1([CH3:27])[O:21][C:20](=[CH:19][C:18]([N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[O:8][CH2:7][C:6]([OH:29])=[O:5])=[O:28])[C:24](=[O:25])[O:23]1
Reactant: CC(C)(C)OC(=O)CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OC(=O)C(=CC(=O)N(Cc2ccc(F)cc2)OCC(=O)O)O1
Reaction time: 2 h
Yield: 100.2 %

Procedure:
A solution [[2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetyl]-(4-fluorobenzyl)-aminooxy]-acetic acid tert-butyl ester (0.60 g, 1.46 mmol) in dichloromethane (15 ml) was treated at 22° C. with trifluoroacetic acid (4 ml) and the resulting mixture was stirred for 2h. Evaporation of the solvent in vacuo gave 0.517 g (100% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.79 (6H, s, CH3), 4.41 (2H, s, CH2), 4.88 (2H, s, CH2), 6.4 (1H, broad, CH), 7.09 (2H, m, aromatics), 7.35 (2H, m, aromatics). HRMS (ES+) calculated for C16H17FNO7[M+H]+: 354.098905. Found: 354.098878.
Reaction SMILES: Cl[C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[NH:11][C:12]([O:14]C(C)(C)C)=[O:13].C(OCC)C>C(Cl)(Cl)Cl>[O:13]1[C@H:2]2[C:10]3[C:5]([CH2:4][C@H:3]2[NH:11][C:12]1=[O:14])=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@H]1Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=C1N[C@@H]2Cc3ccccc3[C@@H]2O1
Yield: 92.6 %

Procedure:
A solution of (±) trans-1-chloro-2-tert-butoxycarbonylaminoindane (10.0 g, 0.037 mol) in chloroform (200 ml) was heated under reflux in an argon atmosphere for 23 h. The mixture was concentrated in vacuo to give a brown solid. Trituration with diethyl ether afforded the title compound as a beige solid (6.0 g, 92%) m.p. 205°-206° C. which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([CH:15]=[CH2:16])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[Sn]Cl>CCO.O.CCOC(C)=O>[Cl:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]([CH:15]=[CH2:16])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=Cc1cc(C(=O)OC)c(Cl)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: C=Cc1cc(N)c(Cl)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of methyl 2-chloro-3-nitro-5-vinylbenzoate (1.75 g, 7.2 mmol) and SnCl2 (4.1 g, 18.1 mmol) in EtOH (50 mL) was stirred at 75° C. for 16 h. The reaction mixture was cooled to RT, diluted with water and EtOAc, stirred at RT for 10 min, and filtered on cellite. The organic layer was separated, washed with brine, dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (120 g silica gel, 0 to 25% EtOAc in hexane) to give methyl 2-chloro-3-amino-5-vinylbenzoate as a yellow oil. MS M+1=212.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1>>[CH3:9][O:10][C:11]1[CH:16]=[C:15]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Br)cc1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccc(N)cc2)c1
Yield: 16.7 %

Procedure:
The title compound (58 mg) was prepared from 4-bromoaniline (300 mg, 1.74 mmol) and 3-methoxyphenylboronic acid (344 mg, 2.26 mmol) as a yellow liquid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:38])[O:39][CH2:40][CH3:41])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCOC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f36) and commercially available ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[OH:8])[CH2:3][CH2:2]1.Cl[CH2:22][CH2:23][CH:24]1[O:28][C:27](=[O:29])[N:26]([CH3:30])[CH2:25]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)([OH:8])[CH:4]1[CH2:5][CH2:6][N:1]([CH2:22][CH2:23][CH:24]2[O:28][C:27](=[O:29])[N:26]([CH3:30])[CH2:25]2)[CH2:2][CH2:3]1
Reactant: CN1CC(CCCl)OC1=O
Reactant: OC(c1ccccn1)(c1ccccn1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: CN1CC(CCN2CCC(C(O)(c3ccccn3)c3ccccn3)CC2)OC1=O

Procedure:
A mixture of 2.69 g (0.01 mol) of α-(4-piperidinyl)-α-(2-pyridinyl)-2-pyridinemethanol, 1.6 g (0.01 mol) of 5-(2-chloroethyl)-3-methyl-2-oxazolidinone, 3.7 g (0.035 mol) of anhydrous sodium carbonate and 0.1 g of potassium iodide in 100 mL of 1-butanol is heated at reflux for 16 hr. The mixture is concentrated and the residue is partitioned between benzene and water. The organic layer is washed with water and brine, dried over sodium sulfate, filtered and concentrated to give the title compound.
Reaction SMILES: [F:1][C:2]([F:9])([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH2:21]([C@H:28]1[CH2:32][O:31][C:30](=[O:33])[NH:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Li]CCCC>C(Cl)Cl.C1COCC1>[CH2:21]([C@H:28]1[CH2:32][O:31][C:30](=[O:33])[N:29]1[C:5](=[O:7])[CH2:4][CH2:3][C:2]([F:1])([F:9])[CH3:8])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(F)(F)CCC(=O)O
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(F)(F)CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.1 %

Procedure:
In a 100 mL round-bottomed flask was added 4,4-difluoropentanoic acid (1.7 g, 12.31 mmol) and DMF (0.019 mL, 0.246 mmol) in DCM (9 mL) to give a colorless solution. Oxalyl chloride (1.077 mL, 12.31 mmol) was added slowly and the resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated to dryness. A separate 100 mL round-bottomed flask was charged with (S)-4-benzyloxazolidin-2-one (2.181 g, 12.31 mmol) in THF (23 mL) and then cooled to −78° C. Next, n-BuLi (4.92 mL, 12.31 mmol) was added slowly over 5 min. A solution of the above acid chloride in THF (10 mL) was slowly added to the reaction at −78° C. The reaction mixture was stirred at −78° C. for about 1 h and then allowed to warm to room temperature and stirred under nitrogen overnight. The reaction mixture was quenched with about 60 mL of saturated aqueous NH4Cl solution. The resulting mixture was diluted with 200 mL of EtOAc and about 60 mL of water. The layers were separated and the aqueous layer was extracted with 250 mL of EtOAc. The combined EtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo to give a dark yellowish oil. The crude material was purified by silica gel chromatography (80 g ISCO column. A: hexane, B: DCM, 20% to 100% elution) to give Intermediate S-5A (1.65 g, 5.55 mmol, 45.1% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.23-7.39 (3 H, m), 7.17-7.24 (2 H, m), 4.67 (1 H, ddd, J=9.85, 3.69, 3.41 Hz), 4.13-4.26 (2 H, m), 3.29 (1 H, dd, J=13.42, 3.30 Hz), 3.16 (2 H, ddd, J=13.98, 8.47, 6.82 Hz), 2.77 (1 H, dd, J=13.31, 9.57 Hz), 2.19-2.41 (2 H, m), 1.53-1.75 (3 H, m).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=O)[CH2:11][N:12]1[N:16]=[C:15]([CH3:17])[O:14][C:13]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:21][NH2:22]>C(O)(C)C>[CH2:1]([O:8][CH2:9][C:10]1[CH2:11][N:12]([NH:16][C:15](=[O:14])[CH3:17])[C:13](=[O:18])[NH:21][N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: Cc1nn(CC(=O)COCc2ccccc2)c(=O)o1
Solvent: CC(C)O
Solvent: O
Product: CC(=O)NN1CC(COCc2ccccc2)=NNC1=O
Temperature: 75 °C

Procedure:
To a solution of 3-(3-benzyloxy-2-oxo-propyl)-5-methyl-1,3,4-oxadiazol-2-one (36.4 g, 139 mmol) in isopropanol (140 mL) was added hydrazine hydrate (62 wt % in water, 11.8 mL, 152 mmol) in at room temperature in one portion. The mixture was heated to 75° C. for 24 h. The volatiles were removed under reduced pressure, and the remaining brown oil was purified by flash chromatography (7% MeOH/dichloromethane) to furnish the desired product as a yellowish solid. 1H NMR (400 MHz, CDCl3) 2.04 (s, 3H), 4.12 (s, 2H), 4.23 (s, 2H), 4.54 (s, 2H), 7.24-7.44 (m, 5H), 8.25 (s, 1H), 8.69 (s, 1H).