Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.O/[N:53]=[C:54](\[NH2:62])/[CH2:55][C:56]1[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=1>ClCCl.O>[NH2:62]/[C:54](=[N:53]\[O:10][C:9]([C@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21])=[O:11])/[CH2:55][C:56]1[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=1
Reactant: N/C(Cc1cccnc1)=N\O
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O/N=C(\N)Cc1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 115.9 %

Procedure:
A solution of (2R)-2-(2-tert-butoxy-2-oxoethyl)-5-cyclohexylpentanoic acid (Preparation 1) (500 mg, 1.67 mmol) in dichloromethane (20 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (354 mg, 1.85 mmol), N-methylmorpholine (203 μl, 1.85 mmol) and 1-hydroxybenzotriazole hydrate (227 mg, 1.67 mmol). (1Z)-N′-hydroxy-2-(3-pyridinyl)ethanimidamide (WO 9600720) (374 mg, 1.67 mmol) followed by N-methylmorpholine (369 μl, 3.34 mmol) were added to the reaction mixture which was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (10 ml) and stirred for 20 minutes. The layers were separated via a 5 micron filter cartridge. The organic solvent was removed under reduced pressure to afford the title compound as a yellow oil (835 mg). This was used without further purification in the following step.
Reaction SMILES: [Na].[S:2](=[C:5]([CH:13]([OH:16])[CH2:14][OH:15])[CH2:6][C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)(=[O:4])=[O:3].[CH3:17]I.O>CO>[CH3:17][N:11]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:6][C:5](=[S:2](=[O:3])=[O:4])[CH:13]([OH:16])[CH2:14][OH:15])[CH2:12]1
Reactant: O=S(=O)=C(Cc1cnccn1)C(O)CO
Reactant: CI
Agent: [Na]
Solvent: CO
Solvent: O
Product: CN1C=CN=C(CC(C(O)CO)=S(=O)=O)C1

Procedure:
1.2 g of 2-(2-sulfonyl-3,4-dihydroxybutyl) pyrazine sodium salt (4106 and 4107) was added to a solution of 10 ml of methyl iodide in 25 ml of methanol. 2 ml of water were added and the mixture was refluxed for 5 days. It was then concentrated, taken up in 100 ml of water and washed with methylene chloride. The aqueous layer was concentrated and the residue chromatographed (Biogel P-2/water) giving 1.1 g of 1-methyl-3-(2-sulfonyl-3,4-dihydroxybutyl)pyrazine (4100) as a mixture of diastereoisomers. UV H2O max: 283 (3.88). These were separated using a Biorad AG-50 W×4 (Ca++) column at 65° with water as the eluent. 13C NMR: 163.89, S (C3); 150.36, D (C5); 138.88, D, 135.81, D (C2, C6); 71.05, D (CHOH); 64.41, T (CH2OH); 61.64, D (CHSO3-); 49.65, Q (NCH3); 32.61, T (--CH2 --). 13C NMR of the epimer; 163.49, S (C3); 150.44, D (C5); 138.77, D, 135.92, D (C2, C6); 71.82, D (CHOH); 63.37, T (CH2OH); 63.25, D (CHSO3-); 49.65, Q (NCH3); 33.26, T (-CH2 -).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[N:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:28])[N:10]2[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:25][CH2:26][CH3:27])[CH:19]=1)[CH3:4].[CH3:29][O:30][C:31](=[O:40])[CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)Br>O1CCCC1>[CH2:3]([C:5]1[N:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:28])[N:10]2[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[CH2:32][C:31]([O:30][CH3:29])=[O:40])=[C:20]([CH2:25][CH2:26][CH3:27])[CH:19]=1)[CH3:4]
Reactant: CCCc1cc(Cn2c(=O)ccc3c(CC)nc(CC)cc32)ccc1O
Reactant: COC(=O)C(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1cc(Cn2c(=O)ccc3c(CC)nc(CC)cc32)ccc1Oc1ccccc1CC(=O)OC
Reaction time: 0.33 h
Yield: 47.9 %

Procedure:
Sodium hydride (60% dispersion in oil, 51 mg) was added to a solution of compound F (440 mg) in tetrahydrofuran (15 ml) under an atmosphere of argon. The mixture was stirred for 20 minutes and then methyl-α-bromophenylacetate (320 mg) in tetrahydrofuran (5 ml) was added. The mixture was stirred for 18 hours and then volatile material was removed by evaporation. The residue was partitioned between ethyl acetate (25 ml) and water (25 ml) and the organic layer was separated, washed with saturated sodium chloride solution (25 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by flash chromatography, eluting with methanol/dichloromethane (1:199 v/v) to give methyl 2-[4-((5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-1-yl)methyl)-2-propylphenoxy]phenylacetate (A) (300 mg) as an oil; NMR: 0.9(t, 3H), 1.2(t, 3H), 1.35(t, 3H), 1.55-1.7(m, 2H), 2.7(t, 2H), 2.8(q, 2H), 3.1(q, 2H), 5.4(s, 2H), 5.6(s, 1H), 6.65(d, 1H), 6.75(d, 1H), 6.9(s, 1H), 6.95(d, 1H), 7.1(s, 1H), 7.3-7.4(m, 3H), 7.5-7.6(m, 2H), 7.95(d, 1H).
Reaction SMILES: I[C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][NH:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1B(O)O>>[N:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7]([NH:6][O:5][CH2:4][C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=2[C:28]2[S:27][CH:31]=[CH:30][CH:29]=2)=[O:22])=[CH:17][CH:18]=1
Reactant: O=C(NOCc1ccccc1I)c1ccccc1NCc1ccncc1
Reactant: OB(O)c1cccs1
Product: O=C(NOCc1ccccc1-c1cccs1)c1ccccc1NCc1ccncc1

Procedure:
Prepared by a similar procedure as described for preparation of example 363. Starting materials: N-(2-Iodo-benzyloxy)-2-[(pyridin-4-ylmethyl)amino]-benzamide (see example 360) and thiophene-2-boronic acid (Aldrich).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[CH:8](=O)[CH2:9][CH2:10][CH3:11]>>[CH2:8]([N:7]([CH2:1][CH2:2][CH2:3][CH3:4])[C:4]1[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=1)[CH2:9][CH2:10][CH3:11]
Reactant: Cc1cc(N)n[nH]1
Reactant: CCCC=O
Product: CCCCN(CCCC)c1cc(C)[nH]n1
Yield: 106.1 %

Procedure:
Following a procedure analogous to that for the synthesis Example 106, 5-methyl-1H-pyrazol-3-amine (Aldrich, 486 mg, 5.00 mmol) and butyraldehyde (541 mg, 7.50 mmol) were converted to the title compound (555 mg, 53%). 1H NMR (CDCl3) δ 5.34 (s, 1H), 3.17 (t, J=7.3 Hz, 4H), 2.21 (s, 3H), 1.55 (td, J=15.1, 7.5 Hz, 4H), 1.34 (qd, J=15.0, 7.3 Hz, 4H), 0.94 (t, J=7.4 Hz, 6H); MS(ESI+) m/z 210.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:8][CH:7](C(OC)=O)[C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2].C(O)(=O)C.S(=O)(=O)(O)O>O>[C:1]([C:3]1([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH2:8][CH2:7][C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2]
Reactant: COC(=O)C1CC(C#N)(c2ccc(F)cc2)CCC1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: N#CC1(c2ccc(F)cc2)CCC(=O)CC1
Yield: 75 %

Procedure:
A mixture of 33.9 g. (0.123 mole) of methyl 5-cyano-5-(4-fluorophenyl)-2-oxocyclohexanecarboxylate (prepared in Example 8) in 900 ml. of acetic acid and 450 ml. of 10% sulfuric acid is stirred mechanically on a steam bath for about 24 hours. The mixture is then allowed to cool and diluted with water. This mixture is extracted thoroughly with benzene. The organic layer is washed successively with water, sodium bicarbonate solution and brine and evaporated to dryness. The solid residue is recrystallized from ether to give 16.32 g. (75% yield) of 4-cyano-4-(4-fluorophenyl)cyclohexanone, having a melting point of 84° to 88°C.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[C:9]1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:25].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.CCOC(C)=O.CCCCCC>CN(C=O)C.CCOCC.CCOCC.C(OCC)(=O)C>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[C:9]1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)([OH:25])=[O:2]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: Cc1c(-c2cccnc2)n(CCCCCC=O)c2ccccc12
Agent: c1cc[nH+]cc1
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(-c2cccnc2)n(CCCCCC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(5-Formylpentyl)-3-methyl-2-(3-pyridyl)indole (127 mg) is dissolved in DMF (0.66 ml) and pyridinium dichromate (298 mg) added all at once. The mixture is stirred overnight at room temperature then diluted with ether:ethyl acetate (25 ml, 4:1) and filtered. The solid is washed with hot chloroform and the combined filtrates concentrated in vacuo to yield a dark brown gum which is slurried in ether:ethyl acetate (4:1) and extracted with 0.1 N aqueous sodium hydroxide (2 ml). The aqueous extract is acidified to pH 5.5-6.0 and extracted with chloroform. The chloroform extract is dried and concentrated in vacuo yielding a yellow oil; TLC (silica gel, EtOAc:hexane 1:1) indicates the presence of the desired acid. Further purification by chromatography on silica gel using ethyl acetate:hexane (1:1) as the eluent yields the desired 1-(5-carboxypentyl)-2-(3-pyridyl)-3-methylindole of Example 3.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH2:15][C:16]([O:18]C)=[O:17])=[CH:7][N:8]2[CH3:14])[CH3:2].[OH-].[Na+].Cl>CO>[CH2:1]([O:3][C:4]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH2:15][C:16]([OH:18])=[O:17])=[CH:7][N:8]2[CH3:14])[CH3:2]
Reactant: CCOc1c(F)ccc2c1c(CC(=O)OC)cn2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1c(F)ccc2c1c(CC(=O)O)cn2C
Temperature: 25 °C
Yield: 93.6 %

Procedure:
To a solution of 30-12 (45 mg, 0.17 mmol) in MeOH (10 mL) was added 2N NaOH (8 mL). The mixture was refluxed for one hour. After cooled to room temperature, the mixture was neutralized with hydrochloric acid to pH=7, extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine (30 mL), dried over MgSO4 and concentrated to afford 30-13 (40 mg, 94%) as a yellow solid. LRMS: calc 251.1 and found: 252.0 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([N+:16]([O-])=O)[CH:3]=1.O.O.Cl[Sn]Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CN(c1ccccc1)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CN(c1ccccc1)c1ccc(Cl)cc1N
Temperature: 40 °C
Reaction time: 6 h
Yield: 86.3 %

Procedure:
To a solution of 4-chloro-N-methyl-2-nitro-N-phenylphenylamine (12.5 g, 46.3 mmol) in ethanol (250 mL) was added SnCl2.2H2O (37.5 gr., 0.17 mol). The solution was heated to 40° C. and stirred for 6 h. The reaction mixture was concentrated in vacuo and subsequently diluted with ethyl acetate (500 mL) and washed with H 20 (500 mL), a cooled (0° C.) aq. solution of NaOH (1 M, 200 mL), H2O (500 mL) and brine (500 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced presssure. The crude compound was applied onto a silica column and eluted with heptane/ethyl acetate (8/2, v/v) affording the title compound (9.3 g, 87% yield). Data: Rf 0.65 (heptane/ethyl acetate, 7/3, v/v), (m/z)=233 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[Cl-].[Cl-].[Cl-].[Al+3].[Cl:16][C:17]1[CH:18]=[C:19]([OH:28])[CH:20]=[CH:21][C:22]=1[CH:23]=[CH:24][N+:25]([O-])=O>C1COCC1>[NH2:25][CH2:24][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([OH:28])=[CH:18][C:17]=1[Cl:16]
Reactant: O=[N+]([O-])C=Cc1ccc(O)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCCc1ccc(O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To lithium aluminum hydride 1.0M in ether (1.50 mL, 1.50 mmol) at 0° C. a solution of aluminum trichloride (201 mg, 1.51 mmol) in THF (2 mL) is added. After 5 min a solution of compound obtained in step 1 above (100 mg, 0.50 mmol) in THF (2 mL) is added and the reaction is allowed to stir at room temperature overnight. Add water and then 3 N HCl, the aqueous layer is extracted with 3/1 n-butanol/toluene. The combined organic layers are dried over sodium sulfate and concentrated. SCX ion-exchange chromatography afforded 70 mg (81%) of the title compound. Electrospray MS M+1 ion=172. 1H-NMR (methanol-d4, 200 MHz): 7.06 (d, 1H, J=8.3 Hz), 6.79 (d, 1H, J=2.4 Hz), 6.65 (dd, 1H, J=2.4 and 8.3 Hz), 2.82 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: C1COCCN1
Reactant: COc1ccc(I)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(N2CCOCC2)cc1Br
Temperature: 45 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, to a solution of 20.0 g of 2-bromo-4-iodoanisole in toluene (250 ml) was added morpholine (6.12 ml), 1.29 g of tri-tert-butyl phosphine, 13.5 g of sodium tert-butoxide, and 359 mg of palladium acetate (II), and the reaction mixture was stirred for two hours at 45° C. Water and EtOAc were added to the reaction solution, liquid separation was performed and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with saturated brine, dried over MgSO4, then, the drying agent was separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (Chromatorex NH; mobile phase: n-hexane/EtOAc=10/1 to 3/1; v/v) to obtain 3.94 g of the title compound (colorless powder).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[C:10]([CH3:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:15][C:10]1[C:9]([NH:8][C:5](=[O:7])[CH3:6])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Cc1ncccc1N
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cccnc1C

Procedure:
Acetic Acid Anhydride (17.9 mmol; 1.7 mL) was added to 3-Amino-2-picoline (17.0 mmol; 1.8 g) in dichloromethane (10 mL) and diisopropylethylamine (17.9 mmol; 3.1 mL) at 25° C. under argon. The reaction aged 30 min at 25° C. then was diluted with dichloromethane and extracted with water and brine. The aqueous layer was extracted with dichloromethane and ether then the combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting yellow oil was purified by chromatography (0% to 66% ethyl acetate in hexane) to afford the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=NCCCC.C(OC(=O)C)(=O)C.[N+:26]([CH2:29][C:30](=[O:32])[CH3:31])([O-:28])=[O:27]>C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=[C:29]([N+:26]([O-:28])=[O:27])[C:30](=[O:32])[CH3:31]
Reactant: CC(=O)C[N+](=O)[O-]
Reactant: CCCCN=Cc1ccccc1SCCCCCl
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)C(=Cc1ccccc1SCCCCCl)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 2 liter 4-neck round-bottom flask fitted with mechanical stirrer and thermowell, under a nitrogen atmosphere, was added 138.2 g of N-{2-[(4-chlorobutyl)thio]phenylmethylene}-1-butanamine and 350 ml of benzene, followed by 91.9 ml of acetic anhydride. The mixture was cooled in an ice water bath as 50.18 g of nitroacetone was added. The bath was permitted to warm to room temperature and the reaction stirred overnight. The solvent was removed by rotary evaporation and the product was partitioned between ether and sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to dryness. Purification via column chromatograph on silica gel, eluting with 15% ethyl acetate in hexane provided the product as a pale orange oil. Mass spectrum: 314 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][O:15][C:14]([CH3:19])([CH3:18])[CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][O:15][C:14]([CH3:19])([CH3:18])[CH2:13]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCOC(C)(C)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CN(C2CNC2)CCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
A mixture of 3-(2,2-dimethylmorpholin-4-yl)azetidine-1-carboxylic acid tert-butyl ester (492 mg, 1.82 mmol) and TFA (5 mL) in DCM (10 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM and eluted with 2M NH3/MeOH affording 4-Azetidin-3-yl-2,2-dimethylmorpholine as a white solid (302 mg, 97%). 1H NMR (CDCl3, 300 MHz): δ 3.73 (t, J=4.8 Hz, 2H); 3.64-3.51 (m, 4H); 3.18-3.11 (m, 1H); 2.23 (t, J=4.8 Hz, 2H); 2.23-2.07 (m, 1H); 2.06 (s, 2H); 1.25 (s, 6H).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH2:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][C@@H:5]([NH2:13])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [N-]=[N+]=NC[C@@H](N)Cc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC[C@@H](N)Cc1ccccc1
Reaction time: 24 h
Yield: 65.2 %

Procedure:
A sample of the compound from step 4a (790 mg, 4.48 mmole) was dissolved in 30 mL of THF and 6 mL of water, triphenylphosphine (5.0 g, 19.1 mmole) was added, and the reaction mixture was stfired for 24 hours at reflux. The solvent was removed, and the residue was dissolved in 2 N HCl. NaCl was added, and the solution was extracted with ethyl ether. The aqueous layer was adjusted to pH 12 with K2CO3, saturated with NaCl, then extracted with GICl3 and CHCl3 containing 15% isopropanol. The solvent was removed under vacuum to afford 439 mg of the title compound. MS m/z (M+H)+: 151, MS m/z (M+NH4)+: 168.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:30][CH2:31][OH:32])[CH2:15][N:16]([CH3:29])[C:17]([C:19]2[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[CH:22]=[CH:21][CH:20]=2)=[O:18])=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH2:30][CH:31]=[O:32])[CH2:15][N:16]([CH3:29])[C:17]([C:19]2[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[CH:22]=[CH:21][CH:20]=2)=[O:18])=[CH:12][CH:13]=1
Reactant: CN(CC(CCO)c1ccc(Cl)cc1)C(=O)c1cccc2c1CCCC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN(CC(CC=O)c1ccc(Cl)cc1)C(=O)c1cccc2c1CCCC2
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
To a stirred cooled (−78° C.) solution of oxalyl chloride (0.39 mL, 4.47 mmol) in DCM (10 mL) was added DMSO (0.64 mL, 9.00 mmol) in DCM (5 mL) dropwise. The solution was stirred at −78 ° C. for 5 min and a solution of N-[2-(4-chlorophenyl)-4-hydroxybutyl]-N-methyl-5,6,7,8-tetrahydro-1-naphthamide (1.11 g, 2.98 mmol) in DCM (6.0 mL) and DMSO (3.4 mL) was added dropwise. The solution was stirred at −78 ° C. for 15 min and triethylamine (2.50 mL, 17.9 mmol) was added. Stirring was continued at −78 ° C. for 30 min and then at room temperature for 2 h. 1N NCI (75 mL) and DCM (75 mL) were added, the layers separated, and the organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Purification by chromatography (silica gel; 50% Et2O/DCM) provided the title compound (1.10 g, 95%) as a tacky solid. MS rm/z 370 (M+H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][O:7][CH2:8][C@@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10](O)=[O:11].Cl.[CH3:31][O:32][NH:33][CH3:34].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:27][C:24]([F:25])([F:26])[C:22]1[CH:21]=[C:5]([CH:4]=[C:3]([C:2]([F:28])([F:1])[F:29])[CH:23]=1)[CH2:6][O:7][CH2:8][C@@H:9]([NH:13][C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[C:10]([N:33]([O:32][CH3:31])[CH3:34])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)[C@@H](COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.5 %

Procedure:
To a solution of (2R)-3-{3,5-bis(trifluoromethyl)benzyloxy}-2-tert-butoxycarbonylaminopropionic acid (76.6 g, 176 mmol), N-methoxy-N-methylamine hydrochloride (18.53 g, 190 mmol) and triethylamine (25.6 mL, 190 mmol) in CH2Cl2 (400 mL) was added WSC.HCl (36.4 g, 190 mmol). The mixture was stirred at room temperature for 20 hours, washed with water and saturated brine in order. The organic extract was dried over sodium sulfate anhydride. Sodium sulfate was filtered off and the solvent was removed by evaporation from the filtrate under reduced pressure to give (2R)-3-(3,5-bis(trifluoromethyl)benzyloxy)-2-tert-butoxycarbonylamino-N-methoxy-N-methylpropionamide (76.4 g, 92%) as a pale brown oil.
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])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH: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])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(C)=O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f25) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)=[O:4].N1C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][CH:5]2[C:3]([O:2][CH3:1])=[O:4])(=[O:30])=[O:29])=[CH:26][CH:27]=1
Reactant: COC(=O)C1Cc2ccccc2N1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1Cc2ccccc2N1S(=O)(=O)c1ccc(OC)cc1
Reaction time: 8 h

Procedure:
Indoline-2-carboxylic acid methyl ester (32.7 g, 151.8 mmol) was dissolved in DCM (400 ml), and pyridine (37.4 ml, 459.0 mmol) was added thereto. A solution of 4-methoxybenzenesulfonyl chloride (31.6 g, 153 mmol) dissolved in DCM (100 ml) was then added, and stirring was carried out overnight at room temperature. The mixture was diluted with DCM and washed in succession with 0.5 M KHSO4, saturated NaHCO3 solution and saturated NaCl solution. The organic phase was dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (heptane/ethyl acetate 2:1).