Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:13][CH2:14][O:15][CH2:16][C:17]([NH2:19])=[O:18].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)(C)C.O.C1(C)C=CC=CC=1>[C:17]([CH2:16][O:15][CH2:14][CH2:13][CH:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:1]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:18])[NH2:19]
Reactant: CCOC(=O)N1CCNCC1
Reactant: NC(=O)COCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCNCC1CCOCC(N)=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 81.3 %

Procedure:
164 g (1.04 mol) of ethyl piperazinecarboxylate, 156.9 g (1.14 mol) of (2-chloroethoxy)acetamide, 241.7 g (2.28 mol) of sodium carbonate, 1g of potassium iodide and 200 ml of toluene are introduced into a 2 l three-necked round-bottomed flask fitted with a water-cooled condenser and a mechanical stirrer. The mixture is brought at the reflux temperature for 3 hours 30. The mixture is allowed to cool to 50° C., and 200 ml of isopropanol are added. The reaction mixture is filtered and the filtration residue is washed with 150 ml of isopropanol. The filtrate is concentrated on a rotary evaporator under reduced pressure. 277.2 g of crude product are obtained, which product is recrystallized from 500 ml of ethyl acetate. 219.2 g (81.6%) of ethyl (2-carbamoylmethoxyethyl)piperazine-1-carboxylate are obtained in the form of a white solid. NMR: δ: 1.24 (3H, t, 7.05 Hz); 2.46 (4H, m); 2.57 (2H, t, 5.2 Hz); 3.44 (4H, m); 3.62 (2H, t, 5.2 Hz); 3.95 (2H, s); 4.1 (2H, 9, 7.1 Hz); 5.72 (1H, bs); 7.34 (1H, bs). Mass spectrum: 260 (MH+). DSC: Onset 106.5° C., Max: 109.7° C. Elemental analysis:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1.Cl[C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][NH:13][C:15](=[O:16])[O:17][CH3:18])=[CH:6][CH:5]=1
Reactant: COc1ccc(SCCN)cc1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCSc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of compound 1-HCl (0.466 g) in CH2Cl2 (20 mL) cooled to ˜0° C. was added methyl chloroformate (1.1 eq.) and triethylamine (2.5 eq.). The reaction mixture was stirred for 2 hours at 0° C. and washed with 1N HCl, and sat. NaHCO3. The solvents were removed by evaporation under reduced pressure to give product 7 as white solid with a yield of 480 mg, 98%.
Reaction SMILES: [CH:1]1([CH2:7]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:18]=[O:19])[C:12]=2[CH:11]=[CH:10]1>>[CH:1]1([CH2:7][N:9]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([CH:18]=[O:19])[C:12]=3[CH:11]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: BrCC1CCCCC1
Product: O=Cc1cccc2c1ccn2CC1CCCCC1
Yield: 84.8 %

Procedure:
The same procedures used in Example 1 were repeated except for using 4.93 g of cyclohexylmethyl bromide and 2.00 g of indole-4-carbaldehyde as a starting material to give 2.82 g of 1-cyclohexylmethylindole-4-carbaldehyde as a yellow oily substance. The yield thereof was found to be 85%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[O:26][CH2:27][C:28]([O:30]CC)=[O:29]>C1COCC1.[OH-].[Na+]>[CH3:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[O:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: CCOC(=O)COc1ccc(SCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(SCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)ccc1OCC(=O)O
Temperature: 60 °C
Yield: 12.2 %

Procedure:
A solution of ethyl {[2-methyl-4-({[4′-(trifluoromethyl)-3-biphenylyl]methyl}thio)phenyl]oxy}acetate (209 mg) in THF (20 mL) and aqueous NaOH (2M, 20 mL) was stirred at rt overnight and then heated to 60° C. for 2 hours. The mixture was then allowed to cool to rt and the THF removed under vacuum. The resulting aqueous mixture was then acidified and extracted with EtOAc (3×) and the organic layer washed with brine dried (MgSO4), filtered and reduced. Purification by mass directed auto-prep HPLC afforded the title compound as a white solid (24 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:16]([CH3:18])[CH3:17])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:19]([OH:21])=O>C1C=CC=CC=1>[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:16]([CH3:18])[CH3:17])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:19]([Cl:3])=[O:21]
Reactant: CC(C)c1ccc2ncc(C(=O)O)c(O)c2c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)c1ccc2ncc(C(=O)Cl)c(O)c2c1

Procedure:
3.8 ml of thionyl chloride were added to a suspension of 10 g of the raw product of Step C in 300 ml of anhydrous benzene and the mixture was refluxed for 21/2 hours and was then cooled. The mixture was vacuum filtered and the precipitate was empasted with a little anhydrous benzene to obtain 10.74 g of 4-hydroxy-6-isopropyl-quinoline-3-carboxylic acid chloride melting at 252° C.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[CH3:19])[N:10]([CH:12]=[O:13])[CH3:11].S(=O)(=O)(O)[OH:21].N([O-])=O.[Na+]>O.ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[CH:12]([N:10]([CH3:11])[CH:9]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[CH3:19])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:21])=[O:13]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccsc1C(Cc1ccccc1N)N(C)C=O
Agent: [Cu+2]
Agent: O=N[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: Cc1ccsc1C(Cc1ccccc1O)N(C)C=O
Temperature: 25 °C

Procedure:
A stirred suspension of 8.87 g of 2-amino-N-formyl-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine and 71 ml of 50% (w/v) sulfuric acid was chilled with an ice water bath for 15 minutes. The suspension was treated dropwise over one minute with a solution of sodium nitrite (2.45 g) and water (13 ml). After stirring with chilling for 15 minutes, the mixture was strained through glass wool into a dropping funnel and then added over a few minutes to a refluxing solution of 63.84 g of copper sulfate and 130 ml of water. After a few minutes of vigorous stirring, the reaction mixture was cooled to room temperature with an ice bath, diluted with water and dichloromethane and transferred to a separatory funnel. The phases were separated and the aqueous phase was extracted with dichloromethane (2×200 ml). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to an oil. The oil was purified by means of preparative HPLC (Water's Associates Prep LC/System 500, silica gel, sample applied in dichloromethane and eluted with ethyl acetate-hexane (1:1)). The appropriate fractions were combined and concentrated to an oil which crystallized on refrigerated storage overnight. Recrystallization from ethyl acetate (20 ml) afforded 1.62 g of N-formyl-2-hydroxy-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine, mp 142°-144° C.
Reaction SMILES: C(O[C:9](=O)[NH:10][CH2:11][C@H:12]([NH:18][C:19](=[O:33])[CH2:20][C:21](=[O:32])[NH:22][C:23]1[S:24][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[N:26][N:27]=1)[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])C1C=CC=CC=1.[CH3:35][C:36]1[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:37]=1C=O.C([BH3-])#N.[Na+]>CO.[Pd]>[C:28]([C:25]1[S:24][C:23]([NH:22][C:21](=[O:32])[CH2:20][C:19]([NH:18][C@@H:12]([CH2:11][NH:10][CH2:9][C:37]2[CH:40]=[CH:41][C:42]([CH3:44])=[CH:43][C:36]=2[CH3:35])[C@@H:13]([OH:17])[CH2:14][CH2:15][CH3:16])=[O:33])=[N:27][N:26]=1)([CH3:29])([CH3:30])[CH3:31]
Reactant: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CC(=O)Nc1nnc(C(C)(C)C)s1
Reactant: Cc1ccc(C=O)c(C)c1
Agent: [Pd]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)NC(=O)CC(=O)Nc1nnc(C(C)(C)C)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of {(25, 3S)-2-[2-(5-tert-butyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-acetylamino]-3-hydroxy-hex-4-ynyl}-carbamic acid benzyl ester (90 mg, 0.19 mmol) in MeOH (4 mL) was charged with 5% Pd/C, Degussa style (18 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (3 mL). The resultant solution was charged sequentially with 2,4-dimethylbenzaldehyde (0.02 mL, 0.14 mmol) and sodium cyanoborohydride (11 mg, 0.18 mmol), stirred for 12 h at RT, quenched with sat. NaHCO3, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the residue by reverse-phase HPLC provided the title compound as a white powder after lyopholization. MS found: (M+H)+=476.5.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[Cl:22]Cl.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[C:21]=1[Cl:22]
Reactant: ClCl
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(N)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN1C(=O)CN=C(c2ccccc2F)c2c1ccc(N)c2Cl

Procedure:
80 g (0.28 M) of 7-amino-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one are dissolved in 220 ml of concentrated hydrochloric acid and chlorine gas is slowly conducted into the solution at -10° C. for 4 hours. The mixture is slowly poured on to a mixture of ice and sodium carbonate solution (250 g of sodium carbonate dissolved in water) and extracted with methylene chloride. The extract is dried over sodium sulphate, filtered and concentrated. The residue is purified on a 1.2 kg silica gel column using methylene chloride and then methylene chloride/ethyl acetate (10:1) as the eluting agent and crystallised from ethyl acetate/ether/n-hexane. There is obtained 7-amino-6-chloro-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one which melts at 240° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][CH2:24]I)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[I-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][CH2:24][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1CCNCC1
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCCI)CC1
Agent: [I-]
Agent: [Na+]
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCCN2CCCCC2)CC1

Procedure:
In analogy to the procedure described in example 5D, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(4-iodo-butyl)-[1,4]diazepan-5-one and piperidine (with no additional sodium iodide) gave the title compound as white powder. MS: 452.2 (MH+, 2Cl).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]1[NH:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:7]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.Cl.N1CCC(C2NN=C(C3C=CC(Cl)=CC=3)C=2C2C=CN=CC=2)C[CH2:26]1>>[CH3:26][N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]1[NH:10][N:9]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C:7]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1
Reactant: Fc1ccc(-c2n[nH]c([C@H]3CCCN3)c2-c2ccncc2)cc1
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Agent: Cl
Product: CN1CCC[C@@H]1c1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1

Procedure:
By following the method of Example C-75 and substituting (R)-5-(2-pyrolidinyl)-4-(4-pyridyl)-3-(4-fluorophenyl)pyrazole Example C-125) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole hydrochloride (Example C-74) the title compound was prepared: MS (M+H): 323 (base peak).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=2)[CH:20]=[CH:19][N:18]=1.N1C=CC=CC=1.ClCCl>O>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=2)[CH:20]=[CH:19][N:18]=1)(=[O:5])=[O:4]
Reactant: COC(=O)c1ccc2ccnc(O)c2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2ccnc(OS(=O)(=O)C(F)(F)F)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
Trifluoromethanesulfonic anhydride (2.1 g) was added to a mixture of methyl 1-hydroxyisoquinoline-7-carboxylate (1.3 g), pyridine (587 mg), and dichloromethane (40 mL), followed by stirring at room temperature for 18 hours. The reaction mixture was diluted with water, extracted with chloroform, and the organic layer was concentrated under reduced pressure. The resulting residue was purified under silica gel column chromatography (chloroform/methanol) to obtain methyl 1-{[(trifluoromethyl)sulfonyl]oxy}isoquinoline-7-carboxylate (1.9 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]#[N:12].S(=O)(=O)(O)[OH:14]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]([NH2:12])=[O:14]
Reactant: N#CCc1nc2ccccc2s1
Reactant: O=S(=O)(O)O
Product: NC(=O)Cc1nc2ccccc2s1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2-(Benzothiazol-2-yl)acetonitrile (2.05 g, 12 mmol) was added in portions to stirred concentrated sulfuric acid (5 mL) over 10 min. The mixture was stirred for 4 hr, then poured over ice/water. The precipitate that formed was extracted into EA and washed with brine, then the organic phase was dried over magnesium sulfate and the solvent removed under vacuum to give 2-(benzothiazol-2-yl)acetamide (1.02 g) as an orange solid.
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[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:35][CH2:34][CH2:33]4)[C:15]=3[NH:14][CH:13]=2)=[O:11])[CH2:5][CH2:4]1.[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1>>[CH:36]1([C:39]([NH:2][C@H:3]2[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]3[C:16]4[N:17]=[CH:18][N:19]=[C:20]([C:21]5[C:29]6[O:28][CH2:27][O:26][C:25]=6[CH:24]=[CH:23][C:22]=5[O:30][CH2:31][CH:32]5[CH2:35][CH2:34][CH2:33]5)[C:15]=4[NH:14][CH:13]=3)=[O:11])[CH2:5][CH2:4]2)=[O:40])[CH2:38][CH2:37]1
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CCC5)ccc5c4OCO5)ncnc23)CC1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](NC(=O)C2CC2)CC1)c1c[nH]c2c(-c3c(OCC4CCC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from trans-4-(5-cyclobutylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide hydrochloride (example A173) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C)C.Cl>CCOCC>[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][N:15]2[C:16](=[O:25])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]2=[O:24])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: O=C1c2ccccc2C(=O)N1OC1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.3 %

Procedure:
1.5 g of 69a was taken up with isopropanol (10 mL) and 1 mL of concentrated HCl. The mixture was stirred at room temperature for 3 h, then 1 mL of concentrated HCl was added and the mixture was stirred at 50° C., cooled to room temperature and 10 mL of ether was added. The mixture was cooled to −78° C., filtered; and the solid was washed with ether to yield 0.6 g of solid 70a as an HCl salt.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f18) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:37]C(=O)OC(C)(C)C)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][NH:13][C:14]2[C:19](=[O:20])[N:18]([CH2:21][C:22]([NH:24][CH2:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[NH:31][CH:30]=[C:29]4[CH3:35])=[O:23])[C:17]([CH3:36])=[CH:16][N:15]=2)[CH:6]=1.Cl.[OH-].[Na+]>CO>[NH2:37][CH:4]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH2:11][CH2:12][NH:13][C:14]1[C:19](=[O:20])[N:18]([CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][CH:30]=[C:29]3[CH3:35])=[O:23])[C:17]([CH3:36])=[CH:16][N:15]=1)[CH2:3][O:2][CH3:1]
Reactant: COCC(NC(=O)OC(C)(C)C)c1cccc(CCNc2ncc(C)n(CC(=O)NCc3ccc4[nH]cc(C)c4c3)c2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCC(N)c1cccc(CCNc2ncc(C)n(CC(=O)NCc3ccc4[nH]cc(C)c4c3)c2=O)c1
Yield: 60.2 %

Procedure:
A solution of tert-butyl (1R/S)-2-methoxy-1-[3-(2-{[5-methyl-4-(2-{[(3-methyl-1H-indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}ethyl)phenyl]ethylcarbamate (preparation 124) (26 mg, 0.043 mmol) in hydrochloric acid (2 ml, 6N, 12 mmol) and methanol (2 ml), was stirred under a nitrogen atmosphere for 3 hrs. The reaction mixture was basified to pH 10 using 1N NaOH solution, extracted with dichloromethane (4×10 ml), and ethyl acetate (3×10 ml). The combined organic extracts were dried over MgSO4, and evaporated under reduced pressure to give the title compound as a white solid, (13 mg, 60%). Both R, and S isomers are present although their relative proportions have not been determined.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:15]2[C:10](=[C:11]([N:16]3[C:25]4[CH:24]=[CH:23][C:22]5[CH2:26][CH2:27][CH2:28][CH2:29][C:21]=5[C:20]=4[NH:19][C:18](=[O:30])[C:17]3=[O:31])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.C(N)CN>>[NH:7]1[C:15]2[C:10](=[C:11]([N:16]3[C:25]4[CH:24]=[CH:23][C:22]5[CH2:26][CH2:27][CH2:28][CH2:29][C:21]=5[C:20]=4[NH:19][C:18](=[O:30])[C:17]3=[O:31])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-n3c(=O)c(=O)[nH]c4c5c(ccc43)CCCC5)cccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: NCCN
Product: O=c1[nH]c2c3c(ccc2n(-c2cccc4[nH]ccc24)c1=O)CCCC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.1 %

Procedure:
A mixture of 4-[1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-4-yl]-1,4,7,8,9,10-hexahydrobenzo[f]quinoxaline-2,3-dione (180 mg, 0.400 mmol), a 1M tetrabutylammonium fluoride/tetrahydrofuran solution (4 mL, 4.00 mmol), and ethylenediamine (260 μL, 4.00 mmol) was refluxed for 18 hours. The solvent was removed by evaporation under reduced pressure. To the obtained residue was added a dilute hydrochloric acid aqueous solution. The mixture was stirred at room temperature for 18 hours. The precipitate was collected by filtration, washed with water, and dried to obtain the titled compound (85 mg, yield 66%).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([F:17])[C:11](S(=S)(O)=O)=[N:12][C:5]=2[N:4]([CH:18]2[CH2:20][CH2:19]2)[C:3]1=[O:21].[C:22]([O:26][C:27](=[O:36])[NH:28][C@@H:29]([C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)[CH3:30])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>C(#N)C>[C:22]([O:26][C:27](=[O:36])[NH:28][C@H:29]([C@@H:31]1[CH2:35][CH2:34][N:33]([C:11]2[C:10]([F:17])=[CH:9][C:6]3[C:7](=[O:8])[N:2]([NH2:1])[C:3](=[O:21])[N:4]([CH:18]4[CH2:20][CH2:19]4)[C:5]=3[N:12]=2)[CH2:32]1)[CH3:30])([CH3:23])([CH3:24])[CH3:25]
Reactant: Nn1c(=O)c2cc(F)c(S(=O)(O)=S)nc2n(C2CC2)c1=O
Reactant: C[C@@H](NC(=O)OC(C)(C)C)[C@H]1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CCN(c2nc3c(cc2F)c(=O)n(N)c(=O)n3C2CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.7 %

Procedure:
A solution of 0.12 g (0.38 mmol) of 3-amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidine-7-thiosulfonic acid (Compound 24c) in 10 mL of acetonitrile is treated with 0.24 g (1.14 mmol) of ((R)-(S)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester (J. Het. Chem., 1992; 29:1481), 0.25 g (2.5 mmol) of triethylamine and stirred at room temperature for 18 hours then 50° C. for 1 hour. The solvent is removed in vacuo and the residue is partitioned between ethyl acetate (50 mL) and water (25 mL). The organic layer is washed with water, dried (MgSO4), filtered and evaporated in vacuo to give 0.28 g. Chromatography on flash grade silica gel (230–400 mesh) column (2×12 cm) eluting with dichloromethane/ethanol (95:5) provided 0.1 g of the title compound, mp 175–177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:18][CH2:19][CH2:20]Cl)[C:9](=O)[O:10]C2C=CC=CC=2)=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>C(O)C>[NH2:23][N:24]1[CH2:20][CH2:19][CH2:18][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]1=[O:10]
Reactant: O=C(Oc1ccccc1)N(CCCCl)c1ccc(Cl)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NN1CCCN(c2ccc(Cl)cc2)C1=O
Temperature: 25 °C

Procedure:
Thionyl chloride (4.4 mL) was added to a solution of 3-(4-chlorophenylamino)propan-1-ol (2.17 g) in toluene (30 mL) at room temperature, and the reaction solution was stirred at 60° C. for five hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ice and a saturated sodium bicarbonate solution were added, followed by extraction with ethyl acetate (200 mL). Heptane (100 mL) was added to the resulting extract to prepare a mixed solution. The solution was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=2:1) to obtain (4-chlorophenyl)-(3-chloropropyl)amine. (4-Chlorophenyl)-(3-chloropropyl)amine was dissolved in THF (45 mL). Triethylamine (4.9 mL) and phenyl chlorocarbonate (1.8 mL) were added at 0° C., and the reaction solution was stirred at room temperature for 15 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain phenyl (4-chlorophenyl)-(3-chloropropyl)carbamate (3.70 g). Phenyl (4-chlorophenyl)-(3-chloropropyl)carbamate (3.70 g) was dissolved in ethanol (60 mL). Hydrazine monohydrate (5.65 mL) was added at room temperature, and the reaction solution was heated under reflux for 17 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 2.19 g of the title compound. The property values of the compound are as follows.