Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][O:8][C:7]=12.C(O)CCC.Cl.[CH3:17][O:18][NH2:19]>O>[CH3:17][O:18][NH:19][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][O:8][C:7]=12
Reactant: Clc1nccc2ccoc12
Reactant: CON
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: CONc1nccc2ccoc12
Temperature: 125 °C

Procedure:
A three-necked flask was charged with 7-chloro-furo[2,3-c]pyridine (40 g, 0.26 mol) and n-butanol (300 mL) and heated at 125° C. Methoxyamine hydrochloride (54 g, 0.65 mol) was added as a solid and then additional methoxyamine hydrochloride (54 g, 0.65 mol) dissolved in water (50 mL) was added slowly. The resulting mixture was heated at reflux overnight. After cooling to RT, the reaction mixture was concentrated in vacuo. The remaining aqueous solution was basified to pH ˜8.5 with saturated NaHCO3 and extracted several times with DCM. The combined DCM extracts were washed with saturated NaHCO3 and brine. This solution was concentrated in vacuo leaving a dark brown syrup which was used without further purification.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C:7]2=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:31])C=CC=CC=1.C(OCC)C>ClCCl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:31])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C:7]2=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1ncc2cc(COC(C)=O)c(=O)n(C3CCCC3)c2n1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)OCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Acetic acid 8-cyclopentyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-ylmethyl ester (0.85 g, 2.55 mmol), prepared as in Example 26, and 2-benzenesulfonyl-3-phenyl-oxaziridine (0.8 g, 3.06 mmol) were mixed in dichloromethane (20 ml) and stirred at room temperature for 5 hours. To this mixture was added diethyl ether giving a solid precipitate which was filtered and dried in vacuo to provide acetic acid 8-cyclopentyl-2-methanesulfinyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-ylmethyl ester as a solid (0.81 g,(91%). MS (APCI) M++1; Calc'd 350.41, Found 350.2.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[CH:17]=4)[O:13][N:12]=3)[CH:9]=2)[N:4]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:37](I)([CH3:39])[CH3:38].CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH:37]([CH3:39])[CH3:38])=[C:18]([Cl:23])[CH:17]=4)[O:13][N:12]=3)[CH:9]=2)[N:4]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:3]=1
Reactant: CC(C)I
Reactant: CCOC(=O)CCn1cc(Cl)c2cc(-c3noc(-c4ccc(O)c(Cl)c4)n3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1cc(Cl)c2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc21
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To ethyl 3-{3-chloro-5-[5-(3-chloro-4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl}propanoate (D108) (180 mg, 0.40 mmol) and K2CO3 (138 mg, 1.0 mmol) in dry DMF (5 ml) was added isopropyl iodide (85 mg, 0.50 mmol) and the mixture stirred at 80° C. for 30 minutes. Cooled mixture and added EtOAc (50 ml). Washed with water (2×50 ml) and dried over MgSO4. Evaporated off the solvent and crystallised from ethanol to yield the title compound as 120 mg of white solid. δH (400 MHz, d6-DMSO) 1.12 (3H, t), 1.37 (6H, d), 2.91 (2H, t), 4.02 (2H, q), 4.50 (2H, t), 4.89-4.98 (1H, m), 7.72-7.85 (5H, m), 7.95-8.00 (1H, m), 8.24 (1H, d). MS (ES) C24H2335Cl2N3O4 requires 487; found 488 (MH+).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][CH:9]([C:25]1[N:26]=[C:27]([CH3:49])[N:28]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=1)[CH:10]1[C:23](=[O:24])[N:14]2[C:15]3[C:20]([C:21]([CH3:22])=[C:13]2[CH2:12][CH2:11]1)=[CH:19][CH:18]=[CH:17][CH:16]=3>N1C=CC=CC=1>[C:1]([O:8][CH:9]([C:25]1[N:26]=[C:27]([CH3:49])[N:28]([C:30]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:29]=1)[CH:10]1[C:23](=[O:24])[N:14]2[C:15]3[C:20]([C:21]([CH3:22])=[C:13]2[CH2:12][CH2:11]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c2n(c3ccccc13)C(=O)C(C(O)c1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(C)n1)CC2
Solvent: c1ccncc1
Product: CC(=O)OC(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C)n1)C1CCc2c(C)c3ccccc3n2C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.1 %

Procedure:
Acetic anhydride (1.31 g) was added to a solution of 8,9-dihydro-7-[(hydroxy)(2-methyl-1-trityl-1H-imidazol-4-yl)methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (1.42 g) in pyridine (20 ml). After being stirred at room temperature for 6 hours, the solution was evaporated in vacuo. The residue was diluted with chloroform, washed with 5% aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous magnesium sulfate. After the solvent was evaporated in vacuo, the residue was subjected to column chromatography on silica gel (5% methanol-chloroform). The fractions containing the product were evaporated in vacuo and crystallized from n-hexane-ether to give 7-[(acetoxy)(2-methyl-1-trityl-1H-imidazol-4-yl)methyl]-8,9-dihydro-10-methylpyrido[1,2-a]indol-6(7H)-one (1.3 g).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:11][C:10]2[CH2:12][N:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[CH2:14][C:9]=2[CH2:8]1)=[O:6].[CH:30]1([CH2:33][NH2:34])[CH2:32][CH2:31]1>>[CH:30]1([CH2:33][NH:34][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([N:13]3[CH2:12][C:10]4[CH2:11][N:7]([C:5](=[O:6])[C:4]5[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=5[C:2]([F:1])([F:28])[F:29])[CH2:8][C:9]=4[CH2:14]3)=[N:16][CH:17]=2)[CH2:32][CH2:31]1
Reactant: O=C(O)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Reactant: NCC1CC1
Product: O=C(NCC1CC1)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Yield: 77 %

Procedure:
6-[5-(2-Trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]nicotinic acid (54 mg, 0.134 mmol) was reacted with C-cyclopropylmethylamine analogously to example 3d. Yield: 77%, M+H+: 457.26.
Reaction SMILES: C([C:3]1[N:8]=[C:7]([C:9]#[N:10])[C:6]([C:11]([O:13][CH3:14])=[O:12])=[C:5]([NH:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[N:4]=1)#N.C(N(CC)C(C)C)(C)C.[CH:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:9]([C:7]1[C:6]([C:11]([O:13][CH3:14])=[O:12])=[C:5]([NH:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[N:4]=[C:3]([NH:38][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[N:8]=1)#[N:10]
Reactant: COC(=O)c1c(C#N)nc(C#N)nc1Nc1cccc(C)c1
Reactant: NC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(C#N)nc(NC2CCCCC2)nc1Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.9 %

Procedure:
A mixture of methyl 2,4-dicyano-6-(m-tolylamino)pyrimidine-5-carboxylate (102.3 mg, 0.349 mmol), N,N-diisopropylethylamine (0.075 mL, 0.429 mmol) and cyclohexylamine (0.05 mL, 0.437 mmol) in DMF (2 mL) was stirred at RT for 14 h. Saturated aq NaHCO3 was added and the mixture was extracted with EtOAc. The organic layers were washed with aq NaHCO3, water, and brine, and were filtered through SiO2. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, hexanes/EtOAc=4/1) to give the title compound as a yellow oil (114.7 mg, 90%). 1H NMR (500 MHz, CDCl3) δ ppm 1.19-1.45 (m, 5H), 1.64-1.67 (m, 1H), 1.73-1.80 (m, 2H), 2.00-2.05 (m, 2H), 2.38 (s, 3H), 3.75-3.82 (m, 1H), 3.98 (s, 3H), 5.57-5.58 (br d, J=7.9 Hz, 1H), 6.97-6.98 (m, 1H), 7.27-7.29 (m, 1H), 7.46-7.51 (m, 2H), 10.62 (br s, 1H). [M+H] calc'd for C20H24N5O2, 366. found, 366.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C.[I-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 70 °C
Yield: 93.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (716 mg, 2.0 mmol) and triethylamine (2 mL, 0.01 mmol) in N,N-dimethylformamide (2 mL) was treated with trimethylsilyl acetylene (0.71 mL, 5.0 mmol). The resulting reaction mixture was degassed with argon and then treated with cooper iodide (10 mg, 0.05 mmol) and bis(triphenylphosphine)palladium (II) chloride (15 mg, 0.02 mmol). The reaction was then heated at 70° C. for 24 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL) and washed with a half-saturated aqueous sodium chloride solution (1×20 mL). The resulting aqueous layer was back extracted with ethyl acetate (1×40 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trimethylsilanylethynyl-phenyl)-propionic acid methyl ester (615 mg, 93.6%) as an orange solid: mp 72-74° C.; EI-HRMS m/e calcd for C20H28O2Si (M+) 328.1858, found 328.1852.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17]O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.CS(Cl)(=O)=O.C(N(CC)CC)C.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>C1COCC1>[N:31]1([CH2:17][CH2:16][CH:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=3)[CH2:15][CH2:14]2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(N2CCC(CCO)CC2)cc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(N2CCC(CCN3CCOCC3)CC2)cc1

Procedure:
2-[1-(4-Nitrophenyl)piperidin-4-yl]ethanol and methanesulfonyl chloride were allowed to undergo the reaction in THF in the presence of triethylamine. The resulting compound and morpholine were allowed to undergo the reaction under heating in 1-methyl-2-pyrrolidine. The resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain 4-[4-(2-morpholin-4-ylethyl)piperidin-1-yl]aniline. NMR2 (CDCl3): 3.21-3.45 (4 H, m), 3.71-3.80 (4 H, m) 6.63-6.66 (2 H, m).
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH:3]([O:9][C:10](=[O:26])[CH2:11][CH:12]([CH2:17][NH:18]C(OC(C)(C)C)=O)[CH2:13][CH:14]([CH3:16])[CH3:15])[O:4][C:5](=[O:8])[CH2:6][CH3:7].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>C(Cl)Cl>[OH:32][C:30]([C:29]([F:34])([F:33])[F:28])=[O:31].[CH3:27][CH:2]([CH3:1])[CH:3]([O:9][C:10](=[O:26])[CH2:11][CH:12]([CH2:17][NH2:18])[CH2:13][CH:14]([CH3:15])[CH3:16])[O:4][C:5](=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)OC(OC(=O)CC(CNC(=O)OC(C)(C)C)CC(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)OC(OC(=O)CC(CN)CC(C)C)C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
Compound 18 (0.196 g, 0.51 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (3.25 mL) was added in an ice water bath and maintained for 30 minutes. The solution was then warmed to room temperature and stirred for 5 hours. After concentrating and drying, 3-aminomethyl-5-methyl-hexanoic acid 2-methyl-1-propionyloxy-propyl ester TFA salt 19 (0.194 g) was obtained with a yield of 95%. 1HNMR (CD3OD, 500 MHz) δ0.88-0.92 (m, 6H), 0.94 (d, J=6.5 Hz, 3H), 1.08 (t, J=7.5 Hz, 2H), 1.20-1.28 (m, 2H), 1.60-1.69 (m, 1H), 1.95-2.02 (m, 1H), 2.16-2.23 (m, 1H), 2.29-2.46 (m, 3H), 2.89-2.98 (m, 2H), 3.27 (s, 1H), 6.59 (d, J=5 Hz, 1H); 13CNMR (CDCl3, 125 MHz) δ9.29, 9.31, 16.74, 16.84, 16.86, 22.58, 22.59, 23.25, 23.27, 23.31, 26.28, 26.32, 28.28, 32.83, 32.90, 32.95, 36.85, 36.93, 37.28, 41.80, 41.89, 42.24, 44.31, 44.34, 44.71, 49.66, 94.54, 94.57, 172.16, 172.18, 174.46. LC/MS: ESI positive mode (M+H): 288.30.
Reaction SMILES: C(OC(=O)[N:7]([CH3:25])[C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](SC)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)(C)(C)C.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH3:25][NH:7][C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1
Reactant: CSc1nccc(-c2cnc3c(N(C)C(=O)OC(C)(C)C)nccn23)n1
Reactant: C1COCCN1
Product: CNc1nccn2c(-c3ccnc(N4CCOCC4)n3)cnc12

Procedure:
Methyl-[3-(2-morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine was prepared by a process analogous to that described in Example 12 starting from methyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamic acid tert-butyl ester (from Example 8 supra), and morpholine. LC-MS: [M+H]+ 312.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][C:3]=1[B:10]([OH:12])[OH:11].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1[B:10]([OH:12])[OH:11]
Reactant: O=Cc1ccc(Cl)c(B(O)O)c1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: OB(O)c1cc(CN2CCCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of (2-chloro-5-formylphenyl)boronic acid (1.00 g, 5.42 mmol) in DCM (30 mL) were added pyrrolidine (0.45 mL, 5.42 mmol) and sodium triacetoxyborohydride (2.39 g, 11.3 mmol). The reaction mixture was allowed to stir at rt for 2.5 h and then diluted with brine. The mixture was extracted with DCM. The organic solutions were combined, dried over Na2SO4, filtered and concentrated to give [2-chloro-5-(pyrrolidin-1-ylmethyl)phenyl]boronic acid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1)[CH2:24][CH3:25])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC>[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4])[CH2:24][CH3:25])[CH3:22]
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: CCN(CC)CC1CCCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCO
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Reaction time: 12 h
Yield: 83.6 %

Procedure:
A mixture of 11-(chloroacetyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-one (97.6 g, 0.339 mol), 2-[(diethylamino)methyl]piperidine (64.0 g, 0.376 mol), sodium carbonate (36.0 g, 0.34 mol) and n-propanol (1.7 liters) is refluxed for 5 hours. The reaction mixture is filtered while hot then left to stand for 12 hours at ambient temperature, after which the desired product is found to have precipitated in crystalline form. The substance is suction filtered, washed 3 times, each time with n-propanol (100 ml), and dried in a vacuum drying chamber. Colorless crystals (119.5 g) are obtained, Mp. 226°-229° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][N:12]([C:16]2[C:28]3[C:27]4[C:22](=[CH:23][C:24]([C:29]([OH:31])=O)=[CH:25][CH:26]=4)[NH:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:32]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][N:12]([C:16]2[C:28]3[C:27]4[C:22](=[CH:23][C:24]([C:29](=[O:31])[NH2:32])=[CH:25][CH:26]=4)[NH:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC1CN(c2ncnc3[nH]c4cc(C(=O)O)ccc4c23)CCO1
Reactant: N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC1CN(c2ncnc3[nH]c4cc(C(N)=O)ccc4c23)CCO1
Reaction time: 0.5 h

Procedure:
4-[2-(tert-Butoxycarbonylamino-methyl)-morpholin-4-yl]-9H-pyrimido[4,5-b]indole-7-carboxylic acid (6 mg, 0.014 mmol) was stirred in DMF (0.25 mL) at 0° C. Carbonydiimidazole (2.5 mg, 0.016 mmol) was added and the reaction allowed to proceed to room temperature for 30 minutes. Ammonia (28% aqueous, 0.04 mL) was added. The reaction mixture was concentrated to dryness and then the reaction was repeated to afford a complete conversion. The reaction mixture was concentrated to give the title compound as a yellow solid (5 mg, 0.012 mmol), which was deprotected without further purification. LC-MS (1) Rt 1.48 min; m/z 427 (ES+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([OH:10])[CH2:7][S:8][CH:9]=1)=[O:4].S(Cl)(Cl)(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:10])=[CH:7][S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)C1=CSCC1O
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cscc1O
Reaction time: 0.5 h
Yield: 77 %

Procedure:
80 Parts of 3-hydroxy-dihydrothiophene-4-carboxylic acid methyl ester are dissolved in 800 parts by volume of methylene chloride. 74.3 parts of sulfuryl chloride in 200 parts by volume of methylene chloride are added in the course of one hour at from 10° to 15° C., whilst passing nitrogen into the mixture. The mixture is then stirred for 30 minutes at from 10° to 15° C., after which it is extracted by shaking with 500 parts of water and 300 parts by volume of a 5 percent strength by weight sodium bicarbonate solution. The organic phase is dried and evaporated. The residue is distilled. 60.5 parts (77% of theory) of 3-hydroxy-thiophene-4-carboxylic acid methyl ester of boiling point 76°-84° C./0.07-0.1 mbar are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[NH:6][C:4](=[O:5])[C:3]=1[CH3:9].[K].[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>[Cl-].C[N+](C)(C)C>[CH2:11]([N:6]1[C:7](=[O:8])[C:2]([CH3:1])=[C:3]([CH3:9])[C:4]1=[O:5])[CH:13]1[O:15][CH2:14]1
Reactant: ClCC1CO1
Reactant: CC1=C(C)C(=O)NC1=O
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [K]
Product: CC1=C(C)C(=O)N(CC2CO2)C1=O

Procedure:
30 g (0.184 mol) of potassium dimethymaleimide are suspended in 175 g (1.89 mols) of epichlorohydrin. After adding 0.05 g of tetramethylammonium chloride, the mixture is heated, whilst stirring, and boiled under reflux for 18 hours and is then filtered. After removing the unconverted chlorohydrin by distillation under a waterpump vacuum, about 30 g of a viscous, pale brown liquid which has an epoxide content of 4.9 equivalents/kg (calculated: 5.5 equivalents/kg) remain. The NMR spectrum of the product corresponds to N-glycidyl-dimethylmaleimide of the formula ##STR31##
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][NH2:14]>C(O)C>[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][NH:14][C:4](=[O:6])[CH2:3][C:1]#[N:2]
Reactant: NCc1cccc(Cl)c1
Reactant: CCOC(=O)CC#N
Solvent: CCO
Product: N#CCC(=O)NCc1cccc(Cl)c1
Reaction time: 8 h

Procedure:
A solution of 38.5 g. (0.34 mole) of ethyl cyanoacetate and 48.1 g. (0.34 mole) of 3-chlorobenzylamine in 120 ml. of 95% ethanol is refluxed for 5 hours and then allowed to stand overnight at ambient temperature. Agitation causes crystallization. Filtration is followed by washing of the solid with a small amount of ether to give 28.7 g. of the desired product as small, white needles, m.p. 123°-5° C.
Reaction SMILES: C(OC([N:11]1[C:16]2[CH:17]=[C:18]([Cl:34])[CH:19]=[C:20]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)[C:15]=2[O:14][CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[C:30]([O:29][C:27]([N:24]1[CH2:23][CH2:22][N:21]([C:20]2[C:15]3[O:14][CH2:13][CH2:12][NH:11][C:16]=3[CH:17]=[C:18]([Cl:34])[CH:19]=2)[CH2:26][CH2:25]1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)cc3c2OCCN3C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)cc3c2OCCN3)CC1
Yield: 71 %

Procedure:
A solution of 8-(4-tert-butoxycarbonyl-piperazin-1-yl)-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid benzyl ester (870 mg, 1.79 mmol) in ethanol (10 mL) was hydrogenated at atmospheric pressure over 10% Pd/C (75 mg) for 0.5 hour. The catalyst was removed by filtration, and the filtrate was concentrated. The crude material was purified by flash chromatography on silica gel (eluting with hexane-ethyl acetate; 1:1, v/v) to give 4-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylic acid tert-butyl ester as a white foam (450 mg, 71%). MS: MH+=354.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4]1.[NH2:14][C:15]1[C:23]([Cl:24])=[CH:22][C:18]([C:19](O)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[NH2:14][C:15]1[C:23]([Cl:24])=[CH:22][C:18]([C:19]([NH:1][CH2:2][CH:3]2[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4]2)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=1
Reactant: CCOC(=O)N1CCOC(CN)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)N1CCOC(CNC(=O)c2cc(Cl)c(N)cc2OC)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.3 %

Procedure:
To a solution of 2-aminomethyl-4-ethoxycarbonylmorpholine (5.8 g) in dichloromethane (100 ml), 4-amino-5-chloro-2-methoxybenzoic acid (5.0 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.2 g) are added, and the resulting mixture is stirred at 25° C. for 4 hours. The reaction mixture is washed successively with water, aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure. The residue is dissolved in chloroform and chromatographed on silica gel. The eluate with chloroform is discarded, and the subsequent eluates with methanol-chloroform (1:9) are pooled and evaporated to give the title compound (7.5 g) as an oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:21]1([CH3:30])[CH:26]=[CH:25][CH:24]=[C:23]([C:27](Cl)=[O:28])[CH:22]=1.Cl>ClCCCl>[CH3:30][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[C:27]([C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:27](=[O:28])[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH3:30])[CH:22]=3)=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)=[O:28]
Reactant: c1ccc(OCCOc2ccccc2)cc1
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1cccc(C(=O)c2ccc(OCCOc3ccc(C(=O)c4cccc(C)c4)cc3)cc2)c1
Temperature: 25 °C

Procedure:
To a stirred suspension of anhydrous aluminum chloride (24 g) in 300 ml dry 1,2-dichloroethane is added 1,2-diphenoxyethane (17.8 g, 0.083 mole) at room temperature. To this mixture is added over a period of thirty minutes m-toluoyl chloride (27 g, 0.17 mole). The temperature of the reaction rises to 40° (all temperatures are Centigrade) and hydrogen chloride gas evolves from the mixture. Following the addition of the m-toluoyl chloride the reaction is externally heated to 65° plus or minus 3°. This temperature and stirring are maintained for twenty-two hours. The mixture is then allowed to cool to room temperature and poured on 1 kg of crushed ice to destroy the aluminum chloride complex. The ice is allowed to melt and the water separates from the organic layer. The latter is washed twice with 200 ml of 10% hydrochloric acid, three times with water and the solvent removed by distillation. The residual crude crystals are crystallized from dichloroethane, yield 15.9 g (43%) mp 164°-167°.