Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O:27]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]([C:23]([O:25][CH3:26])=[O:24])[CH2:4][C:5]1[CH:13]=[C:12]([CH3:14])[C:11]2[C:7](=[CH:8][N:9]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=2)[CH:6]=1.[NH:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:53][C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[NH:46][C:45]2=[O:54])[CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[O:54]=[C:45]1[N:44]([CH:41]2[CH2:42][CH2:43][N:38]([C:1]([O:2][CH:3]([C:23]([O:25][CH3:26])=[O:24])[CH2:4][C:5]3[CH:13]=[C:12]([CH3:14])[C:11]4[C:7](=[CH:8][N:9]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=4)[CH:6]=3)=[O:27])[CH2:39][CH2:40]2)[CH2:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46]1
Reactant: COC(=O)C(Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)OC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A flask was charged with 1-(methoxycarbonyl)-2-(2-((2-(trimethylsilyl)ethoxy)methyl)-7-methyl-2H-indazol-5-yl)ethyl 4-nitrophenyl carbonate (27 mg, 51 mmoles) and 3,4-dihydro-3-(piperidin-4-yl)quinazolin-2(1H)-one (34 mg, 2.8 equiv). The solids were dissolved in dimethylformamide (1 mL) and treated with diisopropylethylamine (0.1 mL, 11 equiv). The reaction was stirred at room temperature for 2 d. The reaction was concentrated, dissolved in ethyl acetate, washed with 20% potassium hydroxide (3×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (100% ethyl acetate) removed baseline material to give 50 mg (quant.). Mass spec.: 622.50 (MH)+.
Reaction SMILES: OC1N=C2C=C(/C=C/C3SC=C(C(C)C)N=3)C=CN2C(=O)C=1.[CH3:23][N:24]([CH3:59])[C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]2[N:34]=[C:35]3[CH:48]=[C:47](/[CH:49]=[CH:50]/[C:51]4[S:52][CH:53]=[C:54]([CH:56]([CH3:58])[CH3:57])[N:55]=4)[CH:46]=[CH:45][N:36]3[C:37](=[O:44])[C:38]=2/C=C/C(O)=O)[CH2:28]1)=[O:26].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C.FC(F)(F)C(O)=O.CN(C)C(C1CCCNC1)=O>O1CCCC1.CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:59][N:24]([CH3:23])[C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]2[N:34]=[C:35]3[CH:48]=[C:47](/[CH:49]=[CH:50]/[C:51]4[S:52][CH:53]=[C:54]([CH:56]([CH3:57])[CH3:58])[N:55]=4)[CH:46]=[CH:45][N:36]3[C:37](=[O:44])[CH:38]=2)[CH2:28]1)=[O:26]
Reactant: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)O)c(N4CCCC(C(=O)N(C)C)C4)nc3c2)n1
Agent: CC(C)c1csc(/C=C/c2ccn3c(=O)cc(O)nc3c2)n1
Agent: CN(C)C(=O)C1CCCNC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)c1csc(/C=C/c2ccn3c(=O)cc(N4CCCC(C(=O)N(C)C)C4)nc3c2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
The 2-hydroxy-8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4H-pyrido-[1,2-a]pyrimidin-4-one (164 mg, 0.523 mmol) obtained in Example 101, (E) was dissolved in anhydrous tetrahydrofuran (2.5 ml) and anhydrous dimethylformamide (2.5 ml), added with 4-dimethylaminopyridine (83.0 mg, 0.680 mmol) and p-toluenesulfonyl chloride (110 mg, 0.576 mmol), and then the mixture was stirred at 0° C. for 3 hours. Subsequently, the reaction solution was added with triethylamine (729 μl, 5.23 mmol) and N3,N3-dimethyl-3-piperidinecarboxamide trifluoroacetic acid salt (707 mg, 2.62 mmol) and stirred at 0° C. for 1 hour, at room temperature for 30 minutes and at 60° C. for 19 hours. Then, the reaction solution was added with triethylamine (40.0 μl , 0.287 mmol) and N3,N3-dimethyl-3-piperidinecarboxamide trifluoroacetic acid salt (400 mg, 1.48 mmol) and stirred at 60° C. for 5 hours. The reaction mixture was concentrated, added with saturated aqueous ammonium chloride, and then extracted with chloroform. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1→100:3, v/v) to obtain the title compound (168 mg, 71%).
Reaction SMILES: [CH:1]1([C@:4]([OH:28])([CH3:27])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12](Br)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)#[CH:30]>>[CH:1]1([C@:4]([OH:28])([CH3:27])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12]([CH2:30][CH2:29][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: C[C@](O)(CNC(=O)c1cnc(Br)c(-c2ccc(OC(F)(F)F)cc2)n1)C1CC1
Reactant: C#Cc1ccccn1
Product: C[C@](O)(CNC(=O)c1cnc(CCc2ccccn2)c(-c2ccc(OC(F)(F)F)cc2)n1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 117, using 5-bromo-6-(4-trifluoromethoxy-phenyl)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide and ortho-ethynylpyridine as starting materials to yield the product as light brown oil, MS (ISP) 487.4 (M+H)+.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[N:20]=[C:19]3[N:21]([CH2:24][C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]=[CH:30][CH:29]=[CH:28]5)[N:22]=[N:23][C:18]3=[CH:17][CH:16]=2)[CH:12]=[N:11]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)(O)[O-].[Na+]>CO.O>[N:31]1[C:32]2[C:27](=[CH:26][C:25]([CH2:24][N:21]3[C:19]4=[N:20][C:15]([C:13]5[CH:12]=[N:11][N:10]([CH2:9][CH2:8][OH:7])[CH:14]=5)=[CH:16][CH:17]=[C:18]4[N:23]=[N:22]3)=[CH:34][CH:33]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: c1cnc2ccc(Cn3nnc4ccc(-c5cnn(CCOC6CCCCO6)c5)nc43)cc2c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCCn1cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
To a solution of example 145 (0.190 g, 0.417 mmol) in methanol (2 ml) and water (2 ml), camphor sulphonic acid (0.968 g, 4.17 mmol) was added and stirred for 1 h. The reaction was poured into ice water and the pH was adjusted to ca 8 with sodium bicarbonate solution, extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated. The crude product was purified by recrystallisation from isopropanol to afford the title compound as a light yellow solid (0.059 g, 38%). M.P.: 179-178° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.2, 1.6 Hz, 1H), 8.51 (d, J=8.7 Hz, 1H), 8.49 (s, 1H), 8.38 (dd, J=8.3, 1.3 Hz, 1H), 8.20 (s, 1H), 8.01 (d, J=8.0 Hz, 2H), 7.82 (dd, J=8.7, 1.7 Hz, 2H), 7.53 (dd, J=8.3, 4.1 Hz, 1H), 6.11 (s, 2H), 4.96 (t, J=5.3 Hz, 1H), 4.22 (t, J=5.5 Hz, 2H), 3.79 (dd, J=10.8, 5.4 Hz, 2H). MS (m/z):: 372.08 (M++1).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH:9]=[C:8]([C:11](OC)=[O:12])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[C:1]([N:5]1[CH2:6][CH:7]=[C:8]([CH2:11][OH:12])[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1=CCN(C(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)N1CC=C(CO)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A solution of methyl 1-tert-butyl-1,2,3,6-tetrahydropyridine-4-carboxylate (D57) (855 mg; 4.3 mmol) in dry tetrahydrofuran (10 ml) was added to a stirred suspension of lithium aluminium hydride (223 mg; 58 mmol) in dry tetrahydrofuran (20 ml) at 0° C. over 5 minutes. After stirring at 0° C. for 1 h, water (0.22 ml), 10% sodium hydroxide (0.33 ml) and water (0.55 ml) were added, and stirring continued for 30 minutes. The mixture was filtered through kieselguhr, and the filtrate evaporated under reduced pressure to give the title compound as an orange oil (610 mg, 83%).
Reaction SMILES: Br[CH:2]([CH:8](Br)[CH3:9])[C:3]([O:5]CC)=O.[NH2:11][C:12]1[N:16]=[C:15]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:14][N:13]=1>N1C=CC=CC=1>[CH2:18]([S:17][C:15]1[N:16]=[C:12]2[N:11]=[C:3]([OH:5])[CH:2]=[C:8]([CH3:9])[N:13]2[N:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C(Br)C(C)Br
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Solvent: c1ccncc1
Product: Cc1cc(O)nc2nc(SCc3ccccc3)nn12
Temperature: 65 °C

Procedure:
Ethyl 2,3-dibromobutyrate (1.33 g, 48.5 mmol) was added dropwise over 15 minutes to a solution of 10 g (49 mmol) of 3-amino-5-benzylthio-1,2,4-triazole in 20 ml of pyridine heated to °C. After the addition was complete, the reaction mixture was heated at 65° C. for 20 hours, cooled to room temperature and filtered. The filtrate was concentrated by evaporation at reduced pressure. The residue was triturated with methanol to separate 1.64 g (13%) of the desired product as a colorless crystalline solid, m.p. 219°-220° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][N:8]1[C:12](=O)[C:11](=[O:14])[N:10]([CH2:15][C:16]([OH:18])=[O:17])[C:9]1=C)([O-:3])=[O:2].[N+](C1C=C(C=CC=1)CN1C(=O)C(=O)N(CC(O)=O)C1=S)([O-])=[O:24]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][N:8]1[CH2:12][C:11](=[O:14])[N:10]([CH2:15][C:16]([OH:18])=[O:17])[C:9]1=[O:24])([O-:3])=[O:2]
Reactant: O=C(O)CN1C(=O)C(=O)N(Cc2cccc([N+](=O)[O-])c2)C1=S
Reactant: C=C1N(CC(=O)O)C(=O)C(=O)N1Cc1cccc([N+](=O)[O-])c1
Product: O=C(O)CN1C(=O)CN(Cc2cccc([N+](=O)[O-])c2)C1=O

Procedure:
The same operations as performed above in paragraphs (1) and (2) were carried out using N-3-nitrobenzyl aminoacetate as a starting material to give 1-(3-nitrobenzyl)-2,4-dioxoimidazolidine-3-acetic acid [Compound 4]. The melting point, MS, IR, NMR, and elementary analysis for the compound were:
Reaction SMILES: [CH3:1][N:2]([CH:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]([C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[CH:27][CH:26]=2)[CH2:16][CH2:15][CH2:14]1)[CH2:3][CH2:4][CH2:5][O:6]C1CCCCO1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C(O)C>[CH3:1][N:2]([CH:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]([C:24](=[O:41])[C:25]2[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[CH:29][CH:30]=2)[CH2:16][CH2:15][CH2:14]1)[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)CCCOC3CCCCO3)c3ccccc32)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)CCCO)c3ccccc32)cc1
Temperature: 60 °C
Yield: 55.7 %

Procedure:
To a solution of 5-{N-methyl-N-[3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propyl]amino}-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.55 g) in ethanol (10 ml) is added pyridinium p-toluenesulfonate (0.03 g) and the mixture is heated at 60° C. overnight. After the mixture is refluxed for more 2 hours, water and pyridinium p-toluenesulfonate (0.03 g) are added thereto. The mixture is refluxed for 4 hours. The reaction solution is concentrated and to the resulting residue is added dichloromethane. The mixture is basified with aqueous sodium hydrogen carbonate solution and extracted three times with dichloromethane. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=30:1) to give 5-[N-methyl-N-(3-hydroxypropyl)amino]-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.26 g) as colorless amorphous.
Reaction SMILES: [NH2:1][C:2]1[C:7](C(O)=O)=[C:6]([CH3:11])[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH3:18])[N:3]=1>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[CH3:11][C:6]1[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH3:18])[N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: Cc1nc(N)c(C(=O)O)c(C)c1-c1ccccc1
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: Cc1cc(N)nc(C)c1-c1ccccc1

Procedure:
2-Amino-4,6-dimethyl-5-phenyl-3-pyridinecarboxylic acid (6.1 grams) and copper powder (1.0 gram) were heated in 50 ml quinoline at 270°-290° C. for approximately 3 hours. The entire reaction mixture was then chromatographed over 600 ml of Grace 923 silica gel with ether followed by ethyl acetate, yield 3.0 grams of dried product, m.p. 105°-112° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][CH3:21]>CN1C(=O)CCC1>[CH2:20]([O:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1)[CH3:21]
Reactant: Cc1ccc2ccc(O)cc2n1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCOc1ccc2ccc(C)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a stirred mixture of 2-methylquinolin-7-ol (400 mg, 2.51 mmol), Cs2CO3 (2.46 g, 7.54 mmol) and NMP (12 mL) was added bromoethane (0.563 mL, 7.54 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction was partitioned between ether and water. The aqueous layer was extracted with ether. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (2:1 to 5:1 hexanes:EtOAc) to give 7-ethoxy-2-methylquinoline (416 mg, 88%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16]CC)=O)[CH2:7][CH2:6]2)OC=C1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=C[C:39]([O:42]C2C=CC=CC=2)=[CH:38]C=1>>[CH2:38]1[O:20][C:19]([C:13]2[CH:12]=[N:11][C:8]3[CH2:9][CH2:10][C:5](=[O:1])[CH2:6][C:7]=3[C:14]=2[OH:16])([O:21][CH2:22][CH3:23])[O:42][CH2:39]1
Reactant: CCOC(=O)C(=CNC1CCC2(CC1)OC=CO2)C(=O)OCC
Reactant: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC1(c2cnc3c(c2O)CC(=O)CC3)OCCO1
Temperature: 25 °C

Procedure:
Diethyl N-(1,4-dioxaspiro[4.5]decen-8-yl)aminomethylenemalonate (53 g) in 100 ml of Dowtherm is added to 400 ml of Dowtherm at reflux and the mixture is heated at 250° for 45 minutes. The low boiling distillate is collected in a Dean-Stark trap. After cooling to room temperature, the mixture is evaporated to dryness in vacuo, and the residue is triturated with Et2O to give ethyl 4-hydroxy-6-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylate ethylene ketal.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[N:15]1([CH2:19][C@@H:20]([NH2:35])[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[CH2:18][CH2:17][CH2:16]1>>[N:15]1([CH2:19][C@@H:20]([NH:35][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:22]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: N[C@H](CN1CCC1)c1ccc(C(F)(F)F)c(C(F)(F)F)c1
Product: NC(=O)c1ccnc2c(N[C@H](CN3CCC3)c3ccc(C(F)(F)F)c(C(F)(F)F)c3)ncnc12

Procedure:
Compound 63 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with (S)-2-Azetidin-1-yl-1-(3,4-bis-trifluoromethyl-phenyl)-ethylamine to give the title compound as a white solid. LC/MS [485 (M+H)].
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(O)(=O)C>[CH3:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N)c(C)c1
Solvent: CC(=O)O
Product: COc1ccc(NC(C)=O)c(C)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
2-methyl-4-(methyloxy)aniline (5 ml, 39 mmol) was dissolved in acetic acid (40 ml) and acetic anhydride (3.7 ml, 39 mmol) was added dropwise. Reaction was heated to 60° C. After 30 min, most of the solvent was removed under reduced pressure and the residue diluted with EtOAc. A saturated solution of sodium bicarbonate was added until solution was pH 8. Organics were then washed with water and a saturated brine solution and dried over sodium sulfate. Solvents were removed under reduced pressure to afford N-[2-methyl-4-(methyloxy)phenyl]acetamide (6.37 g, 35.5 mmol) as a pink fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.95-2.06 (m, 3 H) 2.14 (s, 3 H) 3.71 (s, 3 H) 6.70 (dd, J=8.71, 2.84 Hz, 1 H) 6.77 (d, J=2.75 Hz, 1 H) 7.18 (d, J=8.61 Hz, 1 H) 9.16 (s, 1 H)
Reaction SMILES: C[O:2][C:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)C>[OH:2][CH2:3][CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7]1
Reactant: COC(=O)CC1CCc2ccccc2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCC1CCc2ccccc2O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
At room temperature and while stirring, a solution of 16.91 g (82 mmol) of 2-methoxycarbonylmethylchroman in 150 ml of absolute tetrahydrofuran is added dropwise within a period of 30 minutes to a suspension of 3.11 g (82 mmol) of lithium aluminium hydride in 150 ml of absolute diethyl ether. Stirring is continued for a further 16 hours at room temperature and then the whole is carefully decomposed with 3.1 ml of water, 3.1 ml of sodium hydroxide solution (15% strength) and 9.3 ml of water. The precipitate formed is filtered off with suction and the filtrate is concentrated by evaporation in vacuo. The oily residue is dissolved in diethyl ether. The ethereal solution is washed with water, dried over sodium sulphate and concentrated by evaporation in vacuo. 14.36 g (98.3%) of 2-(2-hydroxyethyl)chroman are obtained in the form of a colourless oil.
Reaction SMILES: O=S(Cl)Cl.[CH:5]1([NH:11][C:12]2([CH2:17]Cl)[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.ClCCN.[CH3:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[N:33]=[C:34]=[O:35]>>[CH:5]1([N:11]2[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:17][O:35][C:34]2=[N:33][C:25]2[CH:26]=[CH:27][C:28]([N+:30]([O-:32])=[O:31])=[CH:29][C:24]=2[CH3:23])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: ClCC1(NC2CCCCC2)CCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=O
Agent: NCCCl
Solvent: O=S(Cl)Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1OCC2(CCCC2)N1C1CCCCC1

Procedure:
1-Aminocyclopentanecarboxylic acid was converted to the methyl ester according to Method B1c, Step 1. The ester reduced to 1-hydroxymethylcyclopentanamine according to Method B1c, Step 2. The hydroxyethylamine was reacted with cyclohexanone according to Method B4a, Step 1 to give 6-aza-13-oxadispiro[4.1.5.2]tetradecane. The oxazolidine was reduced according to Method B4a, Step 2 to give 1-(cyclohexylamino)-1-(hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOCl2 according to Method B7b to 1-(cyclohexylamino)-1-(chloromethyl)cyclopentane. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford 1-cyclohexyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33](Cl)[N:32]=4)=[CH:27][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)#[N:11]>>[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:9])[CH3:1])[N:32]=4)=[CH:27][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)#[N:11]
Reactant: CN(C)CCCCCN
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: CN(C)CCCCCNc1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using 5-dimethylamino-pentylamine (reference example 93a) and and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 496 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8](Cl)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:17][C:18]([F:25])([F:24])[CH2:19][NH:20][C:21]([NH2:23])=[O:22]>>[CH:1]1([N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]([NH:23][C:21]([NH:20][CH2:19][C:18]([F:25])([F:24])[F:17])=[O:22])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)N(C1CCCCC1)C1CCCCC1
Reactant: NC(=O)NCC(F)(F)F
Product: O=C(NCC(F)(F)F)NC(=O)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in General Procedure 1 using dicyclohexyl carbamoyl chloride and N-2,2,2-trifluoroethylurea.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=2)[CH2:3][CH2:2]1.COC(C1C=CC(O)=CN=1)=O.BrCCC=C.COC(C1C=CC(OCCC=C)=CN=1)=O>>[CH2:4]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=1)[CH2:1][CH:2]=[CH2:3]
Reactant: O=C(O)c1ccc(OCC2CC2)cn1
Agent: C=CCCBr
Agent: C=CCCOc1ccc(C(=O)OC)nc1
Agent: COC(=O)c1ccc(O)cn1
Product: C=CCCOc1ccc(C(=O)O)nc1

Procedure:
The 5-but-3-enyloxy-pyridine-2-carboxylic acid was prepared in a reaction sequence analogous to that in example 60 for the preparation of the 5-cyclopropylmethoxy-pyridine-2-carboxylic acid: Alkylation of the 5-hydroxy-pyridine-2-carboxylic acid methyl ester with 4-bromo-1-butene and hydrolysis of the 5-but-3-enyloxy-pyridine-2-carboxylic acid methyl ester yielded the 5-but-3-enyloxy-pyridine-2-carboxylic acid as a light yellow solid. Mass (calculated) C10H11NO3 [193.201]; (found) [M+H]+=194.
Reaction SMILES: C(N(CC)CC)C.F[B-](F)(F)F.[CH3:13][C:14]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[Se+:18]=1)([CH3:16])[CH3:15].[Cl:28][C:29]1[C:30](=[O:36])[C:31]([Cl:35])([Cl:34])[C:32]=1Cl.[OH-].[Na+]>ClCCl>[CH3:16][C:14]([C:17]1[Se:18][C:19]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][C:21](=[CH:23][C:32]2[C:31]([Cl:35])([Cl:34])[C:30](=[O:36])[C:29]=2[Cl:28])[CH:22]=1)([CH3:13])[CH3:15]
Reactant: O=C1C(Cl)=C(Cl)C1(Cl)Cl
Reactant: Cc1cc(C(C)(C)C)[se+]c(C(C)(C)C)c1
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C1=CC(=CC2=C(Cl)C(=O)C2(Cl)Cl)C=C(C(C)(C)C)[Se]1
Reaction time: 1 h
Yield: 71.4 %

Procedure:
A solution of triethylamine (14.8 g, 147 mmol) in dichloromethane (40 mL) was added dropwise under nitrogen to a solution of 2,6-bis(1,1-dimethylethyl)-4-methylselenopyrylium tetrafluoroborate (26.2 g, 73.4 mmol, prepared in Examples 4 and 5 above) and 2,3,4,4-tetrachlorocyclobut-2-en-1-one (15.2 g, 73.4 mmol) in dichloromethane (60 mL), contained in a flask equipped with a condenser and an outlet connected to a gas-washing bottle containing 10% aqueous sodium hydroxide solution; the addition was effected at a rate such that the temperature of the reaction mixture did not exceed 35° C. After the addition had been completed, the reaction mixture was stirred for one hour, then applied to a column packed with silica gel. Elution with dichloromethane, followed by evaporation of the solvent under reduced pressure, provided the crude product which was further purified by trituration with trifluoroethanol for one hour to give 3-[[2,6-bis(1,1,-dimethylethyl)-4H-selenopyran-4-ylidene]methyl]-2,4,4-trichlorocyclobut-2-en-1-one (23 g, 71% yield) as maroon crystals. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.