Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:28])([CH3:27])[C:8]1[CH:9]=[C:10]([C:14]2[N:22]3[C:17]([CH:18]=[N:19][C:20](S(C)(=O)=O)=[N:21]3)=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:29].[Na+].O.Cl>O1CCOCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:28])([CH3:27])[C:8]1[CH:9]=[C:10]([C:14]2[N:22]3[C:17]([CH:18]=[N:19][C:20]([OH:29])=[N:21]3)=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc(-c2ccc3cnc(S(C)(=O)=O)nn23)c1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)[SiH2]OC(C)(C)c1cccc(-c2ccc3cnc(O)nn23)c1
Temperature: 80 °C
Yield: 37 %

Procedure:
7-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-phenyl]-2-methanesulfonyl-pyrrolo[2,1-f][1,2,4]triazine (800 mg, 1.92 mmol) was dissolved in 1,4-dioxane (5.00 mL) and 5.00 M sodium hydroxide in water (5.00 mL, 25.0 mmol) was added. The reaction was heated at 80° C. for 2 hours and then acidified to pH 6 with conc. HCl. The product was then extracted with DCM (100 mL) and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain 7-[3-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol as a yellow solid (252 mg, 37%). m.p.=194-195° C.; LCMS (m/e) 356 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.48 (s, 1H), 8.27 (d, 1H, J=7.7 Hz), 8.07 (s, 1H), 7.52-7.44 (m, 1H), 7.40 (d, 1H, J=7.6 Hz), 7.17 (d, 1H, J=5.1 Hz), 7.05 (d, 1H, J=5.1 Hz), 4.84 (s, 2H), 0.97 (s, 9H), 0.13 (s, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:5][S:4]/[C:3]/1=[N:21]\[CH3:22].C([Li])CCC.CCCCCC.[Cl-].[NH4+].C1C[O:39][CH2:38]C1>CN(C=O)C>[CH:38]([C:5]1[S:4]/[C:3](=[N:21]\[CH3:22])/[N:2]([CH3:1])[C:6]=1[CH2:7][N:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]1)=[O:39]
Reactant: C/N=c1\scc(CN2CCN(C(=O)OC(C)(C)C)CC2)n1C
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C/N=c1\sc(C=O)c(CN2CCN(C(=O)OC(C)(C)C)CC2)n1C

Procedure:
tert-Butyl 4-(((2Z)-3-methyl-2-methylimino-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-1-carboxylate (1.0 g) obtained in Example 11a) was dissolved in THF (20 mL), n-butyllithium (4.6 mL; a 1.6 M hexane solution) was added thereto at −70° C., and the mixture was mixed for 30 minutes. To the reaction solution was added DMF (1.0 mL), mixed at −70° C. for 1 hour, and then an aqueous ammonium chloride solution was added thereto at 0° C. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off to give the title compound (1.1 g) as a pale brown oily matter.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8].[CH3:11][C:12]([CH3:14])=O.S(=O)(=O)(O)O>C(O)(=O)C.[Zn]>[CH3:1][C:2]1[NH:3][C:4]([CH:12]([CH3:14])[CH3:11])=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8]
Reactant: CC(=O)c1c(C)c[nH]c1C
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(=O)c1c(C)[nH]c(C(C)C)c1C
Temperature: 45 °C
Reaction time: 1 h

Procedure:
2,4-Dimethyl-3-acetyl-pyrrole (548 mg), 1 ml of acetone and 10 gm of amalgamated zinc (20 mesh) were added to a solution of 1 ml of concentrated sulfuric acid in 20 ml of acetic acid. The mixture was stirred for 1 hour at 45° C. The liquid was decanted from the zinc into 100 ml of water forming a solution from which the crude product separated at 15° C. (174 mg, m.p. 164°-169° C. after the usual solid phase changes). For analysis, it was extracted into ether (thimble) then recrystallized from 3 ml of aqueous ethanol as nearly colourless elongated prisms, m.p. 170°-172° C. (171°-173° when mixed with the product of Example 8) after a solid phase change at 142°. Anal. Calc. for C11H17NO: C, 73.70; H, 9.56; N, 7.81. Found: C, 73.60; H, 9.40; N, 7.92.
Reaction SMILES: Br.[CH:2]1[N:6]2[C:7]3[C:12]([N:13]=[CH:14][C:5]2=[N:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3.[BH4-].[Na+].O>C(O)C>[CH:2]1[N:6]2[C:7]3[C:12]([NH:13][CH2:14][C:5]2=[N:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: CCOC(=O)c1cn2c(cnc3ccccc32)n1
Agent: Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cn2c(n1)CNc1ccccc1-2
Yield: 99.3 %

Procedure:
To a stirred solution of 1.6 g of ethyl imidazo[1,2-a]quinoxaline-2-carboxylate hydrobromide (British patent application Ser. No. 79-26597, in 50 ml of ethanol was added portionwise 0.5 g of sodium borohydride and at the completion of the reaction (tlc), the mixture was poured into 250 ml of water. The mixture was extracted with ethyl acetate and the organic layer was washed with water, dried and evaporated to dryness to obtain 1.2 g (97% yield) of ethyl 4,5-dihydroimidazo[1,2-a]quinoxaline-2-carboxylate melting at 206°-8° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16](Br)[C:11]=2[N:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[C:37]4=[N:38][CH:39]=[CH:40][CH:41]=[C:36]4[N:35]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:34]3=[O:50])=[CH:29][CH:28]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([C:27]3[CH:32]=[CH:31][C:30]([N:33]4[C:37]5=[N:38][CH:39]=[CH:40][CH:41]=[C:36]5[N:35]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:48])([CH3:47])[CH3:49])[C:34]4=[O:50])=[CH:29][CH:28]=3)[C:11]=2[N:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(-n3c(=O)n(COCC[Si](C)(C)C)c4cccnc43)cc2)OC1(C)C
Reactant: Cc1nc2c(Br)cccc2n1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c(-c3ccc(-n4c(=O)n(COCC[Si](C)(C)C)c5cccnc54)cc3)cccc2n1Cc1ccccc1
Temperature: 100 °C
Yield: 53.5 %

Procedure:
Benzyl chloride (1.527 mL) was added to a solution of 4-bromo-2-methyl-1H-benzimidazole (1.40 g) and sodium hydride (0.531 g) in DMF (10 mL) at 0° C. The mixture was stirred at room temperature under a dry atmosphere for 1 h. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 5%-50% EtOAc in hexane) to give 1-benzyl-4-bromo-2-methyl-1H-benzo[d]imidazole (1.88 g) as tan oil. The mixture of 1-benzyl-4-bromo-2-methyl-1H-benzo[d]imidazole (496 mg), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (700 mg), Pd(Ph3P)4 (87 mg), sodium carbonate (476 mg) and THF (18 mL)-water (0.90 mL) was heated at 100° C. for 1 h under microwave irradiation. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10%-50% EtOAc in hexane) to give 3-[4-(1-benzyl-2-methyl-1H-benzimidazol-4-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (450 mg) as white crystals.
Reaction SMILES: Cl[C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][C:6]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>C(O)(C)C>[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:2]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[O:18])[C:9]3[C:4](=[CH:5][C:6]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][CH:8]=3)[N:3]=2)=[CH:35][CH:34]=1
Reactant: COC(=O)c1ccc2c(=O)n(-c3ccccc3)c(Cl)nc2c1
Reactant: NCc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)c1ccc2c(=O)n(-c3ccccc3)c(NCc3ccc(Cl)cc3)nc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
To a suspension of methyl 2-chloro-4-oxo-3-phenyl-3,4-dihydroquinazoline-7-carboxylate (0.10 g, 0.25 mmol) in isopropyl alcohol (2.8 mL) was added N,N-diisopropylethylamine (93 μL, 0.53 mmol) and p-chlorobenzylamine (77.3 μL, 0.64 mmol). The reaction mixture was heated to 100° C. and stirred for 1 h. The mixture was then cooled to rt and concentrated. The residue was purified by flash silica gel chromatography (0% to 30% EtOAc/hexanes) to afford methyl 2-[(4-chlorobenzyl)amino]-4-oxo-3-phenyl-3,4-dihydroquinazoline-7-carboxylate (30 mg, 30%). LC-MS: (FA) ES+ 420.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[CH:9]=2)=[CH:5][C:4]=1[N+:17]([O-:19])=[O:18].C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>O1CCCC1>[CH3:1][NH:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:29](=[O:30])[CH2:28][Cl:27])[CH:9]=2)=[CH:5][C:4]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)CCl
Reactant: CNc1ccc(Oc2ccnc(N)c2)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNc1ccc(Oc2ccnc(NC(=O)CCl)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-amine (1 eq) and triethylamine (2 eq) in tetrahydrofuran was treated with 2-chloroacetyl chloride and stirred for 15 minutes at room temperature. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated in vacuum to give crude product. Purification on silica gel with 2% methanol in methylene chloride gave N-(4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-yl)-2-chloroacetamide as a bright orange solid. HPLC=3.82 min; MS: MH+=337.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15]>>[OH:15][CH2:14][C:13]([NH:12][C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1)([CH3:17])[CH3:16]
Reactant: CCOC(=O)c1cccnc1
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NC(=O)c1cccnc1

Procedure:
100 g (0.66 mol) Ethyl nicotinate and 88g (0.99 mol) 2-amino-2-methyl-1-propanol were mixed and heated together under reflux for 2 hours. The excess amino alcohol was removed by distillation, bp 50°-60° (1 mm). The yellow residue was recrystallized from ether-acetone to give 87.3 g (0.45 mol), 68%, N-(1-hydroxy-2-methyl-2-propyl) nicotinamide, mp 91°-93°; ir (KBr) 3385, 3200, 1665, and 1590 cm-1 ; pmr (CDCl3) δ 8.8 - 7.3 (m, 4H), 6.7 (bs, 1H), 5.0 (s, 1H), 3.7 (s, 2H) and 1.4 (s, 6H) ppm.
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[Cl:19][C:20]1[CH:21]=[C:22]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31][CH:32](P(=O)(OCC)OCC)[C:33]3=[O:35])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.C(O)C>O1CCCC1>[Cl:19][C:20]1[CH:21]=[C:22]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31]/[C:32](=[CH:8]\[C:7]4[CH:10]=[CH:11][C:12]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:5]([O:4][CH3:3])[CH:6]=4)/[C:33]3=[O:35])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3cccc(Cl)c3)N2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(/C=C2\CC[C@H]3CC[C@@H](c4cccc(Cl)c4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
Lithium hydroxide (0.142 g) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (0.28 g) and diethyl [(3S,8aR)-3-(3-chlorophenyl)-5-oxooctahydroindolizin-6-yl]phosphonate (0.52 g) in tetrahydrofuran (1 mL)-ethanol (4 mL), and the reaction solution was stirred under shading at room temperature for three hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 0.438 g of the title compound as a colorless oil. The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].Br[CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.O>CN(C)C=O>[CH2:7]([O:6][P:4]([CH:9]([CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: BrCCOC1CCCCO1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CCOC1CCCCO1)P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
856 mg of a sodium hydride dispersion (60% in oil) was washed three times with dry pentane under a nitrogen stream to separate the oil. After drying, the powder obtained was suspended in 7.2 ml of dry dimethylformamide under a nitrogen stream, and the suspension was cooled to 0° C. Then, 4.26 ml of ethyl diethylphosphonoacetate was dropwise added thereto over a period of one hour. The mixture was stirred at room temperature for 30 minutes and cooled to 0° C., and 5.4 g of 2-bromo-1-(2-tetrahydropyranyloxy)ethane was added thereto. The mixture was stirred at 65° C. overnight, and the reaction mixture was poured into 40 ml of water and extracted three times with 20 ml of ethyl acetate. The ethyl acetate layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography (60 g of Kieselgel 60) by using a mixture of hexane/ethyl acetate (5/1 followed by 1/1). The product-containing fraction was again purified by silica gel column chromatography (110 g of Kieselgel 60) by using a mixture of hexane/acetone (4/1) to obtain 2.55 g of ethyl 2-diethylphosphono-4-(2-tetrahydropyranyloxy)butanoate as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11](SC)[N:12]=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>O>[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:11]2[N:12]=[N:13][C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=2)[CH2:28][CH2:27]1
Reactant: COc1ccc(-c2nnc(SC)nc2-c2ccc(OC)cc2)cc1
Reactant: CN1CCNCC1
Solvent: O
Product: COc1ccc(-c2nnc(N3CCN(C)CC3)nc2-c2ccc(OC)cc2)cc1

Procedure:
Ten grams of 5,6-bis(4-methoxyphenyl)-3-methylthio-1,2,4-triazine and 40 ml. of N-methylpiperazine were refluxed for 12 hours. The reaction mixture was poured into water and the solid product was collected. The product was crystallized twice from 75 ml. of ethanol and twice from ethyl acetate to yield 1.8 g. of 3-(4-methylpiperazino)-5,6-bis(4-me;thoxyphenyl)-1,2,4-triazine, mp about 158°-160°C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[CH:27]=[CH:28][C:29](O)=[O:30].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[Cl:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[CH:27]=[CH:28][C:29]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:30]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: O=C(O)C=Cc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1Cl
Yield: 76.2 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), 2-chlorocinnamic acid (2.2 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (2.9 g, 76%) as crystals.
Reaction SMILES: C[CH2:2][N:3]([CH2:6][CH3:7])[CH2:4][CH3:5].BrC/C=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13].CC1CN1>C1COCC1.CCOC(C)=O>[CH2:15]([O:14][C:12](=[O:13])/[CH:11]=[CH:7]/[CH2:6][N:3]1[CH2:2][CH:4]1[CH3:5])[CH3:16]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)/C=C/CBr
Agent: CC1CN1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/CN1CC1C
Reaction time: 60 h

Procedure:
Add 10 mL of NEt3 to a solution of 9.2 mL of ethyl 4-bromocrotonate and 4 mL of 2-methylaziridine in 100 mL of THF. Stir for 60 h, during which time a white precipitate forms. Dilute the reaction mixture with 300 mL of EtOAc and wash with water and then with brine. Dry the organic solution over MgSO4, filter, and concentrate in vacuo to yield 6.7 g of crude product. Purify by flash chromatography (silica gel, 1:4 hexane/EtOAc) to yield 5.2 g of E-4-(2-methyl-1-aziridinyl)-2-butenoic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[N+:10]([CH3:13])([O-:12])=[O:11].C([O-])(=O)C.[NH4+].C(O)(=O)C>O>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:13]/[N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 83.8 %

Procedure:
A mixture of 4-bromobenzaldehyde (16.8 g, 91 mmol), nitromethane (24.6 mL, 455 mmol), ammonium acetate (14 g, 182 mmol), and acetic acid (160 mL) was stirred for 4 hours at 100° C. This mixture was cooled to room temperature and poured into water. The precipitate thus produced was collected, washed with water, and dried under a reduced pressure to obtain the title compound (17.4 g). The title compound was used in the following reaction without any further purification.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:25])[NH:12][C@@H:13]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14]2)=CC=1)([O-])=O.[C:26]([NH:33][C@@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].[N-]=C=O>CO.C(Cl)Cl>[C:29]([O:28][C:26](=[O:27])[NH:33][C@@H:34]1[CH2:38][CH2:37][N:36]([C:11](=[O:25])[NH:12][C@@H:13]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:14]2)[CH2:35]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: O=C(N[C@@H]1CCN(Cc2ccccc2)C1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)N[C@@H]2CCN(Cc3ccccc3)C2)C1
Reaction time: 8 h

Procedure:
A solution of ((R)-1-benzyl-pyrrolidin-3-yl)-carbamic acid 4-nitro-phenyl ester (1 eq.) and (3R)-(+)-3-(Boc-amino)pyrrolidine in MeOH is heated using microwave radiation at 100° C. for 1 hour. The reaction mixture is reduced in vacuo. The resulting oil is dissolved in DCM and isocyanate resin (3 eq.) is added and shaken overnight. The resin was filtered off and the DCM was removed in vacuo to yield the title compound. MS (ES+) m/e 299.21 (MH+).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][OH:26])[CH:20]=4)[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F-].[K+].I[CH3:30].[OH-].[K+]>CS(C)=O>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][CH3:30])[CH:20]=4)[CH2:17][CH2:18]3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: OCc1cccc(N2CCN(CCC3CCC4(CC3)OCCO4)CC2)c1
Reactant: CI
Agent: [F-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COCc1cccc(N2CCN(CCC3CCC4(CC3)OCCO4)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
To a solution of 1.2 g (3.42 mmol) of 1-[2-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl]-4-(3-hydroxymethylphenyl)piperazine (preparation A) in 15 mL of dimethyl sulfoxide are added, at room temperature, 1.0 g (17.2 mmol) of potassium fluoride, 0.52 g (3.66 mmol) of iodomethane and 0.68 g (10.3 mmol) of potassium hydroxide. The mixture is stirred overnight at room temperature, partitioned between with ethyl acetate and water. The aqueous phase is separated and the organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated. The oily residue is purified by chromatography over silica gel (eluant hetane/ethyl acetate 1/1) to give 0.3 g of 1-[2-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl]-4-(3-methoxymethylphenyl)piperazine as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16](O)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:19])[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CN(CCCCC(=O)O)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CN(CCCCC(=O)Cl)C(=O)OCc1ccccc1

Procedure:
1.97 g (7.43 mmol) of 5-[[(benzyloxy)carbonyl](methyl)amino]valeric acid are dissolved in 30 ml of dichloromethane, and 4.9 ml (67.3 mmol) of thionyl chloride are added. The mixture is heated under reflux for 1 h. It is then concentrated in vacuo, and the residue is again mixed with dichloromethane and concentrated once again. A viscous oil remains and is dried under high vacuum. 2 g (95% of theory) of the target compound are obtained and are reacted further without further purification and characterization.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:6][C@@H:5]([NH:7][C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]=[C:10](S(C)(=O)=O)[N:9]=2)[C:4]1([CH3:21])[CH3:20].OC[C@H]1C[C@@H](NC2C(C#N)=CN=C(S(C)=O)N=2)C1(C)C.Cl.[F:43][C:44]([F:54])([F:53])[C:45]1[CH:50]=[CH:49][N:48]=[CH:47][C:46]=1[CH2:51][NH2:52].CCN(C(C)C)C(C)C>C(O)C>[OH:1][CH2:2][C@H:3]1[CH2:6][C@@H:5]([NH:7][C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]=[C:10]([NH:52][CH2:51][C:46]3[CH:47]=[N:48][CH:49]=[CH:50][C:45]=3[C:44]([F:54])([F:43])[F:53])[N:9]=2)[C:4]1([CH3:21])[CH3:20]
Reactant: CC1(C)[C@@H](CO)C[C@H]1Nc1nc(S(C)(=O)=O)ncc1C#N
Reactant: NCc1cnccc1C(F)(F)F
Agent: CS(=O)c1ncc(C#N)c(N[C@@H]2C[C@H](CO)C2(C)C)n1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)[C@@H](CO)C[C@H]1Nc1nc(NCc2cnccc2C(F)(F)F)ncc1C#N
Temperature: 80 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
A mixture of 4-(((1R,3S)-3-(hydroxymethyl)-2,2-dimethylcyclobutyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile and 4-(((1R,3S)-3-(hydroxymethyl)-2,2-dimethylcyclobutyl)amino)-2-(methylsulfinyl)pyrimidine-5-carbonitrile (1.0 equiv.), (4-(trifluoromethyl)pyridin-3-yl)methanamine hydrochloride (1.0 equiv.) and DIEA (3.0 equiv.) was combined in ethanol (0.1 M) and heated to 80° C. After 2 h, the reaction mixed was worked up using standard methods to afford the title compound (45% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.71 (d, J=5.08 Hz, 1H), 8.57-8.65 (m, 1H), 8.15-8.25 (m, 2H), 7.65-7.75 (m, 1H), 7.19-7.32 (m, 1H), 4.70 (d, J=5.08 Hz, 2H), 4.23 (t, J=4.88 Hz, 1H), 3.96 (q, J=8.33 Hz, 1H), 3.20-3.29 (m, 1H), 1.73-1.96 (m, 2H), 1.53-1.68 (m, 1H), 1.20 (s, 1H), 0.86 (s, 1H), 0.62-0.77 (m, 6H): MS(ESI) m/z 407.3[M+1]+.
Reaction SMILES: O.[NH2:2][NH2:3].[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:10](O[C:13](=[O:14])[C:5]=12)=[O:11].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[N:4]1[C:5]2[C:13](=[O:14])[NH:2][NH:3][C:10](=[O:11])[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: NN
Reactant: O=C1OC(=O)c2ncccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH][nH]c(=O)c2ncccc12
Yield: 76.2 %

Procedure:
Hydrazine hydrate (13.09 g, 0.261 mol) was added to a stirred solution of pyridine-2,3-dicarboxylic anhydride (30.0 g, 0.201 mol) and sodium acetate (21.45 g, 0.261 mol) in 40% acetic acid/water (400 ml). The reaction was heated at reflux for 3 days under nitrogen. The yellow precipitate was filtered off and washed successively with water (4×200 ml), hexane (3×150 ml) and diethyl ether (3×150 ml) to give the title-compound (25.0 g, 76%), 1H NMR (250 MHz, d6-DMSO) δ 7.90 (1H, q, J=4.5Hz, Ar—H), 8.51 (1H, d, J=4.5Hz, Ar—H), 9.13 (1H, d, J=4.6Hz, Ar—H), 11.65 (2H, br s, 2 of NH); MS (ES+) m/e 164 [MH]+.