Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6].[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)P(N(C)C)(N(C)C)=O>[CH3:3][O:4][C:5]([C:7]1[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:14]([C:15]=1[O:16][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6]
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1c(O)c2ccccc2n1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)c1c(OCc2ccccc2)c2ccccc2n1-c1ccccc1
Reaction time: 1 h
Yield: 53.2 %

Procedure:
A mixture of 1.2 g (0.025 mole) of 50% sodium hydride/mineral oil suspension in 20 ml of hexamethylphosphoramide under a nitrogen atmosphere was cooled in ice and treated over 15 minutes with a solution of 5.3 g (0.020 mole) of 3-hydroxy-1-phenyl-1H-indole-2-carboxlic acid methyl ester [P. Friedlander and K. Kurz, Chem. Ber., 55, 1597 (1922)] in 25 ml of hexamethylphosphoramide. The mixture was stirred in ice an additional one hour, 2.6 ml (2.9 g, 0.023 mole) of benzyl chloride was added in one portion, the ice bath was removed and stirring was continued for a total of 18 hours. The reaction mixture was added to 200 g of ice/water, stirred for one hour, and the precipitated product was filtered and washed with water. Recrystallization from aqueous methanol yielded 3.8 g (54% yield) of the ester product. An additional recrystallization as above yielded analytically pure ester, mp 117°-119° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([NH:19][NH:20][C:21](=[O:36])[CH:22]([C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=2)[CH2:23][CH2:24][CH2:25][Cl:26])=O)[CH:6]=[N:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1>P(Cl)(Cl)(Cl)=O>[Cl:26][CH2:25][CH2:24][CH2:23][CH:22]([C:21]1[O:36][C:17](/[CH:16]=[CH:15]/[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[N:7][CH:6]=2)=[N:19][N:20]=1)[C:27]1[CH:28]=[C:29]([F:35])[C:30]([F:34])=[C:31]([F:33])[CH:32]=1
Reactant: COc1cc(/C=C/C(=O)NNC(=O)C(CCCCl)c2cc(F)c(F)c(F)c2)cnc1-n1cnc(C)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(/C=C/c2nnc(C(CCCCl)c3cc(F)c(F)c(F)c3)o2)cnc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A solution of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid N′-{(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acryloyl}hydrazide (112 mg) in phosphorus oxychloride (2 mL) was stirred at 120° C. for 3.5 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure to obtain 108 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: CS(O[C@@H:6]1[C@@H:10]([CH2:11][O:12]S(C)(=O)=O)[O:9][C@@H:8]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:7]1)(=O)=O.[OH-].[Na+].Cl>O>[C@@H:8]1([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[O:9][C@@H:10]2[CH2:11][O:12][C@@H:6]2[CH2:7]1
Reactant: Cc1cn([C@H]2C[C@H](OS(C)(=O)=O)[C@@H](COS(C)(=O)=O)O2)c(=O)[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cn([C@H]2C[C@H]3OC[C@H]3O2)c(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
3',5'-Di-O-(methanesulfonyl)thymidine (248 g, 0.62M) was added in portions to a stirred solution of sodium hydroxide (74.7 g, 1.87M) in water (1.6 L). On addition the reaction mixture became a yellow-orange solution. This stirred solution was then heated to reflux for 2 hr. the reaction mixture had cooled to room temperature, 6N hydrochloric acid (100 mL) was added. The reaction mixture was concentrated in vacuo by removing 1.3 L of water. The resulting slurry was cooled in an ice bath for 2 hr. The solid was then filtered and washed sparingly with ice water, and then vacuum dried to constant weight (103.7 g, 74%). The product 3, mp 188°-190° C. (lit. 190°-193° C.) was used without further purification. 1H NMR (360 MHz, d6 -DMSO) 11.35 (s, 1H, NH), 8.01 (s, 1H, H-6), 6.49 (q, 1H, H-1'), 5.47 (m, 1H, H-3'), 4.88 and 4.67 (m, 2H, H-5'), 4.22 (d, 1H, H-4'), 2.47 (m, 2H, H-2') 1.77 (S, 3 H, CH3). 13C NMR (75 MHz, d6 -DMSO) 163.64 (C2), 151.10 (C4), 136.57 (C6), 109.62 (C5), 88.29 (C4'), 86.85 (C1'), 79.83 (C3'), 75.14 (C5'), 37.17 (C2'), 12.33 (CH3). Analysis (C10H12N2O4) C, H, N.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[C:34]([C:35]4[CH:40]=[CH:39][C:38](F)=[CH:37][CH:36]=4)=[CH:33][CH:32]=[C:31]([C:42]([N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)=[O:43])[CH:30]=2)[CH:23]=[CH:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:49]([O:51]C(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C(C5C=CC(F)=CC=5)=CC=C(C(N5CCCC5)=O)C=3)C=C4)=NC=2C=1)=O)C>>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[C:34]([C:35]4[CH:40]=[CH:39][C:38]([O:51][CH3:49])=[CH:37][CH:36]=4)=[CH:33][CH:32]=[C:31]([C:42]([N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)=[O:43])[CH:30]=2)[CH:23]=[CH:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(F)cc4)ccc3c1)n2C1CCCCC1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(F)cc4)ccc3c1)n2C1CCCCC1
Product: COc1ccc(-c2ccc(C(=O)N3CCCC3)cc2-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)cc1

Procedure:
Prepared as described for Compound 549 using Compound 561a instead Compound 549a.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:7][CH2:8][C:9](Cl)=[O:10].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Cl:7][CH2:8][C:9]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:10]
Reactant: O=C(Cl)CCl
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)c1ccccc1

Procedure:
Benzene (0.5 mL), chloroacetyl chloride (120 mg), and aluminium chloride (180 mg) were reacted in dichloromethane (1.5 mL) at from −40° C. to room temperature for 2 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (11 mg).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][O:33][C@@H:32]([C:36]([OH:38])=O)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].Cl.[CH3:40][O:41][C:42]1[CH:52]=[CH:51][C:45]([CH2:46][NH:47][CH:48]2[CH2:50][CH2:49]2)=[CH:44][C:43]=1[O:53][CH2:54][CH2:55][CH2:56][O:57][CH3:58]>CN(C)C=O.O.C(N(CC)CC)C>[CH:48]1([N:47]([CH2:46][C:45]2[CH:51]=[CH:52][C:42]([O:41][CH3:40])=[C:43]([O:53][CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:44]=2)[C:36]([C@@H:32]2[O:33][CH2:34][CH2:35][N:30]([C:28]([O:27][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:29])[CH2:31]2)=[O:38])[CH2:49][CH2:50]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)C1
Reactant: COCCCOc1cc(CNC2CC2)ccc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCCOc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)ccc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-Hydroxybenzotriazole (175 mg), triethylamine (145 μl) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (249 mg) were added to a solution of (2R)-(tert-butoxycarbonyl)morpholin-2-carboxylic acid (200 mg) and N-[4-methoxy-3-(3-methoxypropoxy)benzyl]cyclopropanamine hydrochloride (a compound of Reference Example 1(2), 313 mg) in N,N-dimethylformamide (5 ml) successively and the mixture was stirred at room temperature for 3 hours. Water was added to the mixture under ice-cooling and it was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine successively, dried over sodium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=1/1) to give tert-butyl(2R)-2-({cyclopropyl[4-methoxy-3-(3-methoxypropoxy)benzyl]amino}carbonyl)morpholin-4-carboxylate (368 mg) as a colorless oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20]2)=[C:7]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=O)[CH:8]=1.N1C2C=CC=CC=2C=CC=N1>>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:19]3[CH2:20][CH2:21][C:22]4[C:27]3=[C:26]([CH:25]=[CH:24][CH:23]=4)[C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[N:9][C:7]=2[CH:8]=1
Reactant: CSc1ccc(N2CCc3ccccc32)c(NC(=O)N2CCN(C)CC2)c1
Agent: C1=Cc2ccccc2NN=C1
Product: CSc1ccc2c(c1)N=C(N1CCN(C)CC1)c1cccc3c1N2CC3

Procedure:
It is predicted that if the N-[5-methylthio-2-(2,3-dihydro-1H-indol-1-yl)phenyl]-4-methyl-1-piperazinecarboxamide of Example 10c is treated in the manner of Example 4c that 9-methylthio-6-(4-methyl-1-piperazinyl)-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk]-1,4]benzodiazepine will be obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10](Cl)(=[O:12])=[O:11])[S:7][C:6]=2[CH:14]=1.Cl.[NH2:16][C@H:17]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[O:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[C:18]1=[O:32]>>[O:31]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH2:22][N:19]1[CH2:20][CH2:21][C@H:17]([NH:16][S:10]([C:8]2[S:7][C:6]3[CH:14]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH:9]=2)(=[O:12])=[O:11])[C:18]1=[O:32]
Reactant: N[C@H]1CCN(Cc2cc3ncccc3o2)C1=O
Reactant: O=S(=O)(Cl)c1cc2ccc(F)cc2s1
Agent: Cl
Product: O=C1[C@@H](NS(=O)(=O)c2cc3ccc(F)cc3s2)CCN1Cc1cc2ncccc2o1

Procedure:
The title compound is prepared as described in EXAMPLE 1, Part K using 6-fluoro-benzo[b]thiophene-2-sulfonyl chloride and 3-(S)-amino-1-(furo[3,2-b]pyridin-2-ylmethyl)-pyrrolidin-2-one hydrochloride as starting material. The crude product is purified by column chromatography eluting with 66% EtOAc/CH2Cl2 to provide the title compound as a white solid.
Reaction SMILES: [CH:1]1([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[Li+].CC([N-]C(C)C)C>C1COCC1>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][C:1]1([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCOC(=O)C1CCCC1
Reactant: BrCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCOC(=O)C1(CCCCBr)CCCC1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 49 %

Procedure:
Under a N2 atmosphere at −60° C., a solution of butyl cyclopentanecarboxylate (prepared according to Payne, G. B.; Smith, C. W., J. Org. Chem., 1957, 22, 1680-1682, 80.0 g, 0.42 mol) and 1,4-dibromobutane (183.3 g, 0.84 mol) in dry THF (700 mL) was added drop wise to a mixture of LDA (2M in THF/heptane/ethylbenzene, 250 mL, 0.50 mol) and dry THF (250 mL) in 1.5 h. After that, the reaction mixture was allowed to slowly reach rt during 3.5 h. Then, the reaction mixture was poured into ice-cold saturated aqueous NH4Cl (1 L). The organic layer was decanted and concentrated in vacuo to a smaller volume. The aqueous layer was extracted with Et2O (3×250 mL). The combined organic layers were washed with saturated aqueous NH4Cl (250 mL) and brine (2×250 mL), dried (Na2SO4) and evaporated in vacuo. The remaining residue was purified by fractional distillation to give butyl 1-(4-bromo-butyl)-cyclopentanecarboxylate (62.8 g, 49%) as a light yellow liquid. bp: T=116-117° C. (p=0.040-0.051 Torr). 1H NMR (CDCl3): δ=4.07 (t, J=6.6 Hz, 2H), 3.38 (t, J=6.8 Hz, 2H), 2.16-2.10 (m, 2H), 1.83 (quintet, J=7.1 Hz, 2H), 1.65-1.59 (m, 8H), 1.50-1.31 (m, 6H), 0.94 (t, J=7.2 Hz, 3H). 13C NMR (CDCl3): δ=177.6, 64.1, 53.9, 38.2, 36.0 (2×), 33.3, 33.0, 30.6, 24.8 (2×), 24.6, 19.1, 13.6. HRMS calcd for C14H25BrO2 (M+): 304.1038. found: 304.1042.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:22][NH2:23])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(Cc1ccc(C(F)(F)F)cc1)c1ccc(F)cc1
Solvent: CCO
Solvent: O
Product: NN=C(Cc1ccc(C(F)(F)F)cc1)c1ccc(F)cc1

Procedure:
5.1 g (18.1 mmol) of 4'-fluoro-2-(4-trifluoromethylphenyl)acetophenone was dissolved in 100 ml of ethanol, and 8.8 ml (181 mmol) of hydrazine monohydrate was added thereto. The mixture was refluxed under heating for 2 hours. After completion of the reaction, ethanol was distilled off under reduced pressure, and water was added to the residue. The mixture was extracted with dichloromethane. The extract was dried over an hydrous sodium sulfate, and the solvent was distilled off to obtain [4'-fluoro-2-(4-trifluoromethylphenyl)acetophenone]hydrazone as a yellow oily substance.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Sn](CCCC)(CCCC)CCCC)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].Br[C:31]1[N:32]=[C:33]([N:41]2[CH2:46][CH2:45][N:44]([CH2:47][CH3:48])[CH2:43][CH2:42]2)[C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[CH:36][CH:35]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.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>[CH2:47]([N:44]1[CH2:43][CH2:42][N:41]([C:33]2[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:40]=[C:31]([C:14]3[CH:13]=[CH:12][C:11]([C@H:8]4[CH2:7][CH2:6][C@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:10][CH2:9]4)=[CH:16][CH:15]=3)[N:32]=2)[CH2:46][CH2:45]1)[CH3:48]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1[C@H]1CC[C@H](OC(C)=O)CC1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc([C@H]4CC[C@H](OC(C)=O)CC4)cc3)cc3ccccc23)CC1

Procedure:
Trans-4-(tributylstannylphenyl)cyclohexyl acetate (0.56 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (0.46 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.06 g) in xylene in nitrogen atmosphere overnight. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate. Then, it was adjusted to pH 10 by a 8N aqueous solution of sodium hydroxide, extracted with ethyl acetate, washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give a mixture (0.44 g) of 1-(4-ethylpiperazin-1-yl)-3-[4-(trans-4-acetoxycyclohexyl)phenyl]isoquinoline as a brown viscous oil and the starting material.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-])=[O:18])=[C:10]([C:14]([O-:16])=O)[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30][NH2:31])=[CH:27][CH:26]=1.Cl>>[CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2=[CH:11][C:10]3[C:14](=[O:16])[N:31]([CH2:30][CH2:29][C:28]4[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)[C:17](=[O:18])[C:9]=3[CH:8]=[C:7]2[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: COc1ccc(CCN)cc1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(CCc1ccc(OC)cc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with 4-methoxyphenethylamine (0.19 mL, 1.3 mmol). Purification using silica gel, eluting with 3:1 hexane/acetone, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 113 as a white solid (m.p. 211-215° C.).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[C:8]1([C:14]#[C:15][C:16](OCC)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)(=O)C>CCCCCC.O1CCCC1>[O:17]=[C:16]([C:15]#[C:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCOC(=O)C#Cc1ccccc1
Reactant: COP(C)(=O)OC
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)C#Cc1ccccc1)OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
N-Butyl-lithium (13.5 ml. of a 2.29 M solution in hexane) was added dropwise to a stirred solution of dimethyl methylphosphonate (3.84 g.) in anhydrous tetrahydrofuran (25 ml.) at -78° under argon. After 15 minutes, a solution of ethyl phenylpropiolate (2.5 g.) in anhydrous tetrahydrofuran (20 ml.) was added. The reaction mixture was stirred for 2 hours at -78° C., allowed to warm to ambient temperature and stirred for 18 hours, and adjusted to pH 5 by addition of glacial acetic acid. The tetrahydrofuran was evaporated at room temperature under reduced pressure and the residue was partitioned between water and diethyl ether. The diethyl ether layer was separated, washed with water and dried, and the solvent was evaporated. Chromatography of the crude product on silica gel MFC (75 g.)., eluting with diethyl ether/ethyl acetate (9:1), gave unreacted ethyl phenylpropiolate, and subsequent elution with diethyl ether/ethyl acetate (1:1), gave dimethyl 2-oxo-4-phenylbut-3-ynylphosphonate as an oil, RF = 0.28 (ethyl acetate). The n.m.r. spectrum in deuteriochloroform showed the following absorptions (δ values):
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[NH:27])[NH:25][OH:26])[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[CH:28]1([C:32](Cl)=O)[CH2:31][CH2:30][CH2:29]1>>[CH:28]1([C:32]2[O:26][N:25]=[C:24]([N:21]3[CH2:22][CH2:23][CH:18]([N:4]([CH:1]4[CH2:3][CH2:2]4)[C:5](=[O:17])[C:6]4[CH:11]=[CH:10][C:9]([C:12]5[O:16][CH:15]=[N:14][CH:13]=5)=[CH:8][CH:7]=4)[CH2:19][CH2:20]3)[N:27]=2)[CH2:31][CH2:30][CH2:29]1
Reactant: O=C(Cl)C1CCC1
Reactant: N=C(NO)N1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2noc(C3CCC3)n2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-N-[1-(N-hydroxycarbamimidoyl)-piperidin-4-yl]-4-oxazol-5-yl-benzamide and cyclobutanecarbonyl chloride following a procedure analogous to that described in Example 47. LC (method 2): tR=1.27 min; Mass spectrum (ESI+): m/z=434 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:10][C:4]=2[CH:3]=1.[CH2:17]([O:19][C:20](Cl)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([N:10]1[C:4]2[CH:3]=[C:2]([Br:1])[N:7]=[CH:6][C:5]=2[CH:8]=[C:9]1[C:11]1[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=1)=[O:21])[CH3:18]
Reactant: CCOC(=O)Cl
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Product: CCOC(=O)n1c(-c2cnn(C)c2)cc2cnc(Br)cc21

Procedure:
Prepared according to Preparation 128 using 6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22) and ethylchloroformate. 1H-NMR (500 MHz, CDCl3): δ 1.38 (t, J=7.1 Hz, 3H), 3.95 (s, 3H), 4.45 (q, J=7.1 Hz, 2H), 6.56 (s, 1H), 7.62 (s, 1H), 7.63 (s, 1H), 8.12 (s. 1H), 8.53 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]CC[Si](C)(C)C)[N:3]=1.[CH3:15][O:16][C@@H:17]1[C@H:30]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:29]([CH2:40][O:41][C:42](=[O:49])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:28][C@@H:18]1OC(=O)C1C=CC=CC=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C@@H:18]2[O:28][C@H:29]([CH2:40][O:41][C:42](=[O:49])[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@@H:30]([O:31][C:32](=[O:39])[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C@H:17]2[O:16][CH3:15])[C:4](=[O:8])[N:3]=1
Reactant: CO[C@H]1[C@@H](OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: C[Si](C)(C)CCOc1nccc(Cl)n1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CO[C@@H]1[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1ccc(Cl)nc1=O
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
4-Chloro-2-trimethylsilylethoxy-pyrimidine (3.5 g, 15.2 mmole) and 2-O-methyl-1,3,5-tri-O-benzoyl-α-D-ribose (7.0 g, 15.2 mmole) were dissolved in acetonitrile (100 ml). This solution was treated with trimethylsilyl trifluoromethanesulfonate (2.8 g, 15.2 mmole) and stirred for 1.5 hours. The reaction mixture was concentrated to an oil and redissolved in 300 ml CH2Cl2. The CH2Cl2 solution was washed with cold concentrated sodium bicarbonate, dried over magnesium sulfate, filtered, and evaporated to an oil. The oil was coevaporated with acetonitrile and dried to a brown foam to give 6.70 g (91%) crude product.
Reaction SMILES: I[C:2]1[N:6]2[N:7]=[C:8]([CH3:18])[CH:9]=[C:10]([CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[C:5]2=[N:4][C:3]=1[CH3:19].[CH3:20][N:21]1[C:25]([CH3:26])=[C:24](B(O)O)[C:23]([CH3:30])=[N:22]1.C([O-])([O-])=O.[Na+].[Na+].COC.O.C(O)C>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>[CH3:19][C:3]1[N:4]=[C:5]2[C:10]([CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])=[CH:9][C:8]([CH3:18])=[N:7][N:6]2[C:2]=1[C:24]1[C:23]([CH3:30])=[N:22][N:21]([CH3:20])[C:25]=1[CH3:26]
Reactant: CCCC(CCC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cc1nn(C)c(C)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: CCCC(CCC)c1cc(C)nn2c(-c3c(C)nn(C)c3C)c(C)nc12
Yield: 22.8 %

Procedure:
3-Iodo-2,6-dimethyl-8-(1-propyl-butyl)-imidazo[1,2-b]pyridazine (75 mg, 0.20 mmol), 1,3,5-trimethylpyrazole-4-boronic acid (80 mg, 0.52 mmol), 2N Na2CO3 solution (0.22 ml), and 5.0 mg (0.0004 mmol) of Pd(PPh3)4 are combined in microwave pressure vessel with 1.5 ml of dimethylether/H2O/ethanol (7:3:2) solution. The mixture is microwaved at 140° C. for 25 minutes. The mixture is evaporated and chromatographed on silica gel column using hexanes then 3:1 hexane:ethyl acetate, then 1:1 hexane:ethyl acetate to give the title compound (22.8%) as a clear oil. 1H-NMR (DMSO-d6): δ6.88 (s, 1H); 3.72 (s, 3H); 3.06-3.10 (m, 1H); 2.40 (s, 3H); 2.21 (s, 3H); 2.02 (s, 3H); 1.92 (s, 3H); 1.60-1.76 (m, 4H); 1.08-1.21 (m, 4H); 0.82 (t, J=7.49 Hz, 6H) ppm. MS/ES+354 (100%, M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)=[CH:14][CH:13]=2)[CH3:11])=[CH:4][CH:3]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])=[CH:14][CH:13]=2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)c1ccc(OCCCCBr)cc1
Reactant: CCNCC
Product: CCN(CC)CCCCOc1ccc(N(C)C(=O)Oc2ccc(Cl)cc2)cc1

Procedure:
In analogy to example 17.1, reaction of [4-(4-Bromo-butoxy)-phenyl]-methyl-carbamic acid 4-chloro-phenyl ester with diethylamine yielded [4-(4-Diethylamino-butoxy)-phenyl]-methyl-carbamic acid 4-chloro-phenyl ester, MS: 405 (MH+).