Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[C:11]2[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.Cl>CO>[C:10]1([C:12]([O:14][CH3:15])=[O:13])[C:11]2[CH:2]=[CH:3][CH2:4][CH2:5][C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cccc2c1C(O)CCC2
Agent: Cl
Solvent: CO
Product: COC(=O)c1cccc2c1C=CCC2

Procedure:
Methyl 8-hydroxy-5,6,7,8-tetrahydronaphthalene-1-carboxylate (see Tetrahedron, 53, 15969-15982; (1990)) (5.029 g, 32.63 mmol) was heated under reflux in a solution (80 ml) of 10% hydrogen chloride in methanol overnight. The solvent of the reaction solution was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to give the objective substance.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:12][C:13]1[N:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[CH:15][CH:14]=1.[H-].[Na+]>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([NH:12][C:13]2[N:18]=[CH:17][C:16]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])=[CH:15][CH:14]=2)[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cn1
Reactant: Clc1cc(Br)c2nccn2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(Nc2cc(Cl)nn3ccnc23)nc1)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.1 %

Procedure:
A mixture of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (272 mg, 1.17 mmol, Eq: 1.00) and (6-aminopyridin-3-yl)(morpholino)methanone (255 mg, 1.23 mmol, Eq: 1.05) in DMF (10.0 ml) was cooled to 0° C. To this reaction mixture was added sodium hydride (150 mg, (60% in mineral oil), 3.74 mmol, Eq: 3.2). The reaction was allowed to stir at 0° C. for 10 minutes and then allowed to warm to room temperature and stir 18 h. The reaction mixture was quenched with sat. NaHCO3 (aq) and diluted with water and EtOAc. An insoluble solid was collected by filtration to give [6-(6-chloro-imidazo[1,2-b]pyridazin-8-ylamino)-pyridin-3-yl]-morpholin-4-yl-methanone (420 mg, 99%). LC/MS-ESI observed [M+H]+ 358.
Reaction SMILES: [CH2:1]([C:4]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([C:29]([O:31]CC)=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[C:7]2=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]2[N:5]=1)[CH2:2][CH3:3].[OH-].[Na+]>C(O)C>[CH2:1]([C:4]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([C:29]([OH:31])=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[C:7]2=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)ccnc2n1Cc1ccc(OC(C(=O)OCC)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(OC(C(=O)O)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1b from 2-n-propyl-7-methyl-3-[4-[(α-ethoxycarbonyl)benzyloxy]benzyl]-imidazo[4,5-b]pyridine and 1N sodium hydroxide solution in ethanol.
Reaction SMILES: [C:1]([C:3]1([NH:20][CH2:21][CH:22]=[CH2:23])[CH2:12][CH:11]2[N:6]([CH2:7][CH2:8][C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[O:13][C:10]=32)[CH2:5][CH2:4]1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.CCOCC>[NH2:2][CH2:1][C:3]1([NH:20][CH2:21][CH:22]=[CH2:23])[CH2:12][CH:11]2[N:6]([CH2:7][CH2:8][C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[O:13][C:10]=32)[CH2:5][CH2:4]1
Reactant: C=CCNC1(C#N)CCN2CCc3c(oc4ccccc34)C2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCNC1(CN)CCN2CCc3c(oc4ccccc34)C2C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 0.325 grams (1.11 mmol) of (2RS,12bSR)-2-cyano-2-(2-propenylamino)-1,3,4,6,7,12b-hexahydro-2H-benzofuro[2,3-a]quinolizine in 7 milliliters of tetrahydrofuran is added to a solution of 0.084 gram (2.22 mmol) of lithium aluminum hydride in 60 milliliters of ether which has been cooled to 0° C. The reaction mixture is stirred for 1.5 hours and then quenched with water. The resulting mixture is filtered through a pad of celite and the pad then washed with methanol and methylene chloride. The filtrate is dried over sodium sulfate, then filtered and concentrated to obtain (2RS,12bSR)-2-aminomethyl-2-(2-propenylamino)-1,3,4,6,7,12b-hexahydro-2H-benzofuro[2,3-a]quinolizine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([NH2:17])[CH:13]=[C:14]([Br:16])[CH:15]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([NH:17][S:19]([CH3:18])(=[O:21])=[O:20])[CH:13]=[C:14]([Br:16])[CH:15]=1
Reactant: Nc1cc(Br)cc(-c2nc3ccccc3o2)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(Br)cc(-c2nc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 55.1 %

Procedure:
To a solution of 3-benzoxazol-2-yl-5-bromo-phenylamine (0.12 g, 0.42 mmol) in pyridine (2.0 mL) at room temperature was added methanesulfonyl chloride (0.14 g, 1.30 mmol) and catalytic DMAP. The resulting mixture was stirred at room temperature for 17 hours. The solvent was removed under vacuum and the residue was purified by preparative TLC eluting with 4:1/hexanes:ethyl acetate to give N-(3-benzoxazol-2-yl-5-bromo-phenyl)-methanesulfonamide (85.0 mg, 55%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:22][CH:21]=4)[C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>C(Cl)Cl>[C:33]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:22][CH:21]=4)[C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:36])[CH:34]=[CH2:35]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c(-c3cccc(N)c3)ccnc12
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(-c2ccnc3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn23)c1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 10.5 %

Procedure:
To a solution of 7-(3-aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.24 mmol) in DCM (10 mL) was added TEA (3 drops), followed by acryloyl chloride (32 mg, 0.36 mmol). The mixture was stirred at RT for 1 min and partitioned between DCM (50 mL) and brine (50 mL). Organic layer was separated from aqueous layer, dried over Na2SO4, concentrated and purified by Pre-TLC (DCM/CH3OH=10/1) to afford 12 mg (11%) of 7-(3-acrylamido phenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.80 (d, J=4.4 Hz, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.95 (d, J=8.8 Hz, 2H), 7.89 (d, J=8.4 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.47 (br s, 1H), 7.42-7.37 (m, 3H), 7.15 (t, J=7.6 Hz, 1H), 7.06 (d, J=8.0 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 6.44 (dd, J=10.1, 16.9 Hz, 1H), 6.26 (dd, J=1.6, 16.9 Hz, 1H), 5.76 (dd, J=1.6, 10.1 Hz, 1H). MS (ESI) m/e [M+1]+ 476.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[C:11]3[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: CCc1cc2c(NCc3ccc(OC)c(OC)c3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc(OC)c(OC)c3)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-ethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-ethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([S:15]([NH:18][C@H:19]([CH2:23][CH2:24][CH2:25][NH2:26])[C:20]([OH:22])=[O:21])(=[O:17])=[O:16])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.[CH:27](=O)[C:28]1[C:29](=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH:30]=[O:31]>C(O)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([S:15]([NH:18][C@H:19]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:27][C:28]3[C:29](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:31])[C:20]([OH:22])=[O:21])(=[O:17])=[O:16])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: NCCC[C@@H](NS(=O)(=O)c1cc(Cl)ccc1-c1ccccc1)C(=O)O
Reactant: O=Cc1ccccc1C=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)[C@@H](CCCN1Cc2ccccc2C1=O)NS(=O)(=O)c1cc(Cl)ccc1-c1ccccc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
0.32 g (0.76 mmol) of 2-(2R)-(4-chlorobiphenylsulfonylamino)-5-amino-pentanoic acid hydrochloride is dissolved in 30 ml of glacial acetic acid with 0.186 g (1.35 mmol) of phthalaldehyde and stirred at 100° C. for 3 hours. The solution is cooled to 0° C., and the precipitate which is deposited is filtered off with suction and chromatographed on a silica gel column (eluent: ethyl acetate/petroleum ether/glacial acetic acid 10/10/2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH:63]([N:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1)=[O:64]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:68]1[CH2:69][CH2:70][N:65]([CH:63]=[O:64])[CH2:66][CH2:67]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=CN1CCNCC1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCN(C=O)CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 4-formyl-piperazine in DMSO at ambient temperature.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.C(OC(=O)[N:32]([C:44]1[CH:49]=[CH:48][C:47]([C:50](=[O:52])[CH3:51])=[CH:46][N:45]=1)[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=1)(C)(C)C>O1CCCC1>[F:43][C:40]([F:41])([F:42])[C:37]1[CH:38]=[CH:39][C:34]([CH2:33][NH:32][C:44]2[N:45]=[CH:46][C:47]([C:50]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=3)([OH:52])[CH3:51])=[CH:48][CH:49]=2)=[CH:35][CH:36]=1
Reactant: CC(=O)c1ccc(N(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)nc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(C)(O)c2ccc(NCc3ccc(C(F)(F)F)cc3)nc2)c2cccnc21
Temperature: -20 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (96, 485.9 mg, 1.21 mmol) was dissolved in tetrahydrofuran (8 mL) at −20° C. under an atmosphere of nitrogen. 2.0 M isopropylmagnesium chloride in tetrahydrofuran (0.655 mL) was added. The reaction was stirred at −20° C. for 1 hour. Into the reaction was added (5-acetyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (621, 300.0 mg, 0.76 mmol) in tetrahydrofuran (6 mL) The reaction was allowed to warm to room temperature overnight. The mixture was extracted with ethyl acetate and saturated sodium bicarbonate. The organic portions were dried with anhydrous sodium sulfate, filtered and the filtrate was adsorbed onto silica. The mixture was purified by silica gel chromatography on the (ethyl acetate:hexanes), to provide the desired compound as an oil (622, 125 mg, 29%), consistent with the compound structure by 1H-NMR.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:4][N:3]=1.[CH3:13][C:14]1[CH:19]=[C:18]([Sn](CCCC)(CCCC)CCCC)[CH:17]=[CH:16][N:15]=1.CN(C=O)C>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>[CH3:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:4][N:3]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C)c1
Reactant: COC(=O)Cc1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccnc(-c2ccnc(C)c2)c1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
To a flask containing methyl 2-(2-chloropyridin-4-yl)acetate 238-1 (1.00 g, 5.38 mmol), 2-methyl-4-(tributylstannyl)pyridine (2.06 g, 5.38 mmol), Pd(PPh3)4 (594 mg, 0.54 mmol.) under argon was added DMF (15 mL). The reaction mixture was stirred at 120° C. for 10 hours. After cooled to room temperature, the mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The crude was purified by silica gel flash chromatography, eluted with 5% methano in dichloromethane to give methyl 2-(2′-methyl-2,4′-bipyridin-4-yl)acetate 238-2 as dark orange oil. MS m/z 243.1 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[CH3:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:15][N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1
Reactant: CNc1ccccc1
Reactant: Oc1ccc(OCCCCCBr)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCCCOc1ccc(O)cc1)c1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 62.1 %

Procedure:
Compound 13a (0.15 g, 0.58 mmol) and compound N-methylaniline (0.07 mL, 0.64 mmol) were stirred in acetonitrile (5 mL) for 30 mins and then diisopropylethylamine (0.24 mL, 1.74 mmol) was added dropwise. The reaction was then stirred at 60° C. for 12 hours and monitored by TLC. The reaction mixture was concentrated and purified by column chromatography to isolate the compound 13 as a colorless oil (0.05 g, 0.36 mmol, 30% yield). MS (ESI, positive) m/z calcd. for C18H24NO2 [M+H]+: 286.18, found: 285.95. 1H NMR (CDCl3, 400 MHz) δ 7.25 (t, J=8.8 Hz, 2H), 6.70-6.85 (m, 7H), 4.72 (s, 1H), 3.93 (t, J=6.4 Hz, 2H), 3.36 (t, J=7.6 Hz, 2H), 2.95 (s, 3H), 1.85-1.78 (m, 2H), 1.63-1.71 (m, 2H), 1.47-1.55 (m, 2H).
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[CH2:12]([O:19][CH2:20][CH2:21][CH2:22][OH:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[CH2:12]([O:19][CH2:20][CH2:21][CH:22]=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCCOCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a suspension of PCC (606 mg, 2.82 mmol) in anhydrous dichloromethane (8 mL) at room temperature under N2 was added a solution of 3-benzyloxy-1-propanol (310 mg, 1.88 mmol) in anhydrous dichloromethane. The reaction mixture was stirred overnight at room temperature, filtrated through Celite, and concentrated. The residue was purified by column chromatography on silica gel (1-10% ethyl acetate/hexanes) to give 3-(benzyloxy)propanal (243 mg, 79%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:16]2[C:21](=[O:22])[NH:20][C:19]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:18]=3[S:17]2(=[O:30])=[O:29])[CH2:9][CH2:8]1.[CH3:31]N(C=O)C.[H-].[Na+].CI>>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]2[C:21](=[O:22])[N:20]([CH3:31])[C:19]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:18]=3[S:17]2(=[O:29])=[O:30])[CH2:11][CH2:12]1
Reactant: CN(C)C=O
Reactant: COc1ccc2c(c1)S(=O)(=O)N(CCCN1CCN(c3ncccn3)CC1)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COc1ccc2c(c1)S(=O)(=O)N(CCCN1CCN(c3ncccn3)CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.028 mol of 2-(3-(4-(2-pyrimidinyl)-1-piperazinyl)propyl)-7-methoxy-1,2,4-benzothiadiazin-3(4H)one 1,1-dioxide is dissolved in 150 mol of absolute DMF, and 0.028 mol of sodium hydride is added to the solution and the mixture is stirred at room temperature for 0.25 hour. Then 0.028 mol of methyl iodide is added and the mixture is stirred at 25° C. for a further 2 hours. The product is precipitated as crystals by dropwise addition of a total of 18 ml of water. It is purified by crystallisation from isopropanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][C@@H:15]2[CH2:17][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH:27][C@@H:28]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)[CH2:29][OH:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH2:20]([N:27]([C@@H:28]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=1)[CH2:29][OH:30])[CH2:17][C@H:15]([OH:16])[CH2:14][O:13][C:12]1[CH:18]=[CH:19][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(COc2ccc(OC[C@@H]3CO3)cc2)cc1
Reactant: O=[N+]([O-])c1ccc(C[C@@H](CO)NCc2ccccc2)cc1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 81 %

Procedure:
A solution of (2S)-2-[(4-(benzyloxy)phenoxy)methyl]-oxirane (1.19 g) and (2S)-2-(benzylamino)-3-(4-nitrophenyl)-1-propanol (1.33 g) in ethanol (13 ml) was refluxed for 20 hours. After cooling to room temperature, the solvent was removed by evaporation and the residue was chromatographed on silica gel (eluent: chloroform/methanol=98/2) to give (2S)-2-[N-benzyl-N-[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]amino]-3-(4-nitrophenyl)-1-propanol (2.04 g) as a yellow gum.
Reaction SMILES: [BH4-].[Na+].[C:3]12[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=O)[O:7][C:5](=[O:6])[C:4]1=[CH:16][CH:17]=[CH:18][CH:19]=2.Cl>CN(C=O)C.O>[CH:19]1[C:3]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][O:7][C:5](=[O:6])[C:4]=2[CH:16]=[CH:17][CH:18]=1
Reactant: O=c1oc(=O)c2ccccc2c2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1OCc2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
9.0 g (0.24 mol) of sodium borohydride were added in portions at 5° C. in the course of 10 min to a suspension of 50.0 g (0.22 mol) of diphenic anhydride in 220 ml of DMF. After stirring at RT for 1 h, the reaction mixture was poured onto 220 ml of 6 M hydrochloric acid, diluted with 750 ml of water and stirred for 2 h. The deposited precipitate was filtered off with suction and 35.0 g of 7H-dibenzo[c,e]oxepin-5-one were obtained; m.p. 131° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH:13]=[C:14]([C:16]2[S:20][CH:19]=[N:18][CH:17]=2)[CH:15]=1.[Br:32]Br>C1COCC1>[Br:32][C:19]1[S:20][C:16]([C:14]2[CH:13]=[C:12]([NH:21][C:22]3[N:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=3)[CH:11]=[C:10]([CH3:9])[CH:15]=2)=[CH:17][N:18]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Reactant: BrBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(Br)s2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
Lithium diisopropylamide (1.8 M in THF/heptane/ethylbenzene, 11.4 mL, 20.5 mmol) was cooled to −70° C. Intermediate 4 (2.3 g, 6.8 mmol) in THF (23 mL) was added slowly over 15 minutes, keeping the temperature at −65° C. The reaction was allowed to stir for 30 minutes following the addition and then bromine (0.53 mL, 10.3 mmol) was added. The reaction was stirred for 30 minutes and then quenched with 20 mL of water and warmed to rt. The reaction was diluted with EtOAc (50 mL). The layers were separated and the organic portion was washed with Na2SO3 (10% aqueous), brine, dried over MgSO4 and concentrated in vacuo. Purification via column chromatography (ISCO, dry load with silica gel, Hexane-50% EtOAc:Hexane) to provide N-[3-(2-bromo-1,3-thiazol-5-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine (1.88 g, 4.53 mmol, 66%). MS APCI: [M+H]+ m/z 414.8, 416.8. 1H NMR (600 MHz, CDCl3) δ 8.64 (d, 4.9, 1H), 7.88 (s, 1H), 7.74 (s, 1H), 7.33 (s, 1H), 7.05 (t, J=6.4, 1H), 7.01 (s, 1H), 2.38 (s, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH3:19])[C:6]([O:17][CH3:18])=[C:7]([CH:9]([O:12][Si](C)(C)C)[C:10]#[N:11])[CH:8]=1.[CH2:20]([OH:22])[CH3:21]>>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH3:19])[C:6]([O:17][CH3:18])=[C:7]([CH:9]([OH:12])[C:10](=[NH:11])[O:22][CH2:20][CH3:21])[CH:8]=1
Reactant: COc1c(C)cc(Cl)cc1C(C#N)O[Si](C)(C)C
Reactant: CCO
Agent: Cl
Product: CCOC(=N)C(O)c1cc(Cl)cc(C)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
Ethanol (100 ml.) was saturated with hydrogen chloride at 0° C. 2-(5-Chloro-2-methoxy-3-methylphenyl)-2-trimethylsiloxyethanenitrile (2.9 g.) in 5 ml. of ethanol was added dropwise, keeping the temperature less than 10° C. The reaction mixture was stirred at 0° C. for about 1 hour, evaporated to dryness and the residue triturated with ether to yield ethyl 1-(5-chloro-2-methoxy-3-methylphenyl)-1-hydroxymethanecarboximidate hydrochloride [2.67 g., 89%; m.p. 131°-133° C. (dec); ir (KBr) 1653; 1538, 1488, 1227, 1093 cm-1 ].
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:21][C:22]([F:25])([F:24])[F:23])=[C:17]([CH2:19]O)[CH:18]=1.C1C=CC(P([N:40]=[N+:41]=[N-:42])(C2C=CC=CC=2)=O)=CC=1.CCOC(C)=O>C1(C)C=CC=CC=1>[N:40]([CH2:19][C:17]1[CH:18]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=1[O:21][C:22]([F:25])([F:24])[F:23])=[N+:41]=[N-:42]
Reactant: OCc1cc(Cl)ccc1OC(F)(F)F
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1cc(Cl)ccc1OC(F)(F)F
Reaction time: 3 h
Yield: 64.5 %

Procedure:
DBU (1.0 mL, 6.7 mmol) was added to a solution of (5-chloro-2-trifluoromethoxy-phenyl)-methanol (1.2 g, 5.3 mmol) and DPPA (1.4 mL, 6.4 mmol) in toluene (30 mL) at room temperature. After 3 h, the reaction was concentrated in vacuo to yield an yellow oil. Silica gel column chromatography using 95:5 hexanes:EtOAc yielded 0.86g (65%) of 2-azidomethyl-4-chloro-1-trifluoromethoxy-benzene as a colorless oil.
Reaction SMILES: [C:1]([C:4]1([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)(O)=[O:2].O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O>[OH:2][CH2:1][C:4]1([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:5][CH2:6][C:7](=[O:10])[CH2:8][CH2:9]1
Reactant: O=C1CCC(C(=O)O)(c2ccc(F)cc2)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCC(CO)(c2ccc(F)cc2)CC1
Reaction time: 6 h
Yield: 99 %

Procedure:
A solution of 18.2 g. (0.065 mole) of 4-carboxy-4-(4-fluorophenyl)cyclohexanone, ethylene ketal (prepared in Example 26) in 200 ml. of tetrahydrofuran is added to 5.9 g. (0.155 mole) of lithium aluminum hydride in 50 ml. of tetrahydrofuran. Following about 6 hours of heating at reflux, the mixture is cooled in ice and treated with 10 ml. of water and 200 ml. of 2.5 N hydrochloric acid. The organic layer is washed with water and brine and then evaporated to dryness to give 18.18 g. (99% yield) of 4-hydroxymethyl-4-(4-fluorophenyl)cyclohexanone, ethylene ketal as an amorphour gum.