Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:13]3[CH:18]=[CH:17][C:16](O)=[CH:15][C:14]3=[O:20])=[CH:9]2)=[N:4]1)[CH3:2].P(Br)(Br)([Br:23])=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:23][C:16]1[CH:17]=[CH:18][N:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[C:11]([CH3:12])[N:3]([CH2:1][CH3:2])[N:4]=3)[CH:9]=2)[C:14](=[O:20])[CH:15]=1
Reactant: CCn1nc2ccc(-n3ccc(O)cc3=O)cc2c1C
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nc2ccc(-n3ccc(Br)cc3=O)cc2c1C
Temperature: 50 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
To a solution of 1-(2-ethyl-3-methyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (1.07 g) in N,N-dimethylformamide (20 ml) was added phosphorus oxybromide (1.37 g) at room temperature, and the mixture was stirred at 50° C. overnight. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from ethanol-hexane to give the title compound (680 mg).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1>>[OH:25][C:19]1([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=2)[CH2:24][CH2:23][CH2:22][N:21]([C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:20]1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: O=C(Cl)Cc1ccccc1
Product: COc1cccc(C2(O)CCCN(C(=O)Cc3ccccc3)C2)c1

Procedure:
The compound of Example 27 was prepared according to the general preparation protocol A from phenylacetyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:15]=3[N:16]=2)[C:5]([NH:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[CH:22]1[C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]2[C:31]([O:33][C:34](=O)[C:24]=2[CH:23]=1)=[O:32]>>[F:21][C:18]1[CH:19]=[CH:20][C:14]2[O:13][C:12]([C:4]3[CH:3]=[C:2]([N:1]4[C:31](=[O:32])[C:25]5[C:24](=[CH:23][CH:22]=[C:27]([C:28]([OH:30])=[O:29])[CH:26]=5)[C:34]4=[O:33])[CH:7]=[CH:6][C:5]=3[NH:8][CH2:9][CH2:10][CH3:11])=[N:16][C:15]=2[CH:17]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCCNc1ccc(N)cc1-c1nc2cc(F)ccc2o1
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(F)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-propylaminophenyl)-5-fluorobenzoxazole (114 mg, 0.4 mmol) and 1,2,4-benzenetricarboxylic anhydride (96 mg, 0.5 mmol) the title compound was obtained (107 mg, 58%). 1H NMR (DMSO) δ 8.40(m, 2H), 8.30(s, 1H), 8.08(m, 2H), 7.79(m, 1H), 7.70(dd, 1H), 7.48(dd, 1H), 7.28(m, 1H), 7.05(d, 1H), 3.34(m, 2H), 1.74(m, 2H), 1.05(t, 3H). MS 457.6 m/z (M−H)−.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH:19]([O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=1)[CH3:25])[CH3:24]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(C(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
4-Trifluoromethylphenol (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[N:18]=[C:17]([O:19]C)[CH:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=O)C.[ClH:21]>C(O)C>[ClH:21].[ClH:21].[NH:6]1[CH2:7][CH2:8][CH:9]([NH:12][C:13]2[N:18]=[C:17]([OH:19])[CH:16]=[CH:15][N:14]=2)[CH2:10][CH2:11]1
Reactant: CCOC(=O)N1CCC(Nc2nccc(OC)n2)CC1
Agent: Cl
Solvent: CCO
Product: Oc1ccnc(NC2CCNCC2)n1

Procedure:
A solution of 4-(4-methoxy-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid ethyl ester (1.5 g, 5.35 mmol) in ethanol (50 mL) and conc. HCl (75 mL) was heated to reflux for 18 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 194.9 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9](Br)[C:10]#[CH:11].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH2:11]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:10]#[CH:9]
Reactant: Oc1ccccc1Br
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCOc1ccccc1Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 106.2 %

Procedure:
2-bromophenol (6.12 g, 35.3 mmol) and propargyl bromide (5.67 g, 38.1 mmol) were dissolved in DMF (34 ml). This solution was added with potassium carbonate (10.9 g, 78.9 mmol) and stirred at room temperature for 14 hours. The reaction solution was added with ethyl acetate, sequentially washed with water and saturated sodium chloride water, and dried with anhydrous sodium sulfate. Concentration under reduced pressure was carried out to obtain the title compound (7.91 g, 98.0%) as a yellow oily product.
Reaction SMILES: O=[C:2]([NH:9][C:10](=[O:15])[C:11](OC)=[O:12])[CH2:3][C:4]([F:8])=[C:5]([F:7])[F:6].[NH3:16]>CO>[F:8][C:4](=[C:5]([F:7])[F:6])[CH2:3][CH2:2][NH:9][C:10](=[O:15])[C:11]([NH2:16])=[O:12]
Reactant: COC(=O)C(=O)NC(=O)CC(F)=C(F)F
Reactant: N
Solvent: CO
Product: NC(=O)C(=O)NCCC(F)=C(F)F
Yield: 68 %

Procedure:
A solution of Compound 142 (5.0 g, 0.0237 mole) in methanol (50 mL) is saturated with dry gaseous ammonia at room temperature. The precipitate is filtered, washed with methanol and dried to give 3.16 g of the title compound as a white solid, a 68% yield. m.p. 190°-220° C.
Reaction SMILES: [CH2:1]([O:19][CH2:20][C@H:21]([CH2:23][OH:24])[OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:25]1([C:31]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)Cl)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1COCC1.C(#N)C>C(N(CC)CC)C>[CH2:1]([O:19][CH2:20][C@H:21]([CH2:23][O:24][C:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOC[C@@H](O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
39 grams (113 mmol) of (S)-1-octadecyl-glycerol and 40 grams (137 mmol) of triphenylchloromethane were added to a mixture of 500 ml of dry THF and 130 ml of dry acetonitrile. 32 ml of dry triethylamine was added and the reaction mixture was refluxed for 17 hours. The reaction mixture was then cooled to room temperature, poured on ice (1 kilogram), transferred to a separatory funnel and extracted twice with 200 ml diethyl ether. The organic phase was washed consecutively with 200 ml water, twice with 100 ml dilute (1.5%) H2SO4, 200 ml water, 200 ml concentrated aqueous sodium bicarbonate, and again with 200 ml water. The solution was then dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue, a brown oil, was dissolved in 250 ml ethyl acetate and cooled to −20° C. overnight. The mixture was centrifuged (3,500 rotations per minute) at a temperature of −10° C. (3500 RPM), and the mother liquid was then poured off. The remaining solid was dissolved in hexane and refrigerated (5±3° C.) overnight. Filtration of the precipitate yielded 50 grams of pure (R)-1-octadecyl-3-trityl-glycerol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH2:22][CH:23]([CH3:25])[CH3:24])(=[O:11])=[O:10])=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[N:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH2:22][CH:23]([CH3:25])[CH3:24])(=[O:10])=[O:11])=[C:4]([C:26]([F:29])([F:27])[F:28])[CH:3]=2)=[CH:32][CH:31]=1
Reactant: CC(C)Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
Reactant: OB(O)c1ccncc1
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: CCO
Solvent: COCCOC
Product: CC(C)Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2C(F)(F)F)sc2ccc(F)cc12
Yield: 471.7 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-isobutyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.10 g) and 4-pyridineboronic acid (0.036 g) in 1,2-dimethoxyethane (7 ml), ethanol (1 ml) and 2 molar sodium carbonate (2.0 ml) with tetrakis(triphenylphosphine)palladium (0.027 g) to obtain the title compound (0.47 g) as a yellowish solid. MS (ISN): 507.1 (M−H)−
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8](=[O:35])[C@@H:9]([NH:18][C:19]([C:21]1([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1.[CH3:36][N:37]1[CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42](B(O)O)[CH:43]=2)[C:38]1=[O:49]>O.C(#N)C>[NH2:7][C:8](=[O:35])[C@@H:9]([NH:18][C:19]([C:21]1([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:42]2[CH:43]=[C:44]3[C:39](=[CH:40][CH:41]=2)[C:38](=[O:49])[N:37]([CH3:36])[CH2:45]3)=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Reactant: CN1Cc2cc(B(O)O)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN1Cc2cc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)ccc2C1=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
Potassium carbonate (276 mg) in water (2.0 mL) was added to (S)-tert-butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 517 mg), 2-methyl-1-oxoisoindolin-5-ylboronic acid (Example 31, step (iii), 191 mg) and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (98 mg) in degassed acetonitrile (12 mL) at 20° C. under nitrogen. The resulting solution was stirred at 80° C. for 30 min. The reaction mixture was cooled, filtered and diluted with dichloromethane, and washed with water. The organic extract was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by chromatography in silica eluting with methanol/ethyl acetate (5:95 to 15:85). Pure fractions were evaporated to dryness to afford the sub-titled compound (469 mg).
Reaction SMILES: [S:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C([Li])CCC.[CH3:15][Sn:16](Cl)([CH3:18])[CH3:17]>C1COCC1>[CH3:15][Sn:16]([CH3:18])([CH3:17])[C:2]1[S:1][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1
Reactant: C[Sn](C)(C)Cl
Reactant: c1cc2ccsc2cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cc2ccncc2s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
A solution of thieno[2,3-c]pyridine (J. Wikel, et al., J. Heterocycl. Chem., 1993, 30, 289) (2.0 g, 14.8 mmol) in THF (50 mL) at −78° C. was treated with n-butyllithium (2.5 M solution in hexane, 7.1 mL, 17.8 mmol), warmed to 0° C., stirred for 15 minutes, cooled to −78° C., treated slowly with trimethyltin chloride (3.54 g, 17.8 mmol) in THF (10 mL), warmed to room temperature for 2 hours, and partitioned between ethyl acetate and brine. The ethyl acetate solution was washed with water, and concentrated. The residue was purified by flash chromatography (10-35% ethyl acetate in hexane) to provide the desired product (3.15 g, 71%). MS (APCI) m/e 298 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[F:20][C:21]([F:29])([F:28])[C:22](=[O:27])[CH2:23][C:24](=O)[CH3:25].C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[C:8]([C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:24]([CH3:25])[C:23]([C:22](=[O:27])[C:21]([F:29])([F:28])[F:20])=[C:12]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1ccc(N)c(C(=O)c2ccccc2)c1
Reactant: CC(=O)CC(=O)C(F)(F)F
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1nc2ccc(C(C)(C)C)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 37 %

Procedure:
The title compound was prepared from (2-Amino-5-tert-butyl-phenyl)-phenyl-methanone [example A1] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that the solvent was isopropanol, the reaction time was of 16 h and heptane/ethyl acetate (1:2) was used. Yield: 37%; MS: m/z=372 (M+H).
Reaction SMILES: [C:1]([C:3]1[N:7]2[C:8]3[C:13]([N:14]=[C:15]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])[C:6]2=[N:5][CH:4]=1)=[CH:12][C:11]([C:21]([F:24])([F:23])[F:22])=[CH:10][CH:9]=3)#[CH:2].[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Na]>ClCCl>[C:1]([C:3]1[N:7]2[C:8]3[C:13]([N:14]=[C:15]([NH:16][CH2:17][CH2:18][CH2:19][O:20][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][O:25]4)[C:6]2=[N:5][CH:4]=1)=[CH:12][C:11]([C:21]([F:22])([F:23])[F:24])=[CH:10][CH:9]=3)#[CH:2]
Reactant: C1=COCCC1
Reactant: C#Cc1cnc2c(NCCCO)nc3cc(C(F)(F)F)ccc3n12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: ClCCl
Product: C#Cc1cnc2c(NCCCOC3CCCCO3)nc3cc(C(F)(F)F)ccc3n12
Temperature: 0 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 3-{[1-ethynyl-7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-4-yl]amino}propan-1-ol as prepared in example 30 (334 mg, 1.0 mmol) in anhydrous dichloromethane (10 mL) cooled at 0° C., were added 3,4-dihydro-2H-pyran (109 μL, 1.2 mmol) and para-toluenesulfonic acid (19 mg, 0.1 mmol). The mixture was stirred at room temperature overnight and then poured onto a saturated aqueous solution of sodium hydrogenocarbonate and extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (silica gel, dichloromethane/methanol 20/1) to afford the title compound (302 mg, 72%) as a white solid.
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:12][O:13][CH2:14][C:15]1([N:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22](=[O:25])[CH2:23][CH3:24])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CC(NC(C)C)C>CC(C)CC(=O)C>[C:3]([CH:2]([N:18]1[CH2:19][CH2:20][C:15]([N:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22](=[O:25])[CH2:23][CH3:24])([CH2:14][O:13][CH3:12])[CH2:16][CH2:17]1)[CH3:11])(=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCNCC1
Reactant: CC(Br)C(=O)c1ccccc1
Solvent: CC(=O)CC(C)C
Solvent: CC(C)NC(C)C
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(C(C)C(=O)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 3.6 parts of 2-bromo-1-phenyl-1-propanone, 4.1 parts of N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide, 3.5 parts of N-(1-methylethyl)-2-propanamine and 80 parts of 4-methyl-2-pentanone is stirred and refluxed for 16 hours. The reaction mixture is cooled to room temperature and the precipitate is filtered off. The filtrate is evaporated. The oily residue is purified by column-chromatography over silicagel, using a mixture of trichloromethane and 3% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue solidifies on triturating in petroleumether. The product is filtered off and crystallized from 2,2'-oxybispropane. It is filtered off again and dried, yielding N-[1-(1-benzoylethyl)-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide; mp. 123° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@:10]2([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:11](=[O:12])[C@@H:6]([C@:7]([CH3:28])([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C@@H:8]([O:18][CH2:19][O:20][CH3:21])[CH2:9]2)[C:5](=[O:29])[CH:4]=1.Cl[Si:31]([CH3:34])([CH3:33])[CH3:32].[Li]N1C(C)(C)CCCC1(C)C>C1COCC1>[CH3:1][O:2][C:3]1[C@:10]2([CH2:13][CH:14]=[C:15]([CH3:16])[CH3:17])[C:11](=[O:12])[C@@H:6]([C@:7]([CH3:28])([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C@@H:8]([O:18][CH2:19][O:20][CH3:21])[CH2:9]2)[C:5](=[O:29])[C:4]=1[Si:31]([CH3:34])([CH3:33])[CH3:32]
Reactant: COCO[C@H]1C[C@@]2(CC=C(C)C)C(=O)[C@H](C(=O)C=C2OC)[C@]1(C)CCC=C(C)C
Reactant: C[Si](C)(C)Cl
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: C1CCOC1
Product: COCO[C@H]1C[C@@]2(CC=C(C)C)C(=O)[C@H](C(=O)C([Si](C)(C)C)=C2OC)[C@]1(C)CCC=C(C)C
Yield: 95 %

Procedure:
A flame-dried round-bottom flask with magnetic stir bar was charged with 380 mg (0.939 mmol, 1 equiv.) starting material 50 followed by 9.4 mL THF and 596 μL (4.70 mmol, 5 equiv.) of chlorotrimethylsilane with stirring. The solution was cooled in an acetone/dry ice bath for 10 minutes prior to the addition of 9.4 mL of a 0.5M solution of lithium tetramethylpiperidide in THF (4.7 mmol, 5 equiv.). The mixture was stirred at −78° C. for 10 minutes before placing the reaction in a water/ice bath for an additional 10 minutes. The reaction was quenched by the addition of 2 mL of saturated aqueous sodium bicarbonate and transferred to a separatory funnel by the addition of 50 mL hexane. The organic layer was then washed with saturated aqueous sodium bicarbonate, 10% aqueous hydrochloric acid, water, and saturated brine solution. The organic layer was then dried with MgSO4 and concentrated in vacuo to give a yellow oil. Purification by silica gel chromatography (Rf=0.25 in 9:1 hexane:ethyl acetate) gave 425 mg (95% yield) of 51 as a clear oil. 1H NMR (500 MHz, CDCl3) δ ppm 5.06 (tt, J=7.0, 1.3 Hz, 1H), 4.99 (tt, J=6.9, 1.4 Hz, 1H), 4.59 (dd, J=35.6, 6.8 Hz, 2H), 3.92 (s, 3H), 3.60 (dd, J=11.5, 5.2 Hz, 2H), 3.33 (s, 3H), 3.17 (s, 1H), 2.55 (dd, J=14.5, 6.3 Hz, 1H), 2.38-2.38 (m, 0H), 2.40 (dd, J=14.6, 7.4 Hz, 1H), 2.27-2.34 (m, 1H), 2.24 (dd, J=13.5, 5.2 Hz, 4H), 1.84-1.94 (m, 1H), 1.81 (dd, J=13.4, 11.6 Hz, 2H), 1.63-1.68 (m, 12H), 1.55 (ddd, J=13.0, 4.5 Hz, 1H), 1.17-1.26 (m, 1H), 0.91 (s, 3H), 0.23-0.24 ppm (m, 9H). 13C NMR (126 MHz, CDCl3) δ ppm 205.9, 197.8, 185.8, 134.2, 131.8, 127.4, 124.4, 119.4, 97.3, 79.2, 70.8, 64.4, 58.4, 55.8, 46.5, 37.7, 37.4, 29.8, 26.0, 25.9, 21.6, 18.1, 17.8, 16.4, 0.7. HRMS-ESI (m/z): [M+H]+ calculated C27H44O5Si, 477.3031. found 477.3031.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[NH:4][CH2:3]1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=2)[N:22]=[C:21]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:20]=1[CH3:36].[H-].[Na+]>CN(C=O)C>[CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[N:4]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=3)[N:22]=[C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:20]=2[CH3:36])[CH2:3]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)ccc21
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(N3CCOCC3)cc21
Temperature: 130 °C

Procedure:
Prepared according to procedure M using 3,3-dimethyl-6-morpholinoindoline (85 mg, 0.367 mmol) in DMF (6 mL), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (100 mg, 367 μmol) and sodium hydride (18 mg, 733 μmol) and heating at 130° C. overnight. After purification 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-7-fluoro-3-methyl-2-(2-pyridinyl)quinoline was obtained as a yellow film. 1H NMR (500 MHz, chloroform-d) δ ppm 8.73-8.76 (1H, m), 7.80-7.94 (4H, m), 7.40 (1H, ddd, J=7.6, 4.9, 1.5 Hz), 7.20-7.27 (1H, m), 7.08 (1H, d, J=8.3 Hz), 6.31 (1H, dd, J=8.1, 2.2 Hz), 5.59 (1H, d, J=2.4 Hz), 3.69-3.81 (6H, m), 2.89-3.03 (4H, m), 2.37 (3H, s), 1.51 (3H, s), 1.46 (3H, s). Mass Spectrum (ESI) m/e=469 (M+1).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14]O.C(N(CC)CC)C.[CH2:25]([O:28][C:29]([C:31]1[N:32]([NH2:36])[CH:33]=[CH:34][CH:35]=1)=[O:30])[CH:26]=[CH2:27].C([BH3-])#N.[Na+]>ClCCl.C(O)(=O)C>[CH2:25]([O:28][C:29]([C:31]1[N:32]([NH:36][CH2:14][CH2:13][C:12]([CH3:17])([CH3:16])[CH3:11])[CH:33]=[CH:34][CH:35]=1)=[O:30])[CH:26]=[CH2:27]
Reactant: C=CCOC(=O)c1cccn1N
Reactant: CC(C)(C)CCO
Agent: O=C(Cl)C(=O)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: C=CCOC(=O)c1cccn1NCCC(C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 37.5 %

Procedure:
Dimethylsulfoxide (6.80 mL, 95.7 mmol) was added over 5 min to a solution of oxalylchloride (23.9 mL, 47.8 mmol) in dichloromethane at −78° C. The resulting mixture was stirred at −78° C. for 5 min, then 3,3-dimethyl-butan-1-ol (5.22 mL, 43.1 mmol) was added. After stirring an additional 30 min at −78° C., triethylamine (23.3 mL, 167 mmol) was added and the reaction mixture warmed to 0° C. and stirred at that temperature for 45 min. The mixture was then transferred to a separatory funnel and was washed with 0.5 M aqueous hydrochloric acid. The organic layer was dried over sodium sulfate, filtered and was concentrated in vacuo to a volume of about 70 mL (water bath temperature=0° C.). Methanol (100 mL) was added followed sequentially by 1-amino-1H-pyrrole-2-carboxylic acid allyl ester (Example 1b, 7.16 g, 43.1 mmol), acetic acid (6 mL), and sodium cyanoborohydride (5.42 g, 86.3 mmol). The reaction mixture was stirred at 23° C. for 2 h, and then was partitioned between saturated aqueous sodium bicarbonate solution (400 mL) and a 1:1 mixture of ethyl acetate and hexanes (2×200 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (Merck silica gel 60, 40-63 μm, 5→10% ethyl acetate in hexanes) afforded the desired product, 1-(3,3-dimethyl-butylamino)-1H-pyrrole-2-carboxylic acid allyl ester (4.04 g, 16.15 mmol, 37% yield) as a clear liquid. 1H NMR (400 MHz, CDCl3) δ: 0.91 (9H, s), 1.42-1.46 (2H, m), 2.98-3.04 (2H, m), 4.75-4.77 (2H, m), 5.26-5.28 (1H, m), 5.37-5.41 (1H, m), 5.96-5.99 (1H, m), 6.01-6.05 (1H, m), 6.27-6.30 (1H, m), 6.89-6.91 (1H, m), 6.96-6.98 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[S:9](=[O:19])(=[O:18])[NH:8][CH2:7][C:6]=2[CH:20]=1.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25]O>>[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][N:8]1[CH2:7][C:6]2[CH:20]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[S:9]1(=[O:19])=[O:18]
Reactant: O=S1(=O)NCc2cc(F)ccc2N1c1ccccc1F
Reactant: OCCCCBr
Product: O=S1(=O)N(CCCCBr)Cc2cc(F)ccc2N1c1ccccc1F
Yield: 75 %

Procedure:
In an analogous manner to Example 11 step 4, a solution of 6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.51 g, 1.7 mmol) was reacted with 4-bromobutanol (0.53 mL, 3.4 mmol) to afford 3-(4-bromobutyl)-6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.55 g, 74%) as a white solid: