Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[CH2:6][CH2:7][CH2:8][N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)[NH:11][C:10]=12)=[O:4].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([O:30][CH3:31])[CH:24]=1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:3]([CH:5]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)=[CH:13][C:14](=[O:15])[N:9]3[CH2:8][CH2:7][CH2:6]2)=[O:4])=[C:25]([O:30][CH3:31])[CH:24]=1
Reactant: COC(=O)C1=C2NC(c3ccncn3)=CC(=O)N2CCC1
Reactant: COc1cc(Cl)ccc1N
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(Cl)ccc1NC(=O)C1CCCn2c1nc(-c1ccncn1)cc2=O
Yield: 32.2 %

Procedure:
To a suspension of 0.150 g (0.52 mmol) of (+/−)-4-oxo-2-pyrimidin-4-yl-1,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylic acid methyl ester in a sealed tube in 10.00 mL of toluene was added 0.825 g (5.24 mmol) of 4-chloro-2-methoxy-phenylamine and the resulting mixture was stirred under reflux for 16 hours. The mixture was dissolved in water and ethyl acetate. The organic phases were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography (dichloromethane/methanol/ammoniac in proportions of 100/0/0 to 98/2/02) to afford 0.069 g (32%) of a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[NH2:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Br:8][C:4]1[N:3]=[C:2]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])[CH:7]=[CH:6][CH:5]=1
Reactant: NCC(O)CO
Reactant: Brc1cccc(Br)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: OCC(O)CNc1cccc(Br)n1
Yield: 30.2 %

Procedure:
A stirred solution of 2,6-dibromopyridine (0.76 g, 3.20 mmol), 1-amino-2,3-dihydroxypropane (0.29 g, 3.20 mmol) and DIPEA (0.56 mL, 3.24 mmol) in toluene (3.2 mL) was heated to 160° C. under microwave irradiation in a sealed tube for 2 h, and then concentrated in vacuo. Water (5 mL) was added, the mixture sonicated for 10 minutes, and then filtered through Celite®. The filtrate was concentrated in vacuo to yield the title compound (0.239 g, 30%) as a white solid that was used without further purification. δH (DMSO-d6) 7.29-7.18 (1H, m), 6.92-6.79 (1H, m), 6.61 (1H, d, J 7.3 Hz), 6.51 (1H, d, J 8.3 Hz), 4.79 (1H, d, J 4.9 Hz), 4.58 (1H, t, J 5.8 Hz), 3.65-3.54 (1H, m), 3.15-3.04 (1H, m). Exchangeable protons were not observed. LCMS (ES+) 247.0 and 249.0 (1:1 ratio) (M+H)+, RT 2.07 minutes (Method 1).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([N:13]([CH:27]([CH3:29])[CH3:28])[C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)=[O:12])=[C:4]([CH3:30])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:38]([CH3:49])([C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C)C=O>[CH3:49][C:38]([O:1][C:2]1[CH:3]=[C:4]([CH3:30])[C:5]([C:11](=[O:12])[N:13]([C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:15]2)[CH:27]([CH3:28])[CH3:29])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])([C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:44]([O:46][CH2:47][CH3:48])=[O:45]
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CCOC(=O)C(C)(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Oc1cc(C)c(C(=O)N(C(C)C)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-])C(=O)OCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 105.5 %

Procedure:
To a solution of the obtained 2-methyl-2-propanyl (3R)-3-{[(4-hydroxy-2-methyl-5-nitrophenyl)carbonyl](2-propanyl)amino}-1-piperidinecarboxylate (138 g) in N,N-dimethylformamide (1000 ml) were added potassium carbonate (91 g), diethyl 2-bromo-2-methylmalonate (94 g), and the mixture was stirred at 80° C. for 8 hours. The reaction solution was allowed to cool to room temperature, filtered through celite, and to the filtrate were added a 5% aqueous sodium hydrogen sulfate solution and ethyl acetate, and extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium chloride solution, and then dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give diethyl methyl(5-methyl-4-{[(3R)-1-{[(2-methyl-2-propanyl)oxy]carbonyl}-3-piperidinyl](2-propanyl)carbamoyl}-2-nitrophenoxy)propanedioate (205 g).
Reaction SMILES: [CH:1]1([NH:5][C:6](=[O:20])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:8]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=1[F:31].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:17]2[CH2:16][CH2:15][N:14]([CH2:13][C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[C:6]([NH:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)=[O:20])[CH2:19][CH2:18]2)=[O:27])=[CH:24][C:23]=1[F:31]
Reactant: O=C(NC1CCC1)c1cccc(CN2CCNCC2)c1
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1ccc(C(=O)N2CCN(Cc3cccc(C(=O)NC4CCC4)c3)CC2)cc1F
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of N-cyclobutyl-3-(piperazin-1-ylmethyl)benzamide (8.78 mmol, 2.4 g), 4-amino-3-fluorobenzoic acid (8.78 mmol, 1.362 g) and triethylamine (26.3 mmol, 3.67 mL, 2.67 g) in dichloromethane (50 mL) was added 1-propanephosphonic acid cyclic anhydride (13.17 mmol, 7.84 mL, 8.38 g, 50% solution in ethyl acetate). The reaction was stirred for 1 hour then was diluted with ethyl acetate/sodium hydrogen carbonate (aqueous). The organic layer was separated, dried (magnesium sulfate) and concentrated under reduced pressure to give the title compound (2.4 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:13]([Br:16])[C:14]#[CH:15]>C(O)CCC>[BrH:16].[NH:1]=[C:2]1[N:6]([CH2:15][C:14]#[CH:13])[C:5]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:4]=2[S:3]1
Reactant: C#CCBr
Reactant: COc1ccc2nc(N)sc2c1
Solvent: CCCCO
Product: Br
Product: C#CCn1c(=N)sc2cc(OC)ccc21
Temperature: 100 °C
Yield: 302.4 %

Procedure:
In 100 ml of n-butanol was dissolved 5.0 g of 2-amino-6-methoxybenzothiazole. With heating at 100° C., 25.0 g of propargyl bromide was dropwise added to the solution over 2 hours. The mixture was heated for a further 2 hours. After completion of the reaction, the solvent was evaporated to dryness. After the residue was crystallized with acetone, the crystals were recrystallized from isopropyl alcohol to give 25.1 g of 2-imino-6-methoxy-3-propargylbenzothiazole hydrobromide. The hydrobromide, 24.0 g, was added to sodium ethoxideethanol solution(Na, 2.0 g) followed by refluxing for 1.5 hours. After the reaction mixture was evaporated to dryness, water and ethyl acetate were added to the residue followed by separation. The residue obtained from the ethyl acetate phase was dissolved in ethanol and reacted with hydrochloric acid to convert the same into the hydrochloride. Recrystallization from 95% ethanol gave 17.3 g of 7-methoxy-2-methylimidazo[2,1-b]benzothiazole hydrochloride. The hydrochloride, 17.0 g, was added to a mixture of 10 ml of phosphorus oxychloride and 180 ml of dry dimethylformamide. After stirring at room temperature for one hour, the mixture was heated at 60° C. for 7 hours. The reaction solution was evaporated to dryness and the residue was dissolved in water. The solution was alkalized with potassium carbonate and extracted with chloroform. From the chloroform phase, 14.2 g of 3-formyl-7-methoxy-2-methylimidazo[2,1-b]benzothiazole was obtained. The obtained formyl compound, 3.7 g, was suspended in methanol and treated with 1.0 g of sodium borohydride. The reaction mixture was evaporated to dryness, and the obtained residue was recrystallized from ethanol to give 3.5 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1N=[C:7]2[C:9]([C:13]3[N:24]([S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])[C:16]4[N:17]=[CH:18][CH:19]=[C:20]([CH:21]=[N:22]O)[C:15]=4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:35][CH3:36].[CH:37](O)=O>C(O)C.O.[Zn]>[O:2]([C:3]1[CH:37]=[C:7]2[C:6](=[CH:5][C:4]=1[O:35][CH3:36])[N:11]([CH3:12])[CH:10]=[C:9]2[C:13]1[N:24]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)(=[O:26])=[O:27])[C:16]2=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH2:22])=[C:15]2[CH:14]=1)[CH3:1]
Reactant: O=CO
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(C=NO)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: COc1cc2c(-c3cc4c(CN)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Reaction time: 24 h

Procedure:
To a solution of 0.56 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-carbaldehyde oxime in 30 cm3 of ethanol and 25 cm3 of water, at a temperature in the region of 20° C., is added 0.216 g of zinc and 12 cm3 of concentrated formic acid. A further 0.216 g of zinc is added and the mixture is stirred for a further 24 hours. The reaction medium is stirred at this same temperature for 24 hours. The reaction medium is filtered through Celite and the filtrate is concentrated under reduced pressure. The residue obtained is purified by flash-pack chromatography (SiO2, dichloromethane/methanol 95/05, then dichloromethane/methanol/triethylamine 100/10/1, then dichloromethane/methanol/28% aqueous ammonia 100/10/2 by volume as eluents, Ar). The residue obtained is again purified by flash-pack chromatography (SiO2, dichloromethane/methanol/28% aqueous ammonia 460/40/1.5 by volume as eluents, Ar). 0.03 g of [2-(5,6-dimethoxy1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]methylamine is obtained with the following characteristics:
Reaction SMILES: [Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13])=[CH:3][Cl:4].[NH2:18][C:19]1[N:24]=[C:23]([Cl:25])[CH:22]=[C:21]([O:26][CH3:27])[N:20]=1>O1CCOCC1>[Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]([NH:18][C:19]1[N:24]=[C:23]([Cl:25])[CH:22]=[C:21]([O:26][CH3:27])[N:20]=1)=[O:17])(=[O:13])=[O:14])=[CH:3][Cl:4]
Reactant: COc1cc(Cl)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Solvent: C1COCCO1
Product: COc1cc(Cl)nc(NC(=O)NS(=O)(=O)c2ccccc2OC(Cl)=CCl)n1

Procedure:
7.4 g of 2-(1,2-dichlorovinyloxy)phenylsulfonylisocyanate and 4.0 g of 2-amino-4-chloro-6-methoxypyrimidine are heated to 70°-80° C. in 60 ml of absolute dioxane for 3 hours. After cooling the mixture is treated with activated carbon, filtered and evaporated to 1/5 of the original volume. From the residue crystallise 9.0 g of N-[2-(1,2-Dichlorovinyloxy)phenylsulfonyl]-N'-(4-chloro-6-methoxy-pyrimidin-2-yl)urea, m.p. 196°-198° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C@H:10]1[CH2:13][C@H:12]([NH:14]C(=O)OC(C)(C)C)[CH2:11]1.Cl.O1CCOCC1>C(OCC)C>[ClH:1].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C@H:10]1[CH2:11][C@H:12]([NH2:14])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](Oc2cccc(Cl)c2Cl)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N[C@H]1C[C@H](Oc2cccc(Cl)c2Cl)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 184 %

Procedure:
To 1,1-dimethylethyl {trans-3-[(2,3-dichlorophenyl)oxy]cyclobutyl}carbamate (10.78 g, 17.85 mmol) was added 4M hydrochloric acid in dioxane (150 mL, 600 mmol) and the reaction mixture stirred in a sealed vessel at room temperature for 18 hours. The mixture was then diluted with diethyl ether (300 mL), stirred for 10 min and then filtered and the solid dried in vacuo to give the title compound (4.4096 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)=[CH:21][CH:20]=1
Reactant: Cc1ccc(S)cc1
Reactant: O=C1CCc2cc(OCCCCCl)ccc2N1
Product: Cc1ccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc1

Procedure:
Prepared analogous to Example 1 from 6-(4-chlorobutoxy)-3,4-dihydro-carbostyril (m.p. 147°-148° C.) and 4-methyl-thiophenol.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C1OCCOCCOCCOCCOCCOC1.[H-].[K+].Br[CH2:33][C:34]1[CH:49]=[CH:48][C:37]([C:38]([N:40]([CH3:47])[CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:39])=[CH:36][CH:35]=1>C(#N)C>[CH:41]1([N:40]([CH3:47])[C:38](=[O:39])[C:37]2[CH:48]=[CH:49][C:34]([CH2:33][N:8]3[CH:7]=[N:6][C:5]4[C:9]3=[N:10][C:2]([Cl:1])=[N:3][C:4]=4[Cl:11])=[CH:35][CH:36]=2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CN(C(=O)c1ccc(CBr)cc1)C1CCCCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [K+]
Solvent: CC#N
Product: CN(C(=O)c1ccc(Cn2cnc3c(Cl)nc(Cl)nc32)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.1 %

Procedure:
To a stirred solution of 2,6-dichloropurine (500 mg, 2.64 minol) in acetonitrile (40 mL)at -10° C. was added 18-crown-6 (48 mg, 0.18 mmol) and potassium hydride (106 mg after ether wash of 35% dispersion in mineral oil, 2.64 mmol). The reaction was allowed to warm to room temperature and stirred for an additional 30 min. 4-Bromomethyl-N-methyl-N-cyclohexyl benzamide (900 mg, 2.90 mmol) was added in small amounts over 10 min and the mixture stirred under argon at 25° C. After 18 hr, the reaction was quenched by adding drops of acetic acid and the solvent removed under reduced pressure at <45° C. The residue was dissolved in ethyl acetate and washed with aqueous potassium carbonate, water and brine. The solvent was removed and the crude mixture (1.28 g) chromatographed (silica gel, CH2Cl2 /MeOH 100/7) to give pure 6A (278 mg, 25%). m.p. 134°-136° C. Anal calcd. for C20H21N5OCl2.0.25 H2O:C, 56.80; H, 5.08; N, 16.56; Cl, 16.80. Found: C, 57.00; H, 5.09; N, 16.20; Cl, 16.59.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[N:4]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[C:26]=1[C:27](Cl)=[O:28]>C1COCC1>[F:24][C:25]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[C:26]=1[C:27]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[N:4]=1)=[O:28]
Reactant: CNc1cccc(OC2CCN(C)CC2)n1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCC(Oc2cccc(N(C)C(=O)c3c(F)cc(F)cc3F)n2)CC1
Temperature: 55 °C

Procedure:
Dissolve the above amine product in THF (6 mL), add triethylamine (219 mg, 0.29 mL, 2.08 mmol) and 2,4,6-trifluorobenzoyl chloride (303 mg, 1.56 mmol) sequentially, heat at 55° C. overnight. Quench with 0.1N NaOH, extract with methylene dichloride three times. Combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 3.5% 2M NH3-methanol in methylene dichloride provides 204 mg (43% two-step yield) of the title compound as a colorless oil: mass spectrum (ion spray): m/z=380.1 (M+1); 1H NMR (CDCl3, ppm): 7.47 (t, 1H), 6.53 (m, 4H), 4.74 (m, 1H), 3.48 (s, 3H), 2.71 (m, 2H), 2.32 (s, 3H), 2.25 (m, 2H), 1.91 (m, 2H), 1.72 (m, 2H). Mono-hydrochloride salt: Anal. calc for C19H20F3N3O2.HCl.0.5H2O: C, 53.72; H, 5.22; N, 9.89. Found: C, 53.84; H, 5.04; N, 9.73.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][C:23]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:26][C:25]2[CH:28]=[CH:29][C:22]([F:21])=[C:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH:24]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1ccc(F)c(-c2ccccn2)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc(F)c(-c2ccccn2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 4-fluoro-3-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.72 min.; [M+H]+: 421.08 g/mol.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:31][N:30]([C:32]3[CH:37]=[C:36]([CH:38]([CH3:40])[CH3:39])[CH:35]=[CH:34][C:33]=3[CH3:41])[CH2:29][CH2:28][C:4]=2[N:5]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10]([CH3:27])=[CH:11][N:12]3[S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:7]=1.[CH3:42][C@H:43]1[NH:48][CH2:47][CH2:46][N:45]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:44]1.CCN(C(C)C)C(C)C>CN(C)C(=O)C.CCOC(C)=O>[CH:38]([C:36]1[CH:35]=[CH:34][C:33]([CH3:41])=[C:32]([N:30]2[CH2:29][CH2:28][C:4]3[N:5]=[C:6]([C:8]4[CH:16]=[CH:15][CH:14]=[C:13]5[C:9]=4[C:10]([CH3:27])=[CH:11][N:12]5[S:17]([C:20]4[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=4)(=[O:18])=[O:19])[N:7]=[C:2]([N:48]4[CH2:47][CH2:46][N:45]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:44][C@H:43]4[CH3:42])[C:3]=3[CH2:31]2)[CH:37]=1)([CH3:40])[CH3:39]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc(Cl)c5c(n4)CCN(c4cc(C(C)C)ccc4C)C5)cccc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc5c(c(N6CCN(C(=O)OC(C)(C)C)C[C@H]6C)n4)CN(c4cc(C(C)C)ccc4C)CC5)cccc32)cc1
Temperature: 125 °C

Procedure:
A mixture of 4-chloro-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (Example 17-E) (0.274 g, 0.468 mmol), (R)-tert-butyl 3-methylpiperazine-1-carboxylate (0.375 g, 1.87 mmol) and DIEA (0.33 mL, 1.87 mmol) in N,N-dimethylacetamide (3 mL) was heated at 125° C. for 15 h. Reaction mixture was diluted with EtOAc, washed with sat aq NaHCO3 and brine. The organic layer was then dried over Na2SO4, concentrated, purified via FCC (0-40% EtOAc/heptane) to provide the title compound. MS (ESI+) m/z 749.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([O:5][CH2:6][CH2:7][OH:8])[CH2:4][CH2:3]1.[OH-].[Na+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>O1CCCC1.ClCCl>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:8][CH2:7][CH2:6][O:5][C:2]2([CH3:1])[CH2:4][CH2:3]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CC1(OCCO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOC2(C)CC2)cc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
To the crude 2-(1-methylcyclopropoxy)ethanol from the previous step (0.32 g) in a mixture of 4.6N sodium hydroxide (6.3 mL, 2.52 mmol) and tetrahydrofuran (3 mL) was added 4-methylbenzene-1-sulfonyl chloride (2.1 g, 11.2 mmol) in dichloromethane (6 mL) at 0-5° C. The solution was stirred for 3 h at 0-5° C., and then extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to obtain crude product (100 mg), which was used in the next step without further purification.
Reaction SMILES: Cl.[CH:2]1([CH2:5][C:6](=[NH:8])[NH2:7])[CH2:4][CH2:3]1.C[O-].[Na+].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([C:32](=O)[CH2:33][CH2:34][CH2:35][CH3:36])[C:28](OC)=[O:29])=[CH:22][CH:21]=1)#[N:13]>CO>[CH2:33]([C:32]1[N:8]=[C:6]([CH2:5][CH:2]2[CH2:4][CH2:3]2)[NH:7][C:28](=[O:29])[C:27]=1[CH2:26][C:23]1[CH:22]=[CH:21][C:20]([C:15]2[C:14]([C:12]#[N:13])=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:25][CH:24]=1)[CH2:34][CH2:35][CH3:36]
Reactant: N=C(N)CC1CC1
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc(CC2CC2)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 75.6 %

Procedure:
A solution of 2-cyclopropylethanimidamide hydrochloride (3.9 g), 28% sodium methoxide (8.7 mL) and methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (5.0 g) in methanol (50 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and water and 1 M hydrochloric acid were added. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (4.3 g, 76%) as a pale-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10](Br)[CH3:11])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:21]=C[C:19](OC)=[CH:18][CH:17]=1.C[N:25](C)C1C=CC=CC=1.Cl>>[CH3:14][O:15][C:16]1[CH:21]=[C:11]2[C:19](=[CH:18][CH:17]=1)[NH:25][C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[CH:10]2
Reactant: COc1ccc(C(=O)C(C)Br)cc1
Reactant: COc1ccc(OC)cc1
Reactant: CN(C)c1ccccc1
Agent: Cl
Product: COc1ccc(-c2cc3cc(OC)ccc3[nH]2)cc1
Temperature: 25 °C

Procedure:
A solution of p-methoxy-2-bromopropiophenone ((1 g, 4.11 mmol) was added to a solution of p-methoxyanisole in N,N dimethylaniline (1.7 g, 13.82 mmol)) and heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, poured into 2N HCl, and extracted with EtOAc. The organic extract was washed with water and dried over Na2SO4. Removal of the solvent under reduced pressure and flash chromatography on SiO2 using CH2Cl2 gave the desired intermediate compound 2.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4]1.Br[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[CH:27]=[CH:28][CH:29]=[C:20]([C:21]=23)[S:19]1(=[O:31])=[O:30].S1(=O)(=O)C2=CC=CC3=CC=CC(=C23)N1.BrCCCCBr>>[O:30]=[S:19]1(=[O:31])[C:20]2=[CH:29][CH:28]=[CH:27][C:26]3=[CH:25][CH:24]=[CH:23][C:22](=[C:21]23)[N:18]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4]1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCBr
Reactant: NCC1CCc2ccccc2O1
Agent: O=S1(=O)Nc2cccc3cccc1c23
Solvent: BrCCCCBr
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCCNCC1CCc2ccccc2O1

Procedure:
The compound is prepared from 2-aminomethyl-3,4-dihydro-2H-chromene and 2-(4-bromobutyl)-2H-naphth[1,8-cd]isothiazole 1,1-dioxide (available from 2H-naphth [1,8-cd]isothiazole 1,1-dioxide and 1,4-dibromobutane using a base) according to the working directions of
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[C:19]#[C:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:30]([S:27]([C:23]1[CH:22]=[C:21]([C:20]#[C:19][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:17]=[CH:18][C:9]=2[O:8][CH2:7][C:6]([OH:33])=[O:5])[CH:26]=[CH:25][CH:24]=1)(=[O:29])=[O:28])[CH2:31][CH3:32]
Reactant: CCCS(=O)(=O)c1cccc(C#Cc2c(OCC(=O)OC(C)(C)C)ccc3ccccc23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCS(=O)(=O)c1cccc(C#Cc2c(OCC(=O)O)ccc3ccccc23)c1
Reaction time: 1 h

Procedure:
A solution of tert-butyl[(1-{[3-(propylsulfonyl)phenyl]ethynyl}-2-naphthyl)oxy]acetate (Intermediate 218, 60 mg; 0.13 mmol) in DCM (1.2 mL) was treated with trifluoroacetic acid (98 μl; 0.65 mmol). After stirring for 1 hour, the solvents were removed under vacuum to afford a residue, which was purified by preparative HPLC to give the title compound as a beige solid.