Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.Cl[C:7]1[CH:12]=CC=C(Cl)[N+]=1CC.C(O)C.[C:19]1([CH2:25][C:26]([OH:28])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CCCC)CCCC)CCC>C(Cl)Cl>[C:19]1([CH2:25][C:26]([O:28][CH2:7][CH3:12])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: CC[n+]1c(Cl)cccc1Cl
Agent: F[B-](F)(F)F
Solvent: CCCCN(CCCC)CCCC
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)Cc1ccccc1
Yield: 90 %

Procedure:
To a CH2Cl2 (2 ml) solution of 2,6-dichloro-1-ethylpyridinium tetrafluoroborate (630 mg, 2.4 mmol) was added a mixture of ethyl alcohol (92 mg, 2.0 mmol), phenylacetic acid (272 mg, 2.0 mmol) and tri-n-butylamine (888 mg, 4.8 mmol) in CH2Cl2 (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and ethyl phenylacetate was isolated in 90% yield.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:29])[N:11]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[CH2:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[CH:14]=1)[CH2:2]2.[Cl:30][CH2:31][C:32]([C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)=[O:33]>>[Cl-:30].[F:28][C:24]1[CH:23]=[C:22]([N:11]([CH2:12][C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[CH:14]=2)[C:10]([O:9][C@@H:3]2[CH:4]3[CH2:5][CH2:6][N+:1]([CH2:31][C:32](=[O:33])[C:34]4[S:35][CH:36]=[CH:37][CH:38]=4)([CH2:8][CH2:7]3)[CH2:2]2)=[O:29])[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(CCl)c1cccs1
Reactant: O=C(O[C@H]1CN2CCC1CC2)N(Cc1cc(F)c(F)c(F)c1)c1cccc(F)c1
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)N(Cc1cc(F)c(F)c(F)c1)c1cccc(F)c1)C2)c1cccs1
Product: [Cl-]

Procedure:
Analogously (3R)-3-[(3-fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-(2-oxo-2-thiophen-2-yl-ethyl)-1-azoniabicyclo[2.2.2]octane chloride [Compound 7] was prepared starting from the free base of (3R)-(3-fluorophenyl)-(3,4,5-trifluorobenzyl)carbamic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester by reaction with 2-chloro-1-thiophen-2-yl-ethanone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[CH3:10][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI.O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH3:10])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C#Cc1ccc(Br)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CC#Cc1ccc(Br)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 1-bromo-4-ethynyl-benzene (500 mg, 2.8 mmol) in tetrahydrofuran (20 mL) at −30° C. was slowly added sodium bis(trimethylsilyl)amide in tetrahydrofuran solution (1M, 4.2 mL). After stirring 15 min, methyl iodide (1.1 g, 8.4 mmol) was added at −20° C. The resulting reaction mixture was stirred at RT for 50 min before it was added to water. The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate and concentrated. The crude product 1-bromo-4-prop-1-ynyl-benzene was obtained as a volatile liquid (450 mg, 82.8% yield) which was put to next step directly without further purification. 1H NMR (400 MHz, MeOD) δ ppm 7.34 (d, J=8.3 Hz, 10H), 7.14 (d, J=8.3 Hz, 10H), 1.91 (s, 3H); GCMS, (M+1)=195.1, Molecular Formula=C9H7Br.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=O)[CH2:9]2)[CH:7]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl.O>C(O)C>[ClH:26].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]2)[CH:7]=1
Reactant: Cc1ccc(F)cc1C1CC(=O)c2c(C)ccnc2C1
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc(F)cc1C1CC(=NNC(=N)N)c2c(C)ccnc2C1
Yield: 94.7 %

Procedure:
A solution of 7-(5-fluoro-2-methylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.1 g) and aminoguanidine hydrochloride (0.54 g) in ethanol (30 ml) was combined with concentrated hydrochloric acid (1.0 ml) and water (1.0 ml) and heated under reflux for 6 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in water and washed with ethyl acetate. The aqueous layer was made alkaline with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol, combined with 1N hydrochloric acid (10 ml) and concentrated, and then the precipitated crystal was recrystallized from ethanol to obtain 7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound C) (1.4 g) as a colorless crystal.
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)([CH:10]1[O:15][CH2:14][CH2:13][N:12](CC2C=CC=CC=2)[CH2:11]1)[OH:9].CCN(C(C)C)C(C)C.[Cl:43]C(OC(Cl)C)=O>C(Cl)Cl>[ClH:43].[C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27]1)([CH:10]1[O:15][CH2:14][CH2:13][NH:12][CH2:11]1)[OH:9]
Reactant: OC(Cc1ccccc1-c1ccccc1)(C1CCCC1)C1CN(Cc2ccccc2)CCO1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: OC(Cc1ccccc1-c1ccccc1)(C1CCCC1)C1CNCCO1

Procedure:
The free base of 48 is prepared from 47 (1.75 g, 3.95 mmol), solid supported Hünig's base (2.22 g) and α-chloroethyl chloroformate (1.62 mL) in anhydrous DCM (30 mL) following General Procedure 3. Purification by ion exchange chromatography followed by flash column chromatography (eluent, MeOH/DCM 1/99 to 20/80 [v/v]) gives the free base as a viscous oil (805 mg, 58%) which is converted into 48 following General Procedure 4. MW 387.95; C23H29NO2.HCl; 1H NMR (CD3OD): δ 7.66-7.40 (1H, m) 7.19-7.47 (8H, m), 3.92 (1H, dd, 13 Hz, 3.5 Hz), 3.59-3.67 (2H, m), 3.05-3.16 (4H, m), 2.93 (1H, td, 13 Hz, 3.5 Hz,), 2.59 (1H, t, 12 Hz), 1.98-1.88 (1H, m), 1.55-1.19 (8H, m); LCMS: (12 minute method) m/z 351 [M−HCl+H]+, RT 5.68 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:21][CH3:22])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.CN(C=O)C.[CH3:28][C:29]([CH3:33])([CH3:32])[C:30]#[CH:31]>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.[Cu]I>[CH3:28][C:29]([CH3:33])([CH3:32])[C:30]#[C:31][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:21][CH3:22])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc2c(c1)C1(COC(N)=N1)c1cc(Br)cnc1O2
Reactant: C#CC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C1(COC(N)=N1)c1cc(C#CC(C)(C)C)cnc1O2
Temperature: 90 °C

Procedure:
3-Bromo-7-methoxy-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (104186-10-peak 1) (500 mg, 1.381 mmol), tetrakis(triphenylphosphine)palladium (160 mg, 0.138 mmol), copper(i) iodide (52.6 mg, 0.276 mmol) were combined, and to the mixture was added DMF (6903 μL, 1.381 mmol), 3,3-dimethylbut-1-yne (340 mg, 4.14 mmol) and DIPA (4837 μL, 34.5 mmol). The reaction was flushed with argon, sealed and heated at 90° C. for 2 hours. The reaction mixture was diluted with water (100 mL) and poured into a separatory funnel containing EtOAc (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and then brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide the desired product contaminated with triphenylphosphine. The yellow solid was suspended in 25 mL of ether, resulting in the formation of a fine white precipitate. Decanted ether and washed the solid with 10 mL of ether. Dried under reduced pressure to provide 3-(3,3-dimethylbut-1-ynyl)-7-methoxy-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a white solid.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[Li]CCCC.[Cl-].[C:24]1([PH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[NH4+].[Cl-]>C1COCC1>[C:31]1([P:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:2]2[C:15]3[C:16]4=[C:17]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][CH:9]=[C:8]5[CH:7]=[CH:6][C:5]4=[CH:4][CH:3]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Brc1ccc2ccc3cccc4ccc1c2c34
Reactant: c1ccc(Pc2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: c1ccc(P(c2ccccc2)c2ccc3ccc4cccc5ccc2c3c45)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
Bromopyrene (5 mmol, 1.41 g) was charged and dissolved in THF (25 ml). After the solution was cooled to −78° C., n-BuLi (5.5 mmol, 2.08 ml, 2.64 M, 1.1 eq) was slowly added dropwise to the solution and the mixture was stirred for 2 hours. Then, diphenylphosphine chloride (5 mmol, 0.92 ml, 1 eq) was slowly added dropwise to the mixture, followed by stirring overnight. Saturated NH4Cl (10 mL) was added to the mixture. The THF layer was separated from the aqueous layer. The aqueous layer was extracted with dichloromethane (50 mL×3). The organic layer and the THF layer were combined. The resulting mixture was dried over sodium sulfate and concentrated on an evaporator. The residue was purified by silica gel column chromatography (developing solvent: dichloromethane:hexane=1:3). Thus, diphenylpyrenylphosphine (DPPP) was obtained (yield 39%) as white yellow crystals. The crystals were identified by 1H-NMR and 31P-NMR.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[F:39]>>[CH:18]1([N:13]2[C:12]([C:36]3[CH:35]=[CH:34][C:33]([F:32])=[C:38]([F:39])[CH:37]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Fc1ccc(-c2c3c(nn2C2CCCCC2)CCNCC3)cc1F
Yield: 29.4 %

Procedure:
The title compound (42.7 mg) was prepared as in Example 177, Steps C and D, using 205.2 mg of 2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 177, Step B) and 224.9 mg of 3,4-difluorophenylboronic acid. MS (ESI): exact mass calculated for C19H23F2N3, 331.40. found, m/z 332.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.51-7.44 (m, 1H), 7.34-7.28 (m, 1H), 7.17-7.13 (m, 1H), 3.91-3.84 (m, 1H), 3.42-3.38 (m, 2H), 3.18-3.14 (m, 2H), 2.78-2.74 (m, 2H), 1.96-1.78 (m, 6H), 1.70-1.64 (m, 1H), 1.32-1.19 (m, 3H).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:11][C:12]#[N:13].[K+].[NH2:15][C:16]1[CH:37]=[CH:36][C:19]([O:20][C:21]2[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:29])[CH:22]=2)=[C:18]([F:38])[CH:17]=1.CCCCCC>C(#N)C.C(OCC)C>[F:38][C:18]1[CH:17]=[C:16]([NH:15][C:12]([NH:13][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:11])[CH:37]=[CH:36][C:19]=1[O:20][C:21]1[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:29])[CH:22]=1
Reactant: Nc1ccc(Oc2cc(NC(=O)N3CCCCC3)ncn2)c(F)c1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Solvent: CCCCCC
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCCCC3)ncn2)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.8 %

Procedure:
2-Phenylacetyl chloride (0.068 ml) was dissolved in acetonitrile (5 ml) under a nitrogen atmosphere, and then potassium thiocyanate (100 mg) was added thereto at 60° C., followed by stirring at the same temperature for 1.5 hrs. The reaction mixture was cooled down to room temperature, and then a solution of piperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (114 mg) in acetonitrile (3 ml) was added thereto, followed by stirring for 30 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1). Fractions containing the target compound were concentrated to give a residue, which was suspended in diethyl ether (5 ml)-hexane (5 ml). The solid was filtered off and dried under aeration to provide the titled compound (88.8 mg, 50.8%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][CH2:18][C:19]([CH3:22])([CH3:21])[N:20]=2)=[CH:12][CH:11]=1)[OH:9]>[O-2].[O-2].[Mn+4].ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[O:17][CH2:18][C:19]([CH3:22])([CH3:21])[N:20]=2)=[CH:14][CH:15]=1)=[O:9]
Reactant: Cc1ccccc1C(O)c1ccc(C2=NC(C)(C)CO2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1ccccc1C(=O)c1ccc(C2=NC(C)(C)CO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
2-{4-[1-(2-Methylphenyl)-1-hydroxymethyl]phenyl}-4,4-dimethyl-2-oxazoline (3.0 g), manganese dioxide (20 g) and dichloromethane (50 ml) are mixed at room temperature. The mixture is stirred at room temperature for two hours, and refluxed for three hours. The insoluble materials are removed by filtration through celite, and washed with chloroform, and the mother liquor is concentrated to give 2-[4-(2-methylbenzoyl)phenyl]-4,4-dimethyl-2-oxazoline (2.86 g) as pale yellow oil.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[C:6]([O:9][CH:10]=[CH2:11])(=[O:8])[CH3:7].CO>[O-]S(C(F)(F)F)(=O)=O.[Ag+].O>[C:6]([O:9][CH:10]=[CH:11][CH2:4][CH:3]([CH3:5])[CH:2]=[CH2:1])(=[O:8])[CH3:7]
Reactant: C=CC(=C)C
Reactant: C=COC(C)=O
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CO
Solvent: O
Product: C=CC(C)CC=COC(C)=O
Temperature: 100 °C
Reaction time: 6 h
Yield: 6 %

Procedure:
4 mg (0.016 mmol) of (η6-benzene)ruthenium (II) dichloride, 15 mg (0.058 mmol) of silver triflate and 11.2 mg (0.052 mmol) of N-2-aminoethyl-p-toluenesulfonamide were placed in a sealed tube, which was then charged with 2 ml (20 mmol) of isoprene, 2 ml (22 mmol) of vinyl acetate and 2 ml of methanol. The mixture was heated with stirring at 100° C. for 6 hours in an argon atmosphere. The reaction mixture was poured into water and the organic layer was concentrated to obtain 0.17 g (yield: 6% based on isoprene) of a co-dimer (4-methylhexa-1,5-dien-1-yl acetate) (Purity: 75%, regioisomer: 17%, cyclic dimer of dienes: 8%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH3:13])(=[NH:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N+](C1C=C(S(C)(=NC(OCC)=O)=O)C=CC=1)([O-])=O.[CH:32]([N:35]=[C:36]=[O:37])([CH3:34])[CH3:33]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH3:13])(=[N:12][C:36](=[O:37])[NH:35][CH:32]([CH3:34])[CH3:33])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=N)(=O)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)N=C=O
Agent: CCOC(=O)N=S(C)(=O)c1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)N=S(C)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 104 °C
Reaction time: 60 h

Procedure:
8.24 g (41.2 mmol) (RS)-S-(3-nitrophenyl)-S-methylsulfoximide (Intermediate 4, step 1) in 370 ml toluene were treated with 13.6 mL (138.3 mmol) isopropyl isocyanate. The mixture was stirred under argon at 104° C. for 5 hours and at room temperature for 60 hours. 4.5 mL (46 mmol) isopropyl isocyanate were added and the mixture was stirred under argon at 104° C. for 6 hours and at room temperature for 16 hours. 4.5 ml (46 mmol) isopropyl isocyanate were added and the mixture was stirred under argon at 104° C. for 7 hours and at room temperature for 17 hours. The mixture was cooled with ice for 40 minutes.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:3]=1.[CH2:23]([O:26][C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1)[CH2:24][CH3:25]>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:4]2[N:3]=[C:2]([S:33][C:30]3[CH:31]=[CH:32][C:27]([O:26][CH2:23][CH2:24][CH3:25])=[CH:28][CH:29]=3)[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]3)[N:5]=2)=[CH:16][CH:17]=1
Reactant: CCCOc1ccc(S)cc1
Reactant: COc1ccc(-c2nc(Cl)cc(N3CCN(C)CC3)n2)cc1
Product: CCCOc1ccc(Sc2cc(N3CCN(C)CC3)nc(-c3ccc(OC)cc3)n2)cc1

Procedure:
In the same manner, the above prepared 4-chloro-2-(4-methoxyphenyl)-6-(4-methyl-1-piperazinyl)-pyrimidine is reacted with p-propoxythiophenol to afford 2-(4-methoxyphenyl)-6-(4-methyl-1-piperazinyl)-4-(4-propoxyphenylthio)-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[C:18]([C:25]#[C:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:13]1[C:22]2[C:17](=[C:18]([C:25]#[C:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COc1ccc2c(Cl)nncc2c1C#CCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C#CCCCc1ccccc1
Reaction time: 1 h
Yield: 51.5 %

Procedure:
A solution under N2 of 3,5-dichloro-4-methyl-pyridine (1.28 g, 7.9 mmoles) in dry DMF (15 ml) was added under stirring at room temperature with 60% NaH (316 mg, 7.9 mmoles). The mixture was stirred for 1 hour, then dropwise added with 1-chloro-6-methoxy-5-(5phenyl-pent-1-ynyl)-phthalazine (1.33 g, 3.95 mmoles), prepared as described in example 65, in dry DMF (20 ml). After 3 hours the mixture was poured into water, extracted with ethyl acetate, washed with water, anhydrified over Na2SO4 and brought to dryness. The residue was flash chromatographed (eluent: petrolatum/ethyl acetate 1:1). The separated product was taken up in ethanol (10 ml) and crystallised. The resultant product was filtered and dried under vacuum at 40° C. to give 940 mg of the title compound (yield: 51%). m.p.: 130-132° C.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:5][CH:4]=1.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=1>CS(C)=O>[N:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2([CH2:30][C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[S:17][C:18]3[C:23]2=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:7][CH:8]=1
Reactant: ClCc1ccncc1
Reactant: c1ccc2c(c1)Sc1ccccc1C2Cc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc2c(c1)Sc1ccccc1C2(Cc1ccncc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
A quantity of 0.38 g (8.0 mmole) of 50% sodium hydride oil dispersion was added slowly during 15 minutes to 20 ml of dimethyl sulfoxide at room temperature. After completion of addition, the reaction mixture was heated at 45° for 30 minutes. It was cooled to 15° and a solution of 2.3 g (8.0 mmole) of 9-(4-pyridinylmethyl)thioxanthene in 10 ml of dimethylsulfoxide was added dropwise during 15 minutes at room temperature. After completion of addition, the reaction mixture was stirred 30 minutes at room temperature. Then a solution of 4-picolylchloride (8.75 mmole) in 5 ml of dimethylsulfoxide was added dropwise during 30 minutes at ambient temperature. The reaction was then heated at 40° for 30 minutes. The reaction was quenched by addition of water (50 ml). Trituration of the precipitated oil yielded a crystalline solid, which was filtered off, washed with water and dried. The tan solid was dissolved in benzene and decolorized by stirring with 1 g of Magnesol® for 30 minutes. Filtration and evaporation yielded a colorless product (2.0 g) which was recrystallized from ethylacetate, m.p., 201.4°-203.4°.
Reaction SMILES: [O:1]=[C:2]1[C:13]2=[CH:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([O:23]CC)=[O:22])=[CH:19][C:20]=3[N:12]2[CH2:11][C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:4][NH:3]1.[OH-].[Na+].O.C(O)(=O)C>C(O)C>[O:1]=[C:2]1[C:13]2=[CH:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][C:20]=3[N:12]2[CH2:11][C:5]2([CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)[CH2:4][NH:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)CC1(CCOCC1)CNC3=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc2cc3n(c2c1)CC1(CCOCC1)CNC3=O
Temperature: 80 °C
Yield: 63.1 %

Procedure:
To a suspension of ethyl 1-oxo-2,2′,3,3′,5′,6′-hexahydro-1H-spiro[1,4-diazepino[1,2-a]indole-4,4′-pyran]-8-carboxylate (4.2 g, 12.2 mmol) in ethanol (120 mL) is added NaOH (1.22 g, 30.5 mmol) and water (30 mL). The reaction mixture is heated at 80° C. for 2 h. Acetic acid (19 mL) and water (180 mL) are added and the resulting solid is collected by filtration, washed with water and dried to afford the title compound (2.42 g, 64%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([CH3:8])[CH2:6][CH:5]=[C:4]([CH3:9])[C:3]1=[O:10].C[N:12]1CCOCC1.N>[Pd].[Zn]>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[NH2:12].[CH3:1][CH:2]1[CH:7]([CH3:8])[CH2:6][CH2:5][CH:4]([CH3:9])[C:3]1=[O:10]
Reactant: CN1CCOCC1
Reactant: CC1=CCC(C)C(C)C1=O
Agent: [Pd]
Agent: N
Agent: [Zn]
Product: CC1CCC(C)C(C)C1=O
Product: Cc1ccc(C)c(N)c1C
Reaction time: 10 h

Procedure:
In a stirred autoclave having a useful capacity of 300 parts by volume, a solution of 35 parts of 2,3,6-trimethylcyclohex-5-en-1-one in 35 parts of N-methylmorpholine, 34 parts of ammonia and 5 parts of a finely divided catalyst, containing 0.5% by weight of Pd and 0.1% by weight of Zn on Al2O3, are kept for 10 hours at 230° C. and the autogenous pressure (about 150 bar). The mixture is then allowed to cool, filtered and purified by distillation. 18.2 parts of 2,3,6-trimethylaniline and 15.3 parts of 2,3,6-trimethylcyclohexan-1-one are obtained, the latter presumably through partial hydrogenation of the 2,3,6-trimethylcyclohex-5-en-1-one starting material with the hydrogen formed during the reaction. Since 2,3,6-trimethylcyclohexan-1-one can in turn be converted to the desired 2,3,6-trimethylaniline, for example as described in Example 1 or 2, the selectivity of the reaction is 96%.
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[CH2:8]([C:10]1([CH2:16][CH3:17])[CH2:12][CH:11]1[C:13]([NH2:15])=[O:14])[CH3:9].C1(C)C=CC=CC=1>O>[CH2:8]([C:10]1([CH2:16][CH3:17])[CH2:12][CH:11]1[C:13]([NH:15]/[C:2](=[CH:6]\[CH3:7])/[C:3]([OH:5])=[O:4])=[O:14])[CH3:9]
Reactant: CCC(=O)C(=O)O
Reactant: CCC1(CC)CC1C(N)=O
Solvent: Cc1ccccc1
Solvent: O
Product: C/C=C(\NC(=O)C1CC1(CC)CC)C(=O)O
Yield: 9.7 %

Procedure:
A mixture of 2.3 g of 2-ketobutyric acid, 2.0 g of 2,2-diethylcyclopropanecarboxamide, and 25 ml of toluene was heated under reflux for 16 hrs with removal of H2O by a modified Dean-Stark trap containing molecular sieves (4A). No product precipitated upon cooling. Ether (25 ml) was added and the mixture was extracted with saturated NaHCO3 (3 times). The combined extracts were acidified with concentrated HCl. The gummy precipitate crystallized when triturated with water. Recrystallization from ethyl acetate gave 0.31 g of product, m.p. 129°-30°. The NMR spectrum was consistent with the desired structure.