Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.N12CCCN=C1CCCCC2.[Cl:24][C:25]1[C:40]([CH3:41])=[C:39]([N+:42]([O-:44])=[O:43])[C:28]([NH:29][C:30](OC2C=CC=CC=2)=[O:31])=[C:27]([F:45])[CH:26]=1.Cl>CN(C)C=O.O>[Cl:24][C:25]1[CH:26]=[C:27]([F:45])[C:28]([N:29]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:30]2=[O:31])=[C:39]([N+:42]([O-:44])=[O:43])[C:40]=1[CH3:41]
Reactant: Cc1c(Cl)cc(F)c(NC(=O)Oc2ccccc2)c1[N+](=O)[O-]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c1[N+](=O)[O-]
Temperature: -10 °C
Yield: 104.9 %

Procedure:
Ethyl 3-amino-4,4,4-trifluorocrotonate (6.1 g, 33.1 mmol) was dissolved in dimethylformamide (47 ml) and stirred at −10° C. To this solution was slowly added 1,8-diazabicyclo[5.4.0]undec-7-ene (6.3 g, 41.4 mmol) and solution stirred for 0.5 hr. To this solution was slowly added a solution of 4-chloro-2-fluoro-5-methyl-6-nitro-N-phenoxycarbonylaniline (8.5 g) in dimethylformamide (25 ml) followed by stirring at ambient temperature for 14 hr. Solution was then heated to 80° C. and stirred at this temperature for 4 hr. Water was added and pH adjusted to 4 by addition of dilute hydrochloric acid. Product was extracted with ethyl acetate followed by evaporation of the solvent to afford the crude product (10.1 g) which was subjected to N-methylation as follows.
Reaction SMILES: C(OC([N:11]1[C:14]2([CH2:19][CH2:18][CH2:17][N:16]([C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:15]2)[CH:13]([CH3:29])[CH2:12]1)=O)C1C=CC=CC=1>CO.O1CCCC1.[C].[Pd]>[CH3:29][CH:13]1[C:14]2([CH2:19][CH2:18][CH2:17][N:16]([C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:15]2)[NH:11][CH2:12]1
Reactant: CC1CN(C(=O)OCc2ccccc2)C12CCCN(c1ncnc3[nH]ccc13)C2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC1CNC12CCCN(c1ncnc3[nH]ccc13)C2
Reaction time: 14 h
Yield: 89.3 %

Procedure:
To a solution of an optically-active compound of 3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonane-1-carboxylic acid benzyl ester (46 mg) in methanol/tetrahydrofuran (1.8 ml/1.8 ml) was added 10% palladium carbon (15 mg), and the mixture was hydrogenated under 4 atmospheres for 14 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the titled compound (27 mg).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Br:29])=[CH:20][N:21]=[C:22]([O:27]C)[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=O)(C)(C)C.[ClH:30].CO>>[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Br:29])=[CH:20][N:21]=[C:22]([OH:27])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:15])=[O:16])[CH2:10]1.[ClH:30]
Reactant: COc1ncc(Br)c2c(S(=O)(=O)N3CC[C@H](NC(=O)OC(C)(C)C)C3)cccc12
Agent: Cl
Solvent: CO
Product: N[C@H]1CCN(S(=O)(=O)c2cccc3c(O)ncc(Br)c23)C1
Temperature: 50 °C
Reaction time: 50 h

Procedure:
Intermediate 4a (25 mg) obtained in Example 6-1, Step B was added with 10% hydrogen chloride/methanol (10 ml), and the mixture was stirred at 50° C. for 50 hours. The solvent was evaporated under reduced pressure to obtain the title compound as hydrochloride (13 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.[Li]CCCC.[C:15]([N:19]=[C:20]=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([C:20]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])=[N:3][CH:4]=1
Reactant: Cc1cc(Br)ncc1Br
Reactant: CC(C)(C)N=C=O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)NC(C)(C)C)ncc1Br
Temperature: -78 °C
Reaction time: 2 h

Procedure:
2,5-Dibromo-4-methylpyridine (1.83 g, 7.29 mmol) was dissolved in toluene (100 mL), cooled to −78° C. and a solution of nBuLi (4.4 mL, 8.8 mmol, 2.0 M in pentane) was added dropwise and stirred at −78° C. for 2 h. A solution of tBuNCO (1.1 mL, 9.5 mmol) in toluene (3 mL) was added dropwise and stirred for 1 h at −78° C. then warmed to −10° C. and quenched by addition of NH4Cl (aq). After warming to r.t. the reaction was extracted with ether and the organics dried over Na2SO4 and concentrated. The product was used without further purification. MS [M+H]+: 271.0; tR=2.44 min. (method 1)
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:28])[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CN(C)C=O.[Pd]>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:16]([O:15][CH2:14][CH2:13][O:12][C:10](=[O:11])[CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:30][CH:29]=2)=[O:28])=[CH:20][CH:21]=1
Reactant: O=C(COc1ccc([N+](=O)[O-])cc1)OCCOC(=O)COc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc(OCC(=O)OCCOC(=O)COc2ccc(N)cc2)cc1
Yield: 75.8 %

Procedure:
(4—Nitrophenoxy)-acetic acid-2-[2-(4-nitrophenoxy)-acetoxy]-ethyl ester 24 (100 g, 238 mmol) was dissolved in dry dimethyl formamide (500 ml) in a pressure vessel, palladium on carbon (5%, 22 g) was added, and the mixture stirred under an atomsphere of hydrogen (4 kg) for 6 hours. The catalyst was removed by filtration and ice water (2.5 L) was added to the filtrate. Crude 25 was filtered off, dried and recrystallised in a mixture of methanol:chloroform (1:1) to give pure 25 (65 g, 78%) as a light brown shining powder with an m.p. between 124-125.8° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:11])[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.O.C(O)(=O)C.[Br:17]Br>>[Br:17][C:5]1[S:1][C:2]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:3]=2[CH:4]=1
Reactant: O=C1CCCCc2sccc21
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCCCc2sc(Br)cc21
Temperature: -5 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-4-one (4.96 g, 29.8 mmol) in water (23.0 mL, 1200 mmol) and acetic acid (23.0 mL, 4000 mmol) at −5° C. was added a solution of bromine (1.6 mL, 31 mmol) in acetic acid (3.2 mL, 56 mmol) dropwise and the reaction mixture was stirred at −5° C. for 1 hr. The reaction mixture was quenched into aqueous sodium acetate, ethyl acetate (30 mL) was added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated and dried under high vacuum to afford 7.3 g product as a brownish solid (99.0% yield). LCMS: (FA) ES+ , 246. 1H NMR (300 MHz, CDCl3) δ: 7.35-7.36 (br s, 1H), 2.98-3.0 (m, 2H), 2.68-2.73 (m, 2H), 1.85-2.0 (m, 4H).
Reaction SMILES: [OH-].[NH4+:2].[Cl:3][C:4]1[CH:5]=[C:6]2[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([O:33][C@H:34]3[C@H:38]4[O:39][CH2:40][CH:41]([CH2:42][C:43]([O:45]CC)=O)[C@H:37]4[O:36][CH2:35]3)=[N:22][C:7]2=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>C(O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:30])[CH3:32])[C:23]([O:33][C@H:34]3[C@H:38]4[O:39][CH2:40][CH:41]([CH2:42][C:43]([NH2:2])=[O:45])[C@H:37]4[O:36][CH2:35]3)=[N:22][C:7]2=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CC1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Agent: [OH-]
Solvent: CCO
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@@H]3C(CC(N)=O)CO[C@@H]32)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 29 h

Procedure:
Concentrated ammonium hydroxide (0.15 mL) was added to a solution of ethyl 2-[(3aR,6R,6aS)-6-[6-chloro-5-(4-phenylphenyl)-1-(2-trimethylsilylethoxymethyl)-imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]acetate (41.1 mg, 0.063 mmol) in ethanol (0.5 mL). The solution was stirred for 29 hours in a 50 degree oil bath. After cooling to room temperature, additional concentrated ammonium hydroxide (0.3 mL) was added and the mixture was heated for an additional 24 hours in a 50 degree oil bath. The solvents were removed under vacuum to give the title compound. C32H37ClN4O5Si 620.22 observed m/e: 621.38 (M+H)+ (Rt 0.98/2 min)
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B.C1COCC1>CO>[CH3:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: Cc1ncccc1C(=O)O
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ncccc1CO
Temperature: 80 °C
Yield: 78 %

Procedure:
To 2-Methylnicotinic acid (1.00 g, 7.29 mmol) was added BH3.THF (1.0 m in THF, 18 mL, 18 mmol) and the resultant mixture was heated to 80° C. for 20 hours. MeOH (6 mL) was added and the mixture was heated to 80° C. for an additional 2 hours before being cooled to room temperature and concentrated under reduced pressure. The resultant crude syrup was repeatedly dissolved in MeOH (5 mL) and concentrated (3×). Purification by column chromatography on silica gel (4:1—EtOAc:Hexanes) afforded the desired alcohol (700 mg, 80%) as a white solid. 1H NMR (CDCl3) δ 1.96 (t, 1H, J=5.4 Hz), 2.73 (s, 3H), 4.81 (d, 2H, J=5.4 Hz), 7.32 (dd, 1H, J=7.8, 6.3 Hz), 8.03 (d, 1H, J=7.8 Hz), 8.73 (d, 1H, J=5.7 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9]O)=[CH:4][N:3]=1.NC1N=C(N)C(C#N)=CN=1.[CH3:21][O:22][C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:24]=1[NH2:25].Cl>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:28]2[CH:27]=[C:26]([O:30][CH3:31])[C:24]([NH2:25])=[C:23]([O:22][CH3:21])[CH:29]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(CO)c(N)n1
Reactant: COc1cccc(OC)c1N
Agent: Cl
Agent: N#Cc1cnc(N)nc1N
Solvent: CC(=O)O
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1N
Yield: 86.3 %

Procedure:
A mixture of 2,4-diamino-5-hydroxymethylpyrimidine (4.30 g, 30.0 mmol), prepared from 2,4-diamino-5-cyanopyrimidine as described in U.K. Pat. No. 1 413 472, 2,6-dimethoxyaniline (5.05 g, 33.0 mmol), acetic acid (60 mL), and concentrated hydrochloric acid (4.2 mL) was refluxed for 41/2 hours, cooled, and filtered to give the hydrochloride salt of the title compound (7.13 g, 76.2%). The salt was dissolved in water and the solution made basic with concentrated ammonium hydroxide. The resulting precipitate was filtered, washed with water, and dried to give the title compound (5.18 g, 62.7%).
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][C:7]([NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])=[S:8].[CH2:15](I)[CH3:16]>>[CH2:15]([S:8][CH:7]([NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])[NH:6][C:2]1[S:1][CH:5]=[N:4][N:3]=1)[CH3:16]
Reactant: CCOC(=O)NC(=S)Nc1nncs1
Reactant: CCI
Product: CCOC(=O)NC(Nc1nncs1)SCC

Procedure:
[(1,3,4-Thiadiazol-2-ylamino)thioxomethyl]-carbamic acid, ethyl ester (6.96 g) was reacted with 4 ml of ethyl iodide according to the procedure of Prepartion 7 to give 1.83 g of [(ethylthio) (1,3,4-thiadiazol-2-ylamino)methyl]carbamic acid, ethyl ester.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[CH2:16]([NH:23][C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[F:32])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][C:24](=[O:25])[C:26]1[CH:27]=[C:28]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)[CH:29]=[CH:30][C:31]=1[F:32])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(NCc1ccccc1)c1cc(B(O)O)ccc1F
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(F)c(C(=O)NCc2ccccc2)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 2) and 3-(benzylcarbamoyl)-4-fluorophenyl boronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C24H18FN5O, 412. Found, 412.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH:7]([N:20]1[CH2:23][CH:22]([O:24]S(C)(=O)=O)[CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:29][O:30][C:31]([C:33]1[CH:43]=[C:42](O)[C:36]2[CH2:37][C:38]([CH3:41])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32]>CN(C=O)C>[CH3:29][O:30][C:31]([C:33]1[CH:43]=[C:42]([O:24][CH:22]2[CH2:23][N:20]([CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:21]2)[C:36]2[CH2:37][C:38]([CH3:41])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32]
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2c(c1)OC(C)(C)C2
Temperature: 100 °C
Yield: 84 %

Procedure:
Cs2CO3 (1.16 g, 4.95 mmol) was added to a solution of methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (193a) (756 mg, 2.38 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (440 mg, 1.98 mmol) in DMF (6 mL). The mixture was heated to 100° C. for 4 hr, quenched with H2O (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with H2O, dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 30-40% EtOAc in hexanes to give a white sold (740 mg, 84% yield). 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J=7.07 Hz, 4 H) 7.27-7.32 (m, 4 H) 7.18-7.25 (m, 2 H) 7.04 (d, J=1.01 Hz, 1 H) 6.81 (d, J=1.01 Hz, 1 H) 4.87 (t, J=5.81 Hz, 1 H) 3.85 (s, 3 H) 3.76 (ddd, J=7.52, 5.87, 2.02 Hz, 2 H) 3.12 (ddd, J=7.33, 5.56, 1.77 Hz, 2 H) 2.99 (s, 2 H) 1.49 (s, 6 H); LCMS for C28H29NO4 m/z 444.20 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:13])[CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][O:23][CH3:24]>CN(C=O)C>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([C:10](=[O:13])[CH2:11][CH3:12])=[C:2]([O:1][CH2:21][CH2:22][O:23][CH3:24])[CH:7]=1
Reactant: CCC(=O)c1ccc(OC)cc1O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(=O)c1ccc(OC)cc1OCCOC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-(2-hydroxy-4-methoxyphenyl)propan-1-one (1 g, 5.55 mmol) in DMF (50 ml) is treated with potassium carbonate (0.920 g, 6.66 mmol) and stirred at RT for approximately 10 mins. 1-Bromo-2-methoxyethane (0.771 g, 5.55 mmol) is added and the mixture is stirred at RT overnight. The solvent is removed in vacuo and the residue is partitioned between in EtOAc/H2O. The organic phase is separated and washed with sat Na2CO3, 1M HCl, brine, dried (MgSO4) and concentrated in vacuo to afford a dark green/brown oil. Purification by chromatography on silica gel (50 g+70 g) eluting with 20% EtOAc/iso-hexane affords the title compound; MS m/z 239.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[NH2:33][C:34]1[CH:56]=[CH:55][C:54]([N:57]2[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]2)=[CH:53][C:35]=1[C:36]([NH:38][C:39]1[N:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[C:47]([CH3:52])[CH:46]=2)=[CH:41][N:40]=1)=[O:37]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:52][C:47]1[CH:46]=[C:45]([C:42]2[CH:41]=[N:40][C:39]([NH:38][C:36]([C:35]3[CH:53]=[C:54]([N:57]4[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]4)[CH:55]=[CH:56][C:34]=3[NH:33][C:14]([C:13]3[CH:12]=[C:11]([CH:19]=[CH:18][CH:17]=3)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:20])=[O:16])=[O:37])=[N:44][CH:43]=2)[CH:50]=[CH:49][C:48]=1[CH3:51]
Reactant: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3N)nc2)cc1C
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)nc2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 200 %

Procedure:
In a round bottom flask was placed a solution of 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid (88.6 mg, 0.30 mmol, 1.20 equiv) in dichloromethane (15 mL), EDC.HCl (143.2 mg, 0.75 mmol, 3.00 equiv), 4-dimethylaminopyridine (152.1 mg, 1.24 mmol, 5.00 equiv), and 2-amino-N-(5-(3,4-dimethylphenyl)pyrimidin-2-yl)-5-(piperidin-1-yl)benzamide (100 mg, 0.25 mmol, 1.00 equiv). The resulting solution was stirred overnight at 25° C. in an oil bath. The resulting solution was diluted with 50 mL of dichloromethane. The resulting mixture was washed with 1×20 mL of diluted hydrochloric acid and 2×30 mL of brine. The mixture was dried over sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 340 mg of crude product as a brown syrup.
Reaction SMILES: [O:1]=O.[CH:3]([C:6]([O:8][CH2:9][C:10]([CH3:14])(C)[CH:11]=O)=[O:7])([CH3:5])[CH3:4]>>[OH:1][C:10]([CH3:11])([CH3:14])[CH2:9][O:8][C:6]([CH:3]([CH3:4])[CH3:5])=[O:7]
Reactant: O=O
Reactant: CC(C)C(=O)OCC(C)(C)C=O
Product: CC(C)C(=O)OCC(C)(C)O
Yield: 74 %

Procedure:
80 parts of oxygen are passed into 172 parts of isopropylcarbonyloxypivalaldehyde in a stirred reactor at 100° C. in the course of 5 hours. When the reaction has ended, the reaction mixture is subjected to fractional distillation. 118 parts (74% of theory) of 2-hydroxy-1-isopropylcarbonyloxy-2-methylpropane (boiling point 48°-49° C./0.4 mbar) are obtained.
Reaction SMILES: C([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Cl)[CH:13]=2)[N:8]=[C:7]([NH:16][CH2:17][C:18]2[O:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:6]=1)C=C.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][NH2:31])[CH:25]=1>>[CH3:23][C:20]1[O:19][C:18]([CH2:17][NH:16][C:7]2[CH:6]=[C:5]([NH2:4])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([NH:31][CH2:30][C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[CH:13]=3)[N:8]=2)=[CH:22][CH:21]=1
Reactant: C=CCNc1cc(NCc2ccc(C)o2)nc2ccc(Cl)cc12
Reactant: NCc1cccnc1
Product: Cc1ccc(CNc2cc(N)c3cc(NCc4cccnc4)ccc3n2)o1

Procedure:
The title compound, MS: m/e=360.2 (M+H+), was prepared in accordance with the general method of example 44 from N4-allyl-6-chloro-N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,4-diamine and 3-picolylamine.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[C:7](OC)(=O)[C:8](C)=[CH2:9]>C(O)CCC>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OC
Reactant: C=C(C)C(=O)OC
Solvent: CCCCO
Product: C=CC(=O)OCCCC
Reaction time: 2 h
Yield: 97.6 %

Procedure:
The reaction was performed for two hours by adding 172.2 g (2.0 moles) of methyl acrylate in the apparatus of Example 1 instead of the methyl methacrylate. The results of the experiment were 98.4% conversion of n-butanol and 97.6% yield of n-butyl acrylate. When this ester was distilled in the same manner as in Example 1, it was recovered in a 96.6% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)[CH2:13][CH3:14].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:31]1[CH2:30][CH2:29][N:28]([C:25]2[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=2)[CH2:33][CH2:32]1)[CH2:13][CH3:14]
Reactant: CCC1(CCCCCCl)C(=O)Nc2c(Cl)cc(Cl)cc21
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: CCC1(CCCCCN2CCN(c3ccc(Cl)cc3)CC2)C(=O)Nc2c(Cl)cc(Cl)cc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 from 5,7-dichloro-3-(5-chloropentyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(4-chlorophenyl)-piperazine.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=O.[NH2:9][C:10]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]2[C:11]=1[CH2:12][O:13][C:14]2=[O:20].S([O-])([O-])(=O)=O.[Mg+2]>C(#N)C>[F:19][C:17]1[CH:16]=[C:15]2[C:11]([CH2:12][O:13][C:14]2=[O:20])=[C:10](/[N:9]=[CH:7]/[C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)[CH:18]=1
Reactant: Nc1cc(F)cc2c1COC2=O
Reactant: Cn1ccnc1C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: Cn1ccnc1/C=N/c1cc(F)cc2c1COC2=O
Yield: 68.7 %

Procedure:
A solution of 1-methyl-1H-imidazole-2-carbaldehyde (659 mg, 6.0 mmol), 4-amino-6-fluoroisobenzofuran-1(3H)-one (1.0 g, 6.0 mmol), and anhydrous magnesium sulfate (7.2 g, 60.0 mmol) in acetonitrile (100 mL) was heated to reflux for 2 days. The solution was filtered and the solvents were removed in vacuum. The crude product was re-crystallized from isopropanol to afford the title compound (1.068 g, yield 68%) LC-MS (ESI) m/z: 260 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 4.04 (s, 3H), 5.49 (s, 2H), 7.24 (s, 1H), 7.54-7.58 (m, 2H), 7.73-7.76 (m, 1H), 8.70 (s, 1H).
Reaction SMILES: I[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][O:17][CH2:18][CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:11]=1>C1(C)C=CC=CC=1.CN(C)C(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:18]([O:17][CH2:16][C:12]1[CH:11]=[CH:10][C:15]([CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:14][CH:13]=1)[CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCOC(=O)CCI
Reactant: CCCCCC#CCCOCc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CCCCCC#CCCOCc1ccc(CCC(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
A flask was charged with Zn-Cu couple (200 mg, 3 mmol) solution of ethyl 3-iodopropanoate (510 mg, 2 mmol) in dry toluene (4 mL) and dry N,N-dimethylacetamide (2mL) was added. The mixture was vigorously stirred for 1 hour at room temperature and then heated at gentle reflux for 4.5 hours. After the mixture was cooled to 60° C, a solution of tetrakis(triphenylphosphine)palladium(0)(30 mg, 0.026 mmol) in toluene (2 mL) was added over 1 minute and stirring was continued for 5 minutes at the same temperature. A solution of (45) (309 mg, 1 mmol) in dry toluene (2 mL) was added and the mixture was refluxed for 12 hours. The reaction mixture was allowed to cool to 25° C. and filtered through a Celite pad. The filter cake was washed with ether (50 mL). The filtrate was successively washed with a solution of i N ammonium chloride (10 mL), a solution of saturated sodium hydrogen carbonate (10 mL) and a solution of saturated sodium chloride (10 mL). The aqueous phases were back extracted with ether (30 mL), the combined organic extracts were dried (MgSO4), filtered, concentrated by rotary evaporation to yield a yellow oil. Purification by flash silica gel chromatography (97:03 petroleum ether/EtOAc) afforded (46) (165 mg, 51%) as a colorless oil: Rf 0.44 (95:05 petroleum ether/EtOAc); 1H NMR (CDCl3) δ 7.19 (m, 4 H), 4.51 (s, 2 H), 4.12 (q, J=7.2 Hz, 2 H), 3.55 (t, J=7.2 Hz, 2 H), 2.94 (t, J=8.1 Hz, 2 H), 2.61 (t, J=8.1 Hz, 2 H), 2.46 (tt, J1 =6.9 Hz, J2 =2.1 Hz, 2 H), 2.13 (tt, J1 =7.2 Hz, J2 =2.4 Hz, 2 H), 1.40 (m, 6 H), 1.22 (t, J=7.2 Hz, 3 H), 0.88 (t, J=6.9 Hz, 3 H); 13C NMR (CDCl3) δ 173.01, 140.87, 138.58, 128.68, 127.75, 81.64, 76.67, 72.99, 69.15, 60.53, 36.02, 31.01, 31.18, 28.81, 22.34, 20.28, 18.85, 14.32, 14.12. ##STR14##