Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][N:15]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(O)C.O.O.NN>C(OCC)C>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCN(c2ccncc2)CC1
Agent: NN
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: NCCN1CCN(c2ccncc2)CC1
Yield: 62.2 %

Procedure:
A stirred mixture of 2-[2-(4-pyridin-4-yl-piperazin-1-yl)-ethyl]-isoindole-1,3-dione (1.52 g, 4.52 mmol), ethanol (47.5 mL), water (2.5 mL) and hydrazine hydrate (98%, 0.438 mL, 9.04 mmol) was refluxed for 3 h, then cooled and diluted with diethyl ether (100 mL). The precipitated crystals were filtered off, washed with diethyl ether and filtrate was concentrated. The residue was dissolved N sodium hydroxide (25 mL), extracted with dichloromethane (4×25 mL), the combined organic layers were washed with brine (25 mL), dried over sodium sulfate, filtered and concentrated to yield 0.58 g (62%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([CH:13]=O)=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([CH3:15])[O:7]2.CC(O)C.[C:21]([CH:23]=[C:24]([O-])[CH3:25])#[N:22].[Na+].[NH2:28][C:29](=[CH:31][C:32](=[O:37])[CH2:33][CH:34]([CH3:36])[CH3:35])[CH3:30].C(O)(=O)C>>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([CH:13]2[C:31]([C:32](=[O:37])[CH2:33][CH:34]([CH3:36])[CH3:35])=[C:29]([CH3:30])[NH:28][C:24]([CH3:25])=[C:23]2[C:21]#[N:22])=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([CH3:15])[O:7]2
Reactant: CC([O-])=CC#N
Reactant: Cc1cc(=O)c2c(F)c(F)cc(C=O)c2o1
Reactant: CC(N)=CC(=O)CC(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2cc(F)c(F)c3c(=O)cc(C)oc23)C(C(=O)CC(C)C)=C(C)N1

Procedure:
A solution of 100 mg (0.45 mmol) of 5,6-difluoro-2-methyl-4-oxo-4H-chromene-8-carbaldehyde in ml of 2-propanol is mixed with 46.9 mg (0.45 mmol) of sodium 1-cyanoprop-1-en-2-olate, 63 mg (0.45 mmol) of 2-amino-6-methylhept-2-en-4-one and 0.04 ml (0.67 mmol) of acetic acid and stirred under reflux for 3 h. After cooling, the mixture is concentrated. The residue is purified on an Analogix cartridge (F12M) (mobile phase: cyclohexane/ethyl acetate 2:1). 20.9 mg (11.36% of theory) of the title compound are obtained as white crystals.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][C:6]1[CH:7]=[C:8]2[C:15](=[O:16])[O:14][C:12](=[O:13])[C:9]2=[N:10][CH:11]=1>C(Cl)Cl>[CH:1]([NH:4][C:12]([C:9]1[C:8]([C:15]([OH:16])=[O:14])=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:13])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: Cc1cnc2c(c1)C(=O)OC2=O
Solvent: ClCCl
Product: Cc1cnc(C(=O)NC(C)C)c(C(=O)O)c1
Yield: 91.5 %

Procedure:
3.25 g of isopropylamine are added to 8.1 g of 5-methylpyridine-2,3-dicarboxylic anhydride in 50 ml of methylene chloride at from 20° to 30° C. while stirring, and the stirred mixture is refluxed for 3 hours. The reaction mixture is evaporated down under reduced pressure and the residue is stirred in a 1:1:1 mixture of ether, methyl tert-butyl ether and petroleum ether. Filtration under suction and drying give 10.1 g of the title compound as colorless crystals of melting point 95°-105° C.
Reaction SMILES: [N:1]1([C:6]([S-:8])=[S:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([NH+](CC)CC)C.[Cl-].[Li+].O1CCCC1.O(P(O[C:40]1[C@H:41]([CH3:64])[C@H:42]2[C@@H:59]([C@H:60]([OH:62])[CH3:61])[C:58](=[O:63])[N:43]2[C:44]=1[C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([N+:55]([O-:57])=[O:56])=[CH:51][CH:50]=1)=[O:46])(OC1C=CC=CC=1)=O)C1C=CC=CC=1>O.C(OCC)(=O)C>[OH:62][C@@H:60]([C@H:59]1[C:58](=[O:63])[N:43]2[C:44]([C:45]([O:47][CH2:48][C:49]3[CH:50]=[CH:51][C:52]([N+:55]([O-:57])=[O:56])=[CH:53][CH:54]=3)=[O:46])=[C:40]([S:7][C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[S:8])[C@H:41]([CH3:64])[C@H:42]12)[CH3:61]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Reactant: S=C([S-])N1CCCC1
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC(=S)N3CCCC3)[C@H](C)[C@H]12
Reaction time: 8 h
Yield: 73.3 %

Procedure:
Triethylammonium 1-pyrrolidinyldithiocarboxylate (1.0 g, 4.03 mmol) and lithium chloride (171 mg, 4.03 mmol) were added to a tetrahydrofuran solution (50 ml) of p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (2.0 g, 3.36 mmol) at room temperature. The mixture was stirred at that temperature overnight in a nitrogen stream, and poured in a mixed liquid of ethyl acetate and water. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (Wakogel™ C-300, n-heptane-ethyl acetate 1:1→2:3) to give p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-2-[(1-pyrrolidinyl)thiocarbonylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (1.21 g, yield: 74%).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:22][CH:23]=[CH2:24])[CH3:21])[CH2:11][CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:22]([N:20]([CH3:21])[CH2:19][CH2:18][CH2:17][CH2:16][O:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([NH:7][CH3:6])[CH2:10][CH2:11]1)[CH:23]=[CH2:24]
Reactant: C=CCN(C)CCCCO[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCN(C)CCCCO[C@H]1CC[C@H](NC)CC1

Procedure:
2.1 g (5.9 mmol) trans-(4-[4-(Allyl-methyl-amino)-butoxy]-cyclohexyl)-methyl-carbamic acid tert-butyl ester in 28 ml CH2Cl2 were treated with 6 ml TFA at 0° C. for 1 h, the mixture was concentrated in vacuo and dissolved in EtOAc and saturated aqueous NaHCO3 solution. The phases were separated and the inorganic phase was extracted with EtOAc, the combined organic phases were washed with brine, dried over Na2SO4 and evaporated to yield 1.38 g (91%) trans-(4-[4-(Allyl-methyl-amino)-butoxy]-cyclohexyl)-methyl-amine as yellow oil, MS: 255 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:13]([N:16]([CH3:18])[CH3:17])[C:14]#N)[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C([N-][CH:23]([CH3:25])C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[O:39]1CCCC1>CCCCCC.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:13]([N:16]([CH3:18])[CH3:17])[C:14](=[O:39])[CH2:23][CH3:25])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)[N-]C(C)C
Reactant: CN(C)C(C#N)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: C1CCOC1
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCC(=O)C(N(C)C)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: -12 °C

Procedure:
A solution of 2-[1-(3,4-dichlorophenyl)cyclobutyl]-2-dimethylaminoacetonitrile (28.3 g prepared as described in Example A(c)) in dry tetrahydrofuran (150 ml) was added with stirring to a solution of lithium diisopropylamide [prepared by the addition of a 1.6M solution of butyllithium in hexane (100 ml) to a solution of diisopropylamine (22.4 ml) in ether (200 ml) followed by removal of the solvents at 80° C. and disolution of the residue in tetrahydrofuran (100 ml)] at -20° C. The temperature of the solution was maintained at -12° C. for 30 minutes. The mixture was then cooled to -40° C. and propionaldehyde (20 ml) was added. The temperature was allowed to rise to -10° C. and an excess of aqueous ammonium chloride solution was added at the same temperature. The aqueous layer was separated and extracted with ether and the extract combined with the organic phase of the reaction mixture. The resulting organic phase was dried and the solvents removed. The residue was distilled (eliminating hydrogen cyanide) (154° C./6mm Hg to 180° C./1.2 mm Hg) to give an oil which was dissolved in petroleum ether (40°-60° C.). A solid which separated from the solution was collected by filtration and discarded and the filtrate evaporated. The residue was dissolved in methanol, oxalic acid (20 g) was added and the mixture heated at 90°-95° C. for 40 minutes. The solution was poured into water (ca. 1.5 litres) and the resulting mixture was washed with ether, basified and extracted with ether, The extract yielded an oil which was distilled in a Buchi Kugelrohr apparatus (175° C./0.9 mm Hg) to give 1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-dimethylaminobutan-2-one
Reaction SMILES: [CH3:1][C:2](C)([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][C:16]23[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]4)[CH2:17]2)[CH2:23]3)[CH:8]=1)[C:3](O)=O.C([N:29](CC)CC)C.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[CH3:1][C:2]([NH2:29])([CH3:3])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][C:16]23[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]4)[CH2:17]2)[CH2:23]3)[CH:8]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(Cc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1)C(=O)O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(N)Cc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.17 g (6.09 mmol) of the Intermediate 86 are dissolved in 200 ml of acetone. 1.95 ml (13.99 mmol) of triethylamine are added and the solution is cooled to 0° C. A solution of 0.89 ml (6.84 mmol) of isobutyl chloroformiate in 15 ml of acetone is dropped into the system. After 30′ at 0° C. a solution of 0.99 g (15.23 mmol) of sodium azide in 10 ml of water is slowly added, and the stirring at 0° C. is prosecuted for an additional period of 30 min. Excess water is added, the system is extracted with ethyl ether which is washed with water, dried and concentrated at room temperature. The residue is dissolved in 15 ml of toluene and this solution added slowly to 150 ml of refluxing toluene. The reflux is prosecuted for an additional hour and the solution is concentrated. The residue is dissolved in 15 ml of dioxane, 35 ml of 5N HCl are added and the system is stirred at 100° C. for 30′. The solution is neutralised with 2N NaOH and is extracted with ethyl ether. The ethereal layer is washed with water, dried and concentrated. The residue is chromatographied on silicagel eluting with ethyl acetate/methanol 10:1 then 6:1 giving 1.46 g (72%) of yellowish oil.
Reaction SMILES: [Na+].C(OC(N[C:10]([C:12]1[CH:22]=[CH:21][C:15]([CH:16]=[CH:17][C:18]([O-:20])=O)=[CH:14][CH:13]=1)=[NH:11])=O)(C)(C)C.C1CCC([N:29]=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[ClH:48].[NH2:49][CH2:50][CH2:51][N:52]1[CH2:56][C:55](=[O:57])[N:54]([CH:58]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:59]([O:61][CH3:62])=[O:60])[C:53]1=[O:69]>CN(C)C=O>[ClH:48].[NH2:29][N:11]=[CH:10][C:12]1[CH:13]=[CH:14][C:15]([CH:16]=[CH:17][C:18]([NH:49][CH2:50][CH2:51][N:52]2[CH2:56][C:55](=[O:57])[N:54]([CH:58]([C:63]3[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=3)[C:59]([O:61][CH3:62])=[O:60])[C:53]2=[O:69])=[O:20])=[CH:21][CH:22]=1
Reactant: COC(=O)C(c1ccccc1)N1C(=O)CN(CCN)C1=O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(C=CC(=O)[O-])cc1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccccc1)N1C(=O)CN(CCNC(=O)C=Cc2ccc(C=NN)cc2)C1=O
Reaction time: 0.83 h

Procedure:
730 mg (2.34 mmol) of 4-tert-butoxycarbonylamidinocinnamic acid sodium salt are dissolved in 50 ml of dimethylformamide and 531 mg (2.57 mmol) of DCC and 316 mg (2.34 mmol) of HOBt are then added at 0° C. The mixture is stirred for 50 minutes and 355 mg (2.34 mmol) of methyl (3-(2-aminoethyl)-2,5-dioxoimidazolidin-1-yl)phenylacetate hydrochloride are then added. After stirring at room temperature for 20 h, the mixture is concentrated and the residue is chromatographed, for purification, on silica gel using a mixture of methylene chloride, methanol, glacial acetic acid and water=85:15:2:2. The fractions containing the pure substance are concentrated and freeze dried.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17](=[O:19])[CH3:18])[C:12]([CH3:20])=[C:11]2[CH3:21])=[O:7])[CH3:4]>C(O)(=O)C>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17](=[O:19])[CH3:18])[C:12]([CH2:20][Br:1])=[C:11]2[CH3:21])=[O:7])[CH3:4]
Reactant: CCOC(=O)c1ccc2c(c1)c(C)c(C)n2C(C)=O
Reactant: BrBr
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2c(c1)c(C)c(CBr)n2C(C)=O
Yield: 44.9 %

Procedure:
Bromine (0.40 g) was added dropwise over 1 minute to a stirred solution of 1-acetyl-2,3-dimethylindole-5-carboxylic acid ethyl ester (0.65 g) in acetic acid (1.3 ml). After a few minutes a solid precipitated. The mixture was diluted with ca 5 ml. of ether and the solid was filtered off, washed with ether and dried to give 1-acetyl-2-bromomethyl-3-methylindole-5-carboxylic acid ethyl ester (0.38 g), m.p. 125°-130°. The product was unstable and was used directly in the next stage.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[N:11][CH:12]=1)(=O)=O.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21].[Al]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[F:14][C:13]([F:16])([F:15])[C:10]1[N:9]=[CH:8][C:7]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:12][N:11]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=S(=O)(Oc1cnc(C(F)(F)F)nc1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Al]
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc(C(F)(F)F)nc1
Reaction time: 5 h
Yield: 95.5 %

Procedure:
2-(Trifluoromethyl)pyrimidine-5-yl trifluoromethanesulfonate (0.45 g, 1.5 mmol) and dry triethylamine (1.0 mL) were mixed in a screw-cap vial. The solution was purged with dry argon for 10 minutes. Trimethylsilylacetylene (0.43 mL, 3.0 mmol), finely ground CuI (0.010 g, 0.05 mmol) and PdCl2(PPh3)2 (0.020 g, 0.030 mmol) were added. The vial was sealed and heated in an aluminum block at 80° C. After stirring for 5 hours the volatiles were evaporated at room temperature (the product sublimes at 35-40° C./10 mbar). The black residue was taken up in EtOAc (20 mL) and concentrated with silica (about 5 to 10 g) to dryness. Flash chromatography on silica with EtOAc/heptane (1:30) afforded 2-(trifluoromethyl)-5-[(trimethylsilyl)ethynyl]pyrimidine as a white solid (0.35 g, 95%), m.p. 75.5-76.0° C.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:12][B-:13]([F:16])([F:15])[F:14].[N:17]#[O+].[K+].[Br-]>C(#N)C.C(Cl)Cl>[F:12][B-:13]([F:16])([F:15])[F:14].[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N+:9]#[N:17])=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#[O+]
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: F[B-](F)(F)F
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)c1ccc([N+]#N)cc1
Yield: 78 %

Procedure:
The 4-tert-butylaniline was dissolved in a 1:1 mixture of acetonitrile and dry methylene chloride prior to addition to the nitrosonium tetrafluoroborate. Yield: 78%. MP 91° C. IR (KBr) 3364.8, 3107.3, 2968.6, 2277.2, 1579.2, 1482.0, 1418.0, 1373.5, 1269.8, 1056.9, 841.1, 544.6, 621.4 cm−1. 1H NMR (400 MHz, CD3CN) δ 8.16 (ABq, J=9.0 Hz, Δν=298.7 Hz, 4H), 1.30 (s, 12H). 13C NMR (100 MHz, CD3CN) δ 168.85, 133.67, 130.43, 111.88, 37.86, 30.84.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8]2)([O-:4])=[O:3].[C:22](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[ClH:1].[N+:2]([C:5]1[CH:13]=[C:12]2[C:8](=[CH:7][CH:6]=1)[CH:9]([NH:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:10]([CH3:22])[CH2:11]2)([O-:4])=[O:3]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc2c(c1)CC(NCc1ccccc1)C2
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CC1Cc2cc([N+](=O)[O-])ccc2C1NCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 5-nitro-2-(phenylmethyl)aminoindane hydrochloride (2.29 g, 7.52 mmol) in DMF (100 ml) was added potassium carbonate (2.60 g, 18.80 mmol) followed by methyl iodide (0.47 ml, 7.52 mmol). The mixture was warmed to room temperature, stirred for 16 hr, dumped into water (400 ml), and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered through a small plug of silica gel and reduced to a syrup. The titled compound was isolated as the hydrochloride salt: (1.08 g, 45%); m.p. dec 280° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[C:21]2[C:28]([CH3:29])=[CH:27][NH:26][C:22]=2[N:23]=[CH:24][N:25]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[CH3:29][C:28]1[C:21]2[C:20]([NH:18][C@H:16]([C:8]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH3:17])=[N:25][CH:24]=[N:23][C:22]=2[NH:26][CH:27]=1
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1c[nH]c2ncnc(N[C@@H](C)c3nc4ccccc4n3-c3ccccc3)c12
Temperature: 120 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
Into a 10-mL sealed tube was placed (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine from Example 4 (300 mg, 1.26 mmol, 1.00 equiv), 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (250 mg, 1.49 mmol, 1.18 equiv), N-ethyl-N-isopropylpropan-2-amine (322 mg, 2.50 mmol, 1.97 equiv) and BuOH (5 mL). The resulting solution was stirred for overnight at 120° C. and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/hexane (0:100-80:20) to afford 270 mg (58%) of 144 as a white solid. LC-MS (ES, m/z): 369 [M+H]+. H-NMR (300 MHz, CD3OD, ppm): δ 7.98 (s, 1H), 7.70-7.53 (m, 6H), 7.33-7.23 (m, 2H), 7.14-7.11 (m, 1H), 6.83 (d, 1H), 5.68-5.61 (m, 1H), 2.49 (d, 3H), 1.67 (d, 3H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][C:10](=[O:13])[CH:9]([C:14]#N)[S:8][C:7]=2[CH:16]=1.Cl.[OH2:18].[CH3:19][OH:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][C:10](=[O:13])[CH:9]([C:14]([O:20][CH3:19])=[O:18])[S:8][C:7]=2[CH:16]=1
Reactant: CO
Reactant: COc1ccc2c(c1)SC(C#N)C(=O)CO2
Reactant: O
Agent: Cl
Product: COC(=O)C1Sc2cc(OC)ccc2OCC1=O
Reaction time: 96 h

Procedure:
In 200 ml of methanol is dissolved 15 g of 7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carbonitrile, and the solution is saturated with dried hydrogen chloride, followed by allowing the solution to stand at room temperature for 4 days. 10 ml of water is added to the reaction solution, the mixture is allowed to stand overnight and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent; chloroform) to give 6.0 g of methyl 7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate as obtained in Reference Example 2, together with 6.0 g of the starting material being recovered.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C([Si](C)(C)O[CH:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[N:35][C:36]([NH2:39])=[CH:37][CH:38]=2)[CH2:29][CH2:28]1)(C)(C)C.CCC[CH2:45][N+:46](CCCC)(CCCC)[CH2:47]CCC.[F-]>C1COCC1>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:39][C:36]3[N:35]=[CH:34][C:33]([N:30]4[CH2:29][CH2:28][CH:27]([N:46]([CH3:47])[CH3:45])[CH2:32][CH2:31]4)=[CH:38][CH:37]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(c2ccc(N)nc2)CC1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCC(N(C)C)CC4)cn3)nc2n1C1CCCC1
Yield: 61 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (290 mg, 0.939 mmol) and 4-(tert-butyl-dimethyl-silanyloxy)-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamine (336 mg, 1.09 mmol). Followed by deprotection using 7 mL of TBAF in 28 mL of THF to give 7-cyclopentyl-2-(4-dimethylamino-3,4,5,6-tetrahydro-2H-[1,3]bipyridinyl-6′-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (110 mg, 61%). MS (ESI) m/z 450.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=4[O:15][N:14]=3)=[C:9]([CH2:23][CH2:24][CH3:25])[CH:8]=2)=[CH:4][CH:3]=1.C(NCC(C)C)C(C)C.S(Cl)([Cl:40])(=O)=O>C1(C)C=CC=CC=1>[Cl:40][C:18]1[C:17]2[C:13]([C:10]3[CH:11]=[CH:12][C:7]([O:6][C:5]4[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][CH:4]=4)=[CH:8][C:9]=3[CH2:23][CH2:24][CH3:25])=[N:14][O:15][C:16]=2[CH:21]=[CH:20][C:19]=1[OH:22]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2ccc(O)cc12
Agent: CC(C)CNCC(C)C
Solvent: Cc1ccccc1
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2ccc(O)c(Cl)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the phenol product obtained from step 6 of Example 3 (0.38 g, 1.0 mmol) and diisobutylamine (18 μL, 0.10 mmol) in toluene (5 mL) was added dropwise sulfuryl chloride (80 μL, 1.0 mmol) over 10 min. The resulting solution was stirred at 25° C. for 1 h and then quenched with a saturated solution of aqueous sodium bicarbonate. The organic layer was extracted with ethyl acetate and the combined organic layer was washed with 2 N solution of sodium sulfite. After removal of the solvent, the crude product was purified by chromatography on silica gel eluting with 7:3 hexane:ethyl acetate to give the title product as a solid.
Reaction SMILES: [C:1](Cl)([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)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]=[C:22]([CH2:25][OH:26])[CH2:23][OH:24].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[C:2]1([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:24][CH2:23][C:22](=[CH2:21])[CH2:25][OH:26])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=C(CO)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=C(CO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
To a solution of trityl chloride (4.05 g; 14.3 mmol) and 2-methylenepropane-1,3-diol (1.20 mL; 14.3 mmol) in dry CH2Cl2 (20 mL) was added triethylamine (4.0 mL; 28.5 mmol) slowly at room temperature. The reaction was stirred at room temperature for 1 h and then ethyl acetate (100 mL) and saturated aqueous NaHCO3 (30 mL) were added. The organic layer was separated and washed by saturated aqueous NaHCO3 and NaCl respectively, and dried over anhydrous Na2SO4. After evaporation of the solvent, the residue was purified by flash column chromatography over silica gel using ethyl acetate-hexane (1:10˜5) as the eluent to afford 10 as white solid (2.89 g; 62% yield): 1H NMR (400 MHz, CDCl3) δ 7.42-7.48 (m, 6H, six of ArH), 7.27-7.33 (m, 6H, six of ArH), 7.20-7.27 (m, 3H, three of ArH), 5.26 (s, 1H, one of C═CH2), 5.17 (s, 1H, one of C═CH2), 4.13 (d, J=6.1 Hz, 2H, CH2OH), 3.70 (s, 2H, Ph3COCH2), 1.72 (t, J=6.1 Hz, 1H, CH2OH); 13C NMR (100 MHz, CDCl3) δ 145.4, 143.6, 128.3, 127.6, 126.8, 111.6, 87.0, 65.3, 64.5, (8).