Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C:12]([C:13]3[CH2:14][CH2:15][CH:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C@H:18](O)[CH2:17]4)=[CH:11][CH2:10]1)[CH3:8])[CH3:3].C(N(S(F)(F)[F:35])CC)C.O>C(Cl)Cl>[F:35][C@@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[CH:16]([CH2:15][CH2:14][C:13]3[C:12]4[C@:26]([CH3:27])([CH2:25][CH2:24][C:23]=32)[C@@H:9]([C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:10][CH:11]=4)[CH2:17]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)CC1CC3
Solvent: ClCCl
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@@H](F)CC1CC3
Temperature: -78 °C

Procedure:
Cholesta-8,14-diene-3β-ol (1.17 g, 3 mmol) was dissolved in 10 ml of methylenechloride and cooled to −78° C. Over 10 min a solution of diethylaminosulfur trifluoride (1.4 g, 8.7 mmol) in 10 ml of methylenechloride was added at −78° C. The mixture was stirred for 1½ hour at −78° C. and was then slowly heated to room temperature. To the reaction mixture was added 15 ml of water while stirring was continued. The organic phase was separated and washed with 30 ml of 5% NaHCO3 and then with water. The organic phase was dried with MgSO4 and evaporated to dryness. The residue was purified by column chromatography using heptane for a first fraction and heptane/acetone, 95:5 (w/w) for a second fraction containing 3α-fluorocholesta-8,14 diene, 0.14 g (12%). Melting point: 98.6° C. Elementary analysis: Cal C: 83.88; H: 11.21; F: 4.91. Found C: 83.92; H: 11.75. 19F-NMR: d 181.0 and 181.2 (JHCF 45.2 Hz, C3-aF).
Reaction SMILES: [CH2:1]([C:3]1([O:35][C:36](=[O:45])[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:34])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH2:26][CH2:27][CH2:28][OH:29])([CH3:25])[CH3:24])=[C:14]2[CH:30]=[CH:31][CH:32]=[CH:33][C:13]2=[N:12][C:11]3=1)[CH3:2].[C:46](Cl)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:38]([O:37][C:36]([O:35][C:3]1([CH2:1][CH3:2])[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:34])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH3:25])([CH3:24])[CH2:26][CH2:27][CH2:28][O:29][C:46](=[O:53])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[C:14]2[CH:30]=[CH:31][CH:32]=[CH:33][C:13]2=[N:12][C:11]3=1)=[O:45])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(=O)c1ccccc1
Temperature: 21 °C
Reaction time: 5 h

Procedure:
A mixture of Compound 53 (200 mg, 0.32 mmol), 4-dimethylaminopyridine (78 mg, 0.64 mmol), and benzoyl chloride (55 μL, 0.48 mmol) in 6.4 mL of dichloromethane was stirred at 21° C. for 5 hours. The reaction was quenched with saturated sodium bicarbonate solution, and aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to afford a crude product, which was chromatographed to give the desired product.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH:15][C:16](=[O:32])[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:20]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:20]=3)[CH2:17][C:16](=[O:32])[NH:15][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2ccc(F)cc2N1

Procedure:
The title compound was prepared from {4-fluoro-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M4) (94 mg, 0.21 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (55 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][OH:16])[CH2:9]2)[CH:5]=[C:4]([Cl:17])[N:3]=1.CCN(C(C)C)C(C)C.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)(Cl)Cl>[C:27]1([NH:33][C:34](=[O:35])[O:16][CH2:15][C@H:10]2[O:11][CH2:12][C@@H:13]([CH3:14])[N:8]([C:6]3[CH:5]=[C:4]([Cl:17])[N:3]=[C:2]([NH2:1])[N:7]=3)[CH2:9]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C[C@@H]1CO[C@H](CO)CN1c1cc(Cl)nc(N)n1
Reactant: O=C=Nc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CO[C@H](COC(=O)Nc2ccccc2)CN1c1cc(Cl)nc(N)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a 20-mL screw-cap vial was added [(2S,5R)-4-(2-amino-6-chloro-4-pyrimidinyl)-5-methyl-2-morpholinyl]methanol (100 mg, 0.387 mmol), Hunig's base (0.135 mL, 0.773 mmol) and CHCl3 (10 mL). The reaction was cooled to 0° C., then phenyl isocyanate (0.046 mL, 0.425 mmol) in CHCl3 (2 mL) was added dropwise via syringe. The solution was allowed to warm to room temperature and then stirred overnight. An additional portion of Hunig's base (0.135 mL, 0.773 mmol) and phenyl isocyanate (0.046 mL, 0.425 mmol) was added, and the reaction stirred at 60° C. overnight. The solvents were removed in vacuo, and the residue was purified by flash chromatography to afford the title compound (123 mg). LC-MS (ES) m/z=378 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[CH:16]([CH2:18][C:19]([O:21]CC)=[O:20])[O:15][B:14]([OH:24])[C:13]=2[CH:12]=[C:11]([OH:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>CCO.O>[CH2:1]([O:8][C:9]1[C:17]2[CH:16]([CH2:18][C:19]([OH:21])=[O:20])[O:15][B:14]([OH:24])[C:13]=2[CH:12]=[C:11]([OH:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(OCc3ccccc3)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CC1OB(O)c2cc(O)cc(OCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of ethyl 2-(4-(benzyloxy)-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (195 mg, 0.57 mmol) in EtOH (4 mL) was added dropwise an aqueous solution of lithium hydroxide (47.9 mg, 1.14 mmol) in water (4 mL). The reaction mixture was stirred at room temperature overnight and acidified with 1N HCl to pH=3. The resulting mixture was extracted with EtOAc (2×20 mL). Combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound as a white powder (41.2 mg, Yield: 23%). 1H NMR (400 MHz, CDCl3) δ 9.46 (s, 1H), 9.14 (s, 1H), 7.44-7.33 (m, 5H), 6.66 (d, J=1.2 Hz, 1H), 6.54 (s, 1H), 5.36 (m, 1H), 5.12 (s, 2H), 3.15 (m, 1H), 2.07 (m, 1H). MS (ESI) m/z=315 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]([Br:24])(Br)Br.OC[CH2:27][N:28]1[C:36]2[C:31](=[C:32]([O:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29]1.C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[Br:24][CH2:21][CH2:27][N:28]1[C:36]2[C:31](=[C:32]([O:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29]1
Reactant: COC(=O)COc1cccc2c1ccn2CCO
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)COc1cccc2c1ccn2CCBr
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
Under argon atmosphere, triphenylphosphine (1.05 g) and tetrabromomethane (2.00 g) were added to methyl (1-(2-hydroxyethyl)indole-4-yloxy)acetate (500 mg) in methylene chloride (10 ml) at room temperature, and the resulting mixture was stirred at room temperature for 15 minutes. Since the reaction had not been completed, triphenylphosphine (1.00 g) was added and the reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture, aqueous sodium hydrogen carbonate solution (5 ml) and water (10 ml) were added and the resultant was extracted with ethyl acetate (3×20ml). The obtained organic layers were washed with saturated brine and dried over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain the desired compound (602 mg, yield: 96%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH2:21][CH2:20]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][C:7]=1Br.C[Sn](C)(C)[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][N:33]=1)[C:30](=[O:34])[NH:29][CH2:28][CH2:27]2>O1CCOCC1.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>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH2:21][CH2:20]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][C:7]=1[C:24]1[N:33]=[CH:32][C:31]2[C:30](=[O:34])[NH:29][CH2:28][CH2:27][C:26]=2[CH:25]=1
Reactant: Nc1ncc(-c2ccc(S(=O)(=O)NC3CC3)cc2)nc1Br
Reactant: C[Sn](C)(C)c1cc2c(cn1)C(=O)NCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Nc1ncc(-c2ccc(S(=O)(=O)NC3CC3)cc2)nc1-c1cc2c(cn1)C(=O)NCC2
Yield: 4.5 %

Procedure:
A solution of 4-(5-amino-6-bromopyrazin-2-yl)-N-cyclopropylbenzenesulfonamide (150 mg, 0.41 mmol), 6-(trimethylstannyl)-3,4-dihydro-2,7-naphthyridin-1(2H)-one (150 mg, 0.48 mmol) and Pd(PPh3)4 (23 mg, 0.02 mmol) in dioxane (2 mL) was heated in the microwave 20 min at 150° C. At completion, the reaction mixture was purified by reverse phase preparatory HPLC to provide 4-(5-amino-6-(8-oxo-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)pyrazin-2-yl)-N-cyclopropylbenzenesulfonamide (8 mg, 5% yield) as an orange solid after lyophilization. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.02 (s, 1H), 8.87 (s, 1H), 8.59 (s, 1H), 8.35 (d, J=8.5 Hz, 2H), 8.17 (br. s., 1H), 7.84-7.99 (m, 3H), 3.51 (t, 2H), (t, J=6.3 Hz, 2H), 0.29-0.57 (m, 4 H); MS (EI) m/z=437.5 [M+1]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[N+:1]1([O-:18])[CH:2]=[CH:3][C:4]2[C:9]=1[NH:8][CH:7]=[CH:6][CH:5]=2
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: [O-][n+]1ccc2ccc[nH]c1-2
Temperature: 25 °C
Reaction time: 14 h
Yield: 58.2 %

Procedure:
7-Azaindole (100 g, 846 mmol) was dissolved in 1 L of ethyl acetate, and an ethyl acetate solution (400 mL) of m-CPBA (65%, 520 g) was dropwise added thereto under ice-cooling over two hours. The resulting mixture was stirred at room temperature for 14 hours. The precipitated solid was collected by filtration under reduced pressure, washed with ethyl acetate, and dried under reduced pressure. Distilled water (600 mL) was added to the obtained solid, and an aqueous solution prepared by dissolving potassium carbonate (125 g, 907 mmol) in water (350 mL) was added thereto while stirring. The resulting solution was cooled at 4° C. for 2 hours to precipitate crystals. The crystals were collected by filtration under reduced pressure, washed with a minimum amount of iced water, and dried under reduced pressure to give 7-azaindole N-oxide (66.0 g) as an off-white solid (yield: 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[O:9][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: O=Cc1ccc(F)cc1
Product: O=Cc1ccc(Oc2cc(Cl)cc(Cl)c2)cc1

Procedure:
Using 3,5-dichlorophenol and 4-fluorobenzaldehyde, the reaction was carried out in the same manner as in Reference Example 1 to obtain 4-(3,5-dichlorophenoxy)benzaldehyde. Subsequently, the same procedure as in Reference Example 99 was followed using sodium borohydride in place of the lithium aluminum hydride. This gave 4-(3,5-dichlorophenoxy)benzyl alcohol. The resulting alcohol (2.03 g), along with carbon tetrabromide (2.75 g), was dissolved in methylene chloride (30 mL). While this solution was stirred at 0° C., triphenyl phosphine (2.17 g) was added. The mixture was stirred at 0° C. for 1 hour and at room temperature for the subsequent 30 min. The solvent was removed under reduced pressure and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate=20:1) to give the desired product as a colorless oil (3.12 g).
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]([S@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14]>S([O-])([O-])(=O)=O.[Cu+2].ClCCCl>[Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5](/[CH:6]=[N:18]/[S@@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])=[C:4]([F:11])[CH:3]=1
Reactant: O=Cc1cc(F)c(Br)cc1F
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1cc(F)c(Br)cc1F
Temperature: 60 °C
Yield: 92.5 %

Procedure:
To a round bottom flask with stir bar was added 4-bromo-2,5-difluorobenzaldehyde (5.3 g, 24.0 mmol), (R)-2-methylpropane-2-sulfinamide (3.2 g, 26.4 mmol) and DCE (80 mL). To this mixture was then added copper (II) sulfate (5.74 g, 36.0 mmol). The reaction mixture was heated in a preheated oil bath at 60° C. for 18 hours. The reaction mixture was filtered through a pad celite, washing the solids with DCE. The filtrate was concentrated to afford a viscous green oil of (R,E)-N-(4-bromo-2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide (7.2 g, 22.2 mmol, 93% yield). Material was taken onto next step without further purification. LCMS m/z 326.0 (M+H)+, Rt 1.04 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:8][C@@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11].[Cl:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C(#N)C.CCOCC>[NH2:12][C:10]([C@@H:9]([NH:8][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][Cl:15])[CH2:13][CH3:14])=[O:11]
Reactant: CC[C@H](N)C(N)=O
Reactant: O=C(Cl)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CC[C@H](NC(=O)CCCCl)C(N)=O
Temperature: 0 °C
Yield: 78.7 %

Procedure:
345.6 g (2.5 moles) of ground potassium carbonate are mixed with 138.5 g (1 mole) of (S)-2-amino-butanamide hydrochloride in 2.5 liters of acetonitrile. The reaction mixture is cooled to 0° C. and a solution of 129.2 g (1.2 mole) of 4-chlorobutyryl chloride in 500 ml of acetonitrile is introduced dropwise. After the addition, the reaction mixture is allowed to return to ambient temperature; the insoluble matter is filtered off and the filtrate evaporated under reduced pressure. The crude residue obtained is stirred in 1.2 liter of anhydrous ether for 30 minutes at a temperature between 5° and 10° C. The precipitate is filtered off, washed twice with 225 ml of ether and dried in vacuo to obtain 162.7 g of (S)-N-[1-(aminocarbonyl)propyl]-4-chlorobutanamide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[N:10]([OH:11])[C:5]2=[CH:4][CH:3]=1.[CH3:19][SH:20]>>[CH3:19][S:20][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[N:10]([OH:11])[C:5]2=[CH:4][CH:3]=1
Reactant: On1c(C(F)(F)C(F)(F)F)nc2nc(Cl)ccc21
Reactant: CS
Product: CSc1ccc2c(n1)nc(C(F)(F)C(F)(F)F)n2O

Procedure:
5-Chloro-1-hydroxy-2-(pentafluoroethyl)-1H-imidazo(4,5-b)-pyridine is reacted with methanethiol to obtain 5-(methylthio)-1-hydroxy-2-(pentafluoroethyl)-1H-imidazo(4,5-b)pyridine which is subsequently oxidized to obtain the corresponding 5-(methylsulfonyl)-1-hydroxy-2-(pentafluoroethyl)-1H-imidazo(4,5-b)-pyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[O:16]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([O:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:24][CH:25]=3)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2ccc(CN)cn2)ccn1
Reactant: O=C(O)c1ccc(Oc2ccccc2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(CNC(=O)c3ccc(Oc4ccccc4)nc3)cn2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2′-methyl-[2,4′-bipyridin]-5-yl)methanamine 18-2 (20 mg, 0.10 mmol), 6-phenoxynicotinic acid 56-1 (21.5 mg, 0.10 mmol), and HATU (40 mg, 0.105 mmol) were added N,N-diisopropylethylamine (DIEA, 26 μL, 0.15 mmol) and DMF (0.5 mL). The solution was stirred overnight at room temperature and was subjected to reverse phase preparative HPLC separation to yield N-((2′-methyl-[2,4′-bipyridin]-5-yl)methyl)-6-phenoxynicotinamide 94 as a solid. MS m/z 397.2 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]=[O:8])[C:5](=[O:9])[CH2:4][N:3]1[CH2:10][C:11]#[CH:12].[C-:13]#[N:14].[Na+].S(=O)(O)[O-].[Na+]>CCOCC.O>[C:13]([CH:7]([N:6]1[C:5](=[O:9])[CH2:4][N:3]([CH2:10][C:11]#[CH:12])[C:2]1=[O:1])[OH:8])#[N:14]
Reactant: C#CCN1CC(=O)N(C=O)C1=O
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: C#CCN1CC(=O)N(C(O)C#N)C1=O
Reaction time: 2 h

Procedure:
To a solution of 2,4-dioxo-1-propargyl-3-imidazolidine-carbaldehyde (1.8 mmol) in 25 ml of ether is added 25 ml of water followed by sodium cyanide (3.04 mmol). The mixture is stirred vigorously while a solution of sodium bisulfite (2.45 mmol) in 15 ml of water is added over about 5 minutes. The reaction mixture is stirred for two hours. The organic phase is separated, washed with water, dried over calcium sulfate and solvent evaporated to give cyano(2,4-dioxo-1-propargyl-3-imidazolidinyl)methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[NH:11][C:12](=S)[CH2:13][N:14]=1.O.[NH2:22][NH2:23]>C(O)C>[NH:22]([C:12]1[CH2:13][N:14]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[N:11]=1)[NH2:23]
Reactant: CCc1cc2c(s1)NC(=S)CN=C2c1ccccc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCc1cc2c(s1)N=C(NN)CN=C2c1ccccc1Cl

Procedure:
[d] 32.1 g of 5-o-chlorophenyl-7-ethyl-1,2-dihydro-3H-thieno[2,3-e][1,4] diazepine-2-thione obtained in the above example [a] is suspended in 200 ml of ethanol, and to the suspension is added 8 g of hydrazine hydrate. Several minutes stirring turns the suspension into a homogeneous, red, transparent solution. Then crystals begin to precipitate. After stirring at room temperature for 2 hours and subsequent ice-cooling, the crystals are collected by suction filtration and washed well with methanol to give 28.6 g of almost pure 2-hydrazino-5-o-chlorophenyl-7-ethyl-3H-thieno[2,3-e][1,4]diazepine as yellowish crystals. The crystals, when recrystallized from a mixture of ethanol and diemethylformamide, show a melting point of 214° - 216°C (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[O:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[S:12][C:8]=2[C:7]=1[C:21]#[N:22].[N:27]([C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1)=[C:28]=[O:29]>CN(C)C=O.C(OCC)(=O)C>[C:21]([C:7]1[C:8]2[S:12][C:11]([NH:13][C:14]([CH:16]3[CH2:17][CH2:18]3)=[O:15])=[N:10][C:9]=2[CH:19]=[CH:20][C:6]=1[O:5][C:4]1[CH:23]=[CH:24][C:25]([F:26])=[C:2]([NH:1][C:28](=[O:29])[NH:27][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:32][CH:31]=2)[CH:3]=1)#[N:22]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: N#Cc1c(Oc2ccc(F)c(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1c(Oc2ccc(F)c(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.5 %

Procedure:
N-[6-(3-Amino-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (150 mg, 0.402 mmol) produced in Example 30(vi) was dissolved in N,N-dimethylformamide (2 mL), 1-isocyanato-4-(trifluoromethyl)benzene (75 μL, 0.522 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 ml), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=60/40→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from acetone/n-hexane to give the title compound (115 mg, 51%) as a white powder.
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].ClCC#N.[CH2:12]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:12]([CH:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:1]#[N:3])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCN(CC)CC
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: N#CCCl
Solvent: Cc1ccccc1
Product: N#CCN1CCC(Cc2ccccc2)CC1

Procedure:
40.8 ml of triethylamine and 22.2 g of chloroacetonitrile are dissolved in 180 ml of toluene, and 51.6 g of 4-benzylpiperidine are then added dropwise all at once.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][NH2:10])[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.F[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]3[CH:37]=[CH:36][NH:35][C:29]=3[N:30]=[C:31]([C:33]#[N:34])[N:32]=2)=[CH:23][C:22]=1[C:38]([F:41])([F:40])[F:39]>CN1CCCC1=O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][NH:10][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]4[CH:37]=[CH:36][NH:35][C:29]=4[N:30]=[C:31]([C:33]#[N:34])[N:32]=3)=[CH:23][C:22]=2[C:38]([F:39])([F:40])[F:41])[CH2:4][CH2:3]1
Reactant: N#Cc1nc(-c2ccc(F)c(C(F)(F)F)c2)c2cc[nH]c2n1
Reactant: CN1CCC(CCN)CC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(CCNc2ccc(-c3nc(C#N)nc4[nH]ccc34)cc2C(F)(F)F)CC1
Temperature: 140 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
2-(1-Methylpiperidin-4-yl)ethanamine (93 mg) and N,N-diisopropylethylamine (0.22 mL) were added to a mixture of 4-[4-fluoro-3-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (100 mg) and N-methylpyrrolidone (2 mL), and the mixture was stirred at 140° C. for 1 hour under microwave irradiation. After the reaction mixture was cooled to room temperature, the reaction mixture was purified by silica gel column chromatography (CHCl3:MeOH=98:2 to 85:15), whereby 4-[4-{[2-(1-methylpiperidin-4-yl)ethyl]amino}-3-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (66 mg) was obtained as a white solid.
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(OP(OC2C=CC=CC=2)OC2C=CC=CC=2)C=CC=CC=1>O>[C:13]1([NH:12][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1cccc2ccccc12
Reactant: Nc1ccccc1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: c1ccc(Nc2cccc3ccccc23)cc1
Temperature: 180 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
144 parts of α-naphthol, 150 parts of aniline and 5 parts of triphenylphosphite are mixed and first heated to 180° C. The reaction commences, with elimination of water. The water is removed by means of a water separator and the aniline evolved is returned. The temperature rises to 210° in the course of 4 hours. After a further 4 hours at 212° C, the elimination of water has ended (18 parts of H2O). The reaction mixture is cooled to 150° C and the excess aniline is distilled off under reduced pressure. Thereafter, 208 parts of phenyl-α-naphthylamine distil at 202° - 203° C/5 mm Hg; this product has a melting point of 55° - 58° C and corresponds to a yield of 95% of theory.