Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[CH:4]([N:8](Cl)[Cl:9])[C:5]([O-:7])=[O:6])[CH3:2].C(C(N)(C([O-])=O)N(C(=O)C(C)C)C=O)C.[H][H]>Cl.O1CCCC1.[Pd]>[ClH:9].[CH2:1]([N:3]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[CH:4]([NH2:8])[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: [H][H]
Reactant: CCN(C(=O)C(C)C)C(C(=O)[O-])N(Cl)Cl
Agent: [Pd]
Agent: CCC(N)(C(=O)[O-])N(C=O)C(=O)C(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCN(C(=O)C(C)C)C(N)C(=O)O

Procedure:
Preparation of ethyl-α-N,N-dichloroaminoisobutyrylglycinate: To a solution of 2.16 g (0.01 mol) of ethyl-N-formyl-α-aminoisobutyrylglycinate in 50 ml of dry hydrogen chloride in tetrahydrofuran (1 M), there was added 1 g of 10% palladium-on-charcoal. The mixture was shaken at room temperature under at atmosphere of hydrogen at 50 psi for several days. Following filtration, the solvent was removed under reduced pressure to afford 1.18 g (0.005 mol), 50%, ethyl-α-aminoisobutyrylglycinate hydrochloride, pmr (D2O) δ 4.43 (s, 2H), 4.33 (q, 2H), 1.70 (s, 6H) and 1.23 (t, 3H) ppm.
Reaction SMILES: [OH-].[CH2:2]([N+:8]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1C=C[C:30]2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)[O:35][C:33](=[O:34])[C:31]=2C=1.C(O)(=O)C=C>CO>[C:33]([O-:35])(=[O:34])[CH:31]=[CH2:30].[CH2:21]([N+:8]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: C=CC(=O)O
Agent: CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC
Agent: [OH-]
Solvent: CO
Product: C=CC(=O)[O-]

Procedure:
The AgOH is resuspended in 400 ml of methanol. The purified tetraalkylammonium iodide (0.1 moles or 48.2 g) (Aldrich Chemical Co., Milwaukee, WI) is dissolved separately in 100 ml. of methanol and added to the AgOH suspension. Almost immediately, the AgOH develops a greenish cast. The mixture is stirred for an hour and then filtered through a sintered-glass funnel. The filtrate now contains 0.1 moles of tetrahexylammonium hydroxide. A small amount of phenolphthalein is added, turning the solution red indicating that the solution is basic. Acrylic acid is added until the red color disappears. The methanol is removed by evaporation in a rotary flash evaporator leaving tetrahexylammonium acrylate. The resulting tetrahexylammonium acrylate was found to be electrically conductive.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:24])([F:23])[C@@:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])([NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH2:7][F:8])C.[Cl-].[NH4+]>O1CCCC1.[BH4-].[Li+]>[F:24][C:5]([F:23])([CH2:4][OH:3])[C@@:6]([NH:9][S:10]([C:12]([CH3:13])([CH3:14])[CH3:15])=[O:11])([CH2:7][F:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22]
Reactant: CCOC(=O)C(F)(F)[C@](CF)(N[S@](=O)C(C)(C)C)c1ccccc1F
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N[C@](CF)(c1ccccc1F)C(F)(F)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
(S)-2,2,4-trifluoro-3-(2-fluoro-phenyl)-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester (intermediate F3.1) (177 mg, 461 μmol) was dissolved in tetrahydrofuran (4 ml) and at 0° C. lithium borohydride (2 M solution in tetrahydrofuran; (461 μl, 921 μmol) was added dropwise. After 30 minutes the reaction was complete. For the workup, the reaction mixture was poured into a mixture of ice water and a saturated solution of ammonium chloride. Thereafter, the mixture was extracted with ethyl acetate (3×), the organic layers were combined, washed with brine, dried over sodium sulphate and evaporated at reduced pressure. The resulting product was pure enough to be engaged in the next step without further purification. The 2-methyl-propane-2-sulfinic acid [(S)-2,2-difluoro-1-fluoromethyl-1-(2-fluoro-phenyl)-3-hydroxy-propyl]-amide (153 mg, 97% yield) was obtained as a white foam. MS (ISN): m/z=342.2 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[NH2:18])[C:9]1=[O:19])[CH3:7])(=O)C.C(Cl)Cl.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][C:25]=1[F:34].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CO.C(=O)([O-])[O-].[K+].[K+]>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([NH:18][C:14]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:15]=2[CH:16]=[CH:17][N:8]([C@H:6]([CH3:7])[CH2:5][OH:4])[C:9]3=[O:19])=[O:32])=[CH:26][C:25]=1[F:34]
Reactant: O=C(O)Cc1ccc(Cl)c(F)c1
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[C@H](CO)n1ccc2c(NC(=O)Cc3ccc(Cl)c(F)c3)cccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2-(5-amino-1-oxoisoquinolin-2(1H)-yl)propyl acetate (800 mg, 0.003 mol) in methylene chloride (20 mL, 0.2 mol) was added 2-(4-chloro-3-fluorophenyl)acetic acid (870 mg, 0.0046 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (2900 mg, 0.0077 mol) and N,N-diisopropylethylamine (3000 μL, 0.02 mol). The reaction mixture was stirred overnight at room temperature and then concentrated. methanol (20 mL, 0.6 mol) and potassium carbonate (1000 mg, 0.009 mol) were added and the mixture was allowed to stir at room temperature for one hour. Volatiles were removed and the residue was taken up in methylene chloride (100 ml). The mixture was washed with aqueous NaHCO3 (150 ml), brine (150 ml) and water (200 ml). The layers were separated and the organics dried over Na2SO4 and concentrated under reduced pressure. The mixture was then purified by flash chromatography (Ethyl acetate: Hexanes, 0-40%). The combined pure fractions were reduced in vacuo to yield the title compound as a yellow solid. M+1=389.1
Reaction SMILES: [ClH:1].[C:2]1([C:8]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][CH:10]2[C:15](=O)[CH:14]3[CH2:17][CH2:18][N:11]2[CH2:12][CH2:13]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.O.[OH-].[K+]>C(O)COCCO>[ClH:1].[C:25]1([C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:9][CH:10]2[CH2:15][CH:14]3[CH2:17][CH2:18][N:11]2[CH2:12][CH2:13]3)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1C2CCN(CC2)C1CC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: O
Solvent: OCCOCCO
Product: c1ccc(C(CC2CC3CCN2CC3)(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
A mixture of 2.25 grams (5.38 mmol) of 2-(2,2,2-triphenylethyl)-1-azabicyclo[2.2.2]octane-3-one hydrochloride (XI), 1.14 grams (19.4 mmol) 85% H2NNH2.H2O, 1.5 grams (23 mmol) 85% KOH and 160 ml of diethylene glycol is heated to reflux for 2 hours. The resultant solution is cooled to room temperature and poured into 1.0 liter of ice-water. The aqueous layer has a pH of about 12.0 which is adjusted to about 14.0 with aqueous KOH. The solution is extracted twice with diethyl ether, and the combined ether extracts are shaken with dilute HCl (400 ml. containing 4 ml. of concentrated HCl) resulting in the formation of a fine solid precipitate. The precipitate is filtered and washed with water and diethyl-ether, and air-dried to provide 892 mg. of a white powder. The white powder is recrystallized from methanolether and dried in vacuo (0.1 mm. Hg) at 100° for 18 hours and then at 140° for 2 hours to provide the product, 2-(2,2,2-triphenylethyl)-1-azabicyclo[2.2.2]octane hydrochloride (VIII); MW:403.99.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.Cl.[NH2:13][OH:14].O>CO>[OH:14][N:13]=[CH:7][C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: O
Product: ON=Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
Piperonal(15.0 g, 0.10 mol) was dissolved in methanol(150 ml), and hydroxylamine hydrochloride(10.5 g, 0.15 mol) and water(15 ml) were added thereto. The mixture was stirred for 1 hour at room temperature, then excess water was added, and the resulting mixture was stirred for further 1 hour. The white solid thus obtained was washed with water under reduced pressure, filtered, and dried to give (hydroxyimino)-(benzo[3,4-d]1,3-dioxolan-5-yl)methane(15.7 g, Yield 95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[O:12][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=1)[C:19]([C:23](Cl)=[O:24])=[CH:18][CH:17]=[CH:16]3)=[CH:9][C:8]([O:26][CH3:27])=[C:7]([O:28][CH3:29])[CH:6]=2.FC1C=NC2C(C=1OC1C=C3C(=CC=1)C(C(O)=O)=CC=C3)=CC(OC)=C(OC)C=2.C(Cl)(=O)C(Cl)=O.[NH2:65][C:66]1[CH:70]=[C:69]([C:71]([CH3:74])([CH3:73])[CH3:72])[O:68][N:67]=1>N1C=CC=CC=1>[CH3:72][C:71]([C:69]1[O:68][N:67]=[C:66]([NH:65][C:23]([C:19]2[C:20]3[C:15](=[CH:14][C:13]([O:12][C:11]4[C:10]5[C:5](=[CH:6][C:7]([O:28][CH3:29])=[C:8]([O:26][CH3:27])[CH:9]=5)[N:4]=[CH:3][C:2]=4[F:1])=[CH:22][CH:21]=3)[CH:16]=[CH:17][CH:18]=2)=[O:24])[CH:70]=1)([CH3:74])[CH3:73]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: COc1cc2ncc(F)c(Oc3ccc4c(C(=O)Cl)cccc4c3)c2cc1OC
Agent: COc1cc2ncc(F)c(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Product: COc1cc2ncc(F)c(Oc3ccc4c(C(=O)Nc5cc(C(C)(C)C)on5)cccc4c3)c2cc1OC
Temperature: 80 °C
Reaction time: 10 h

Procedure:
Pyridine (1.0 mL) was added to a mixture of 6-(3-fluoro-6,7-dimethoxyquinolin-4-yloxy)-1-naphthoyl chloride (prepared from 6-(3-fluoro-6,7-dimethoxyquinolin-4-yloxy)-1-naphthoic acid and oxalyl chloride by the procedure described in Example 273) (0.044 g, 0.107 mmol) and 3-amino-5-t-butylisoxazole (0.075 g, 0.535 mmol). The mixture stirred at 80° C. for 10 h and was then cooled to RT. The mixture was concentrated and the residue was purified by preparative thin layer chromatography on silica gel plates (eluting with 5% MeOH—CH2Cl2). Further purification via preparative thin layer chromatography on silica gel plates (eluting with 90:10:1 CH2Cl2:MeOHl:NH4OH) afforded N-(5-(1,1-dimethylethyl)-3-isoxazolyl)-6-((3-fluoro-6,7-bis(methoxy)-4-quinolinyl)oxy)-1-naphthalenecarboxamide as an off-white solid. MS (ESI, pos. ion) m/z: 516.0 (M+H). Mass Calc'd for C29H26FN3O5: 515.5
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[O:10])[CH:5]=[N:6][C:7]=1Cl.[OH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CC(N(C)C)=O>[Cl:1][C:2]1[C:7]([O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=2)=[N:6][CH:5]=[C:4]([CH:9]=[O:10])[CH:3]=1
Reactant: O=Cc1cnc(Cl)c(Cl)c1
Reactant: NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc(Oc2ncc(C=O)cc2Cl)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
Combine 5,6-dichloro-pyridine-3-carbaldehyde (1.37 g, 7.80 mmol), 4-hydroxy-benzamide (1.18 g, 8.58 mmol), potassium carbonate (1.62 g, 11.7 mmol) in toluene (10 mL) and DMA (30 mL). Stir the reaction mixture at 100° C. for 1 h. Pour the reaction mixture onto H2O (100 mL) and extract with Et2O (100 mL). Wash the organic layer with H2O (2×100 mL), dry the organic phase extracts over magnesium sulfate, filter and concentrate to give the title compound (1.09 g, 51%).
Reaction SMILES: [P:1]([OH:4])([OH:3])[OH:2].[NH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.P(Cl)(Cl)Cl>>[CH2:7]([CH2:6][NH2:5])[CH2:8][C:9]([P:1]([OH:4])([OH:3])=[O:2])([P:1]([OH:4])([OH:3])=[O:2])[OH:11]
Reactant: OP(O)O
Reactant: NCCCC(=O)O
Solvent: ClP(Cl)Cl
Product: NCCCC(O)(P(=O)(O)O)P(=O)(O)O
Temperature: 70 °C

Procedure:
The mixture of 5 eq. phosphorous acid, 4-aminobutyric acid and morpholine. HCl is melted together until uniform solution is formed. The reaction mixture is cooled to about 70° C. and 2 eq. of PCl3 are carefully added. The mixture is heated for about 5.5 hours before the reaction mixture is hydrolyzed in aqueous acid at about 80° C. and alendronate is isolated from an ethanolic solution.
Reaction SMILES: Cl.[NH2:2][O:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:10]1[C:19]2[N:20]3[C:24]([C:25](=O)[C:17]4[C:18]=2[C:13]([CH:14]=[CH:15][N:16]=4)=[CH:12][CH:11]=1)=[CH:23][CH:22]=[CH:21]3>O.C(O)C.N1C=CC=CC=1>[CH2:8]([O:7][C:5]([CH2:4][O:3][N:2]=[C:25]1[C:17]2[C:18]3[C:13]([CH:14]=[CH:15][N:16]=2)=[CH:12][CH:11]=[CH:10][C:19]=3[N:20]2[C:24]1=[CH:23][CH:22]=[CH:21]2)=[O:6])[CH3:9]
Reactant: CCOC(=O)CON
Reactant: O=c1c2nccc3cccc(c32)n2cccc12
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)CON=c1c2nccc3cccc(c32)n2cccc12
Yield: 56.1 %

Procedure:
A solution of ethyl aminooxyacetate hydrochloride (18.0 g.) in water (64 cc.) is added to a stirred boiling solution of 7H-indolizino[5,6,7-ij]isoquinolin-7-one (16.0 g.) in ethanol (320 cc.) and pyridine (9.1 g.). Boiling is maintained for 3 hours 30 minutes. After cooling, water (640 cc.) is added. The greenish yellow crystals thus obtained are filtered off and washed with 25% ethanol and then with water. After drying, crude 7-ethoxycarbonylmethoxyimino-7H-indolizino[5,6,7-ij isoquinoline (21.6 g.) is obtained and is recrystallised from a mixture of ethyl acetate (110 cc.) and cyclohexane (165 cc.). 7-Ethoxycarbonylmethoxyimino- 7H-indolizino[5,6,7-ij]isoquinoline (13.1 g.), melting at 134° C., is thus obtained.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][C:18](=[O:35])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:22]=2)[CH:9]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:18](=[O:35])[CH2:17][N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([C:6]([OH:7])=[O:5])=[CH:9]2)=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCc1ccc(OCC(=O)Cn2cc(C(=O)OC(C)(C)C)c3ccccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCc1ccc(OCC(=O)Cn2cc(C(=O)O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.072 g (0.151 mmol) tert-butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-3-carboxylate is dissolved in 10 ml absolute dichloromethane and mixed with 1.56 g (13.7 mmol) trifluoroacetic acid. Having stirred at room temperature for 1 hour, concentration to dryness is carried out on the rotary evaporator. Two dissolution steps in toluene and respective concentration on the rotary evaporator leave as the crude product a reddish solid which is recrystallized from petroleum ether/ethyl acetate (67:33) and yields the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Cl:21][CH:22]([CH:26]=[CH2:27])[C:23](=O)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:26]([CH3:27])[CH:22]([Cl:21])[CH:23]=[CH2:24])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: C=CC(Cl)C(C)=O
Product: C=CC(Cl)C(C)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino -5-phenyl-3H-1,4-benzodiazepine can be reacted with 3-chloro-4-penten-2-one to give 7-chloro-2-[(2-chloro-2 -vinyl-1-methylethylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([CH2:7][C:8]1([CH3:18])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)([OH:6])[CH2:4][OH:5].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl.CS(C)=O>[F:1][C:2]([F:19])([F:20])[C:3]([OH:6])([CH2:7][C:8]1([CH3:18])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[CH:4]=[O:5]
Reactant: CC1(CC(O)(CO)C(F)(F)F)CCCc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC1(CC(O)(C=O)C(F)(F)F)CCCc2ccccc21
Temperature: 21 °C
Reaction time: 17 h
Yield: 78 %

Procedure:
To a solution of 3,3,3-trifluoro-2-[(1-methyl-1,2,3,4-tetrahydro-1-naphthalenyl)methyl]-1,2-propanediol (Intermediate 5) (1.6 g, 5.55 mmol) in anhydrous dichloromethane (36 ml), anhydrous dimethylsulphoxide (12 ml) and triethylamine (4.9 ml, 35 mmol) stirred under nitrogen in a bath at 8.5° C., was added pyridine-sulphur trioxide complex (4.45 g, 28 mmol) portionwise over 20 min. The solution was stirred in the ice-water bath for a further 1.5 h and then allowed to warm to 21° C. and stirred for 17 h. The reaction mixture was added to aqueous ammonium chloride solution (100 ml) and dichloromethane (100 ml) and the layers were separated. The aqueous layer was re-extracted with dichloromethane (100 ml) and the combined organic layers were washed successively with water (6×100 ml) and saturated brine (100 ml), dried over anhydrous magnesium sulphate and evaporated. The yellow oil obtained was purified by flash chromatography on a 90 g Biotage cartridge eluting with 5% ether in cyclohexane to give the title compound as an oil (1.24 g, 78%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[OH:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:12]([CH3:20])[N:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[C:9]=1[C:25](OCC)=[O:26]>>[OH:7][C:8]1[C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:12]([CH3:20])[N:11]=[C:10]([C:21]([F:24])([F:22])[F:23])[C:9]=1[C:25]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)=[O:26]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C)c(-c2ccccc2)c1O
Reactant: Nc1nccs1
Product: Cc1nc(C(F)(F)F)c(C(=O)Nc2nccs2)c(O)c1-c1ccccc1
Yield: 79.3 %

Procedure:
Using the procedure of Example 5, 6.25 g of 2-aminothiazole and 4 g of the product of Step F were reacted to obtain 3.7 g of the expected product melting greater than 260° C. after crystallizing from acetonitrile.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[CH:13][C:14]([CH2:19][CH3:20])=[C:15]([CH:18]=1)[CH:16]=[O:17]>>[CH2:19]([C:14]1[CH:13]=[CH:12][C:11]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:18][C:15]=1[CH:16]=[O:17])[CH3:20]
Reactant: CCc1ccc(Br)cc1C=O
Reactant: OB(O)c1ccncc1
Product: CCc1ccc(-c2ccncc2)cc1C=O

Procedure:
Pyridine-4-boronic acid (75 mg, 0.52 mmol) is coupled to aryl bromide 235 (111 mg, 0.52 mmol) using Method A to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:18]=1.[Cl:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:23]([NH:22][CH2:21][CH2:20][Cl:19])=[O:24])[CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:18]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCCN2
Reactant: O=C=NCCCl
Solvent: ClCCl
Product: O=C(NCCCl)N1CCN=C(c2ccccc2)c2cc(Cl)ccc21
Reaction time: 48 h

Procedure:
10 parts of 7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine is dissolved in 75 parts by volume of methylene chloride. To this solution is added 6 parts of 2-chloroethylisocyanate and the resultant mixture left standing at ambient temperature for about 48 hours. Then, additional 2 parts of 2-chloroethylisocyanate is added to the mixture, the mixture heated on a steam bath for about 4 hours and the solvent removed to give a solid. The solid is washed with ether and crystallized from a mixture of methylene chloride and hexane to give 7-chloro-N-(2-chloroethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-1-carboxamide, as yellow crystals melting at about 160°-161° C. This compound is represented by the following formula ##STR17##
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:6]([OH:8])=O)[CH3:2].[C:13]([O:17][C:18]([NH:20][NH2:21])=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.[OH-].[Na+]>[C:13]([O:17][C:18]([NH:20][NH:21][C:6]([C:5]1[CH:9]=[C:10]([CH3:12])[N:11]=[C:3]([CH2:1][CH3:2])[CH:4]=1)=[O:8])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCc1cc(C(=O)O)cc(C)n1
Reactant: CC(C)(C)OC(=O)NN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)NNC(=O)OC(C)(C)C)cc(C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-ethyl-6-methyl-isonicotinic acid (0.53 g, 3.2 mmol), hydrazinecarboxylic acid tert.-butyl ester (0.43 g, 3.2 mmol) and DIPEA (0.85 mL) in DMF (10 mL) is added TBTU (1.23 g, 3.8 mmol). The mixture is stirred at rt for 3 h. The mixture is diluted with 1M aq. NaOH (50 mL) and extracted with Et2O-EA (1:1, 3×50 mL). The organic extracts are dried (Na2SO4), filtered and evaporated to give crude N′-(2-ethyl-6-methyl-pyridine-4-carbonyl)-hydrazinecarboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH3:17])[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]2([CH3:16])[CH3:15])=[CH:5][CH:4]=1.Cl.Br[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH3:17])[CH:9]2[CH2:14][CH2:13][N:12]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:11][C:10]2([CH3:16])[CH3:15])=[CH:18][CH:19]=1
Reactant: Brc1ccncc1
Reactant: COc1ccc(CN(C)C2CCNCC2(C)C)cc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(C)C2CCN(c3ccncc3)CC2(C)C)cc1
Yield: 40 %

Procedure:
N-(4-Methoxybenzyl)-N,3,3-trimethylpiperidin-4-amine (5.17 mmol, 1 eq) and 4-bromopyridine hydrochloride (1.509 g, 7.76 mmol, 1.5 eq) were dissolved in n-butanol (40 ml) and DIPEA (4.26 ml, 25.87 mmol, 5 eq) and refluxed for 16 h. After monitoring by thin-layer chromatography, the reaction solution was concentrated under reduced pressure. After purification by column chromatography (silica gel, 5% MeOH in dichloromethane), the desired product was obtained in the form of a white solid. Yield: 40% (700 mg, 2.06 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]1[CH2:24][CH2:23][CH2:22][CH:21]([N:25]2[CH:29]=[C:28]([NH2:30])[CH:27]=[N:26]2)[CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:30][C:28]1[CH:27]=[N:26][N:25]([CH:21]2[CH2:22][CH2:23][CH2:24][N:19]([CH3:18])[CH2:20]2)[CH:29]=1
Reactant: CN1CCCC(n2cc(N)cn2)C1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CN1CCCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Yield: 22.5 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (305 mg, 0.98 mmol) was reacted with 1-(1-methylpiperidin-3-yl)-1H-pyrazol-4-amine (265 mg, 1.47 mmol) to afford the desired product (100 mg, 22%) as a yellow solid: ESI MS m/z 454 [C22H24BrN5O+H]+.
Reaction SMILES: C(OC([N:8]=[C:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH:12]=[C:11]([CH2:24][CH3:25])[S:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O.O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[NH:8]=[C:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[CH:12]=[C:11]([CH2:24][CH3:25])[S:10]1
Reactant: CCc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)OC(C)(C)C)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
A mixture of 2-(t-butoxycarbonylimino)-3-(3-trifluoromethylphenyl)-5-ethylthiazoline (1 g) and trifluoroacetic acid (3 g) in chloroform (20 ml) was stirred at room temperature for 3 hours, followed by addition of water (50 ml) thereto. The resultant mixture was neutralized with potassium carbonate, extracted with chloroform and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was subjected to column chromatography to give 0.3 g of 2-imino-3-(3-trifluoromethylphenyl)-5-ethylthiazoline (Compound (x)).