Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([O:12][C:13]1[CH:14]=[CH:15][C:16]3[N:20]=[C:19]([CH2:21][O:22][C:23]4[CH:36]=[CH:35][C:26]([CH2:27][CH:28]5[S:32][C:31](=[O:33])[NH:30][C:29]5=[O:34])=[CH:25][CH:24]=4)[N:18]([CH3:37])[C:17]=3[CH:38]=1)[CH:8]=[CH:7]2.[CH:39]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH:48]([CH3:50])[CH3:49])[C:43]=1[N:51]=[C:52]=[O:53])([CH3:41])[CH3:40]>CN(C)C=O>[CH:39]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH:48]([CH3:49])[CH3:50])[C:43]=1[NH:51][C:52]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:14]=[CH:15][C:16]4[N:20]=[C:19]([CH2:21][O:22][C:23]5[CH:24]=[CH:25][C:26]([CH2:27][CH:28]6[S:32][C:31](=[O:33])[NH:30][C:29]6=[O:34])=[CH:35][CH:36]=5)[N:18]([CH3:37])[C:17]=4[CH:38]=3)[CH:10]=2)[CH:5]=[CH:4][CH:3]=1)=[O:53])([CH3:40])[CH3:41]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc4cccc(N)c4c3)cc21
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)Nc1cccc2ccc(Oc3ccc4nc(COc5ccc(CC6SC(=O)NC6=O)cc5)n(C)c4c3)cc12
Reaction time: 120 h
Yield: 34.6 %

Procedure:
To a mixture of 5-[4-[6-(8-aminonaphthalen-2-yloxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.5 g) and N,N-dimethylformamide (10 ml) was added 2,6-diisopropylphenyl isocyanate (0.20 g) and the mixture was allowed to stand at room temperature for 5 days. The reaction mixture was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=3/2→3/1 as the eluant. The product was recrystallized from methanol to afford the title compound (0.24 g, mp 164-169° C.).
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:8]=[C:9]([S:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[F:24])[N:20]=[C:19]([NH2:25])[C:18]([CH2:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:17]3)[CH:10]=[CH:11][CH:12]=1.Cl.O>C(OCC)C>[NH2:25][C:19]1[C:18]([CH2:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:17][C:16]2[C:21](=[CH:22][C:23]([F:24])=[C:14]([S:13][C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[CH:2]=[O:1])[CH:15]=2)[N:20]=1
Reactant: Nc1nc2cc(F)c(Sc3cccc(C4OCCCO4)c3)cc2cc1CC1CCOCC1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: Nc1nc2cc(F)c(Sc3cccc(C=O)c3)cc2cc1CC1CCOCC1

Procedure:
In a μwave tube, 6-(3-[1,3]dioxan-2-yl-phenylsulfanyl)-7-fluoro-3-(tetrahydro-pyran-4-ylmethyl)-quinolin-2-ylamine (45 mg, 0.1 mmol) was placed with HCl (conc.) (0.5 mL), H2O (0.5 mL) and diethyl ether (0.2 mL) were reacted via μwave @ 300W, 130° C. for 12 min. The resulting mixture was worked up by removal of solvent to yield a residue, which was purified by silica column chromatography (50% EtOAc/heptanes) to yield a solid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([Si:22](OC)([O:25][CH3:26])[O:23][CH3:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([Si:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([O:25][CH3:26])[O:23][CH3:24])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[Si](OC)(OC)c1ccccc1
Reactant: Br[Mg]c1ccc(Oc2ccccc2)cc1
Product: CO[Si](OC)(c1ccccc1)c1ccc(Oc2ccccc2)cc1

Procedure:
Another suitable approach to making the (thio)phenoxyphenyl phenyl silane of the present invention is the sequential formation of a Grignard reagent [a (thio)phenoxyphenyl magnesium halide] followed by introduction of a phenyl trialkoxy silane. A reaction scheme illustrative of this approach follows in which p-phenoxyphenyl bromide is reacted with magnesium metal to form p-phenoxyphenyl magnesium bromide. The p-phenoxyphenyl magnesium bromide intermediate is then reacted with phenyl trimethoxy silane to produce p-phenoxyphenyl phenyl dimethoxy silane. Typically, this Grignard approach is carried out in an anhydrous ether solvent such as tetrahydrofuran (“THF”) or diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([NH2:9])=[N:6][C:7]=1Cl.[I-:13].[Na+]>CC(O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([NH2:9])=[N:6][C:7]=1[I:13]
Reactant: [I-]
Reactant: Nc1nc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(I)c(Cl)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 5,6-dichloro-3-nitropyridin-2-amine (15 g, 72.1 mmol) in AcOH (70 mL) was added sodium iodide (43.2 g 149.9 mmol). The mixture was stirred at 90° C. for 2 h, cooled to rt, diluted with water (70 mL) and filtered. The solid residue was washed with water, and then dried under vacuum to afford the desired product as a pale yellow solid, which was used in the next step without further purification. LC-MS: calculated for C5H3ClIN3O 2299.45, observed m/e: 299.94 (M+H)+ (Rt 2.18/5 min).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15]([NH:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)(=[O:17])[CH3:16]>>[NH2:8][C:5]1[N:6]=[N:7][C:2]([C:23]2[CH:24]=[C:19]([NH:18][C:15](=[O:17])[CH3:16])[CH:20]=[CH:21][CH:22]=2)=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: CC(=O)Nc1cccc(-c2nnc(N)nc2-c2ccccc2)c1
Yield: 64.6 %

Procedure:
N-[3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)phenyl]acetamide (59 mg, 62%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3-acetamidophenylboronic acid (61.5 mg, 0.344 mmol) according to the general procedure of Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([C:18]#[C:19][CH:20]([C:22]3[N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:24]=[CH:25][CH:26]=3)[OH:21])[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([C:18]#[C:19][C:20]([C:22]3[N:23]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH:24]=[CH:25][CH:26]=3)=[O:21])[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Oc1cc2c(C#CC(O)c3cccn3C(=O)OC(C)(C)C)c(F)ccc2n1C(=O)OC(C)(C)C
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Oc1cc2c(C#CC(=O)c3cccn3C(=O)OC(C)(C)C)c(F)ccc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-tert-butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-hydroxy-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester (from Example 3 above) (7.60 g, 13.3 mmol) in CH2Cl2 (400 ml) was added MnO2 (Aldrich, 11.5 g, 130 mmol) in one portion. The reaction mixture was stirred at room temperature overnight and then filtered through Celite® and the solid was washed with CH2Cl2 (200 mL). The combined filtrates was concentrated in vacuo. 2-tert-Butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-oxo-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester was obtained as a light orange amorphous solid which was used in the next step without further purification. (Yield 7.0 g, 92.5%).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([C:26]3([C:29]([F:32])([F:31])[F:30])[CH2:28][CH2:27]3)=[N:24][N:25]=[C:20]2[C@H:19]([NH:33]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1>ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([C:26]3([C:29]([F:32])([F:30])[F:31])[CH2:27][CH2:28]3)=[N:24][N:25]=[C:20]2[C@H:19]([NH2:33])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c1nnc2C1(C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c1nnc2C1(C(F)(F)F)CC1
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (7.5 mL, 101.3 mmol) was added to a solution of tert-butyl {(6S,9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl)cyclopropyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl}carbamate (0.38 g, 0.80 mmol) in dichloromethane (15 mL). After 1 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 373.1 (M+1).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)CCOC[N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH:29]=O.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:29][C:21]2[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c(C=O)nc2ccccc21
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: c1ccc(CC2CCN(Cc3nc4ccccc4[nH]3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 144.8 %

Procedure:
A mixture of 0.5 g of 4-benzyl-piperidine, 0.5 g of 1-(2-trimethylsilylethoxymethyl)-1H-benzoimidazole-2-carbaldehyde, 5 mL of 1,2-dichloroethane and 0.5 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was diluted with 50 mL chloroform and 10 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×25 mL of chloroform and the combined organic layers dried over magnesium sulfate and concentrated under reduced pressure. The crude SEM ether was heated to reflux in 50 mL of ethanol containing 5 mL of 3N HCl for 2 h, cooled, concentrated and partitioned between 10 mL of saturated aqueous sodium carbonate and 3×25 mL of chloroform. The chloroform extracts were dried over magnesium sulfate and concentrated. Purification by chromatography eluting with 90:10 CHCl3: MeOH gave 0.8 g of 2-[4-benzyl-piperidin-1-ylmethyl]-1H-benzimidazole: MS (m+1)=: 1H NMR (400MHz, CDCl3).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: Fc1ccc(Cl)nc1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ccc(F)cn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 2-chloro-5-fluoro-pyridine following a procedure analogous to that described in Example 19. LC (method 5): tR=1.79 min; Mass spectrum (ESI+): m/z=407 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[OH:9])=[CH:4][CH:3]=1.Br[CH:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[O:9][CH:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19])=[CH:6][CH:7]=1
Reactant: COC(=O)C(Br)CC(C)C
Reactant: OC(c1ccc(Br)cc1)c1cccnc1
Product: COC(=O)C(CC(C)C)OC(c1ccc(Br)cc1)c1cccnc1

Procedure:
Using the same protocol as described in example 23, step 2, (4-bromophenyl)(pyridin-3-yl)methanol from step 1 (644 mg, 2.4 mmol) was added to methyl 2-bromo-4-methylpentanoate (412 μL, 2.52 mmol). The crude residue was chromatographed on silica gel using 50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C.C(=O)([O-])[O-].[K+].[K+].Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33].C1(C)C=CC=CC=1>O>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][CH:8]([C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)Cl
Reactant: CN(C)CCCOC(CCCc1ccccc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N(C)CCCOC(CCCc1ccccc1)c1ccc(F)cc1

Procedure:
A mixture of 1.0 g of 1-[3-(N,N-dimethylamino)propoxy]-1-(p-fluorophenyl)-4-phenylbutane, 2.75 g of potassium carbonate, 11 ml of ethyl chloroformate and 20 ml of toluene was heated under refluxing for 2 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-[3-(N-methyl-N-ethoxycarbonylamino)propoxy]-1-(p-fluorophenyl)-4-phenylbutane.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C@@:7]12[CH2:18][CH2:17][CH2:16][C:14]3[C:15]1=[C:10]([CH:11]=[CH:12][CH:13]=3)[NH:9][C:8]2=[O:19])([OH:3])=[O:2].Cl.[CH:21](OC(C)C)(C)C>CO>[CH3:21][O:2][C:1]([CH2:4][CH2:5][CH2:6][C@@:7]12[CH2:18][CH2:17][CH2:16][C:14]3[C:15]1=[C:10]([CH:11]=[CH:12][CH:13]=3)[NH:9][C:8]2=[O:19])=[O:3]
Reactant: CC(C)OC(C)C
Reactant: O=C(O)CCC[C@@]12CCCc3cccc(c31)NC2=O
Agent: Cl
Solvent: CO
Product: COC(=O)CCC[C@@]12CCCc3cccc(c31)NC2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
(S)-2a-(3-carboxypropyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (7.00 g, 27 mmol) was dissolved in methanol (200 ml). Then, 36% hydrochloric acid 0.1 ml was added thereto and stirred at room temperature for two days. The solvent was evaporated from the reaction mixture, and ethyl acetate and water were added to the resulting residue. A reaction product was extracted with ethyl acetate, and the extracted product was washed with saturated saline solution, successively dried over anhydrous sodium sulfate, followed by evaporating the solvent. The resulting product was crystallized from diisopropyl ether, whereby 6.89 g (yield 93%) of the above-described object compound could be obtained.
Reaction SMILES: [CH3:1][Si:2]([N-:5][Si](C)(C)C)([CH3:4])[CH3:3].[Li+].[P:11]([Cl:14])([Cl:13])[Cl:12].S(Cl)(Cl)(=O)=O>C(OCC)C>[Cl:12][P:11]([Cl:14])([Cl:13])=[N:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: ClP(Cl)Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: O=S(=O)(Cl)Cl
Product: C[Si](C)(C)N=P(Cl)(Cl)Cl
Reaction time: 1.5 h

Procedure:
Diethyl ether (250 ml) was added with stirring to a flask cooled in an ice/water bath containing lithium bis(trimethylsilyl)amide (27.7 g, 0.17 mol). Phosphorus trichloride (14.5 ml, 0.17 mol) was then added and the mixture stirred for a further 5-10 minutes before removing the ice water bath. Stirring was continued at ambient temperature for a further 1-2 hours. The reaction flask was then cooled again in an ice/water bath and sulfuryl chloride (13.3 ml, 0.17 mol) added. The mixture was stirred for a further 10-15 minutes before removing the ice/water bath and stirring at ambient for a further 1-2 hours or until the reaction was complete, as indicated by 31P {1H} NMR spectroscopy. The product was isolated in pure form via vacuum distillation.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C@H:12]([NH:14][S@@](C(C)(C)C)=O)[CH3:13])=[CH:7][CH:6]=2.Cl.O1CCOCC1>CO>[ClH:1].[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C@H:12]([NH2:14])[CH3:13])=[CH:7][CH:6]=2
Reactant: C[C@@H](N[S@](=O)C(C)(C)C)c1ccc2cnc(Cl)cc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H](N)c1ccc2cnc(Cl)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 213.1 %

Procedure:
A solution of (R,R)-2-methyl-propane-2-sulfinic acid [1-(3-chloro-isoquinolin-6-yl)-ethyl]-amide (932 mg, 3 mmol) in methanol (9 mL) was stirred at room temperature under nitrogen. 4M HCl in dioxane (3 mL, 12 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated and the residue was triturated with ether. The orange solid was collected, washed with ether and dried to afford the title compound (777 mg). 1H NMR (300 MHz, d6-DMSO) δ 1.61 (d, J=6.7 Hz, 3H), 4.58-4.67 (m, 1H), 7.90 (dd, J=8.5, 1.4 Hz, 1H), 8.04 (br, 1H), 8.05 (br, 1H), 8.26 (d, J=8.5, 1H), 8.65-8.8 (br, 3H), 9.25 (s, 1H). LCMS (m/z) 207/209 [M+H], Tr 0.72 minutes.
Reaction SMILES: [ClH:1].[C:2]1([CH2:14][NH2:15])[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH:7]=[CH:6][CH:5]=[C:4]3[CH:3]=1.[H][H]>CO.[Pd]>[ClH:1].[CH:2]1([CH2:14][NH2:15])[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH:7]=[CH:6][CH:5]=[C:4]3[CH2:3]1
Reactant: NCC1=Cc2cccc3cccc1c23
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCC1Cc2cccc3cccc1c23
Yield: 83 %

Procedure:
The N-[(1-acenaphthylenyl)methyl]amine hydrochloride, A as prepared in Example A above (1.8 g, 8.3 mmol) was dissolved in methanol (100 ml) and 5% Pd/C (0.2 g) added. The mixture was stirred at room temperature, under 51 psi of hydrogen, for 2.5 hours (hydrogen uptake: AP=6.8 psi, calculated 7.1). The catalyst was removed by filtration and the solvent evaporated in vacuo. The residue was treated with ether (150 ml) and filtered to collect precipitate. The solid was dried at 45° C., in vacuo, overnight, to give 1.5 g (83%) of a white N-[(1,2-dihydro-1-acenaphthylenyl)methyl]amine hydrochloride salt, mp >250° C. Anal (C13H13N.HCl.0.15H2O), calc: C=71.20, H=6.48, N=6.30, Cl=15.54; found: C=70.14, H=6.51; N=6.42; Cl=16.11.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[NH:4][C:5](=[O:9])[CH2:6][C:7]#[N:8].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[NH:4][C:5](=[O:9])[C:6]([C:7]#[N:8])=[CH:17][N:18]([CH3:19])[CH3:20]
Reactant: N#CCC(=O)Nc1ccc(F)cc1Cl
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C#N)C(=O)Nc1ccc(F)cc1Cl

Procedure:
As for Example 1, 2'-chloro-2-cyano-4'-fluoroacetanilide as colorless needles, m.p. 138°-139° C. (prepared by the procedure described in U.S. Pat. No. 3,116,312), is heated with N,N-dimethylformamide dimethylacetal to give 2'-chloro-2-cyano-3-dimethylamino-4'-fluoroacrylanilide as colorless needles, m.p. 155.5°-156.5° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH:25]=O>>[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1nccs1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4nccs4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1,3-thiazole-2-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1,3-thiazol-2-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.C(O)(C(F)(F)F)=O.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[C:31](=[O:35])[CH:30]=[CH:29]2>C(Cl)Cl>[CH2:10]([N:4]1[CH2:3][CH:29]2[C:28]3[CH:27]=[C:26]([O:25][CH3:24])[CH:34]=[CH:33][C:32]=3[C:31](=[O:35])[CH:30]2[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COc1ccc2c(c1)C=CC2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)C1CN(Cc3ccccc3)CC1C2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(Methoxymethyl)-N-(trimethylsilylmethyl) benzylamine (17.3 mL, 67.6 mmol) and TFA (3.4 mL) were added to a solution of 5-methoxy-inden-1-one (5.4 g, 33.8 mmol) in CH2Cl2 (165 mL) at 0° C. The reaction was stirred for 3 hours at room temperature and quenched with saturated aqueous NaHCO3 (165 mL). The organic layer was separated, washed with brine (100 mL), dried over MgSO4, and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C19H19NO2+H: 294, observed: 294.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.C[N:19](C=O)C.C1(C)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH2:19])=[O:6]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C

Procedure:
3-Bromo-4-chlorobenzoic acid (2.35 g, 10 mmol) was suspended in CH2Cl2 (50 mL) and stirred under argon at room temperature. Oxalyl chloride (2.53 g, 20 mmol) was added followed by DMF (10 μL). Gas evolution began, and the mixture was stirred until gas evolution ceased. The solvents were pumped off and toluene was added and stripped off to remove excess oxalyl chloride. The residue was taken up in EtOAc and added to concentrated ammonium hydroxide (10 mL). This was stirred for 30 min. The phases were separated and the organic washed 1× with brine dried over anhydrous Na2SO4, filtered, and evaporated. The residue was crystallized from EtOAc/hexane to give the title compound as a white crystalline solid. LC-MS m/z 233.7 (M+H)+, 1.54 min (ret time); mp 146-147° C.; analytical HPLC shows 100% purity, (ret time: 11.835 min).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[CH:7]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6][CH:5]1[CH3:22])(=[O:3])[CH3:2].[CH3:23][N:24](C=O)C>[C-]#N.[Zn+2].[C-]#N.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.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:23]#[N:24])=[CH:11][CH:12]=2)[CH:7]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6][CH:5]1[CH3:22])(=[O:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(=O)N1c2ccc(Br)cc2C(Nc2ccccc2)CC1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(=O)N1c2ccc(C#N)cc2C(Nc2ccccc2)CC1C
Temperature: 120 °C
Reaction time: 2 h

Procedure:
100 mg (0.278 mmol) of 1-acetyl-6-bromo-2-methyl-4-phenylamino-1,2,3,4-tetrahydroquinoline), 36 mg (0.31 mmol) of zinc cyanide, and 18 mg (0.015 mmol) of tetrakis(triphenylphosphine)palladium(0) were added to 1.5 mL of DMF, and the mixture was stirred for 2 hours at 120° C. under an argon atmosphere. After completion of the reaction, water was added to the reaction liquid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue (104 mg) was purified by using silica gel preparatory thin layer chromatography (ether:hexane=5:1), and thus 63 mg (cis:trans=3:1, 74.1%) of the title compound was obtained as a colorless amorphous solid.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(Cl)(Cl)Cl>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:16](=[O:18])[CH3:17])=[CH:4][CH:3]=1
Reactant: NCc1ccc(I)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)NCc1ccc(I)cc1
Reaction time: 4 h

Procedure:
4-Iodobenzylamine (5.32 g) was dissolved in chloroform (50 ml), and, under ice-cooling, pyridine (2.76 ml) and acetic anhydride (2.58 ml) were added and the mixture was stirred for 4 hr. The reaction mixture was washed successively with water, 1N-hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2-1:3) to give the title compound (5.18 g).