Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:24])=[C:11]([CH2:13][C:14]([NH:16][CH2:17][C@@H:18]3[O:23][CH2:22][CH2:21][NH:20][CH2:19]3)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH:34]=O)=[CH:28][CH:27]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][N:20]2[CH2:21][CH2:22][O:23][C@@H:18]([CH2:17][NH:16][C:14](=[O:15])[CH2:13][C:11]3[N:12]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[O:9][C:10]=3[CH3:24])[CH2:19]2)=[CH:28][CH:27]=1
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CC(=O)NC[C@H]1CNCCO1
Reactant: O=CCCc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1oc(-c2ccc(F)cc2)nc1CC(=O)NC[C@H]1CN(CCCc2ccc(Cl)cc2)CCO1
Temperature: 20 °C
Reaction time: 72 h
Yield: 94.3 %

Procedure:
A mixture of Intermediate 28 (0.04 g), 3-(4-chlorophenyl)propanal (0.026 g) and acetic acid (0.02 ml) in dichloromethane (4 ml) was treated with sodium triacetoxyborohydride (0.080 g). The mixture was stirred at 20° C. for 72 h. The mixture was partitioned between chloroform (6 ml) and saturated aqueous sodium hydrogen carbonate (6 ml). The phases were separated and the organic phase applied to an ion exchange cartridge (2 g Isolute SCX, prewashed with methanol). The SCX cartridge was eluted with methanol (10 ml) followed by 10% 0.880 ammonia in methanol (10 ml) and the appropriate fractions were concentrated in vacuo to give the title compound as a colourless gum (0.055 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12]Cl.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(CC(C)C)=O.ClCCl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: COC(=O)c1ccccc1OCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)CC(C)C
Product: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Reaction time: 3 h
Yield: 59.7 %

Procedure:
0.22 g (0.5 mmol) of 2-(2-chloro-ethoxy)-benzoic acid methyl ester were added to a mixture of 0.1 g (0.5 mmol) of 3-piperidin-4-yl-1H-indole, 0.08 g (0.6 mmol) of potassium carbonate and 0.04 g (0.2 mmol) of potassium iodide in 1.5 mL of isobutyl methyl ketone under nitrogen atmosphere and the reaction mixture was refluxed for 18 hours. After cooling at room temperature 1.5 mL of dichloromethane and 0.08 g (0.1 mmol) of polystyrene methyl isocyanate were added and the mixture was stirred at this temperature for 3 hours. After filtering, the solution was placed directly on a 500 mg Varian SCX ion exchange column. The columns were washed with 5 mL of methanol and the product was eluted with 5 mL of methanol/ammonia 20:1 affording, after removal of the solvent at reduced pressure, 0.113 g (60% yield) of 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])=[N:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:6][CH:7]=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C(#N)C>[C:21]([C:20]1[CH:19]=[C:18]([CH:25]=[CH:24][CH:23]=1)[O:17][C:3]1[C:2]([NH:1][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=[C:5]([O:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:11]([C:12]#[N:13])[CH:10]=2)[N:4]=1)#[N:22]
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1cccc(Oc2ccc(N)c(Oc3cccc(C#N)c3)n2)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1cccc(Oc2ccc(NC(=O)c3ccccc3)c(Oc3cccc(C#N)c3)n2)c1
Reaction time: 3 h

Procedure:
To 3,3'-[3-amino-2,6-pyridinediylbis(oxy)]bis(benzonitrile) (1.0 g, 2.9 mmol) dissolved in acetonitrile (50 mL) was added benzoyl chloride (0.50 g, 3.5 mmol) and triethylamine (0.45 g, 0.60 mmol). After stirring for 3 hours, the reaction was partitioned between ether and water. The organic layer was separated, washed with water, saturated aqueous sodium bicarbonate, and brine, dried (MgSO4), and the solvent was removed in vacuo. Chromatography on silica gel with ethyl acetate/hexane (1/3) as eluent gave N-[2,6-bis(3-cyanophenoxy)pyridin-3-yl]benzamide; NMR (CDCl3) 8.95 (d,1), 8.25 (s,1), 7.9 (d,1), 7.2-7.7 (m,12), 6.8 (d,1) ppm.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[N:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:33]3[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=3)[CH2:36][NH2:37])=[N:22][N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=2)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[N:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21]([C:33]3[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=3)[CH2:36][NH:37][C:7](=[O:8])[C:6]3[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)=[N:22][N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])[CH:24]=2)=[CH:18][CH:19]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c(-c2cccc(CN)c2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c(-c2cccc(CNC(=O)c3ccc(C(F)(F)F)cc3)c2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.9 %

Procedure:
4-Trifluoromethylbenzoylchloride (0.054 g, 0.26 mmol) was added to a solution of 3-[4-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-benzylamine (0.10 g, 0.26 mmol) (prepared as described in Example 17) and triethylamine (0.08 g, 0.79 mmol) in dry DCM (2.0 ml) at 0° C. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 6 h. The organic layer was washed with water (2.0 mL) and dried over Na2SO4. The filtrate was evaporated to dryness to give an oil which was purified by flash chromatography, over silica gel, using dichloromethane/MeOH (98:0.2) as eluent, to afford N-{3-[4-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-benzyl}-4-trifluoromethyl-benzamide (0.110 g, 0.20 mmol, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH3:19].C(OC(=O)C)(=O)C.[CH3:27][C:28]1[S:29][CH:30]=[C:31]([CH:33]=O)[N:32]=1>O.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:19]=[CH:33][C:31]1[N:32]=[C:28]([CH3:27])[S:29][CH:30]=1
Reactant: Cc1nc(C=O)cs1
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccccc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1nc(C=Cc2nc3ccccc3c(=O)n2-c2ccccc2Cl)cs1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
Anhydrous zinc chloride (0.136 g, 1.0 mmol) was fused with a nitrogen purge in a round bottom flask with an open flame. The reaction vessel was allowed to return to ambient temperature, at which time dioxane (10 mL) was then added. To this mixture was added 3-(2-chloro-phenyl)-2-methyl-3H-quinazolin-4-one (0.135 g, 0.50 mmol), acetic anhydride (0.141 mL, 1.5 mmol), and 2-methylthiazole-4-carboxaldehyde (0.191 g, 1.5 mmol). The reaction was refluxed for 3 hours, and was then allowed to cool to ambient temperature. Once the reaction had cooled to abient temperature it was diluted with water. The resulting mixture was repeatedly extracted with chloroform. The combined chloroform layers were washed with water and brine, dried over sodium sulfate and then concentrated to yield a waxy tan solid. This residue was triturated with ether, filtered and dried to afford 0.139 g (73%) of 3-(2-chloro-phenyl)-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-one as tan solid.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7]>C(O)C>[Cl:3][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[CH:6]([C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)[OH:7]
Reactant: O=C(c1ccc(Cl)cc1)c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(c1ccc(Cl)cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.8 %

Procedure:
Under a nitrogen atmosphere, 1.7 grams ( 0.044 mole) of sodium borohydride pellets was added to 100 ml of stirred ethanol. To this was added 10.0 grams (0.040 moles) of 2,4′-dichlorobenzophenone in one portion. Upon completion of the addition the reaction mixture was stirred at ambient temperature for about 18 hours. After this time the ethanol was removed under reduced pressure, and the resulting residue was taken up in 250 mL of aqueous 5% sodium hydroxide solution. The solution was extracted with two 100 mL portions of diethyl ether. The combined ether extracts were washed with aqueous saturated sodium chloride solution. The organic layer was filtered and the filtrate concentrated under reduced pressure, yielding 9.5 grams of (2-chlorophenyl)(4-chlorophenyl)methanol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C@@:2]12[C@H:11]3[CH2:12][CH:13]=[C:14]4[C@@H:19]5[CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23][C@:18]5([C:26]([OH:28])=[O:27])[CH2:17][CH2:16][C@@:15]4([CH3:29])[C@:10]3([CH3:30])[CH2:9][CH2:8][C@H:7]1[C:6]([CH3:32])([CH3:31])[C@@H:5]([OH:33])[CH2:4][CH2:3]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][C@@:18]2([C:26]([OH:28])=[O:27])[CH:19]([C:14]3[C@@:15]([CH3:29])([CH2:16][CH2:17]2)[C@@:10]2([CH3:30])[CH:11]([C@:2]4([CH3:1])[CH:7]([CH2:8][CH2:9]2)[C:6]([CH3:32])([CH3:31])[C:5](=[O:33])[CH2:4][CH2:3]4)[CH2:12][CH:13]=3)[CH2:20]1
Reactant: CC1(C)CC[C@]2(C(=O)O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]2C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC1(C)CC[C@]2(C(=O)O)CC[C@]3(C)C(=CCC4[C@@]5(C)CCC(=O)C(C)(C)C5CC[C@]43C)C2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of oleanolic acid (Ia, 5.0 g, 10.9 mmol) and CH2Cl2 (200 mL) was added the Dess-Martin reagent (6.0 g, 14.2 mmol) under nitrogen at room temperature. After stirring at room temperature for 1 hour, the starting material was consumed, as indicated by TLC (1:1 hexanes:diethyl ether). The reaction mixture was quenched with the addition of a solution of sodium thiosulfate and NaHCO3 (50 g sodium thiosulfate in 200 mL saturated NaHCO3 solution). The mixture was stirred at room temperature for 10 minutes. The layers were separated and the aqueous layer was extracted with EtOAc (3×250 mL).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:30])[C@H:19]([CH2:28][SH:29])[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[CH3:16][O:17][C:18](=[O:30])[CH:19]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:28][S:29][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: BrCc1ccc(-c2ccc(Br)cc2)cc1
Reactant: COC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(CSCc1ccc(-c2ccc(Br)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4′-Bromo-4-bromomethyl-biphenyl, 9.1 g (27.9 mmol), N-(tert-Butoxy-carbonyl)-L-cysteine methyl ester, 5.74 mL (27.9 mmol), cesium carbonate, 18.2 g (55.8 mmol), and 100 mL of N,N-dimethylformamide was stirred at room temperature for 4 h. The mixture was diluted with 200 mL of water and extracted with 2×200 mL of ethyl acetate. The organic layer was washed with 2×200 mL portions of aq. LiCl, sat. aq. NaHCO3, sat. aq. NaCl, and dried (MgSO4). After the solution was concentrated, the residue was purified through a short plug of silica gel (eluted with 20% EtOAc-Heptane) to afford the desired product in 8.8 g (66%) as a white solid. 1H NMR (CDCl3) 7.55 (d, 2H, J=9.3 Hz), 7.50 (d, 2H, J=9.0 Hz), 7.43 (d, 2H, J=9.3 Hz), 7.37 (d, 2H, J=9.0 Hz), 5.31 (d, 1H, J=9.0 Hz), 4.62-4.51 (m, 1H), 3.76 (s, 5H), 2.93 (dd, 1H, 15.7, 5.7 Hz), 2.84 (dd, 1H, 15.7, 6.3 Hz), 1.47 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][S:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21]>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH:28]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: CCCNC(=O)c1nnc2c(-c3cccc(S(C)(=O)=O)c3)cccc2c1N
Yield: 83.1 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 3-(methylsulfonyl)phenylboronic acid (200 mg, 1.000 mmol) were reacted to afford the title compound (155 mg, 83% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.51 (br, 1H), 8.21 (m, 1H), 8.11-7.67 (m, 6H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 3.12 (s, 3H), 1.67 (apparent sextet, J=7.0 Hz, 2H), 1.01 (t, J=7.0 Hz, 3H). MS APCI, m/z=385 (M+H) HPLC 1.75 min.
Reaction SMILES: N1(O[C:11](=[O:24])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][CH:13]=2)C2C=CC=CC=2N=N1.[NH2:25][NH:26][C:27]([NH2:29])=[S:28].C(OC(C)C)(C)C>CN(C)C=O>[CH2:19]([O:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([NH:25][NH:26][C:27]([NH2:29])=[S:28])=[O:24])=[CH:17][CH:16]=1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCOc1ccc(C(=O)On2nnc3ccccc32)cc1
Reactant: NNC(N)=S
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: CCCCCOc1ccc(C(=O)NNC(N)=S)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 115.6 %

Procedure:
To a solution of 4-n-pentyloxybenzoic acid benzotriazole-1-yl ester (20 g) in N,N-dimethylformamide (100 ml) was added thiosemicarbazide (6.73 g) and stirred for 7 hours at ambient temperature. The reaction mixture was pulverized with diisopropyl ether. The precipitate was collected by filtration to give 1-(4-n-pentyloxybenzoyl)-3-thiosemicarbazide (20 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][N:9]2[CH:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1.C(#N)C.C1([N:30]=[C:31]=[O:32])CCCCCC1.C(O)C(N)(CO)CO>C(Cl)CCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:11]3([CH2:16][CH2:15][N:14]([C:31]([NH2:30])=[O:32])[CH2:13][CH2:12]3)[CH2:10][N:9]2[CH:17]([CH3:19])[CH3:18])=[CH:6][CH:7]=1
Reactant: O=C=NC1CCCCCC1
Reactant: CC(C)N1CC2(CCNCC2)C1c1ccc(Cl)cc1
Agent: NC(CO)(CO)CO
Solvent: ClCCCl
Solvent: CC#N
Product: CC(C)N1CC2(CCN(C(N)=O)CC2)C1c1ccc(Cl)cc1
Reaction time: 20 h

Procedure:
Treat 1-(4-Chlorophenyl)-2-isopropyl-2,7-diazaspiro[3.5]nonane, Isomer A (0.015 g) in ClCH2CH2Cl (1 mL) and acetonitrile (1 mL) with cycloheptyl isocyanate (18 uL), and the resulting mixture stirred at RT for 424 h. P—S Trisamine (Argoonaut, 4.64 mmol/g) (120 g) and ClCH2CH2Cl (2 mL) were added and the resulting mixture was shaken to 20 h. The reaction mixture was filtered, the resin washed with CH2Cl2 (2 mL). The resulting filtrate was concentrated in vacuo and then placed on a silica gel plate (1000 u) and eluted with CH2Cl2:MeOH (95:5) to give of 1-(4-chlorophenyl)-2-isopropyl-2,7-diazaspiro[3.5]nonane-7-carboxamide, white residue (0.0208 g). Add MeOH (0.5 mL) and 0.1N HCl in MeOH (1 mL), and concentrate in vacuo to give the title compound, as a white solid (0.0222 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C@@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[C:25](OC)=[O:26])(=[O:16])=[O:15])=[CH:10][CH:9]=1>O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C@@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[CH2:25][OH:26])(=[O:15])=[O:16])=[CH:10][CH:9]=1
Reactant: COC(=O)[C@@H]1CCCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(N[C@@H]1CCCCC[C@H]1CO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
A 1.0 M solution of lithium aluminum hydride in tetrahydrofuran (1.10 mL, 1.10 mmol) was added dropwise to a solution of trans-methyl 2-(4-chlorophenylsulfonamido)cycloheptanecarboxylate (253 mg, 0.73 mmol) in anhydrous tetrahydrofuran at −60° C. under nitrogen. The reaction was stirred at room temperature for 1.5 h and quenched by the addition of 25 mL ethyl acetate. The reaction was extracted twice with 25 mL saturated aqueous ammonium chloride. The organic layer was dried over sodium sulfate and concentrated to yield 4-chloro-N-(trans-2-(hydroxymethyl)cycloheptyl)benzenesulfonamide (216 mg, 93%). 1H NMR (400 MHz, CDCl3) δ ppm 7.81-7.83 (1H, m), 7.79-7.80 (1H, m), 7.47-7.49 (1H, m), 7.44-7.46 (1H, m), 5.40 (1H, d, J=8.06 Hz), 3.64 (1H, dd, J=11.08, 4.78 Hz), 3.48 (1H, dd, J=10.95, 4.41 Hz), 3.15-3.27 (1H, m), 2.27 (1H, br. s.), 1.58-1.72 (2H, m), 1.42-1.55 (5H, m), 1.21-1.39 (4H, m). LC/MS R.T.=2.18 min; [M+H]+=318.08; [M+Na]+=340.09; [M−H]−=316.07.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([NH:24][C:25]1[N:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1)=[O:23]>>[CH:1]1[C:11]2[CH2:10][N:9]([C:31]([C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:22]([C:17]4[C:16]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:23])=[N:30][CH:29]=3)=[O:32])[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1ccccc1N2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Nc3ccccc32)cn1)c1ccccc1-c1ccccc1

Procedure:
As described for example 12, 5,11-dihydro-10H-dibenz[b,e][1,4]diazepine is reacted with 6-[([1,1'-biphenyl]-2-ylcarbonyl)amino]-3-pyridinecarbonyl chloride to give the product as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31](OCC)=[O:32])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])(=[O:20])=[O:19])=[C:13]([F:29])[CH:12]=3)[C:3]=12.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[O:32])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])(=[O:20])=[O:19])=[C:13]([F:29])[CH:12]=3)[C:3]=12
Reactant: CCOC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21
Reactant: C1COCCN1
Product: Nc1ncnc2c1c(-c1ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c1)nn2CC(=O)N1CCOCC1

Procedure:
Ethyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate was treated with morpholine using the representative procedure for amide formation. Purification by preparative HPLC (25 to 100% CH3CN in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersi1HS C18, 250×21 mm column, Rt 9.3-9.8 min) afforded N1-{4-[4-amino-1-(2-morpholino-2-oxoethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluorophenyl}-2,3-dichloro-1-benzenesulfonamide as a white solid (0.005 g, 0.009 mmol): RP-HP (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersi1HS C18, 250×4.6 mm column) Rt 8.22 min. 1H NMR (DMSO-d6, 400 MHz) δ 10.82 (s, 1H), 8.21 (s, 1H), 7.96 (d, 1H), 7.94 (m, 1H), 7.53 (t, 1H), 7.39 (m, 3H), 6.97 (br, 2H), 5.32 (s, 2H), 3.5 (m, 8H); MS: MH+ 580.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Temperature: 80 °C
Yield: 80.9 %

Procedure:
Alternative preparation: [4-(Methylsulfonyl)phenyl]boronic acid (0.17 g, 0.84 mmol) and 1-methylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 81, Step 1, 0.25 g, 0.70 mmol) were mixed with DME (4 mL) and 2M Na2CO3 (4 mL). The mixture was degassed with N2, then PdCl2(PPh3)2 (50 mg, 0.07 mmol) was added. The reaction mixture was degassed again with N2 and heated at 80° C. for 6 h, then cooled to ambient temperature, and diluted with EtOAc. The mixture was washed with water and brine and the organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a brown solid. The crude product was purified by chromatography on a silica gel column eluted with 25% EtOAc/CH2Cl2 followed by trituration with hexane containing 1% of MeOH to give 0.245 g (81%) of the title compound as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.[Na].O[CH:8]=[CH:9][C:10]#[N:11].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[NH:12]([CH:8]=[CH:9][C:10]#[N:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CC=CO
Reactant: Nc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCO
Product: N#CC=CNc1ccccc1
Reaction time: 5 h
Yield: 67.4 %

Procedure:
12.25 g (0.125 mol) of sulfuric acid in 30 ml of ethanol is added drop by drop, at 0° C., to a suspension of 32.5 g (0.25 mol) of sodium-3-hydroxyacrylonitrile and 32.6 g (0.35 mol) of aniline in 150 ml of ethanol, and the mixture is held at 25° C. for 5 h. After removal of the solid by filtration and withdrawal of the solvent, the product is dissolved with water, acidified with dilute sulfuric acid, and extracted with ether. After recrystallization of the concentrated ether extract from carbon tetrachloride, 24.3 g (67.6%) of 3-anilinoacrylonitrile is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:24]=1>>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([N:16]2[CH:17]=[C:13]([C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:9][O:10][C:11]=3[C:18]([F:21])([F:19])[F:20])[N:14]=[CH:15]2)=[N:24][CH:25]=1
Reactant: Fc1ccc(-c2noc(C(F)(F)F)c2-c2c[nH]cn2)cc1
Reactant: COC(=O)c1ccc(Cl)nc1
Product: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Yield: 71 %

Procedure:
As described for Example 4, 3-(4-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (700 mg, 2.4 mmol) instead of 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole was converted, using methyl 6-chloronicotinate instead of 4-fluorobenzotrifluoride, to the title compound (720 mg, 71%) which was obtained as a white solid. MS: m/e=433.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[N:19]1([CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:28][CH2:27][CH2:26][CH2:25][CH2:24][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: NCCCCN1CCCC1
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Product: COc1ccc2nc3cc(Cl)ccc3c(NCCCCN3CCCC3)c2c1

Procedure:
Following the general procedure of Example 1 and making non-critical variations, but using 6,9-dichloro-2-methoxyacridine and 4-(pyrrolidin-1-yl)butan-1-amine (Step 3), the title compound was obtained; MS (Found M+1=384).