Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[H-].[Na+].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1F)[C:18]#[N:19]>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:11][CH2:10][C:4]1[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=1)[C:18]#[N:19]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: COc1ncc(CO)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncc(COc2ccc(C#N)cc2Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 5-chloro-3-hydroxymethyl-6-methoxypyridine (50 mg, 0.29 mmol) in DMF (3 mL) was added sodium hydride dispersion in oil (60%, 13.8 mg, 0.576 mmol) and the reaction stirred at 0° C. for 30 minutes. 3-Chloro-4-fluorobenzonitrile (45 mg, 0.288 mmol) was then added and the reaction stirred, warming to room temperature for 2 hours. The reaction was poured onto water (10 mL) and extracted with EtOAc (10 mL), dried over sodium sulfate and concentrated in vacuo to afford the title compound (89 mg, 72%).
Reaction SMILES: IC.[Br:3][C:4]1[CH:10]=[CH:9]C(N)=[C:6]([Cl:11])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][N:19]([CH:21]=O)[CH3:20]>>[Br:3][C:4]1[CH:10]=[CH:9][C:21]([N:19]([CH3:20])[CH3:18])=[C:6]([Cl:11])[CH:5]=1
Reactant: Nc1ccc(Br)cc1Cl
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CN(C)c1ccc(Br)cc1Cl
Yield: 78 %

Procedure:
Under nitrogen, 11.6 mL (186 mmol) of iodomethane was added to a stirred solution of 12.8 g (62 mmol) of 4-bromo-2-chloroaniline and 42.8 g (310 mmol) of powdered K2CO3 in 200 mL of DMF. Purification by silica gel chromatography (Waters Prep-500A)with ethyl acetate/hexane (5:95) gave 11.3 g (78%) of 4-bromo-2-chloro-N,N-dimethylaniline as a colorless liquid: NMR (CDCl3) δ 2.79 (s, 6H), 6.92(d, J=9 Hz, 1H), 7.25-7.34 (m, 1H), 7.49 (d, J=2 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:22])[S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH3:23][C:24]1[CH:33]=[CH:32][C:27]2[N:28]=[C:29]([NH2:31])[S:30][C:26]=2[CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:22])[S:10]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:31][C:29]3[S:30][C:26]4[CH:25]=[C:24]([CH3:23])[CH:33]=[CH:32][C:27]=4[N:28]=3)=[O:19])=[CH:20][CH:21]=2)(=[O:11])=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Reactant: Cc1ccc2nc(N)sc2c1
Product: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)Nc3nc4ccc(C)cc4s3)cc2)cc1

Procedure:
4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (7) (100 mg, 0.31 mmol) was treated with 6-methylbenzo[d]thiazol-2-amine (43 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)-N-(6-methylbenzo[d]thiazol-2-yl)benzamide as an off white solid. Yield: 57 mg (47%). 1H-NMR: 8.28 (d, J=8.5 Hz, 2H), 7.83 (s, 1H), 7.74-7.63 (m, 3H), 7.30 (dd, J=8.0, 1.5 Hz, 1H), 7.00 (d, J=8.5 Hz, 1H), 6.90 (d, J=8.5 Hz, 2H), 3.75 (s, 3H), 3.16 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O[CH2:24][CH:25]1[CH2:29][CH2:28][CH:27]([CH2:30]O)[O:26]1.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[OH-].[Na+]>CO>[CH2:32]([N:39]1[CH2:30][CH:27]2[O:26][CH:25]([CH2:29][CH2:28]2)[CH2:24]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OCC1CCC(CO)O1
Reactant: NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1ccc(CN2CC3CCC(C2)O3)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 94.9 %

Procedure:
A mixture of 2,5-bis(hydroxymethyl)tetrahydrofuran bis(p-toluenesulfonate) (10 g) and benzylamine (9.7 g) was stirred at 70° C. for 24 hours. To the mixture was added a solution of sodium hydroxide (1.85 g) in methanol (30 ml). After stirring at room temperature for 30 minutes, the mixture was filtered. The filtrate was evaporated, added dichloromethane, and filtered. The filtrate was evaporated under reduced pressure, and purified with column chromatography (silica gel, 250 ml, ethyl acetate:hexane=1:4) to give 3-benzyl-8-oxa-3-azabicyclo[3.2.1]octane (4.05 g) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.[Cl:36][CH2:37][C:38]([CH2:40]Cl)=[CH2:39].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:36][CH2:37][C:38](=[CH2:39])[CH2:40][O:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[N:11]=[C:10]([NH:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: C=C(CCl)CCl
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(CCl)COc1ccc(CNc2nc(Nc3ccc(C(=O)OC(C)(C)C)cc3)nc(OCC(F)(F)F)n2)cc1
Yield: 36.7 %

Procedure:
A suspension of tert-butyl 4-((4-((4-hydroxybenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoate (3 g), 3-chloro-2-(chloromethyl)prop-1-ene (1.15 g) and K2CO3 (1.69 g) in acetone (20 mL) was heated to reflux for 16 hours. The solvent was removed under vacuum. The residue was purified by silica gel column (hexanes:EtOAc=10:1 to 4:1) to give tert-butyl 4-(4-(4-(2-(chloromethyl)allyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (1.3 g).
Reaction SMILES: C(OC([NH:8][C@:9]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][C:13](=[O:15])[NH:12][C:10]1=[O:11])=O)(C)(C)C.[ClH:21]>C(OCC)(=O)C>[ClH:21].[NH2:8][C@:9]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][C:13](=[O:15])[NH:12][C:10]1=[O:11]
Reactant: CCOC(=O)[C@@]1(NC(=O)OC(C)(C)C)CC(=O)NC1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@]1(N)CC(=O)NC1=O
Reaction time: 1 h
Yield: 97 %

Procedure:
(R)-2-t-Butyloxycarbonylamino-2-ethoxycarbonylsuccinimide (380 mg) obtained in Example 16 was dissolved in a 4 mol/L solution of hydrochloric acid in ethyl acetate (8 mL), and the reaction mixture was stirred for 1 hour, and then concentrated under reduced pressure. The residue was suspended in ether and filtered to obtain the title compound (288 mg, yield: 97%) as white crystals. Optical rotation [α]D25 was −14.8° (c 1.0, methanol). Optical purity was 75.6% ee.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:12][CH:13]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:23]=1)[CH2:14][NH:15][C:16]([NH:18][NH2:19])=S>C1COCC1>[C:1]([NH:9][C:10]1[S:11][C:16]([NH:15][CH2:14][CH:13]([OH:12])[CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[CH:23]=2)=[N:18][N:19]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NNC(=S)NCC(O)COc1cccc(CN2CCCCC2)c1
Solvent: C1CCOC1
Product: O=C(Nc1nnc(NCC(O)COc2cccc(CN3CCCCC3)c2)s1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.33 g (2 mmol) of benzoyl isothiocyanate are added to 0.68 g (2 mmol) of N-[2-hydroxy-3-[3-(1-piperidinylmethyl)phenoxy]propyl]-hydrazine carbothioamide in 20 ml of THF and the reaction mixture is stirred overnight at room temperature. After removal of the THF by evaporation, the solid residue is washed with ether and dissolved in 30 ml of ethanol with heating, and 1 ml of 30% hydrogen peroxide is added. The sulphur which separates is filtered off, the filtrate is concentrated by evaporation and the oily residue is purified by preparative layer chromotography.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[CH:14]=[CH:13][NH:12][C:6]=2[N:7]=[C:8]([S:10][CH3:11])[N:9]=1.[CH2:15]([O:22][C@H:23]1[C@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:26]([CH2:36][O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:25][C@@H:24]1Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[Cl:3][C:4]1[C:5]2[CH:14]=[CH:13][N:12]([C@@H:24]3[O:25][C@H:26]([CH2:36][O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@@H:27]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C@@H:23]3[O:22][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[N:7]=[C:8]([S:10][CH3:11])[N:9]=1
Reactant: CSc1nc(Cl)c2cc[nH]c2n1
Reactant: Cl[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c2ccn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A suspension of 3.1 g sodium hydride, 25.9 g of 4-chloro-2-methylmercapto-7H-pyrrolo[2,3-d]pyrimidine, and 250 ml of dry dimethylformamide (DMF) is stirred at 50° C. for 0.5 hour, cooled, and added to 62.8 g of 2,3,5-tri-O-benzyl-α-D-arabinofuranosyl chloride. The solution is stirred at ambient temperature for 15 hours, concentrated in vacuo, and distributed between a mixture of ethyl acetate and water. Chromatrography of the dried (MgSO4) layer over silica gel with 4:1 toluene-ethyl acetate provides 76 g of yellow, syrupy 4-chloro-2-methylmercapto-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH3:9].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C=O)C>[Si:15]([O:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH3:9])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: Cc1cc(Br)ccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 96.6 %

Procedure:
To a 0° C. mixture of 2-hydroxy-5-bromotoluene(48.63 g, 260 mmol), DMF (260 ml), imidazole (18.58 g, 273 mmol) is added t-butyldimethylsilyl chloride (41.15 g, 273 mol) in portions. After stirring for 30 m, the reaction is warmed to RT and stirred for 16 h. The reaction mixture is poured into ice/water (1.25 l) and extracted with Et2O. The organic layer is washed with water (2×100 ml), 1N NaOH (2×5 ml), water, brine, MgSO4 dried, concentrated, chromatographed (hex), and azeotroped with toluene to give the title compound as an oil (75.7 g, 97%)
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)C.C(O)C.O.[NH2:17][NH2:18]>O>[Br:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([NH:17][NH2:18])=[O:3]
Reactant: NN
Reactant: CCOC(=O)c1cccc(Br)c1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cccc(Br)c1
Yield: 86 %

Procedure:
First, 10 g (44 mmol) of ethyl-3-bromobenzoate was put in a 200-mL three-neck flask, 50 mL of ethanol was added therein, and the mixture was stirred. Thereafter, 12 mL of hydrazine monohydrate was added therein, and the mixture was stirred at 78° C. for 5 hours so as to be reacted. After the reaction, water was added to the reaction solution, and a solid was precipitated. The precipitated solid was collected by suction filtration. The obtained solid was put in approximately 500 mL of water, washed, and again collected by suction filtration; thus, 8.1 g of a white solid that was an object was obtained (yield: 86%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1>C(Cl)Cl.C1COCC1.O=[Mn]=O>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1
Reactant: OCc1ccc(-c2nc3ccccc3[nH]2)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2nc3ccccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42 %

Procedure:
4-(Benzimidazol-2-yl)-benzyl alcohol from above (0.175 g, 0.78 mmol) was dissolved in CH2Cl2 (5 mL) and THF (8 mL), treated with activated MnO2 (0.68 g, 7.8 mmol) and stirred at room temperature for 1.5 h. The mixture was filtered through celite, the cake washed with CH2Cl2 and the solvent from the eluent removed under reduced pressure to afford 4-(benzimidazol-2-yl)-benzaldehyde (92 mg, 42%). 1H NMR (CD4OD) δ 7.28 (m, 2H), 7.60 (br, 1H (NH)), 7.65 (d, 2H, J=7.8 Hz), 8.09 (d, 2H, J=7.8 Hz), 8.30 (d, 2H, J=9.0 Hz), 10.08 (s, 1H (CHO)).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH2:42])=[CH:37][CH:36]=1)C>>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH:42][CH2:41][C:38]1[CH:37]=[CH:36][C:35]([C:34]([OH:33])=[O:43])=[CH:40][CH:39]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CCOC(=O)c1ccc(CN)cc1
Product: O=C(O)c1ccc(CNCc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and 4-aminomethyl-benzoic acid ethyl ester according to the procedure of Example 66. MS m/z 541; MS m/z 539.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH:8]1[C:16]2[NH:15][C:14]3[C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[S:19][C:13]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1>C(Cl)Cl.CCCCCC>[CH3:5][N:15]1[C:16]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[C:14]1=2
Reactant: COS(=O)(=O)OC
Reactant: c1ccc2c(c1)[nH]c1c3ccccc3sc21
Solvent: CCCCCC
Solvent: ClCCl
Product: Cn1c2ccccc2c2sc3ccccc3c21
Yield: 91.9 %

Procedure:
Using the procedure outlined in Example 34A except that dimethyl sulfate was used as the alkylating agent, 10H-[1]benzothieno[3,2-b]indole (prepared by the method of K. E. Chippendale and B. Iddon, JCS Perkin Trans. I, 2023 (1972)) gave a 91.9% yield of 10-methyl-10H-[1]benzothieno[3,2-b]indole, mp 175°-176°, (CH2Cl2 /hexane), (C,H,N,S).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH3:17])[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[O:7]1)=[O:5])[CH3:2].[CH2:18](Br)[CH3:19]>>[CH2:1]([O:3][C:4]([C:6]1([CH3:17])[C:11](=[O:12])[N:10]([CH2:18][CH3:19])[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[O:7]1)=[O:5])[CH3:2]
Reactant: CCBr
Reactant: CCOC(=O)C1(C)Oc2ccccc2NC1=O
Product: CCOC(=O)C1(C)Oc2ccccc2N(CC)C1=O

Procedure:
The title compound was prepared from ethyl-3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazine-2-carboxylate and ethyl bromide according to the procedure described in Example 16. The title product was a viscous oil, which was purified by column chromatography (silica gel; dichloromethane/methanol 100:1).
Reaction SMILES: [C:1]1(=[O:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.[OH-:11].[Na+:12]>>[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:1]([O-:10])=[O:11].[Na+:12]
Reactant: O=C1CCCCCCCN1
Reactant: [OH-]
Agent: [Na+]
Product: NCCCCCCCC(=O)[O-]
Temperature: 110 °C

Procedure:
A 5 L three-neck round bottom flask was fitted with a heating mantle, an overhead mechanical stirrer, a reflux condenser, and a thermometer. A suspension of 2-azacyclononanone (83 g, 0.59 moles, 1.0 equiv.) in 5 M aqueous sodium hydroxide (650 mL, 3.23 moles, 5.5 equiv.) was charged into the round bottom flask. The mixture was heated to reflux (internal temperature about 110° C.) for 4 hours to yield a clear yellow solution. The heating mantle and reflux condenser were removed. After the solution cooled to room temperature, it was diluted with water (650 mL) and cooled further in an ice bath.
Reaction SMILES: [CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12](F)=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14])[CH2:2][CH2:3][CH3:4].[CH2:15]([Mg]Br)[CH3:16]>O1CCCC1.CCOCC>[CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14])[CH2:2][CH2:3][CH3:4]
Reactant: CC[Mg]Br
Reactant: CCCC/N=C/c1c(F)cccc1Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC/N=C/c1c(Cl)cccc1CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
This compound was prepared using methodology described in Synthesis 1999, 2138-2144. To a solution of 21.2 g (99.2 mmol) butyl-[1-(2-chloro-6-fluoro-phenyl)-meth-(E)-ylidene]-amine in 150 ml tetrahydrofuran at 0° C. was added dropwise 38.0 ml (114 mmol) of a 3 M solution of ethylmagnesium bromide in ether at such a rate that the temperature of the reaction mixture was maintained below 20° C. After the addition was complete, the reaction mixture was stirred for a further 1 h at room temperature. The reaction mixture was then quenched by dropwise addition of water and diluted with ethyl acetate. The mixture was washed sequentially with water and with saturated brine, then the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was resuspended in carbon tetrachloride and concentrated in vacuo again to afford 19.7 g (89%) of the title compound as a yellow oil which was used in the next step without further purification. MS (ISP): 226.3 ([{37Cl}M+H]+), 224.3 ([{35Cl}M+H]+). 1H NMR and MS analysis indicated that this material contained ca 13% of the by-product butyl-[1-(2-ethyl-6-fluoro-phenyl)-meth-(E)-ylidene]-amine. MS (ISP): 208.3 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.O1CCOCC1.CCN(C(C)C)C(C)C.[C:49]1([SH:55])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[C:49]1([S:55][C:2]2[CH:3]=[C:4]([CH:8]([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: Sc1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(Br)c4)c3)ncnc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(Sc5ccccc5)c4)c3)ncnc21
Yield: 80.1 %

Procedure:
To the 3-(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (0.130 g, 0.000248 mol) from Example 429 Step 2, in dry 1,4-dioxane (1.60 mL, 0.0205 mol) was added DIPEA (0.085 mL, 0.00049 mol). The solution was degassed with nitrogen, followed by addition of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.007 g, 0.00001 mol), bis(dibenzylideneacetone)palladium(0) (0.0036 g, 0.0000062 mol), and benzenethiol (0.025 mL, 0.00025 mol). Again the solution was purged with nitrogen. The reaction mixture in a sealed tube was heated to reflux for 3 h. The reaction mixture was diluted with ethyl acetate, washed with water (2×), brine (1×), dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo. The crude product was triturated with hexane-ethyl acetate 9:1 to yield 3-[5-(phenylthio)pyridin-3-yl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (110 mg, 80%). LC/MS (M+H)+: m/z=554.2.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]([CH3:21])([CH3:20])[C:9](=[O:19])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N+:12]=2[O-:18])=[CH:5][CH:4]=1)#[N:2].[BH4-].[Na+]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]([CH3:21])([CH3:20])[CH:9]([OH:19])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N+:12]=2[O-:18])=[CH:22][CH:23]=1)#[N:2]
Reactant: Cc1cccc(CC(=O)C(C)(C)Oc2ccc(C#N)cc2)[n+]1[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(CC(O)C(C)(C)Oc2ccc(C#N)cc2)[n+]1[O-]
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
7.3 g of 2-[3-(4-cyanophenoxy)-3-methyl-2-oxobutyl]-6-methylpyridine N-oxide in 160 ml of ethanol were treated with 0.96 g of sodium borohydride and the mixture was stirred for 30 minutes. The solvent was removed by evaporation and the residue was taken up in water and dichloromethane. The organic phase was separated, dried over sodium sulphate and evaporated. The residue was crystallized from diethyl ether to give 7.1 g of 2-[3-(4-cyanophenoxy)-2-hydroxy-3-methylbutyl]-6-methylpyridine N-oxide of melting point 89°-92° C.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C@H:14]([OH:26])[CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20](CCN)=[CH:19][CH:18]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>CO>[C:8]1([C@H:14]([OH:26])[CH2:15][NH:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NCCc1ccc(NC[C@@H](O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O[C@H](CNc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N-(2-phenyl-2-(S)-hydroxyethyl)-4-(2-aminoethyl)aniline trifluoroacetate 31 (0.144 g, 0.3 mmole) in methanol (10 mL) was added aq. NaOH solution (1.0 M, 0.625 mL). The solution was concentrated to dryness and the residue was dissolved in anhydrous THF (5 mL). α,α-Dihydroxy-4-hydroxy-3-methoxycarbonylacetophenone 12 (0.067 g, 0.3 mmole) was added and the reaction mixture was stirred for 12 h at rt. BH3-Me2S (0.2 mL, 2M) was added at 0° C. and the reaction mixture was heated at 75° C. for 6 h. After cooling the reaction mixture in ice bath, MeOH (5 mL) was slowly added to it to quench the reaction, and the reaction mixture was stirred for 30 min., at rt. The organics were removed and the residue was dissolved in TFA/MeOH (1/9; 20 mL), and concentrated. The crude product was dissolved in 20% MeCN/H2O, and purified by preparative HPLC: 5 to 20% MeCN/H2O; 20 mL/min; 254 nm.) to give 1-{2-[N-2-(4-hydroxy-3-hydroxy-methylphenyl)-2-hydroxyethyl]amino]ethyl}-4-[N-(2-phenyl-2-(S)-hydroxyethyl)-amino]benzene 33.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.CC[N:17](CC)CC.ClC(OCC(C)C)=O.[NH4+].[OH-]>C1COCC1>[O:1]1[C:5]([C:6]2[CH:14]=[CH:13][C:9]([C:10]([NH2:17])=[O:11])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1ccc(-c2cnco2)cc1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1ccc(-c2cnco2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 48.7 %

Procedure:
A mixture of 4-(5-oxazolyl)benzoic acid (1.0 g, 5.46 mmol) and Et3N (552 mg, 5.46 mmol) in 25 mL of THF was cooled to 0° C. and ClCOOi-Bu (745 mg, 5.46 mmol) was added dropwise. After the addition was over, the reaction mixture was stirred for additional 5 min and then aq NH4OH (0.63 mL of 28% solution, 10.46 mmol) was added. After overnight stirring, the solvent was evaporated, the residue was taken up in water and basified to pH 9. The precipitated solid was filtered, washed with water and dried over P2O5 in a vacuum desiccator to provide 500 mg (48%) of the 4-(5-oxazolyl)-benzamide: 1H NMR (DMSO-d6) δ 8.50 (s, 1H), 8.20–7.80 (m, 5H).