Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30]Cl>CN(C)C=O>[N:1]1([C:7]2[O:8][C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)=[CH:16][CH:15]=3)=[CH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=c1cc(-c2ccc(O)cc2)oc(N2CCOCC2)c1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccc(OCc3ccccn3)cc2)oc(N2CCOCC2)c1
Temperature: 55 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
2-Morpholinyl-6-(4-hydroxyphenyl)-4-pyrone, as prepared in Example 5, (273 mg, 1.0 mmole) was suspended in 6 ml dimethylformamide in a 25 ml one neck round bottom flask under nitrogen. The suspension was treated with sodium hydride suspension (192 mg, 4.0 mmole) and the reaction mixture was warmed to 55° C. for 40 minutes. The reaction was treated with 2-picolyl chloride hydrochloride (492 mg, 3.0 mmole) and the mixture was stirred 4 hours at 55° C. The reaction was poured into 50 ml 2N sodium hydroxide/ice and the precipitated solid was collected, washed with water and diethyl ether and was dried (188 mg). The crude material was recrystallized from ethyl acetate to give 123 mg (34%) of Compound 6 as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][OH:23])[CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)CCC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](CCC(=O)OCc1ccccc1)COS(C)(=O)=O

Procedure:
10.8 g (33.4 mmol) of benzyl (4R)-4-t-butoxycarbonylamino-5-hydroxypentanoate and 3.4 g (33.4 mmol) of triethylamine were stirred in 200 ml of dichloromethane. 3.83 g (33.4 mmol) of methanesulfonyl chloride was added to the obtained mixture under cooling with ice. Crude benzyl (4R)-4-t-butoxycarbonylamino-5-methanesulfonyloxypentanoate was obtained by an ordinary method with dichloromethane as the extracting solvent. The crude product was stirred together with 7.2 g (170 mmol) of lithium chloride in 50 ml of DMF at 50° C. overnight. The solvent was evaporated, and the crude title compound obtained by an ordinary method with ethyl acetate as the extracting solvent was washed with a solvent mixture of hexane and ethyl acetate to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.COC(=O)C1C=CC(OCC2[C:36]([C:41]3[CH:46]=[CH:45]C=C(F)C=3)=[N:37]OC=2C)=NC=1>>[CH:41]1([CH2:36][NH:37][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:46][CH2:45]1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Reactant: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)NCC2CC2)cn1
Yield: 63 %

Procedure:
As described for example 90, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (93 mg, 0.3 mmol), instead of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, was converted to the title compound (69 mg, 63%) which was obtained as an off white solid. MS: m/e=365.1 [M+H]′.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH2:10])[C:4]([CH2:11][CH2:12][CH3:13])=[N:3]1.[CH2:14]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19](Cl)=O)[CH3:15]>>[CH3:13][CH2:12][CH2:11][C:4]1[C:5]2[N:10]=[C:19]([C:18]3[CH:22]=[C:23]([S:26]([N:29]4[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)(=[O:27])=[O:28])[CH:24]=[CH:25][C:17]=3[O:16][CH2:14][CH3:15])[NH:9][C:7](=[O:8])[C:6]=2[N:2]([CH3:1])[N:3]=1
Reactant: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1C(=O)Cl
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12

Procedure:
An reaction between 1-methyl-3-propyl-4-aminopyrazole-5-carboxamide and 2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-benzoyl chloride is performed, and then Sildenafil is obtained by ring closure.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[NH:7][CH:8]=1)(=O)[NH2:2].C([O-])([O-])=O.[Na+].[Na+]>>[C:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[NH:7][CH:8]=1)#[N:2]
Reactant: COc1ccc(-c2nc(C(N)=O)c[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(-c2nc(C#N)c[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
A mixture of 64 (7.6 g, 0.035 mol) and POC13 (100 ml) was heated at reflux for 5.5 hours. After stirring at room temperature overnight, the suspension was poured into saturated Na2CO3 and the mixture extracted with 20% CH3OH--CHCl3 (3 X). The organic extracts were washed with saturated NaCl, dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel and the product eluted with 5% CH3OH--CHCl3 to yield 5.0 g (71%) of 65; m.p. 219°-20° C. (CH3CN). Analysis calculated for C11H9N3O.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(O)(=O)C.Br([O-])(=O)=O.[Na+].BrBr>O>[CH:15]([C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=2)=[CH:14][CH:13]=1)=[O:16]
Reactant: OCc1ccc(-c2ccc(CO)cc2)cc1
Agent: BrBr
Agent: [Na+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1ccc(-c2ccc(C=O)cc2)cc1
Temperature: 75 °C
Yield: 101.1 %

Procedure:
In a 50 ml three-necked flask equipped with a magnetic stirrer, a reflux condenser and a thermometer, 4.28 g (20 mmols) of 4,4′-bishydroxymethylbiphenyl and 10 ml of (166 mmols) of acetic acid were charged, followed by heating to 75° C. An aqueous solution prepared by dissolving 2.04 g (13.5 mmols) of sodium bromate in 10 ml of water was added dropwise, and then the mixture was stirred at 75° C. until a color of bromine disappears. To the system, 50 ml of water was added and, after filtration, the resulting substance was dried to obtain 4.25 g of 4,4′-bisformylbiphenyl as a white crystal. Yield: 99.9%. It was confirmed by GS-MS that a molecular ion peak is 209.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=1.[CH3:25][P:26]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([CH2:36][CH3:37])[CH:30]=1)([CH3:28])=[O:27]>>[CH3:28][P:26]([C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=2)=[C:31]([CH2:36][CH3:37])[CH:30]=1)([CH3:25])=[O:27]
Reactant: CCc1cc(P(C)(C)=O)ccc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Cl)ncc1C(F)(F)F
Product: CCc1cc(P(C)(C)=O)ccc1Nc1cc(Nc2ccccc2S(=O)(=O)C(C)C)c(C(F)(F)F)cn1

Procedure:
This compound can be prepared as described in Example 80 by reacting 2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-4-amine with 4-(Dimethylphosphoryl)-2-ethylaniline.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH3:13][NH:14][CH3:15]>>[CH3:13][N:14]([CH3:15])[C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CNC
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Product: CN(C)C(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 87 %

Procedure:
3-Nitrobenzoyl chloride (1.03 g, 5.5 mmol) was treated with dimethylamine (40% aqueous solution) (5 ml). The reaction mixture was stirred under Argon for 2 hours, and then extracted with dichloromethane (70 ml). The organic extract was dried (Na2SO4) and concentrated in vacuo to afford the title compound as a pale yellow solid (0.94 g, 87%).
Reaction SMILES: I[CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[Br:14][C:15]1[C:20]([F:21])=[CH:19][C:18]([N:22]2[C:31]3[C:26](=[CH:27][C:28]([S:32]([N:35]([C:45]4[CH:49]=[CH:48][O:47][N:46]=4)[CH2:36][C:37]4[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=4)(=[O:34])=[O:33])=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]2=[O:50])=[C:17]([OH:51])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Br:14][C:15]1[C:20]([F:21])=[CH:19][C:18]([N:22]2[C:31]3[C:26](=[CH:27][C:28]([S:32](=[O:33])(=[O:34])[N:35]([C:45]4[CH:49]=[CH:48][O:47][N:46]=4)[CH2:36][C:37]4[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=4)=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]2=[O:50])=[C:17]([CH:16]=1)[O:51][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(I)C1
Reactant: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(F)c(Br)cc3O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(F)c(Br)cc3OC3CCN(C(=O)OC(C)(C)C)C3)c2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Tert-butyl 3-iodopyrrolidine-1-carboxylate (0.029 g, 0.097 mmol) was added to a solution of 1-(4-bromo-5-fluoro-2-hydroxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.058 g, 0.097 mmol) and cesium carbonate (0.063 g, 0.193 mmol) in acetonitrile (0.242 ml) and stirred for 48 hr. The reaction vessel was cooled to room temperature. The reaction mixture was then transferred to a sep. funnel and the aqueous layer was washed 3× with EtOAc. The organic layers were combined, dried with MgSO4, filtered and concentrated to an oil. The crude mixture was taken onward to the next step assuming quantitative yield. m/z (ESI) 670.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].[C:11]([NH:18][CH2:19][CH2:20]Br)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:20][CH2:19][NH:18][C:11](=[O:12])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCn1cc(Br)ccc1=O
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of 5-bromo-2(1h)-pyridone (550 mg, 3161 μmol) in DMF (5 mL) under nitrogen was added NaH (60% dispersion in mineral oil; 152 mg, 6322 μmol). After for 10 min, 2-(boc-amino) ethyl bromide (779 mg, 3477 μmol) was added. The mixture was stirred for 18 h at 23° C. The mixture was partitioned between CH2Cl2 and 5% NaHCO3. The aqueous was extracted with CH2Cl2 (10 mL) twice. The combined organics were dried over MgSO then concentrated to a solid from toluene under reduced pressure. The residue was purified on silica (40 g) eluting with 0-30% of 5% MeOH/CH2Cl2 to give the product as a white solid. MS (ESI pos. ion) m/z (MH+): 317/319. Calc'd exact mass for C12H17BrN2O3: 316. 1H NMR (400 MHz, Chloroform-d) δ ppm 1.44 (s, 9H) 3.45 (q, J=6.02 Hz, 2H) 4.03-4.09 (m, 2H) 4.92 (br. s., 1H) 6.48 (d, J=10.04 Hz, 1H) 7.34-7.39 (m, 2H). 13C NMR (101 MHz, Chloroform-d) δ ppm 26.08, 37.26, 47.20, 95.56, 119.79, 135.87, 140.53
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:16]=[C:15]2[C:6]([S:7][C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([C:17](Cl)=[O:18])[C:13]=3[NH:14]2)=[CH:5][CH:4]=1.[S-:22][C:23]#[N:24].[K+]>CC(C)=O>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:16]=[C:15]2[C:6]([S:7][C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([C:17]([N:24]=[C:23]=[S:22])=[O:18])[C:13]=3[NH:14]2)=[CH:5][CH:4]=1
Reactant: N#C[S-]
Reactant: O=C(Cl)c1cccc2c1Nc1cc(C(F)(F)F)ccc1S2
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(N=C=S)c1cccc2c1Nc1cc(C(F)(F)F)ccc1S2
Reaction time: 1.5 h

Procedure:
A solution of 56.5 g. (0.172 mol.) of 8-trifluoromethylphenothiazine-1-carboxylic acid chloride in 450 ml. of acetone was added over a 15 minute period to a stirred solution of 25.0 g. (0.257 mol.) of potassium thiocyanate in 200 ml. of acetone. The resulting reddish brown suspension was stirred at 25° for 1.5 hours. The reaction mixture was concentrated under reduced pressure to approximately 300 ml. then diluted with 700 ml. of water. The product was collected by filtration and washed thoroughly with water to give 8-trifluoromethylphenothiazine-1-carboxylic acid isothiocyanate, m.p. 145°-150°.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][S:10][CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:13]([NH2:15])=[O:14].CO[C:18]([C@H:20]1[C@H:24]([CH3:25])[CH2:23][N:22]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:21]1)=O>>[CH2:26]([N:22]1[CH2:23][C@@H:24]([CH3:25])[C@H:20]([C:18]2[NH:15][C:13](=[O:14])[C:3]3[CH:4]=[N:5][N:6]([CH:7]4[CH2:12][CH2:11][S:10][CH2:9][CH2:8]4)[C:2]=3[N:1]=2)[CH2:21]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C
Reactant: NC(=O)c1cnn(C2CCSCC2)c1N
Product: C[C@@H]1CN(Cc2ccccc2)C[C@H]1c1nc2c(cnn2C2CCSCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 6-[(3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl]-1-(2-methoxyphenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 5-amino-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole-4-carboxamide and (3S,4S)-methyl-1-benzyl-4-methylpyrrolidine-3-carboxylate provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.02 (s, 1H), 7.41-7.26 (m, 5H), 4.60-4.53 (m, 1H), 3.86-3.83 (m, 1H), 3.65 (m, 1H), 3.41-3.37 (m, 1H), 3.02 (m, 1H), 2.94-2.75 (m, 4H), 2.60-2.31 (m, 3H), 2.25-2.16 (m, 2H), 1.99-1.94 (m, 1H), 1.62 (m, 2H), 1.20 (t, J=7.1 Hz, 3H). MS: (M+H m/z 410.2).
Reaction SMILES: [N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=5)[C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:31][CH:32]1[O:36][CH2:35][CH2:34][O:33]1>>[N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH2:31][CH:32]6[O:36][CH2:35][CH2:34][O:33]6)[CH:23]=5)[C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: BrCC1OCCO1
Reactant: O=c1c2ccc(O)cc2ccn1-c1ccc(N2CC[C@@H](N3CCCC3)C2)c(F)c1
Product: O=c1c2ccc(OCC3OCCO3)cc2ccn1-c1ccc(N2CC[C@@H](N3CCCC3)C2)c(F)c1

Procedure:
2-((R)-4-[1,3′]Bipyrrolidinyl-1′-yl-3-fluoro-phenyl)-6-hydroxy-2H-isoquinolin-1-one was reacted with 2-Bromomethyl-[1,3]dioxolane by method K. The product with the molecular weight of 479.56 (C27H30FN3O4) was obtained in this way; MS (ESI): 480 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1I)[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1.CN(C=O)C.CCN(CC)CC>O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:25]#[C:24][C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCn1c(I)c(C#N)c2ccc(OC)cc21
Reactant: C#Cc1ccc(F)cc1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1c(C#Cc2ccc(F)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Yield: 81.9 %

Procedure:
A mixture of 1-ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile (150 mg, 0.46 mmol), prepared as described in example 1Ga, step A, 4-fluorophenylacetylene (80 mg, 0.0.69 mmol), bis(triphenylphosphine)palladium (II) dichloride (6 mg, 0.009 mmol) and CuI (4 mg, 0.018 mmol) is added to a sealable tube and alternately evacuated and flushed with N2. To the tube is then added DMF (4 mL) and Et3N (0.25 mL, 1.84 mmol) and the reaction is heated at 80° C. for 20 h and then cooled to room temperature. The reaction mixture is diluted with H2O and extracted with EtOAc (2×). The combined organic phases are washed with H2O (3×) and saturated NaCl and then dried over MgSO4 and concentrated. The crude reaction mix is absorbed on silica gel (0.6 g) and chromatographed over silica gel using EtOAc/hexanes (10-20%) as eluent to afford 120 mg (82%) of 1-ethyl-2-(4-fluorophenylethynyl)-6-methoxy-1H-indole-3-carbonitrile as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[C:4]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH:3]=1.[CH2:19]([O:21][C:22](=[O:29])[CH2:23][C:24](=O)[CH:25]([CH3:27])[CH3:26])[CH3:20]>>[CH2:19]([O:21][C:22]([C:23]1[C:24]([CH:25]([CH3:27])[CH3:26])=[N:9][C:5]2[C:4]([C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=2[CH3:8])=[O:29])[CH3:20]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: Cc1cc(Cl)cc(C#Cc2ccccc2Cl)c1N
Product: CCOC(=O)c1c(C(C)C)nc2c(C)cc(Cl)cc2c1Cc1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 10 step B from 4-chloro-2-(2-chloro-phenylethynyl)-6-methyl-phenylamine (400 mg, 1.45 mmol) and 4-methyl-3-oxo-pentanoic acid ethyl ester (0.351 ml, 2.17 mmol). Brown solid. LC-MS (ESI): 416 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:23][C@@H:24]([C@@H:26]4[CH2:30][C:29](=[O:31])[NH:28][CH2:27]4)[CH3:25])=[N:10][C:11](C4C=C5C(CC(=O)N5)=CC=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[CH3:32][C:33]1([CH3:51])[C:41]2[C:36](=[CH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:40]=2)[NH:35][CH2:34]1>>[CH:1]1([N:4]2[C:8]3[C:9]([O:23][C@@H:24]([C@H:26]4[CH2:27][NH:28][C:29](=[O:31])[CH2:30]4)[CH3:25])=[N:10][C:11]([C:38]4[CH:37]=[C:36]5[C:41]([C:33]([CH3:32])([CH3:51])[CH2:34][NH:35]5)=[CH:40][CH:39]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C[C@@H](Oc1nc(-c2ccc3c(c2)NC(=O)C3)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: CC1(C)CNc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: C[C@@H](Oc1nc(-c2ccc3c(c2)NCC3(C)C)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Yield: 19 %

Procedure:
Prepared by Suzuki coupling reaction procedure, as previously described for the synthesis of 6-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)indolin-2-one:, using instead 3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline as a starting material to afford 22.0 mg (19%) of (R)-4-((R)-1-((3-cyclopropyl-6-(3,3-dimethylindolin-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, d6-DMSO) δ 8.24 (s, 1H), 7.56 (s, 2H), 7.25 (dd, J=7.7 Hz, J=1.4 Hz, 1H), 7.15 (d, J=1.5 Hz, 1H), 7.01 (d, J=7.7 Hz, 1H), 5.53 (m, 2H), 3.68 (m, 1H), 3.41 (m, 1H), 3.20 (m, 3H), 2.82 (m, 1H), 2.33 (m, 2H), 1.40 (d, J=6.2 Hz, 3H), 1.23 (s, 6H), 1.18 (m, 5H). MS (ESI+) m/z 432.2 (M+H).
Reaction SMILES: [C:1]1([C:7]2([CH2:13][CH2:14]OS(C)(=O)=O)[CH:12]=[CH:11][CH2:10][CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][NH2:21].[ClH:22]>>[ClH:22].[CH3:20][NH:21][CH2:14][CH2:13][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=[CH:11][CH2:10][CH:9]=[CH:8]1
Reactant: CS(=O)(=O)OCCC1(c2ccccc2)C=CCC=C1
Reactant: CN
Agent: Cl
Product: CNCCC1(c2ccccc2)C=CCC=C1

Procedure:
Methanesulfonic acid 2-(1-phenyl-2,5-cyclohexadien-1-yl)-ethyl ester is reacted with methylamine by an analogous procedure to that described in Example 7. The crude product obtained is converted in the usual manner into the hydrochloride which is recrystallized from isopropanol. There is obtained N-methyl-1-phenyl-2,5-cyclohexadien-1-ethylamine hydrochloride having a melting point of 172°-173° C.
Reaction SMILES: [S:1]([Cl:5])(=O)(=[O:3])[OH:2].[C:6]1([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[O:15]1[CH2:16][CH2:17][N:12]([C:6]2[CH:11]=[CH:10][C:9]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:8][CH:7]=2)[CH2:13][CH2:14]1
Reactant: c1ccc(N2CCOCC2)cc1
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1ccc(N2CCOCC2)cc1
Temperature: 90 °C
Reaction time: 20 h
Yield: 14.7 %

Procedure:
Sulfurochloridic acid (71.0 g, 612.07 mmol) was cooled to 0° C. and 4-phenylmorpholine (20.0 g, 122.53 mmol) was added in several batches, while keeping the temperature at 0° C. The resulting solution was then stirred at 90° C. for 20 hours. The reaction mixture was then added dropwise to 200 mL of ice/salt. The resulting solution was extracted with ethyl acetate (2×200 mL) and the organic layers were combined, dried (MgSO4) and filtered. The filtrate was concentrated, and the residue was purified by column chromatography using a 20:1 ethyl acetate/petroleum ether solvent system to give 4.7 g of 4-morpholinobenzene-1-sulfonyl chloride as a yellow solid. 1H NMR (CDCl3) δ 7.9 (d, 2H), 6.9 (d, 1H), 7.5 (d, 2H), 3.87 (t, 2H), 3.4 (t, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([N:28]1[C:33](=[O:34])[CH:32]=[CH:31][NH:30][C:29]1=[O:35])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:36]([O:55][CH2:56]/[CH:57]=[CH:58]/[CH2:59]O)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCCCCC.CCOC(C)=O>[C:20]([N:28]1[C:33](=[O:34])[CH:32]=[CH:31][N:30]([CH2:59]/[CH:58]=[CH:57]/[CH2:56][O:55][C:36]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:29]1=[O:35])(=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(c1ccccc1)n1c(=O)cc[nH]c1=O
Reactant: OC/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(c1ccccc1)n1c(=O)ccn(C/C=C/COC(c2ccccc2)(c2ccccc2)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.7 %

Procedure:
Polymer bound triphenylphosphine (0.75 g, 2.25 mmol) was shaken in THF (5 ml) for 15 minutes, then 3-benzoyluracil (290 mg, 1.35 mmol), trityl alcohol (11) (300 mg, 0.90 mmol) were added to the suspension of the resin. A solution of DIAD (0.354 ml, 1.80 mmol) in THF (2 ml) was added to the mixture. The reaction was shaken 24 hours at room temperature and monitored by TLC (Hexane/EtOAc 50:50). The resin was filtered and washed twice with THF (5 ml). The filtrate was concentrated under reduced pressure and taken in EtOAc (5 ml), a white solid precipitated. The precipitate was filtered; the filtrate was concentrated again and purified by flash chromatography using Hexane/EtOAc 40:60→60:40 as gradient which gave the title compound as a white foam (222 mg, 48%). Rf: 0.55 in Hexane/EtOAc 50:50 (UV/PMA).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:29])[CH2:15][CH2:16][C@@H:17]3[C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:21]4=[CH:20][CH:19]=[C:18]3[C@@H:13]2[CH2:12][CH2:11]1)/[CH:3]=[CH:4]/[C@@H:5]([CH:7]([CH3:9])[CH3:8])[CH3:6].[CH3:30][O:31][CH2:32]OC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:30][O:31][CH2:32][O:27][CH:25]1[CH2:24][CH2:23][C@@:22]2([CH3:28])[C:21](=[CH:20][CH:19]=[C:18]3[C@@H:17]2[CH2:16][CH2:15][C@@:14]2([CH3:29])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[C@H:2]([CH3:1])[CH:3]=[CH:4][C@H:5]([CH3:6])[CH:7]([CH3:8])[CH3:9])[CH2:26]1
Reactant: COCOC
Reactant: CC(C)[C@@H](C)/C=C/[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COCOC1CC[C@@]2(C)C(=CC=C3[C@@H]4CC[C@H]([C@H](C)C=C[C@H](C)C(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
Ergosterol (35.7 g, 90.0 mmol) was dissolved in dimethoxymethane (350 mL, 6.3 mol), and diphosphorous pentoxide (17.9 g, 126 mmol) was added thereto, followed by stirring at room temperature for 1 hour. Diatomaceous earth was added to the reaction mixture, followed by stirring for 30 minutes and filtration, and the filtrate was concentrated. Ethyl acetate was added to the resulting residue for trituration to obtain the title compound (35.1 g, 89%).