Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[OH:39][CH2:38][C:37]([NH:36][S:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=1)(=[O:35])=[O:34])([CH3:41])[CH3:40]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Product: CC(C)(CO)NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (370 mg, 1.04 mmol) and 3-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.6) (321 mg, 1.04 mmol) according to general procedure II. Obtained as an orange solid (164 mg, 27%). MS (ISN) 581 [(M−H)−]; mp 201–204° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH2:19][OH:20])(=[O:11])=[O:10].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[Cl:8][C:7]1[CH:2]=[C:3]([S:9]([O:12][C:13]2[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[O:16][CH2:17][CH2:18][CH:19]=[O:20])(=[O:11])=[O:10])[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(Cl)c2Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
Sulfur trioxide pyridine complex (480 mg, 4.0 mmol) was added to a solution of 3-[3-(2,3-dichlorophenylsulfonyloxy)-5-methylphenoxy]propanol (460 mg, 1.3 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.5 mL, 3.9 mmol) and anhydrous dimethyl sulfoxide (0.3 mL, 4.2 mmol) in anhydrous dichloromethane (10 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (50 mL). The mixture was extracted into dichloromethane (3×50 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a colorless oil (420 mg, 91%). 1H-NMR (300 MHz, CDCl3) δ 9.84 (s, 1H), 7.86 (s, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 6.63 (s, 1H), 6.44 (s, 1H), 6.37 (s, 1H), 4.20 (t, J=6.1 Hz, 2H), 2.87 (t, J=6.1 Hz, 2H), 2.26 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[NH:15])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.O=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]1[C:31](=O)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[O-]CC.[Na+]>C(O)C>[CH2:32]([C:31]1[C:19]2[CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23][C:18]=2[N:15]=[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])=[CH:12][CH:11]=2)[N:16]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)Cc2ccccc2)C1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Yield: 54.2 %

Procedure:
1-(4-(2-Methyl-1H-imidazol-1-yl)phenyl)guanidine (224 mg, 1.04 mmol), tert-butyl 4-oxo-3-(2-phenylacetyl)piperidine-1-carboxylate (330 mg, 1.04 mmol) and sodium ethoxide (70.8 mg, 1.04 mmol) in ethanol (5 mL) were heated to 110° C. in a microwave reactor for 1 h 20 min. The reaction was allowed to reach room temperature and the solvent was evaporated under reduced pressure. The crude was dissolved in ethyl acetate and washed with water. The organic phase was dried under MgSO4 and the solvent evaporated under reduced pressure yielding tert-butyl 4-benzyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (280 mg, 54.2%) which was used in the subsequent step as such.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:38])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]4[CH:24]=[CH:25][C:26]([C:28]5[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=5)=[CH:27][C:22]4=[N:21][CH:20]=3)=[CH:15][C:14]=2[F:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([C:26]3[CH:25]=[CH:24][N:23]4[C:19]([C:16]5[CH:17]=[CH:18][C:13]([NH:12][C:11]([NH:10][C:7]6[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[O:9][N:8]=6)=[O:38])=[C:14]([F:37])[CH:15]=5)=[CH:20][N:21]=[C:22]4[CH:27]=3)=[CH:29][CH:30]=2)[CH2:48][CH2:47]1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cnc4cc(-c5ccc(C(=O)O)cc5)ccn34)cc2F)no1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3ccn4c(-c5ccc(NC(=O)Nc6cc(C(C)(C)C)on6)c(F)c5)cnc4c3)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Combine 4-(3-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-3-fluoro-phenyl}-imidazo[1,2-a]pyridin-7-yl)-benzoic acid (2.00 g, 3.89 mmol), piperazine-1-carboxylic acid tert-butyl ester (1.09 g, 5.84 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.821 g, 4.28 mmol), triethylamine (1.63 mL, 11.68 mmol), and 1-hydroxybenzotriazole (0.579 g, 4.28 mmol) in DMF (50 mL). Stir at room temperature for 14 hours. Partition between ethyl acetate and 1 N NaOH, wash with aqueous saturated sodium chloride, dry over magnesium sulfate, filter, and concentrate. Triturate the resulting solid from CH2Cl2/hexanes, filter, and dry to give off-white solid as product (1.53 g, 58%). MS (ES), m/z 683 (M+1).
Reaction SMILES: [C:1]1([CH:7]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][CH2:26][C:27]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][N:28]=1>CCOC(C)=O.C(#N)C>[Cl-:25].[C:32]1([C:30]2[O:29][N:28]=[C:27]([CH2:26][N+:13]34[CH2:18][CH2:17][CH:16]([CH2:15][CH2:14]3)[C@@H:11]([O:10][C:8](=[O:9])[CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:12]4)[N:31]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCCCC1
Reactant: ClCc1noc(-c2ccccc2)n1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(O[C@H]1C[N+]2(Cc3noc(-c4ccccc4)n3)CCC1CC2)C(c1ccccc1)N1CCCCC1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 30 h
Yield: 72 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-phenyl-2-(piperidin-1-yl)acetate (100 mg, 0.30 mmol) in EtOAc (2 ml) and acetonitrile (1 ml), was added 3-(chloromethyl)-5-phenyl-1,2,4-oxadiazole (71.1 mg, 0.36 mmol). The reaction was stirred at room temperature for 30 hours and then the solvents were evaporated. The residue was triturated with EtOAc (10 ml) and the solid was collected by suction filtration to obtain the title compound (113 mg, 71% yield) as a yellow solid.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1([C:26]([NH:28][CH:29]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH2:30][C:31](OC)=[O:32])=[O:27])[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[CH:25]=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CCO.O>[Cl:41][C:38]1[CH:37]=[CH:36][C:35]([CH:29]([NH:28][C:26]([C:11]2([NH:10][C:8](=[O:9])[O:7][C:3]([CH3:5])([CH3:4])[CH3:6])[CH2:12][CH2:13][N:14]([C:17]3[C:18]4[CH:25]=[CH:24][NH:23][C:19]=4[N:20]=[CH:21][N:22]=3)[CH2:15][CH2:16]2)=[O:27])[CH2:30][CH2:31][OH:32])=[CH:40][CH:39]=1
Reactant: COC(=O)CC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 70 h
Yield: 30 %

Procedure:
Sodium borohydride (1.019 g, 26.93 mmol) was added in one portion to a stirred suspension of methyl 3-(4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamido)-3-(4-chlorophenyl)propanoate (Intermediate 35) (1.0 g, 1.80 mmol) dissolved in EtOH (400 mL) under argon. The resulting suspension was stirred at 20° C. for 70 hours. A few drops of water were added to quench the excess of hydride and the mixture stirred for 1 hour. The mixture was evaporated to dryness and the residue was partitioned between CH2Cl2 and water saturated with NaCl. The organic phase was dried and concentrated to provide crude product as white crystals. The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% methanol in dichloromethane. The pure fractions were evaporated to dryness to afford tert-butyl 4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (286 mg, 30.1%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2([OH:17])[CH2:16][CH2:15][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH3:19].[H-].[Na+].O>CN(C)C=O.CCOCC>[CH3:19][O:17][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1
Reactant: CI
Reactant: OC1(c2ccccc2)CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: COC1(c2ccccc2)CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 7.5 h

Procedure:
To a solution of 8-phenyl-1,4-dioxaspiro[4.5]decan-8-ol (5.76 g) and iodomethane (4.59 ml) in N,N-dimethylformamide (58 ml) was added sodium hydride (60% dispersion in mineral oil) (1.97 g) at 0° C. The solution was stirred for 2 hours at 0° C. and at room temperature for 7.5 hours. The reaction mixture was added to a mixture of water and ether. The organic layer was washed with brine and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (5:1 hexane-ethyl acetate elution) to give 8-methoxy-8-phenyl-1,4-dioxaspiro[4.5]decane (5.968 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([O:22][CH3:23])[C:17]=3[N+:19]([O-])=O)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH4+].[Cl-].O.C(Cl)(Cl)Cl>CO.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:17]([NH2:19])=[C:16]([O:22][CH3:23])[C:15]([O:24][CH3:25])=[CH:14][C:13]=3[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3)c2c([N+](=O)[O-])c1OC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: COc1cc2ncnc(Nc3cccc(Cl)c3)c2c(N)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3-chloro-phenyl)-(6,7-dimethoxy-5-nitro-quinazolin-4-yl)-amine (0.2 g, 0.55 mmol) (from Example 11, Step A, supra) and NH4Cl (0.24 g, 4.43 mmol) in a mixture of MeOH, H2O and CHCl3 (50 mL, 2:1:12), was added Zn powder (0.72 g, 11 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was then filtered. The filtrate was concentrated and then extracted with chloroform (100 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2 /NEt3 (1:1:0.05) as eluent to give the desired N4-(3-chloro-phenyl)-6,7-dimethoxy-quinazoline-4,5-diamine as an orange gum. (Yield 0.1 g, 55%).
Reaction SMILES: [C:1]([CH2:3][C:4]([C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[CH:12]=O)([CH3:6])[CH3:5])#[N:2].[ClH:17].Cl.[C:19]1([C@H:25]2[C@@H:30]([NH2:31])[CH2:29][CH2:28][CH2:27][NH:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.Cl.C(C1(C2C=CC(OC)=C(C=2)CN[C@H]2CCCN[C@H]2C2C=CC=CC=2)CC1)#N>>[ClH:17].[ClH:17].[C:1]([CH2:3][C:4]([C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[CH2:12][NH:31][C@H:30]1[CH2:29][CH2:28][CH2:27][NH:26][C@H:25]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:6])[CH3:5])#[N:2]
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Reactant: COc1ccc(C(C)(C)CC#N)cc1C=O
Agent: COc1ccc(C2(C#N)CC2)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: Cl
Product: COc1ccc(C(C)(C)CC#N)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 47 and Compound 3 in the same manner of Compound 5.
Reaction SMILES: Cl.[CH3:2][CH:3](NCCC(O)=O)[CH2:4][CH2:5][CH2:6]C.[CH3:14][NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.BrCCCCC.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][N:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CNCc1ccccc1
Reactant: CCCCC(C)NCCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCBr
Product: CCCCCN(C)Cc1ccccc1

Procedure:
The present invention provides an alternate process for the synthesis of 3-[N-(methylpentyl)amino]propionic acid (III) wherein N-methyl benzyl amine is condensed with 1-bromo pentane in presence of potassium carbonate, using acetone as solvent to give N-methyl N-pentyl benzyl amine. This is debenzylated using palladium on carbon as catalyst and alcohol as solvent. The resulting product N-methyl pentyl amine is condensed with methyl acrylate in toluene to get 3-[N-(methylpentyl)amino]propionate, which is further hydrolysed to obtain Intermediate III.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[C:35]([N:21]1[CH2:22][CH2:23][N:18]([C:17]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:24]([O:26][CH3:27])=[O:25])=[CH:12][CH:11]=3)[CH2:19][CH2:20]1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCNCC3)nc2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCN(C(=O)c4ccccc4)CC3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(piperazin-1-yl)quinoxaline-6-carboxylate (180 mg, 0.49 mmol) in dichloromethane (10 ml) was added Et3N (200 mg, 2 mmol) followed by benzoyl chloride (170 mg, 1.18 mmol) dropwise. The resulting solution was stirred for 1 hour at room temperature and then quenched by the addition of ice-water (150 ml) and extracted with dichloromethane (3×30 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford methyl 3-(4-benzoylpiperazin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (130 mg, 56%).
Reaction SMILES: [CH2:1]1[CH2:31][O:30][C:3]2([CH2:25][CH2:24][C@@:23]3([CH3:26])[C:5](=[CH:6][CH2:7][C@@H:8]4[C@:22]3([OH:27])[CH2:21][CH2:20][C@@:19]3([CH3:28])[C@H:9]4[CH2:10][C@H:11]([CH3:29])[C:12]3=[C:13]([NH:16][CH:17]=[O:18])[CH2:14][OH:15])[CH2:4]2)[O:2]1.C(Cl)Cl.[OH2:35].N1[CH:41]=[CH:40]C=CC=1>C(OC(=O)C)(=O)C>[C:40]([O:15][CH2:14][C:13]([NH:16][CH:17]=[O:18])=[C:12]1[C@:19]2([CH3:28])[C@H:9]([C@H:8]3[C@:22]([OH:27])([CH2:21][CH2:20]2)[C@:23]2([CH3:26])[C:5]([CH2:4][C:3]4([O:2][CH2:1][CH2:31][O:30]4)[CH2:25][CH2:24]2)=[CH:6][CH2:7]3)[CH2:10][C@@H:11]1[CH3:29])(=[O:35])[CH3:41]
Reactant: c1ccncc1
Reactant: C[C@H]1C[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@@]3(O)CC[C@]2(C)C1=C(CO)NC=O)OCCO5
Reactant: O
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)OCC(NC=O)=C1[C@@H](C)C[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@@]3(O)CC[C@]12C)OCCO5

Procedure:
A solution of 3,3-ethylenedioxy-20-formamido-16β-methylpregna-5,17(20)-diene-9α,21-diol (80 mg) in pyridine (0.25 ml) and acetic anhydride (0.12 ml) was stirred at room temperature for 7 hours after which TLC indicated the conversion to be complete. Methylene chloride and water were added to the reaction mixture. The organic phase was washed with water to neutral pH, dried and concentrated under reduced pressure to afford 50 mg of the title compound as a mixture of the two rotamer forms of the 20-formamido group.
Reaction SMILES: CC(P(C(C)(C)C)C1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=CC=1)(C)C.C(N(CC)CC)C.[C:29]1([C:35]#[C:36][P:37](=[O:42])([OH:41])[O:38][CH2:39][CH3:40])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(C1C=CC=CC=1)C#C>[Au].ClC(Cl)C>[C:29]1([C:35]#[C:36][P:37](=[O:41])([O:42][C:10]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH2:9])[O:38][CH2:39][CH3:40])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOP(=O)(O)C#Cc1ccccc1
Reactant: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: [Au]
Agent: C#CCc1ccccc1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=C(Cc1ccccc1)OP(=O)(C#Cc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71 %

Procedure:
A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) and triethylamine (Et3N) (3.0 mg, 0.03 mmol) were put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen phenylethynylphosphonate (63.0 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, prop-2-ynylbenzene (70 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain ethyl 3-phenylprop-1-en-2-yl phenylethynylphosphonate (68.9 mg, 71%) which is a title compound.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].[Se](=O)=[O:58]>C(O)(=O)C.O>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([OH:58])[CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Solvent: CC(=O)O
Solvent: O
Product: CCC1C=C(C)C(O)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 22 °C
Reaction time: 21 h
Yield: 27.4 %

Procedure:
A solution of 6 g (7.59 mmole) of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclo-hexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10,16-tetraone (containing approximately 10% of the 17-methyl analog) and 0.87 g (7.8 mmole) selenium dioxide in 60 ml glacial acetic acid and 10 ml water was stirred at 22° C. for 21 hours. The solution was lyophilyzed and the residue was chromatographed on 300 g silica gel using methylene chloride and methanol/methylene chloride as eluent. The new product was rechromatographed on silica gel with 4% methanol/methylene chloride as eluent to yield 1.68 g (27% yield) 17-ethyl-1,14,20-trihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos -18-ene-2,3,10,16-tetraone.
Reaction SMILES: [N:1]1([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:24]5[C:25]([CH3:48])=[N:26][N:27]([C:29]([C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=6)([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[C:30]6[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=6)[CH:28]=5)[CH:22]=4)[N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[O:7])[CH:5]=[CH:4]N=[CH:2]1.N1CC[O:52][CH2:51]C1.C(OCC)(=O)C>O>[CH3:48][C:25]1[C:24]([C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[C:14]3[N:11]2[CH2:10][CH2:9][N:8]([C:6]([N:1]3[CH2:5][CH2:4][O:52][CH2:51][CH2:2]3)=[O:7])[CH2:13][CH2:12]2)=[CH:28][N:27]([C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:26]=1
Reactant: C1COCCN1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(C(=O)n4ccnc4)CC3)c2c1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(C(=O)N4CCOCC4)CC3)c2c1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
A mixture of 100 mg 1H-1-imidazolyl{4-[6-(3-methyl-1-trityl-1H-pyrazolyl)-4-quinolyl]piperazin-1-yl}methanone obtained in Example 195 and 1 mL morpholine was stirred overnight at 140° C. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 96 mg of the title compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH2:11][CH2:10][C:9]2[CH2:8][CH2:7][N:6]3[C:12]([C@@H:15]([NH2:17])[CH3:16])=[N:13][CH:14]=[C:4]([C:5]=23)[CH:3]=1.[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23](Cl)[N:22]=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([NH:17][C@H:15]([C:12]2[N:6]3[CH2:7][CH2:8][C:9]4[CH2:10][CH2:11][C:2]([F:1])=[CH:3][C:4]([C:5]=43)=[CH:14][N:13]=2)[CH3:16])[N:22]=[CH:21][N:20]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)C1=NC=C2C=C(F)CCC3=C2N1CC3
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)C1=NC=C2C=C(F)CCC3=C2N1CC3
Temperature: 90 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
A mixture of (S)-1-(5-fluoro-6,7,8,9-tetrahydro-2,9a-diazabenzo[cd]azulen-1-yl)ethylamine (70 mg, 0.30 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (46.4 mg, 0.30 mmol), and DIPEA (102 μL, 0.60 mmol) in isopropanol (1.5 mL) was stirred at 90° C. for 3 h. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 2-7% 2M NH3/MeOH in DCM). Crystallisation from MeOH (5 mL) afforded 406 as a white solid (43.2 mg, 41%). LCMS (Method K): RT 2.91 min [M+H]+ 352.1. 1H NMR ((CD3)2SO, 400 MHz): 8.07 (1H, s), 7.69 (1H, d, J=7.5 Hz), 7.45 (1H, dd, J=8.8, 4.8 Hz), 7.31 (2H, bs), 7.00 (1H, dd, J=10.8, 8.7 Hz), 5.67 (1H, quintet, J=6.9 Hz), 4.25-4.14 (2H, m), 3.05-3.01 (2H, m), 2.08-1.93 (4H, m), 1.58 (3H, d, J=6.7 Hz)