Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[CH3:23].ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH2:36]([NH2:40])[CH2:37][CH2:38][CH3:39].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:36]([NH:40][C:28]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[C:17]([CH3:23])[CH:18]=1)=[O:34])[CH2:37][CH2:38][CH3:39]
Reactant: CCCCN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3C)c2cc1OC
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-3-methylaniline (50 mg) was dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and a solution of triphosgene (48 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, butylamine (24 μl) was added to the reaction solution, and the mixture was further stirred at room temperature overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 31 mg (yield 47%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[N+]=[N-])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.ClCCl.[CH:19]1([OH:25])[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1>CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh].O>[CH3:1][O:2][C:3](=[O:15])[CH:4]([O:25][CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1
Reactant: OC1C=CCCC1
Reactant: COC(=O)C(=[N+]=[N-])c1ccc(Cl)c(Cl)c1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(OC1C=CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
In a dry 25 mL round bottom flask under argon was placed diazo-(3,4-dichloro-phenyl)-acetic acid methyl ester (from Example 1, 552 mg, 2.25 mmol), dichloromethane (10 mL) and rac-2-cyclohexen-1-ol (0.45 mL, 4.51 mmol). The solution was stirred at 25° C. and then the rhodium (II) acetate dimer (20 mg, 0.045 mmol) was added. Gas evolution began immediately and the color changed from bright yellow to an aquagreen color. After the solution was stirred at 25° C. for a period of 1 h, it was poured into water and the layers were separated. The aqueous layer was washed with dichloromethane (3×15 mL), then the combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The residual oil was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 98/2 hexanes/ethyl acetate to afford rac-(cyclohex-2-enyloxy)-(3,4-dichloro-phenyl)-acetic acid methyl ester (552 mg, 78% yield) as a light yellow oil: EI-HRMS m/e calcd for C15H16Cl2O3 (M+) 314.0468, found 314.0476.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.S(OC)(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:28](OCC)[CH3:29]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]=[CH:9][C:10]([O:12][CH2:28][CH3:29])=[O:11])=[O:7])=[CH:13][CH:14]=1
Reactant: O=C(O)C=CC(=O)c1ccc(Cl)cc1
Reactant: CCOCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)C=CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4.22 g of 3-(4-chlorobenzoyl)-acrylic acid in 40 ml of dimethylformamide were added 3.68 g of dimethyl sulfate and 1.36 g of potassium carbonate, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added diethyl ether. The mixture was washed, in turn, with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over magnesium sulfate. The diethyl ether was removed from the mixture by evaporation, and the residue was recrystallized from hexane to give 2.68 g of ethyl 3-(4-chlorobenzoyl)acrylate.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:9])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH:20]1[CH2:26][C:25](=O)[O:24][C:22](=[O:23])[CH2:21]1.[Cl:28]CCl>>[ClH:28].[CH3:1][C:2]1[C:3]2[NH:9][C:25]([CH2:26][CH:20]([C:11]3[CH:12]=[CH:13][C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:10]=3)[CH2:21][C:22]([OH:24])=[O:23])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(N)c1N
Reactant: O=C1CC(c2ccc3ccccc3c2)CC(=O)O1
Reactant: ClCCl
Product: Cc1cccc2nc(CC(CC(=O)O)c3ccc4ccccc4c3)[nH]c12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Methyl-1,2-phenylenediamine (61 mg) and 3-(2-naphthyl)glutaric anhydride (120 mg) were dissolved in dichloromethane (2 ml) with heating. The solution was stirred at rt for 1 h. The solvent was removed and the residue was dissolved in 1,4-dioxane (1 ml) with heating. 4M HCl in 1,4-dioxane (1 ml) was added and the solution was heated to reflux for 1 h. The precipitate formed was isolated by suction filtration, washed with 1,4-dioxane, and dried to give 4-(4-methyl-2-benzimidazolyl)-3-(2-naphthyl)butanoic acid HCl (162 mg) as beige coloured solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].C(N(C(C)C)CC)(C)C.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([O:11][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:10]
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cccc(CCCCO)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)c1cccc(CCCCO)c1
Reaction time: 65 h

Procedure:
A solution of 3-(4-hydroxybutyl)benzoic acid (100 mg) in dry DMF (10 ml) was treated with diisopropylethylamine (0.134 ml) and benzyl bromide (106 mg) and the reaction mixture was stirred for 65 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed with sat. NH4Cl(aq), dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (SPE, gradient Cyclohexane to cyclohexane-EtOAc 1:1) to give the title compound LCMS RT=3.38 min.
Reaction SMILES: C(OC1N=NC(C#CC2C=CC(C(F)(F)F)=CN=2)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[CH:58])=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[F:59][CH:60]([F:69])[O:61][C:62]1[CH:67]=[CH:66][CH:65]=[C:64](I)[CH:63]=1>>[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[C:58][C:64]2[CH:65]=[CH:66][CH:67]=[C:62]([O:61][CH:60]([F:69])[F:59])[CH:63]=2)=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: FC(F)Oc1cccc(I)c1
Agent: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)nc1
Product: FC(F)Oc1cccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Yield: 87 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 1-(difluoromethoxy)-3-iodobenzene in 87% yield.
Reaction SMILES: Cl.[C:2]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[N:9]=1)(=[NH:4])[NH2:3].[Br:15][C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=1[CH:18]=O.O=[C:26]([CH3:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[Br:15][C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=1[CH:18]1[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[NH:3][C:2]([C:5]2[S:6][CH:7]=[C:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[N:9]=2)=[N:4]1
Reactant: O=Cc1ccc(F)cc1Br
Reactant: CCOC(=O)CC(C)=O
Reactant: COC(=O)Cc1csc(C(=N)N)n1
Agent: Cl
Product: CCOC(=O)C1=C(C)NC(c2nc(CC(=O)OC)cs2)=NC1c1ccc(F)cc1Br
Yield: 50 %

Procedure:
Methyl 2-(2-carbamimidoylthiazol-4-yl)acetate hydrochloride (2.35 g, 10 mmol) was reacted with 2-bromo-4-fluorobenzaldehyde (2.03 g, 10 mmol) and ethyl 3-oxobutanoate (1.56 g, 12 mmol) according to the procedure as described in Example 1, Step A to give the title compound as a yellow solid (2.48 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Cl[CH2:45][C:46]1[N:47]=[N:48][CH:49]=[CH:50][CH:51]=1.BrCC1OC(C(F)(F)F)=CC=1>>[N:48]1[CH:49]=[CH:50][CH:51]=[C:46]([CH2:45][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([CH2:13][O:12][C:11]4[CH:14]=[C:15]5[C:19](=[CH:20][C:10]3=4)[CH2:18][CH2:17][O:16]5)[C:2]2=[O:21])[N:47]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: ClCc1cccnn1
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2cccnn2)c2ccccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1H)-one, and 3-(chloromethyl)pyridazine to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-(pyridazin-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (13%) as a colorless solid: mp 81-82° C.; 1H NMR (300 MHz, CDCl3) δ9.18-9.14 (m, 1H), 7.58-7.44 (m, 2H), 7.28-7.15 (m, 2H), 7.12-7.02 (m, 2H), 6.47 (s, 1H), 6.43 (s, 1H), 5.39-5.22 (m, 2H), 4.84 (ABq, 2H), 4.60-4.49 (m, 2H), 3.10-2.91 (m, 2H); 13C NMR (75 MHz, CDCl3) δ178.1, 161.9, 161.4, 158.4, 151.1, 141.6, 132.4, 129.0, 127.3, 126.0, 123.9, 123.8, 120.0, 119.9, 118.8, 109.6, 93.3, 80.6, 72.4, 57.8, 44.6, 29.0; MS (ES+) m/z 372.3 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].C([O-])([O-])=O.[K+].[K+].I[CH:30]([CH3:32])[CH3:31].O>CN(C=O)C>[CH:30]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])([CH3:32])[CH3:31]
Reactant: CC(C)I
Reactant: NCCCCNS(=O)(=O)c1ccc(-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NCCCCNS(=O)(=O)c1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 3 h

Procedure:
4′-Bromobiphenyl-4-sulfonic acid (4-amino-butyl) amide (0.6 g) was dissolved in DMF (30 mL). K2CO3 (1 g) was added followed by 2-iodo-propane (0.3 mL). The mixture was stirred for 3 hrs, poured into water, extracted with ether and dried. Addition of petrol and evaporation caused the title compound to precipitate as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:10]=1)#[N:2].[NH2:28][CH2:29][C@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:28][CH2:29][C@H:30]2[CH2:34][CH2:33][CH2:32][N:31]2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:14])=[C:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:10]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CN
Reactant: N#Cc1ccccc1-c1ccc(C(=O)O)c(NCCc2cccc(F)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CNC(=O)c1ccc(-c2ccccc2C#N)nc1NCCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a mixture of 6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinic acid (510 mg, 1.41 mmol), (R)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate (424 mg, 2.11 mmol), HOBT (285 mg, 2.11 mmol), and HBTU (800 mg, 2.11 mg) in RB flask was added DMF and the mixture was stirred at r.t. for 1 h. LC/MS indicated the reaction was complete and the mixture was filtered and purified on RP-HPLC using a mixture of acetonitrile and water to give (R)-tert-butyl 2-((6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamido)methyl)pyrrolidine-1-carboxylate (695.1 mg, 91%). LRMS (M+H+) m/z 544.2.
Reaction SMILES: C(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].F[C:10](F)(F)[C:11](O)=O.[NH2:16][C:17]1[CH:21]=[CH:20][S:19][CH:18]=1.[OH-].[Na+]>ClCCl.O.C(OCC)C>[CH2:7]([N:16]1[C:17]2=[CH:21][CH2:20][S:19][C:18]2=[CH:17][C:18]2[S:19][CH:20]=[CH:10][C:11]1=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: Nc1ccsc1
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCCCC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: CCCCCCN1C2=CCSC2=Cc2sccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 238.4 %

Procedure:
A solution of heptanal (0.59 g, 5.16 mmol) and trifluoroacetic acid (100 mg) in anhydrous dichloromethane (50 mL) was added dropwise to a solution of 3-aminothiophene (0.93 g, 9.38 mmol) in anhydrous dichloromethane (50 mL) at −5° C. The reaction mixture was stirred at room temperature for 1.5 h. Trifluoroacetic acid (1.07 g, 9.38 mmol) was added and the reaction mixture was then heated at reflux for 6 h. The solution was cooled and diethyl ether (150 mL) and water (30 mL) were added. The aqueous layer was basified with 0.5 N aqueous sodium hydroxide solution. The organic layer was separated. The aqueous layer was again extracted into diethyl ether (150 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (eluent: 90% petroleum ether 80-100/10% dichloromethane to 100% dichloromethane) afforded 4-hexyldithieno[3,2-b:2′3′-e]pyridine (0.58 g, 45%) as a red oil: δH(CDCl3, 250 MHz) 7.75 (2H, d, 3JHH=6 Hz), 7.59 (2H, d, 3JHH=6 Hz), 3.16 (2H, t, 3JHH=8 Hz), 1.90 (2H, m), 1.27-1.49 (6H, m), 0.89 (3H, t, 3JHH=7 Hz); δC(CDCl3, 63 MHz) 156.2, 140.4, 130.7, 129.7, 34.8, 31.9, 29.8, 28.3, 22.9, 14.4.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:13])[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl([O-])=[O:15].[Na+].Cl([O-])=O.P([O-])([O-])([O-])=O>O.CC(O)C>[Br:1][C:2]1[N:3]([CH3:13])[C:4]2[C:9]([C:10]=1[C:11]([OH:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: [O-][Cl+][O-]
Reactant: Cn1c(Br)c(C=O)c2ccccc21
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cn1c(Br)c(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87 %

Procedure:
To a vigorously stirred solution of 2.38 g (10 mmol) of 2-bromo-1-methylindole-3-carboxaldehyde [XXVI: R1 =H, R3-dioxane at 25° C. was added dropwise over ca. 15 minutes a solution of 5 (55 mmol) of sodium chlorite and 5 g (36 mmol) of NaH2PO4.H2O in 25 mL of water. The solution was maintained at 25° C. After 3.5 hours, the mixture was treated with an additional 2.5 g each of the chlorite and phosphate. After a total reaction time of 24 hours, the mixture was extracted 3 times with dichloromethane, then the aqueous phase was acidified to pH 2 with aqueous HCl, and extracted once more. The combined organic extracts were washed with water, dried, and evaporated to leave a solid residue that was boiled in 2-propanol. After cooling, the solids were collected by filtration, washed with a little 2-propanol, and dried to leave 2.21 g (87%) of 2-bromo-1-methyl indole-3-carboxylic acid [XXVII: R1 =H, R3 =CH3, X=Br] as a beige solid; mp ca. 198° C. (dec), in 2 crops.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:9]2[N:10]=[C:11]([CH2:13][CH3:14])[O:12][C:8]=2[C:7]([C:15]([OH:17])=O)=[CH:6][CH:5]=1.[CH2:19]([C:21]1[C:25]([NH2:26])=[C:24]([CH3:27])[O:23][N:22]=1)[CH3:20]>C(OCC)C.CCCCCC>[CH2:19]([C:21]1[C:25]([NH:26][C:15]([C:7]2[C:8]3[O:12][C:11]([CH2:13][CH3:14])=[N:10][C:9]=3[C:4]([O:3][CH:2]([F:1])[F:18])=[CH:5][CH:6]=2)=[O:17])=[C:24]([CH3:27])[O:23][N:22]=1)[CH3:20]
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)O)c2o1
Reactant: CCc1noc(C)c1N
Solvent: CCOCC
Solvent: CCCCCC
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Nc3c(CC)noc3C)c2o1
Yield: 54.6 %

Procedure:
Starting from 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid (0.20 g) and 3-ethyl-5-methylisoxazol-4-ylamine (0.20 g). Purification by column chromatography on silica eluting 20-50% ethyl acetate in heptane afforded, after trituration with diethyl ether-hexane, the title compound as a white solid (0.155 g).
Reaction SMILES: Br[C@H:2]1[C:19]2[C@:14]([CH3:21])([CH:15]=[CH:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C)C=O.O>[N:23]([C@@H:2]1[C:19]2[C@:14]([CH3:21])([CH:15]=[CH:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@]12C=CC(=O)C=C1[C@H](Br)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]12C=CC(=O)C=C1[C@@H](N=[N+]=[N-])C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 100 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a solution of 6β-bromoandrosta-1,4-diene-3,17-dione (5.0 g) in 250 ml of dimethylformamide, 1,15 g of powdered sodium azide dissolved in 14 ml of water are added and the mixture is warmed to 100° C. and maintained with stirring at the same temperature for 120 minutes. The entire mixture is then poured into 1 l of water and extracted with four 200 ml portions of ethyl acetate. The combined extracts are washed with saturated aqueous sodium chloride solution and dried. The solvent is then removed in vacuum to yield a crude product which is purified by chromatography on Al2O3 (neutral activity) with ethyl acetate:n-hexane 40:60 as eluant so obtaining 3.4 g of pure 6α-azido androsta-1,4-diene-3,17-dione. The analytical sample was crystallized from methanol, m.p. 168°-170° C.; [α]D20° +93.2° (c=1, CHCl3); U.V. (95% EtOH) λmax=244; ε=17,420; N.M.R. (CDCl3) δ: 0.98 (3H, s); 1.3 (3H, s); 4.31 (1H, ddd); 6.44 (1H, dd); 6.26 (1H, dd); 7.02 (1H, d). Following analogous procedure the 6β-azido androsta-1,4-diene-3,17-dione can be prepared, starting from 6α-bromo androsta-1,4-diene-3,17-dione.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].[Cl:13][C:14]1[C:15](C(O)=O)=[N:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=1>C1(OC)C=CC=CC=1>[Cl:13][C:14]1[C:15]([CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[O:3][CH:2]([F:12])[F:1])[OH:7])=[N:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=1
Reactant: CSc1ncc(Cl)c(C(=O)O)n1
Reactant: O=Cc1ccccc1OC(F)F
Solvent: COc1ccccc1
Product: CSc1ncc(Cl)c(C(O)c2ccccc2OC(F)F)n1
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 54.9 %

Procedure:
A mixture of 780 mg of 2-(difluoromethoxy)benzaldehyde and 300 mg of 5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxylic acid 1 in 15 ml of anisole is microwave-heated at 130° C. for 45 min and then again for 15 min and again at 140° C. for 15 min. 160 mg of 5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxylic acid 1 is then added and the mixture is again heated at 130° C. for 30 min. The mixture is concentrated under vacuum and purified on 40 g of silica, elution being carried out with 0-10% of ethyl acetate in heptane, so as to obtain 268 mg of [5-chloro-2-(methylsulfanyl)pyrimidin-4-yl][2-(difluoromethoxy)phenyl]methanol 6 in the form of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:17]([Si:21]([O:24][CH2:25][CH2:26]I)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.O>[Si:21]([O:24][CH2:25][CH2:26][N:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCCI
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (307 mg) in N,N-dimethylformamide (2.0 mL) was added cesium carbonate (977 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added tert-butyl(2-iodoethoxy)dimethylsilane (839 mg), and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated brine (30 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=85/15→10/90). The object fraction was concentrated under reduced pressure and dried to give the title compound (591 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[C:13](OC)=[O:14])=[O:6])[CH:2]=[CH2:3].[BH4-].[Na+].Cl>O1CCCC1.C(O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][OH:14])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1CO
Temperature: 27.5 °C
Yield: 108 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-4-hydoxy2-methoxycarbonylpyrrolidine (10 g) in tetrahydrofuran (20 ml) and ethanol (30 ml) was added by portions sodium borohydride (3.30 g) with stirring at 25-30° C., and the mixture was stirred at the same temperature for 4 hours. To the reaction mixture was added dropwise conc. hydrochloric acid (7.27 ml) with stirring at 0-2° C. The resulting precipitates were filtered off and the filtrate was evaporated in vacuo. The resulting residue was dissolved in a mixture of tetrahydrofuran (20 ml), ethanol (20 ml) and saturated aqueous sodium chloride (50 ml). The organic layer was evaporated in vacuo to give (2S,4R)-1-allyloxycarbonyl-4-hydroxy-2-hydroxymethylpyrrolidine (9.48 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13]>N1C=CC=CC=1>[Cl:8][C:3]1[C:2]([NH:1][C:12](=[O:13])[C:11]2[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:10]=2[F:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1Cl
Reactant: O=C(Cl)c1cccc(F)c1F
Solvent: c1ccncc1
Product: O=C(Nc1cccnc1Cl)c1cccc(F)c1F
Yield: 92.3 %

Procedure:
3.31 g 3-amino-2-chloropyridine (25.8 mmol) and 20 mL pyridine were mixed in an ice bath. 5.0 g 2,3-difluoro-benzoyl chloride (28.4 mmol) was then added. After return to room temperature and reaction for 4 hr, the reaction was quenched by water. After extraction three times by ethyl acetate, an ethyl acetate layer was collected and washed by 1M HCl solution. After drying, filtration, concentration, and purification by silicon-gel column, 6.4 g solid was obtained, with a yield of 93%.
Reaction SMILES: C([Cl:4])(=O)C.C(OC(=O)[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]([CH3:26])[CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH:13]=1)(C)(C)C>CO>[ClH:4].[ClH:4].[ClH:4].[CH3:25][N:22]1[CH2:21][CH2:20][CH:19]([N:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([NH2:11])[CH:13]=2)[CH3:26])[CH2:24][CH2:23]1
Reactant: CN1CCC(N(C)c2cccc(NC(=O)OC(C)(C)C)c2)CC1
Reactant: CC(=O)Cl
Solvent: CO
Product: CN1CCC(N(C)c2cccc(N)c2)CC1
Product: Cl
Reaction time: 1 h
Yield: 66 %

Procedure:
Combine acetyl chloride (5 mL) with dried methanol (10 mL) at 0° C. under nitrogen atmosphere. Stir for 1 hr. at 0° C. Add a solution of (3-(methyl-(1-methylpiperidin-4-yl)amino)phenyl)carbamic acid tert-butyl ester (Preparation 10, 990 mg, 3.1 mmol) in methanol (2 mL). Stir overnight. Concentrate under reduced pressure. Triture with diethyl ether (1 mL) to provide the title intermediate (671 mg, 66%): mass spectrum (free base, ion spray): m/z=220.3 (M+1). Analysis calculated for C13H24Cl3N3Cl3: C, 47.50; H, 7.36; N, 12.78. Found: C, 47.28; H, 7.28; N, 12.46.