Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1.[CH3:12][C:13]1([CH3:31])[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][C:15]2([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[O:14]1.C(N(CC)CC)C>C(#N)C>[OH:11][CH2:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][N:28]1[CH2:29][CH2:30][C:15]2([O:14][C:13]([CH3:12])([CH3:31])[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]2)[CH2:26][CH2:27]1
Reactant: OCCc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)OC2(CCNCC2)C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(C)(C)OC2(CCN(Cc3cccc(CCO)c3)CC2)C1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
2-(3-(Bromomethyl)phenyl)ethanol (0.416 g) was added portionwise over 1 hour to a solution of tert-butyl 2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (Example 271, step c) (0.55 g) and triethylamine (0.809 mL) in acetonitrile (20 mL). The mixture was stirred for 2 hours at 20° C. The solvent was evaporated under reduced pressure and the residue partitioned between saturated sodium bicarbonate solution and DCM, the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with 2% methanol in dichloromethane with 1% triethylamine to afford the subtitled compound. Yield 0.78 g.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([CH:14]=O)=[CH:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:22]([O:24][C:25](=[O:28])[NH:26][NH2:27])[CH3:23]>C(O)(=O)C.C(O)C>[CH2:22]([O:24][C:25]([NH:26][N:27]=[CH:14][C:13]1[C:9]([C:7]2[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:10][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:12]=1)=[O:28])[CH3:23]
Reactant: CCOC(=O)NN
Reactant: O=Cc1cn(-c2ccccn2)nc1-c1ccc([N+](=O)[O-])o1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)NN=Cc1cn(-c2ccccn2)nc1-c1ccc([N+](=O)[O-])o1
Yield: 97 %

Procedure:
Heat 0.6 g of 3-(5-nitro-2-furyl)-1-(2-pyridyl)pyrazole-4-carboxaldehyde together with 0.27 g of ethylcarbazate and 2 drops of glacial acetic acid in 8 ml of ethanol for 1.5 hours at boiling point. Cool the resulting product for a 97% yield of 3-(5-nitro-2-furyl)-1-(2-pyridyl)pyrazole-4-carboxaldehyde-ethoxycarbonylhydrazone [m.p. 215° to 216° C (with decomposition) from toluene].
Reaction SMILES: C([O:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:14])[CH2:6]1)(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[NH2:14][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][CH:5]([OH:4])[CH2:6]2
Reactant: CC(=O)OC1Cc2cccc(N)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)O
Product: Nc1cccc2c1CC(O)C2
Yield: 98.6 %

Procedure:
A slurry of 4-amino-2,3-dihydro-1H-inden-2-yl acetate (12.6 g, 65.9 mmol; prepared according to US2003109700), MeOH (63 mL), and potassium carbonate (13.7 g, 99.0 mmol) was stirred at ambient temperature for 15 minutes. The reaction mixture was diluted with IPA (630 mL), passed through a plug of silica gel, washed with IPA (100 mL), and concentrated to give the title compound (9.70 g, 65.0 mmol, 99%). MS (DCI) m/z 267 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:21]CC2C=CC=CC=2)[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=1.B(Br)(Br)Br.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:17])[F:18])=[CH:11][N:10]=1
Reactant: FC(F)(F)c1cnc(Oc2c(Cl)cc(OCc3ccccc3)cc2Cl)c(Cl)c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Oc1cc(Cl)c(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Yield: 92.7 %

Procedure:
Then, 1.39 g of 3,5-dichloro-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-1-benzyloxybenzene, and 20 ml of methylene chloride were charged into a reaction vessel, and a solution of boron tribromide (1.63 g) in methylene chloride (10 ml) was added dropwise with stirring under ice cooling (-10° C. to 0° C.). After stirring for one hour under ice cooling, the mixture was poured into 10% hydrochloric acid and extracted twice with 50 ml of methylene chloride. Then, the organic layers were combined, washed with water, dried over anhydrous magnesium sulfate and concentrated to give a crude product. This crude product was subjected to silica gel column chromatography to give 1.03 g of 3,5-dichloro-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenol (yield, 93%), m.p., 152.6° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[C:21]2[C:28]([CH3:29])=[CH:27][NH:26][C:22]=2[N:23]=[CH:24][N:25]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[CH3:29][C:28]1[C:21]2[C:20]([NH:18][C@H:16]([C:8]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH3:17])=[N:25][CH:24]=[N:23][C:22]=2[NH:26][CH:27]=1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1c[nH]c2ncnc(N[C@@H](C)c3nc4ccccc4n3-c3ccccc3)c12
Temperature: 120 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
Into a 10-mL sealed tube was placed (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine from Example 4 (300 mg, 1.26 mmol, 1.00 equiv), 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (250 mg, 1.49 mmol, 1.18 equiv), N-ethyl-N-isopropylpropan-2-amine (322 mg, 2.50 mmol, 1.97 equiv) and BuOH (5 mL). The resulting solution was stirred for overnight at 120° C. and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/hexane (0:100-80:20) to afford 270 mg (58%) of 144 as a white solid. LC-MS (ES, m/z): 369 [M+H]+. H-NMR (300 MHz, CD3OD, ppm): δ 7.98 (s, 1H), 7.70-7.53 (m, 6H), 7.33-7.23 (m, 2H), 7.14-7.11 (m, 1H), 6.83 (d, 1H), 5.68-5.61 (m, 1H), 2.49 (d, 3H), 1.67 (d, 3H)
Reaction SMILES: [CH3:1][C:2]([C:22]1[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][N:23]=1)([CH2:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:3](=O)[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=O.C([O-])(=O)C.[NH4+:34].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH3:1][C:2]([C:22]1[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][N:23]=1)([C:3]1[NH:34][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:5][CH:4]=1)[CH2:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: [NH4+]
Reactant: CSc1ccc(C(C)(CC2CCOCC2)C(=O)CCC(=O)c2ccccn2)nc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CSc1ccc(C(C)(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)nc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 145.1 %

Procedure:
To a solution of 5-methyl-5-[5-(methylsulfanyl)pyridin-2-yl]-1-(pyridin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (60.7 mg) in acetic acid (1 mL) was added ammonium acetate (181 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (84.0 mg, yield 82%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:28]#[N:29])[C:10]([CH3:27])=[C:11]([C:21]4[CH2:25][CH2:24][CH:23](O)[CH:22]=4)[C:12]=3[N:13]3[CH2:17][CH2:16][C@H:15]([N:18]([CH3:20])[CH3:19])[CH2:14]3)[N:8]=2)[CH2:3][CH2:2]1.Cl.C(O)C>C(O)C.C(OCC)C>[CH:21]1([C:11]2[C:12]([N:13]3[CH2:17][CH2:16][C@H:15]([N:18]([CH3:19])[CH3:20])[CH2:14]3)=[C:6]3[O:5][C:4]([CH:1]4[CH2:2][CH2:3]4)=[N:8][C:7]3=[C:9]([C:28]#[N:29])[C:10]=2[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22]1
Reactant: Cc1c(C2=CC(O)CC2)c(N2CC[C@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: Cc1c(C2C=CC=C2)c(N2CC[C@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Reaction time: 4 h
Yield: 78839.7 %

Procedure:
2-Cyclopropyl-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-6-(3-hydroxycyclopent-1-enyl)-5-methyl-1,3-benzoxazole-4-carbonitrile (I-306) (83 mg, 0.21 mmol) was dissolved in ethanol (0.85 ml) and diethyl ether (1.7 ml), and at room temperature, 1 M hydrochloric acid/ethanol solution (222 μl, 0.22 mmol) was added. After stirring at the same temperature for 4 hours, the solvent was evaporated away under reduced pressure. Ether was added to the residue, and this was concentrated under reduced pressure. This operation was repeated once again. Ether was added to the residue, followed by sonication, and the solvent was removed with a pipette. The residue was dried at 60° C. under reduced pressure for 2 hours to obtain the entitled compound (62 g, 65%) as a brown solid.
Reaction SMILES: [H-].[Na+].C1COCC1.C(O[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)C.[C:20](#[N:22])[CH3:21]>CCOCC>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([CH2:21][C:20]#[N:22])=[O:19])=[CH:17][CH:16]=1
Reactant: CC#N
Reactant: CCOC(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 50% oil dispersion of NaH (24 grams) was placed in a 2 l. 3-necked flask and covered with 250 ml. THF. After heating to reflux, a solution composed of 55 ml. THF, ethyl-4-chlorobenzoate (57 grams), and acetonitrile (20.5 grams) was added in dropwise fashion. The reaction mixture started to solidify after the reactants were added so an additional 200 ml. of THF was added. The mixture was then heated to reflux for 21/2 hours, cooled to room temperature, treated with 1 l. ether, and allowed to stand for 72 hours.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.[Cl:14]N1C(=O)CCC1=O.Cl.CCOCC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:14][C:2]1[NH:1][C:9]2[C:4]([C:3]=1[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1c(Cl)[nH]c2ccccc12
Yield: 47.7 %

Procedure:
A stirred suspension of methyl indole-3-carboxylate (6.0 g, 0.034 mole) in chloroform (200 ml) was treated with N-chlorosuccinimide (5.04 g, 0.038 mole) to afford a clear solution within 15 minutes. After 2 h at room temperature this was treated with 1M HCl/ether (34 ml, 0.034 mole) and allowed to stir for a further 1h, then treated with excess 10% Na2CO3 solution and the chloroform layer separated, dried (Na2SO4) and concentrated in vacuo. The residual yellow solid was recrystallised from chloroform/60-80 petrol to afford the title compound (D11a) as a beige solid (3.4 g, 48%).
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3](OC)=[O:4].Cl.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][NH2:20].C(N(CC)CC)C>CO>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[C:3]([OH:4])=[CH:2][C:1]([C:7]([O:9][CH3:10])=[O:8])=[N:20]1
Reactant: COC(=O)C#CC(=O)OC
Reactant: NNc1ccccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc(O)n(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dimethyl acetylenedicarboxylate (87.4 g, 757 mmol) was added to a solution of 2-fluoro-phenylhydrazine hydrochloride (100 g, 615 mmol) in methanol (1 l) at 0° C. Then triethylamine (125 g, 1.23 mol) was added slowly during 60 min. The solution was stirred for 16 h at room temperature, the solvent then removed under reduced pressure and the residue dissolved in EA (500 ml). After washing with aqueous hydrochloric acid (500 ml), the solvent was removed under reduced pressure. The title compound was obtained as an almost white solid in quantitative yield.
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]1([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:26][C:27]([F:43])([F:42])[C:28]1[O:32][N:31]=[C:30]([C:33]2[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=2)[C:36](O)=[O:37])[N:29]=1>>[C:8]1([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([N:20]3[CH2:25][CH2:24][N:23]([C:36]([C:35]4[CH:39]=[CH:40][CH:41]=[C:33]([C:30]5[N:29]=[C:28]([C:27]([F:42])([F:26])[F:43])[O:32][N:31]=5)[CH:34]=4)=[O:37])[CH2:22][CH2:21]3)[N:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(-c2ccnc(N3CCNCC3)n2)cc1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCN(c2nccc(-c3ccccc3)n2)CC1
Yield: 53 %

Procedure:
This compound was synthesized from 4-phenyl-2-(piperazin-1-yl)pyrimidine TFA salt and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (100 mg, yield 53%). 1H NMR (400 MHz, MeOD) δ 8.31-8.25 (m, 5H), 7.78-7.72 (m, 2H), 7.47-7.45 (m, 3H), 6.77-6.75 (d, J=6.3 Hz, 1H), 3.99-3.87 (m, 6H), 3.66 (s, 2H). MS (ESI) m/z: Calculated for C24H19F3N6O2: 480.15. found: 481.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:25](Br)(=[O:27])[CH3:26]>C(Cl)Cl>[C:25]([N:10]1[C:11]2[CH2:12][CH2:13][C:4]3[CH:3]=[C:2]([Cl:1])[CH:17]=[CH:16][C:5]=3[C:6]=2[C:7]([CH3:14])([CH3:15])[CH2:8][CH2:9]1)(=[O:27])[CH3:26]
Reactant: CC1(C)CCNC2=C1c1ccc(Cl)cc1CC2
Reactant: CC(=O)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(C)(C)C2=C1CCc1cc(Cl)ccc12
Reaction time: 1 h

Procedure:
10.6 g (0.043 mol) of 8-chloro-1,1-dimethyl-1,2,3,4,5,6-hexahydrobenzo[f]quinoline and 6.6 ml (0.047 mol) of triethylamine are dissolved in 100 ml of methylene chloride and 3.5 ml (0.047 mol) of acetyl bromide dissolved in 20 ml of methylene chloride are added dropwise thereto at 0°. After stirring for 1 hour, the mixture is extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Recrystallization from methylene chloride/hexane gives 4-acetyl-8-chloro-1,1-dimethyl-1,2,3,4,5,6-hexahydrobenzo[f]quinoline as white crystals with melting point 126°-127°.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].CO>C(OCC)(=O)C>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:24]3[CH2:25][CH2:26][CH:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:22][CH2:23]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-phenylpiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 80% overall yield. FDMS m/e=351 (M+ of free base). α[D]589 =-15.49 (c=0.86, methanol).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]([NH:11][NH2:12])=[CH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[CH:27]=O>CN(C=O)C>[CH:1]1([CH2:4][N:5]2[C:10]([NH:11][N:12]=[CH:27][C:20]3[C:19]4[C:24](=[CH:25][CH:26]=[C:17]([Cl:16])[CH:18]=4)[N:23]=[CH:22][CH:21]=3)=[CH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:2][CH2:3]1
Reactant: Cn1c(=O)cc(NN)n(CC2CC2)c1=O
Reactant: O=Cc1ccnc2ccc(Cl)cc12
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(NN=Cc2ccnc3ccc(Cl)cc23)n(CC2CC2)c1=O

Procedure:
A solution of 49 mg (0.23 mmol) 1-(cyclopropylmethyl)-6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione and 44 mg (0.23 mmol) 6-chloroquinoline-4-carbaldehyde in 1 mL DMF was stirred at room temperature for 5 h to form 6-chloroquinoline-4-carbaldehyde[3-(cyclopropylmethyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]hydrazone. Added was 38 mg (0.34 mmol) 1-methyl-1H-imidazole-5-carbaldehyde and 20 μL piperidine. The mixture was heated at 110° C. for 12 via microwave irradiation. Purification was achieved by preparative HPLC (20%-40% gradient of CH3CN-water with 0.1% TFA) to give the title compound as the bis-TFA salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[CH:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:34])C(=O)C1>ClCCCl>[Cl:34][C:9]1[N:10]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH2:17])[C:16]=2[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ncnc2c1c(-c1ccc(Cl)cc1)cn2-c1ccc([N+](=O)[O-])cc1
Solvent: ClCCCl
Product: Nc1ncnc2c1c(-c1ccc(Cl)cc1)c(Cl)n2-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
A suspension of 5-(4-chlorophenyl)-7-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (26) (527 mg, 1.4 mmol) and NCS (289 mg, 2.2 mmol) in DCE (95.0 mL) was heated to reflux for 2 hr. The reaction was then cooled down to r.t., before it was quenched with H2O (10.0 mL). The layers were separated. Aqueous phase was extracted with DCM (15.0 mL×2). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated to afford 6-chloro-5-(4-chlorophenyl)-7-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (27) (550 mg, 95% yield) as a red solid. LC-MS (ESI): m/z (M/M+2) 399.9/401.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([NH:14]C)[CH2:11][C@@H:10]([C:16](=[O:39])[N:17](C2CC2)[C:18]2[CH:19]=[CH:20][C:21]3[O:26][C:25]([CH3:28])([CH3:27])[C:24](=[O:29])[N:23]([CH2:30][CH2:31][CH2:32][O:33][CH3:34])[C:22]=3[CH:35]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:40]1([C:46]2([C:49]([OH:51])=O)[CH2:48][CH2:47]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([NH:14][C:49]([C:46]2([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:47][CH2:48]2)=[O:51])[CH2:11][C@@H:10]([C:16](=[O:39])[NH:17][C:18]2[CH:19]=[CH:20][C:21]3[O:26][C:25]([CH3:27])([CH3:28])[C:24](=[O:29])[N:23]([CH2:30][CH2:31][CH2:32][O:33][CH3:34])[C:22]=3[CH:35]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN[C@H]1C[C@@H](C(=O)N(c2ccc3c(c2)N(CCCOC)C(=O)C(C)(C)O3)C2CC2)CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)C1(c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCCN1C(=O)C(C)(C)Oc2ccc(NC(=O)[C@@H]3C[C@H](NC(=O)C4(c5ccccc5)CC4)CN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (3R,5S)-3-{Cyclopropyl-[4-(3-methoxy-propyl)-2,2-dimethyl-3-oxo-3,4-di hydro-2H-benzo[1,4]oxazin-6-yl]-carbamoyl}-5-methylamino-piperidine-1-carboxylic acid tert-butyl ester (110 mg, 0.2 mmol) and 1-phenyl-1-cyclopropanecarboxylic acid (40 mg, 0.24 mmol) in DMF (2 mL) are added EDCI. HCl (60 mg, 0.3 mmol) and HOAt (40 mg, 0.3 mmol) at 0° C. After stirred at rt overnight, the reaction mixture is diluted with EtOAc. The mixture is washed with water and dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography to afford (3R,5S)-3-[4-(3-Methoxy-propyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylcarbamoyl]-5-[(1-phenylcyclopropanecarbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white amorphous, which is treated with 4 N HCl in 1,4-dioxane (3 mL). The solution is concentrated under reduced pressure to give the title compound as a yellow powder. MS: 589 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.01 min.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1)#N.CC(C[AlH]CC(C)C)C.C[OH:24].Cl>ClCCl.C1(C)C=CC=CC=1>[CH3:13][O:12][C:11]1[C:5]2[O:4][C:3]([CH:1]=[O:24])=[CH:7][C:6]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CO
Reactant: COc1cccc2cc(C#N)oc12
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cccc2cc(C=O)oc12
Reaction time: 1 h

Procedure:
2-Cyano-7-methoxybenzofuran (0.736 g) was dissolved in dichloromethane (10 ml), and a 1.02N DIBAL solution (5.4 ml) in toluene was added thereto at −4 to −30° C., followed by stirring for one hour. Methanol and dilute hydrochloric acid were added to the mixture, and the solvent was distilled off. The obtained residue was purified by column chromatography (hexane/ethyl acetate=10/1) to give Compound IIad-a (0.371 g, 50%) as an oily substance.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57][C:58]#[C:59][C:60]([CH2:71][CH3:72])([O:63][Si:64]([CH2:69][CH3:70])([CH2:67][CH3:68])[CH2:65][CH3:66])[CH2:61][CH3:62]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:57][C:58]#[C:59][C:60]([CH2:71][CH3:72])([O:63][Si:64]([CH2:69][CH3:70])([CH2:65][CH3:66])[CH2:67][CH3:68])[CH2:61][CH3:62])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCC(C#CCBr)(CC)O[Si](CC)(CC)CC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C#CCO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Yield: 92.6 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 21.0 mg, 0.525 mmol), 15-crown-5 (10 μl) and 1-bromo-4-ethyl-4-triethylsilyloxy-2-hexyne (134 mg, 0.420 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (79.0 mg, 92%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:11](I)([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:11]([O:10][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][CH:7]=1)([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1cccc([N+](=O)[O-])c1
Yield: 85.9 %

Procedure:
3-Nitrophenol (50.0 g, 360 mmol), isopropyl iodide (76.19 g, 450 mmol), and potassium carbonate (60 g) were combined and refluxed under nitrogen overnight in 400 ml of acetone. The reaction mixture was cooled, and the solvent was removed in vacuo . The reaction was combined with about 300 ml of water and thereafter extracted with four 100 ml portions of ethyl acetate. The ethyl acetate extracts were combined and washed twice with 1N sodium hydroxide and brine, dried over anhydrous sodium sulfate, and evaporated to provide 56 g (86%) of 3-isopropoxynitrobenzene as a clear yellow oil.