Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:6]2[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]3[CH:11]=[C:10]([C:18]#[C:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([O-:26])=[O:25])=[CH:22][CH:21]=4)[CH:9]=[CH:8][C:7]2=3)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>C(O)C.O1CCCC1>[N:1]1([CH:6]2[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]3[CH:11]=[C:10]([C:18]#[C:19][C:20]4[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=4)[CH:9]=[CH:8][C:7]2=3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC1(C)CCC(n2ccnc2)c2ccc(C#Cc3ccc(C(=O)[O-])cc3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CCC(n2ccnc2)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
Using General Procedure 1; a solution of ethyl[4-(5-imidazol-1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-benzoate (Compound 138, 50.0 mg, 0.13 mmol) in ethanol (3 mL) and tetrahydrofuran (1 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 40.0 mg (87%) of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[C:10]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[CH:21][N:22]([CH3:24])[CH3:23]
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1ccc(F)cc1)c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Product: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(F)cc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To a solution of the ketone product from Step A (6.0 g; 21.3 mmol) in DMF (100 mL) in a dried round bottom flask was added N,N-dimethylformamide dimethyl acetal (11.3 mL; 85.1 mmol) under a N2 atmosphere, and the reaction was stirred at 75° C. for 16 hours. Most of the volatiles were removed in vacuo to afford the crude product as a oil which was used in the next step without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[N:32]=[C:33]=[O:34].C(N(CC)CC)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:33]([NH:32][C:23]3[CH:24]=[CH:25][C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)=[O:34])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C=Nc1ccc2ccccc2c1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCC(N2Cc3c(CNC(=O)Nc4ccc5ccccc5c4)cccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.6 %

Procedure:
A heterogeneous mixture of 3-(4-aminomethyl-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.6 mmol), 2-naphthyl isocyanate (0.26 g, 1.6 mmol), and triethylamine (4.9 g, 4.9 mmol) in 25 mL THF was stirred under nitrogen at ambient temperature for 18 hours. The solvent was removed under vacuum. The residue was triturated with 3% aqueous HCl (100 mL) for 1 hour and then filtered, and the filter was washed with additional 3% HCl. The resulting solid was dried, triturated with 30 mL refluxing acetone for 1 hour, and filtered, and the filter was washed with additional hot acetone. The resulting solid was dried and then triturated with 30 mL refluxing acetonitrile, filtered, and dried, to provide 0.45 g of the product in 63% yield: 1H NMR (DMSO-d6) δ 2.01-2.08 (m, 1H), 2.38-2.45 (m, 1H), 2.57-2.65 (m, 1H), 2.86-2.93 (m, 1H), 4.41 (d, J=5.0 Hz, 2H), 4.43 (d, J=17.4 Hz, 1H), 4.57 (d, J=17.4 Hz, 1H), 5.16 (dd, J=13.2 Hz, J=5.1 Hz, 1H), 6.83 (t, J=5.8 Hz, 1H), 7.28-7.79 (m, 9H), 8.02 (d, J=1.8 Hz, 1H), 8.85 (s, 1H), 11.03 (s, 1H); 13C NMR (DMSO-d6) δ 22.6, 31.2, 39.8, 46.2, 51.6, 112.8, 119.6, 121.6, 123.6, 126.2, 126.8, 127.4, 128.2, 128.3, 128.8, 130.4, 131.7, 133.8, 135.6, 138.0, 139.9, 155.3, 168.1, 171.0, 172.8; Anal. calcd for C25H22N4O4.0.2H2O: C, 67.31; H, 5.06; N, 12.56. Found: C, 67.37; H, 4.90; N, 12.53.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].[CH:8](OCC)=[O:9]>>[CH:8]([NH:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5])=[O:9]
Reactant: CCOC=O
Reactant: CC(C)(N)CCO
Product: CC(C)(CCO)NC=O
Temperature: 25 °C

Procedure:
3-Amino-3-methyl-1-butanol (20.60 g, 0.20 mol) was added to ethyl formate (29.60 g, 0.40 mol), and the resulting clear solution was heated to reflux under nitrogen for 2 hours, and then allowed to cool to room temperature. The ethyl formate and ethanol by-product were removed by rotary evaporation (35° C., 25 Torr). The resulting oil was dried under vacuum (25° C., 0.1 Torr) to yield 25.86 g (99%).
Reaction SMILES: [CH3:1][N:2]([C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]3[CH:20]=2)=[C:8]([CH3:10])[N:9]=1)C=O.Cl>C(O)C>[CH3:1][NH:2][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]3[CH:20]=2)=[C:8]([CH3:10])[N:9]=1
Reactant: Cc1ccn2cc(-c3sc(N(C)C=O)nc3C)nc2c1
Agent: Cl
Solvent: CCO
Product: CNc1nc(C)c(-c2cn3ccc(C)cc3n2)s1
Yield: 73.3 %

Procedure:
To a solution of 2-[2-(N-methylformamido)-4-methylthiazol-5-yl]-7-methylimidazo[1,2-a]pyridine (4.87 g) in ethanol (200 ml) was added 36% hydrochloric acid (2.6 ml) and refluxed for 1.5 hours. The reaction mixture was evaporated. The residue was dissolved in water, and the aqueous mixture was adjusted to pH 8 with saturated potassium carbonate. Extraction with chloroform, and evaporation afforded 2-(2-methylamino-4-methylthiazol-5-yl)-7-methyl-imidazo[1,2-a]pyridine (3.22 g). mp 220°-221° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:33](=[O:35])[CH3:34])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (22 mg, 48 mmol) was dissolved in abs. pyridine (5 ml). At room temperature, acetic anhydride (98 mg, 960 μmol, 20 eq.) was added. Once analysis of the reaction by TLC showed substantial conversion (a few hours), the reaction mixture was concentrated under reduced pressure and directly purified by preparative HPLC (Reprosil C18 column, 30×200 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (20.6 mg, 93% of theory).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]([CH:10]=[O:11])=[CH:8][N:7]=[CH:6]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([Si](C)(C)C)([F:21])[F:20]>CN(C)C=O>[CH:1]1([CH2:4][N:5]2[C:9]([CH:10]([OH:11])[C:19]([F:21])([F:20])[F:18])=[CH:8][N:7]=[CH:6]2)[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1cncn1CC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(c1cncn1CC1CC1)C(F)(F)F
Yield: 66.4 %

Procedure:
According to Reference Example 8-2, by use of 1-(cyclopropylmethyl)-1H-imidazole-5-carbaldehyde (212 mg, 1.41 mmol) dissolved in N,N-dimethylformamide (4.2 mL), potassium carbonate (39 mg, 0.28 mmol) and (trifluoromethyl)trimethylsilane (0.626 mL, 4.23 mmol), the mixture was stirred and reacted at room temperature for 2 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=12/1) was performed to give 1-[1-(cyclopropylmethyl)-1H-imidazol-5-yl]-2,2,2-trifluoroethanol (Compound DW) (206 mg, yield: 66%).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[S:24][CH:25]=[CH:26][N:27]=1)=[CH:8]2)=[O:4].[NH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:28])[C:5]([C:3]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[S:24][CH:25]=[CH:26][N:27]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3nccs3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3nccs3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 20 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-thiazol-2-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (28 mg, 0.071 mmol), β-alanine (844 mg, 9.5 mmol) and NaOMe solution (14 mL, 7.1 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3. The organic layer was dried over MgSO4 and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 6.4 mg of the title compound. MS: (+) m/z 451.18 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:12][N:5]([CH2:4][CH2:3][CH2:2][O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Oc1ccccc1
Reactant: CN(CCCBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCCOc1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 62 %

Procedure:
To a solution of 23a (0.20 g, 0.88 mmol) and phenol (0.75 g, 0.79 mmol) in DMF (5.0 mL) was added K2CO3 (0.24 g, 1.75 mmol). The reaction was then stirred at 80° C. for 12 hours. The reaction mixture was concentrated and purified by column chromatography to isolate the compound 23 as a colorless oil (0.12 g, 0.49 mmol, 56.7% yield). MS (ESI, positive) m/z calcd. for C16H20NO [M+H]+: 242.15, found: 241.93. 1H NMR (CDCl3, 400 MHz) δ7.22-7.33 (m, 4H), 6.92-6.99 (m, 3H), 6.69-6.77 (m, 3H), 4.04 (t, J=6.0 Hz, 2H), 3.58 (t, J=6.8 Hz, 2H), 2.97 (s, 3H), 2.06-2.12 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:22])[O:13][CH:14]2[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1>>[N:23]1[CH:28]=[C:27]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:22])[O:13][CH:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)([CH3:10])[CH3:9])=[CH:4][CH:3]=2)[CH:26]=[N:25][CH:24]=1
Reactant: OB(O)c1cncnc1
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(Br)cc1
Product: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(-c2cncnc2)cc1
Yield: 40.4 %

Procedure:
Using general procedure E, quinuclidin-3-yl 2-(4-bromophenyl)propan-2-ylcarbamate (200 mg, 0.540 mmol), pyrimidin-5-ylboronic acid (136 mg, 1.12 mmol) and [PdCl2(pddf)]CH2Cl2 gave the title compound as a white solid (80 mg, 40%). 1H NMR (500 MHz, CDCl3) δ 9.17 (s, 1H), 8.92 (s, 2H), 7.58-7.51 (m, 4H), 5.34 (s, 1H), 4.61 (m, 1H), 3.20-3.10 (m, 1H), 2.92-2.41 (m, 5H), 2.00-1.76 (m, 2H), 1.72-1.53 (m, 7H), 1.52-1.32 (m, 2H) ppm. 13C NMR (125 MHz, CDCl3) δ 157.4, 154.8, 154.5, 148.2, 134.0, 132.5, 127.0, 126.0, 71.2, 55.6, 55.0, 47.4, 46.3, 29.7, 29.4, 25.4, 24.5, 19.5 ppm. Purity: >96% LCMS (214 nm & 254 nm); retention time 1.34 min; (M+1) 366.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.OCC([C:31]1[C:36]([N+:37]([O-])=O)=[C:35]([CH3:40])[CH:34]=[CH:33][C:32]=1[S:41]([NH2:44])(=[O:43])=[O:42])(C)C>>[OH:13][CH2:12][C:11]([NH:44][S:41]([C:32]1[CH:33]=[CH:34][C:35]([CH3:40])=[C:36]([NH:37][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:13])[CH:31]=1)(=[O:42])=[O:43])([CH3:10])[CH3:7]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1ccc(S(N)(=O)=O)c(C(C)(C)CO)c1[N+](=O)[O-]
Product: Cc1ccc(S(=O)(=O)NC(C)(C)CO)cc1NC(=O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-4-methyl-benzenesulfonamide (example B.11) according to general procedure II. Light yellow solid. MS (ISP) 596.1 [(M−H−]; mp 214° C.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)(=[O:5])=[O:4]>CO.[Pd]>[NH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[S:3]([NH:2][CH3:1])(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNS(=O)(=O)c1ccccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
To a solution of N-methyl-2-nitrobenzenesulfonamide (26 g, 0.12 mol) in methanol (500 mL) was added palladium on carbon (10%, 2 g). The mixture was stirred under an atmosphere of hydrogen at room temperature for 3 hours. The catalyst was filtrated and the filtrate was evaporated to afford the product 2-amino-N-methylbenzenesulfonamide (22 g, yield 98%). 1H NMR (400 MHz, CDCl3) δ ppm 7.45-7.48 (dd, 1H, J=1.6 Hz, 8.0 Hz), 7.24-7.31 (m, 2H), 6.81-6.83 (dd, 1H, J=0.6 Hz, 8.0 Hz), 6.60-6.65 (m, 1H), 5.89 (s, 2H), 2.370-2.374 (d, 3H, J=1.6 Hz).
Reaction SMILES: [Mg].II.Br[CH2:5][C@@H:6]([CH3:9])[CH2:7][CH3:8].ClC[C@@H](C)CC.[CH3:16][Si:17](Cl)([Cl:19])[Cl:18]>C(OCC)C.CCCCCC.O1CCCC1>[CH3:16][Si:17]([CH2:5][C@@H:6]([CH3:9])[CH2:7][CH3:8])([Cl:19])[Cl:18]
Reactant: C[Si](Cl)(Cl)Cl
Reactant: CC[C@H](C)CBr
Agent: CC[C@H](C)CCl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC[C@H](C)C[Si](C)(Cl)Cl

Procedure:
Anhydrous tetrahydrofuran (125 mL) was put into a reactor with magnesium (9.5 g, 0.41 mol) and molecular sieves 4A which had been dehydrated and deaerated, followed by charging of argon gas. A small amount of iodine was slowly added to the mixture. (S)-(+)-1-bromo-2-methylbutane (4.5 g, 0.03 mol) was added dropwise to the slowly stirred mixture. In addition, (S)-(+)-1-chloro-2-methylbutane (36 g, 0.34 mol) was added dropwise to the stirred mixture so that the reaction mixture was gradually refluxed. After the reaction was complete, the obtained Grignard reagent was transferred to a dropping funnel. The Grignard reagent was added dropwise to a solution being stirred containing methyltrichlorosilane (80 g, 0.54 mol) in anhydrous diethyl ether (150 mL) in another reactor which had been dehydrated and deaerated, followed by charging of argon gas, at 2° C.-5° C. The reaction mixture was then stirred overnight at room temperature. Hexane (500 mL) was added to the reaction mixture, and the resulting mixture was filtered under pressure, followed by fractional distillation of the filtrate to provide the desired product.
Reaction SMILES: C1C2C(COC([NH:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:49])[C:23]([CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([O:33][C:34](=[O:48])[NH:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH2:29][CH2:28]3)=[O:24])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)Cl>[NH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:49])[C:23]([CH2:25][CH2:26][N:27]1[CH2:28][CH2:29][CH:30]([O:33][C:34](=[O:48])[NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:31][CH2:32]1)=[O:24]
Reactant: CN(CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CN(CCCN)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To biphenyl-2-ylcarbamic acid 1-(2-{[3-(9H-fluoren-9-ylmethoxycarbonyl-amino)propyl]methylcarbamoyl}ethyl)piperidin-4-yl ester (2.2 g, 3.3 mmol) was added a 10% solution of piperidine (0.31 g, 3.3 mmol) in DCM (3.2 mL) and the resulting mixture was shaken at room temperature for 1 h. The mixture was concentrated under reduced pressure and the residue was dissolved in DCM (100 mL). This mixture was washed with water (2×20 mL) and then extracted with ammonium chloride (1 N, 2×20 mL). The layers were separated and DCM was added to the aqueous layer. The aqueous layer was made basic by addition of aqueous potassium hydroxide (1 N) and the layers were separated. The organic layer was washed with aqueous potassium hydroxide (1 N, 2×20 mL) and brine (1×20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.0 g, 66% yield) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1.N1C=CC=CC=1.[Cl:20][CH2:21][C:22](Cl)=[O:23]>CCOCC>[N+:8]([C:6]1[CH:5]=[C:4]([O:11][CH2:12][CH3:13])[N:3]=[C:2]([NH:1][C:22](=[O:23])[CH2:21][Cl:20])[CH:7]=1)([O-:10])=[O:9]
Reactant: CCOc1cc([N+](=O)[O-])cc(N)n1
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOc1cc([N+](=O)[O-])cc(NC(=O)CCl)n1
Reaction time: 0.33 h

Procedure:
A solution of 2-amino-4-nitro-6-ethoxypyridine (29.4 grams) in absolute ether (150 ml), and pyridine (25 grams) are charged into a glass reaction vessel equipped with stirrer, thermometer and addition funnel. The mixture is cooled to a temperature of about 0° C and chloroacetyl chloride (11.3 grams) dissolved in ether (50 ml) is then slowly added thereto with stirring over a period of about 20 minutes. Stirring and cooling are continued for an additional period of about 30 minutes. The resulting precipitate is then recovered from the reaction medium by filtration, is washed first with aqueous sodium carbonate and then with water, and is dried to yield the desired product N-(4-nitro-6-ethoxy-2-pyridyl)-α-chloroacetamide.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][NH:11][CH:12]2[CH2:15][CH2:16][CH3:17])=[CH:7][CH:6]=1)([O-:4])=[O:3].[OH-].[NH4+].Cl.[CH:21](O)=O>C=O.C(O)C>[ClH:1].[CH3:21][N:11]1[CH2:10][CH2:9][C:8]2[C:13](=[CH:14][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=2)[CH:12]1[CH2:15][CH2:16][CH3:17]
Reactant: CCCC1NCCc2ccc([N+](=O)[O-])cc21
Reactant: O=CO
Agent: C=O
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Product: CCCC1c2cc([N+](=O)[O-])ccc2CCN1C
Yield: 49 %

Procedure:
A solution of 7-nitro-1-propyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.50 g, 9.74 mmol) in formic acid (6.0 ml) and aqueous formaldehyde (9.0 ml) was heated at reflux for 1 h. The cooled solution was poured onto ice, made basic with concentrated ammonium hydroxide, and extracted twice with dichloromethane. The dried (magnesium sulfate) extracts were concentrated to give an oil which was taken up in ethanol and hydrochloric acid in ethanol was added until acidic. Since no precipitate formed on standing, the solvent was evaporated in vacuo and the residue was taken up in isopropanol (35 ml) and allowed to stand for several hours. The precipitate was collected to give the title compound (1.30 g, 49%) as an off-white solid, m.p. 198.5-200.5° C.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].NC1OC(C2C=CC(C3CCCCC3)=CC=2)=CC=1C(OC)=O>CO.C(OCC)(=O)C.[C].[Pd]>[CH:17]1([C:14]2[CH:15]=[CH:16][C:11]([C:4]3[NH:3][CH:2]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=3)=[CH:12][CH:13]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COC(=O)c1cc(-c2ccc(C3CCCCC3)cc2)[nH]c1Cl
Agent: [Pd]
Agent: COC(=O)c1cc(-c2ccc(C3CCCCC3)cc2)oc1N
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1c[nH]c(-c2ccc(C3CCCCC3)cc2)c1
Temperature: 50 °C
Reaction time: 14 h
Yield: 41.1 %

Procedure:
To a solution of a nearly 1:1 mixture (3.41 g) of methyl 2-chloro-5-(4-cyclohexylphenyl)-1H-pyrrole-3-carboxylate and methyl 2-amino-5-(4-cyclohexylphenyl)-3-furoate in methanol (30 mL) and ethyl acetate (10 mL) was added 10% palladium carbon (50% containing water, 0.34 g), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 14 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=3:1→2:1) to give the title compound as crystals (yield 1.25 g, 41%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Na].[Cl:10][C:11]1[N:12]=[N:13][C:14](Cl)=[C:15]([O:18][CH3:19])[C:16]=1Cl>C1(C)C=CC=CC=1>[Cl:10][C:11]1[N:12]=[N:13][C:14]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[C:15]([O:18][CH3:19])[C:16]=1[O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: COc1c(Cl)nnc(Cl)c1Cl
Reactant: Cc1ccccc1O
Agent: [Na]
Solvent: Cc1ccccc1
Product: COc1c(Oc2ccccc2C)nnc(Cl)c1Oc1ccccc1C
Reaction time: 4 h
Yield: 34.1 %

Procedure:
In toluene (100 mL) was dissolved 5.32 g (49.3 mmol) of 2-methylphenol, and 1.13 g (49.1 mmol) of sodium, and then, 5.80 g (27.2 mmol) of 3,4,6-trichloro-5-methoxypyridazine were added to the solution and the resulting mixture was stirred for 4 hours under reflux. The reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, gradient) and recrystallized from isopropyl ether to obtain 3.0 g (8.4 mmol, Yield: 31%) of 3-chloro-5-methoxy-4,6-bis(2-methylphenoxy)pyridazine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH:22]([CH3:23])[CH2:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>>[CH3:23][CH:22]1[C:15]2[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:19][CH:18]=[N:17][C:16]=2[NH:20][CH2:21]1.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]
Reactant: CC1CNc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: O=C(O)C(F)(F)F
Product: CC1CNc2ncnc(N3CCNCC3)c21

Procedure:
A solution of 4-(5-Methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.30 g, 0.68 mmol) in TFA (20 mL) was heated to 65° C. overnight. After cooling, the excess TFA was evaporated under vacuum to give 5-Methyl-4-piperazin-1-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine as TFA salt (0.15 g, 99%). MS (APCI+) [M+H]+220.