Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9]1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:19][C:17]1([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:31]([CH3:30])(=[O:33])=[O:32]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1N)N2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NS(C)(=O)=O)N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 2-(2-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (1.0 g, 3.22 mmol, 1.0 eq.) in pyridine (5 mL, 0.0644 mL, 20.0 eq.) and dichloro methane (20 mL) at 0 C was added dropwise a solution of methanesulfonyl chloride in dichloromethane (30 mL). The mixture was stirred at room temperature for 4 h. Thin layer chromatography and LC-MS showed the reaction was complete. The mixture was quenched with 50 mL water and extracted with ethyl acetate (100 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to afford 1.475 g of methyl 3,3-dimethyl-2-(2-(methylsulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (pyridine included) as light yellow solid, which was used in next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:14][C:15]([O:17]C)=[O:16])[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH2:6]1)=[O:4].[ClH:19]>>[ClH:19].[C:3]([C:5]1([CH2:14][C:15]([OH:17])=[O:16])[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH2:6]1)([OH:4])=[O:2]
Reactant: COC(=O)CC1(C(=O)OC)CN=C2C=CC=CN21
Agent: Cl
Product: O=C(O)CC1(C(=O)O)CN=C2C=CC=CN21
Yield: 51 %

Procedure:
The imidazopyridine ester product of Example 2 (0.057 g, 0.23 mmol) was dissolved in 4N HCl (4 mL) and heated to reflux for 14 h. All solvent was removed in vacuo and the residue triturated with diethyl ether to yield clean title compound (0.021 g, 51%). Anal. Calcd for C11H8 N2O4.1.1 HCl.0.9 H2O: C, 43.44; H, 3.97; N, 10.13; Cl, 14.10. Found: C, 43.32; H, 3.60; N, 10.18; Cl, 14.22. 1H NMR (300 MHz, DMSO): 4.5 (2H, s), 7.5 (1H, t, J=6.25 Hz), 7.95 (2H, m), 9 (1H, d, J=12.5 Hz).
Reaction SMILES: [C:1](=O)([O-])[OH:2].[Na+].[N:6]1[C:13]([Cl:14])=[N:12][C:10]([Cl:11])=[N:9][C:7]=1Cl>CO>[CH3:1][O:2][C:7]1[N:9]=[C:10]([Cl:11])[N:12]=[C:13]([Cl:14])[N:6]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)nc(Cl)n1
Temperature: 0 °C

Procedure:
7 parts of sodium hydrogencarbonate was added to 50 parts of methanol. This mixture was cooled to 0° C. from outside. Then, 15 parts of cyanuric chloride was added to conduct a reaction for 60 minutes (First condensation). To the reaction mixture was added 100 parts of ice water, and the crystal precipitated was collected by filtration to obtain 2-methoxy-4,6-dichloro-1,3,5-triazine.
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4C(=O)CCCC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:35][C:36]1([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[C:55]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[CH:54][C:53]4[C:52](=[O:62])[NH:51][CH2:50][CH2:49][C:48]=4[N:47]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37]1)(C)(C)C>>[NH2:35][C:36]1([C:40]2[CH:41]=[CH:42][C:43]([C:46]3[C:55]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[CH:54][C:53]4[C:52](=[O:62])[NH:51][CH2:50][CH2:49][C:48]=4[N:47]=3)=[CH:44][CH:45]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)NCC4)cc2)CCC1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)NCC4)cc2)CCC1
Yield: 90.2 %

Procedure:
Following the procedure for 2-(4-(1-aminocyclobutyl)phenyl)-3-phenyl-7,8-dihydroquinolin-5(6H)-one, tert-butyl(1-(4-(5-oxo-3-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)phenyl)cyclobutyl)carbamate (10 mg, 0.021 mmol) was reacted to afford the title compound (7 mg, 69%). LCMS (Method A): RT=3.62 min, M+H+=370. 1H NMR (500 MHz, MeOD) 8.30 (1H, s), 7.51 (2H, d), 7.45 (2H, d), 7.31 (3H, m), 7.22 (2H, m), 3.70 (2H, t), 3.27(2H, t), 2.85-2.70 (2H, m), 2.65-2.50 (2H, m), 2.30-2.20 (1H, m), 2.05-1.90 (1H,m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[NH:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CNCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 60.2 %

Procedure:
In a 32 mL reaction vial was placed a stir bar and 4-methylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (0.97 g) dissolved in 12.8 mL anhydrous THF. The solution was cooled to 0° C. with an ice-bath. A 65% toluene solution of Red-A1 (3.66 mL) was added dropwise at 0° C. After the addition was completed, the mixture was stirred under N2 at room temperature until all the starting materials were just consumed. The reaction mixture was worked up with H2O at 0° C., extracted with EtOAc (×3). The EtOAc extract was washed with saturated NaCl solution. After drying over Na2SO4, the organic layer was concentrated to give 550 mg of crude product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH2:19][OH:20])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:31]([O:33][C@@H:34]([CH2:40][C:41]1[CH:46]=[CH:45][C:44](O)=[CH:43][CH:42]=1)[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:32]>>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([C:13]2[CH:14]=[C:15](/[CH:17]=[CH:18]/[CH2:19][O:20][C:44]3[CH:43]=[CH:42][C:41]([CH2:40][C@H:34]([O:33][CH2:31][CH3:32])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:46][CH:45]=3)[CH:16]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:10][CH:9]=3)[CH:12]=2)=[CH:22][CH:23]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: CC(C)(C)c1ccc(-c2cc(/C=C/CO)cc(-c3ccc(C(C)(C)C)cc3)c2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2cc(-c3ccc(C(C)(C)C)cc3)cc(-c3ccc(C(C)(C)C)cc3)c2)cc1)OCC
Yield: 79.3 %

Procedure:
The title compound (368 mg, 79%) was prepared from (E)-3-(4,4″di-tert-butyl-[1,1′;3′,1″]terphenyl-5′-yl)-prop-2-en-1-ol (300 mg, 0.75 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (188 mg, 0.79 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:23])[C:5]([NH:10][CH2:11][C:12]2[CH:22]=[CH:21][C:15]3[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=3[CH:13]=2)=[CH:6][C:7]=1[O:8][CH3:9].[CH2:24](OC(OCC)OCC)C>C(O)=O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]2[N:10]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=4[CH:13]=3)[CH:24]=[N:23][C:4]=2[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: COc1cc(NCc2ccc3nc(SC)sc3c2)c(N)cc1Br
Solvent: O=CO
Product: COc1cc2c(cc1Br)ncn2Cc1ccc2nc(SC)sc2c1
Yield: 40 %

Procedure:
To a stirred mixture of 4-bromo-5-methoxy-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine (120 mg, 0.3 mmol) from Step 2 of this Example and triethylorthoformate (20 mL) was added formic acid (1 mL). The mixture was heated under reflux for 2 h, then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% EtOAc to afford 6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (50 mg, 40%) as an oil. 1H NMR (300 MHz, CDCl3) δ 8.01 (s, 1H), 7.78-7.91 (m, 2H), 7.46 (s, 1H), 7.25 (m, 1H), 6.69 (s, 1H), 5.42 (s, 2H), 3.81 (s, 3H), 2.78 (s, 3H). LCMS (ESI) m/z 420 and 422 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:18](Br)([CH3:20])[CH3:19].O>CN(C=O)C>[F:1][C:2]1[C:10]2[N:9]([CH:18]([CH3:20])[CH3:19])[C:8]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Br
Reactant: O=C1NCCc2[nH]c3c(F)cccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1c2c(c3cccc(F)c31)C(=O)NCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
A stirred solution of 6-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (1.006 g) in dry DMF (50 ml) was treated with sodium hydride (73.2% dispersion in oil; 333 mg) and stirred under nitrogen for 1 h. Isopropyl bromide (663 mg) was then added, and the solution was stirred at room temperature for 30 min and then at 50° for 12 h. A further portion of isopropyl bromide (150 mg) was then added, and the reaction was then stirred under nitrogen at 50° for ca. 60 h. The mixture was then cooled to room temperature and added to water (300 ml). The mixture was then extracted with dichloromethane (3×200 ml), adsorbed onto silica, and purified by FCC eluting with System A (150:8:1) to give a solid (240 mg) which was triturated with ether to give the title compound (130 mg), m.p. 183°-184°.
Reaction SMILES: ClC1N(CC2C=CC=CC=2C#N)C(=O)NC(=O)C=1.[Br:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br.C(O)(=O)C1C=CC=CC=1.[NH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][N:40]([C:44]2[N:49](CC3C=CC=CC=3C#N)[C:48](=[O:59])[N:47](C)[C:46](=[O:61])[CH:45]=2)[CH2:39]1>>[NH2:37][C@@H:38]1[CH2:43][CH2:42][CH2:41][N:40]([C:44]2[N:49]([CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=3[Br:19])[C:48](=[O:59])[NH:47][C:46](=[O:61])[CH:45]=2)[CH2:39]1
Reactant: BrCc1ccccc1Br
Reactant: Cn1c(=O)cc(N2CCCC(N)C2)n(Cc2ccccc2C#N)c1=O
Agent: N#Cc1ccccc1Cn1c(Cl)cc(=O)[nH]c1=O
Agent: O=C(O)c1ccccc1
Product: N[C@@H]1CCCN(c2cc(=O)[nH]c(=O)n2Cc2ccccc2Br)C1

Procedure:
The title compound was prepared in two steps. The first step was accomplished using the procedure for the preparation of compound 2, except that 2-bromobenzylbromide was used in the place of α-Bromo-o-tolunitrile. The crude product was then converted to the title compound by the method used in the preparation of compound 4. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1): δ 7.52 (d, J=8.1 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H), 7.10 (t, J=7.8 Hz, 1H), 6.89 (d, J=7.579 Hz, 1H), 5.27 (s, 1H), 4.92-5.04 (ABq, J=34.1, 15.0 Hz, 2H), 3.27 (bd, J=10.4 Hz, 1H), 3.09-3.18 (m, 1H), 2.89 (m, 1H), 2.70 (t, J=10.9 Hz, 1H), 2.48 (t, J=12.0 Hz, 1H), 2.03 (m, 1H), 1.60-1.71 (m, 1H), 1.42-1.53 (m, 2H). MS (ES) [m+H] calc'd for C16H20BrN4O2, 379.1; found, 379.1.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH:27]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH2:34])[CH2:28]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:26][CH:27]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH:34][C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:28]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NCCN1CCC(CN2CCCCC2)C1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CC#N
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCC(CN3CCCCC3)C2)c2ccccc21
Yield: 39 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[(piperidin-1-yl)methyl]-pyrrolidin-1-yl]ethanamine in a yield of 39% of theory. Colourless crystals, m.p. 168°-169° C. (acetonitrile).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1/[CH:7]=[CH:8]/[C:9]1[C:17]2[C:12](=[CH:13][C:14](/[CH:18]=[C:19]3/[C:20](=[O:28])[NH:21][C:22]4[C:27]/3=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:15][CH:16]=2)[N:11](COCC[Si](C)(C)C)[N:10]=1.[ClH:37]>CCO.CC#N.CCOCC>[ClH:37].[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1/[CH:7]=[CH:8]/[C:9]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]=[C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:28])=[CH:15][CH:16]=2)[NH:11][N:10]=1
Reactant: Cn1ccnc1/C=C/c1nn(COCC[Si](C)(C)C)c2cc(/C=C3/C(=O)Nc4ccccc43)ccc12
Agent: Cl
Solvent: CC#N
Solvent: CCO
Solvent: CCOCC
Product: Cn1ccnc1/C=C/c1n[nH]c2cc(C=C3C(=O)Nc4ccccc43)ccc12
Temperature: 77.5 °C
Reaction time: 8 h

Procedure:
A sealed, degassed mixture of (E)-3-((3-((E)-2-(1-methyl-1H-imidazol-2-yl)vinyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)methylene)indolin-2-one (35.4 mg, 0.071 mmol) in EtOH (4 mL) and aq HCl (4 M, 1 mL) was heated at 75-80° C. under Ar for 1 d. The reaction mixture was cooled to rt, diluted with MeCN (10 mL) and Et2O (5 mL) and stored at −20° C. overnight. The precipitate was collected by filtration, washed with MeCN to provide the title compound as a 1.5:1.0 (E:Z) mixture of isomers: a yellow solid (14.5 mg, 51%). 1H NMR (400 MHz, CD3OD) δ ppm 8.93 (s, 0.44H), 8.25 (d, J=8.28 Hz, 1.00H), 8.13 (d, J=8.53 Hz, 0.65H), 8.02-8.06 (m, 0.45H), 8.02 (s, 1.78H), 7.92-8.00 (m, 1.78H), 7.86-7.91 (m, 1.47H), 7.58-7.71 (m, 5.0H), 7.53 (d, J=16.81 Hz, 1.29H), 7.25 (t, J=7.65 Hz, 1.52H), 7.05 (t, J=7.78 Hz, 0.66H), 6.94 (d, J=7.78 Hz, 1.01H), 6.83-6.91 (m, 1.73H), 4.04 (s, 2.46H), 4.03 (s, 1.41H); MS ESI 368.1 [M+H]+, calcd for [C22H17N5O+H]+ 368.4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C@H:4]([CH3:38])[NH:5][C:6](=[O:37])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[CH:17][C:18]2[CH:27]=[CH:26][C:25]([O:28]CC3C=CC=CC=3)=[C:24]3[C:19]=2[CH:20]=[CH:21][CH:22]=[N:23]3)[C:9]1=[O:36].FC(F)(F)S(O)(=O)=O.ClCCl.C([O-])(O)=O.[Na+]>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:39])[C@H:4]([CH3:38])[NH:5][C:6](=[O:37])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[CH:17][C:18]2[CH:27]=[CH:26][C:25]([OH:28])=[C:24]3[C:19]=2[CH:20]=[CH:21][CH:22]=[N:23]3)[C:9]1=[O:36]
Reactant: COC(=O)[C@H](C)NC(=O)CN1C(=O)C(=Cc2ccc(OCc3ccccc3)c3ncccc23)c2ccccc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](C)NC(=O)CN1C(=O)C(=Cc2ccc(O)c3ncccc23)c2ccccc21
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a solution of N-{2-[3-(8-benzyloxyquinol-5-ylmethylen)-2-oxindol-1-yl]acetyl}alanine methyl ester (45 mg, 0.09 mmol) in trifluoroacetic acid (5 ml) was added trifluoromethanesulfonic acid (0.1 ml) and the mixture was stirred at 0-5° C. for 0.5 h. Then dichloromethane was added, the mixture neutralized with 5% NaHCO3 and the organic layer concentrated under vacuum to give 30 mg of title compound (77% yield).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]#[C:5][CH2:6][CH3:7].[Cl:9][C:10]1[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:9][C:10]1[CH:15]=[C:14]([O:8][CH2:3][C:4]#[C:5][CH2:6][CH3:7])[N:13]=[CH:12][N:11]=1
Reactant: CCC#CCO
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC#CCOc1cc(Cl)ncn1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
In 1 ml of tetrahydrofuran was suspended 0.03 g of sodium hydride (60% in oil), to which 0.5 ml of a tetrahydrofuran solution containing 0.06 g of 2-pentyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes and then cooled to 0° C., to which 0.5 ml of a tetrahydrofuran solution containing 0.1 g of 4,6-dichloropyrimidine was slowly added dropwise, followed by further stirring for 30 minutes. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with t-butyl methyl ether. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.12 g of 4-chloro-6-(2-pentynyloxy)pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28](Cl)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32](=[O:34])[CH3:33])=[CH:16][N:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([F:52])[C:38]=1[OH:53]>>[C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:41]5[CH:40]=[C:39]([F:52])[C:38]([OH:53])=[C:37]([Cl:36])[CH:42]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32](=[O:34])[CH3:33])=[CH:16][N:15]=2)[CH2:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 59.3 %

Procedure:
Following general procedure II, (S)-tert-butyl(1-{5-[(3-acetyl-6-chloro-1,5-naphthyridin-4-yl)amino]pyridin-2-yl}piperidin-3-yl)carbamate (100 mg, 0.20 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (82 mg, 0.30 mmol) to afford the crude product (72 mg) which was carried forward without any purification: ESI MS m/z 607 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:21][C@@H:20]2[C@:7]([CH3:24])([CH2:8][CH2:9][C@H:10]3[C@H:19]2[CH2:18][CH2:17][C:16]2[C@:11]3([CH3:23])[CH:12]=[CH:13][C:14](=[O:22])[CH:15]=2)[C@H:3]1[C:4](=[O:6])[CH3:5].[Cl-].[Ca+2].[Cl-].[O-2].[Ca+2].[I:30]I>CO.C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[I:30][CH2:5][C:4](=[O:6])[C@@H:3]1[C@:7]2([CH3:24])[C@H:20]([C@H:19]3[C@H:10]([CH2:9][CH2:8]2)[C@:11]2([CH3:23])[C:16](=[CH:15][C:14](=[O:22])[CH:13]=[CH:12]2)[CH2:17][CH2:18]3)[CH2:21][C@H:2]1[CH3:1]
Reactant: II
Reactant: CC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@@]21C
Agent: [Ca+2]
Agent: [Cl-]
Agent: [O-2]
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]2(C)[C@H]1C(=O)CI
Reaction time: 0.25 h

Procedure:
16α-Methylpregna-1,4-diene-3,20-dione (2.26 g), carbon tetrachloride (15 ml), methanol (7.3 ml) and calcium chloride in methanol (10%, 0.24 ml) are combined and stirred for 15 min at 20°-25°. Calcium oxide (2.50 g) is added and the mixture stirred an additional 5 min. A mixture of iodine (3.54 g), calcium chloride (10%, 5.4 ml) and methanol (2.4 ml) is added dropwise over 1 hr to the steroid mixture. After an additional 30 min the mixture is diluted with methylene chloride (100 ml), filtered through celite and concentrated. The residue is partitioned between methylene chloride and water, the phases are separated, the organic phase is washed with sodium sulfite, dried over magnesium sulfate and then concentrated to give the title compound, NMR (CDCl3) 0.7, 0.9, 1.2, 5.25, 5.35, 6.0, 6.2 and 7.0 δ.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10])([CH3:3])[CH3:2].Br[C:12]1[O:16][CH:15]=[C:14]([C:17]([OH:19])=[O:18])[CH:13]=1>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:12]1[O:16][CH:15]=[C:14]([C:17]([OH:19])=[O:18])[CH:13]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1S
Reactant: O=C(O)c1coc(Br)c1
Product: CC(C)c1ccccc1Sc1cc(C(=O)O)co1

Procedure:
Following the procedure of Example 9, o-isopropylthiophenol [4.77 g., 31.4 mmoles; Hansch and Blondon, J. Am. Chem. Soc. 70, 1561 (1948)] was reacted with 5-bromofuran-3-carboxylic acid. Rather than recover the initial crude product by filtration, the mixture was reextracted with ethyl acetate, the ethyl acetate back-washed with water and saturated brine, dried over anhydrous sodium sulfate and evaporated to yield crude product. Recrystallization from hexane produced purified 5-(2-isopropylphenylthio)furan (785 mg., m.p. 117°-120° C., m/e 262).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[C:18]([O:20][CH2:21][C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O>CO.Cl.C(O)(C)C.C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:19]=[C:18]([O:20][CH2:21][C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:8][CH:9]=1
Reactant: O=C(COc1cc(-c2ccc([N+](=O)[O-])cc2)nc2ccccc12)N1CCOCC1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: Nc1ccc(-c2cc(OCC(=O)N3CCOCC3)c3ccccc3n2)cc1
Reaction time: 0.5 h
Yield: 28.9 %

Procedure:
4-{[2-(4-Nitrophenyl)-4-quinolyl]oxyacetyl}morpholine (3.93 g), prepared according to Example 31, dissolved in methanol (80 cc) is hydrogenated at 40° C. for 30 minutes and then at room temperature (approximately 20° C.) and under atmospheric pressure in the presence of a 5N solution (4 cc) of hydrochloric acid in isopropanol and palladinized charcoal (10% Pd) (0.4 g) as catalyst. After absorption of the theoretical amount of hydrogen, normal sodium hydroxide solution (25 cc) is added to the reaction mixture in order to redissolve the precipitate formed. After filtration, the solvent is removed under reduced pressure and the residual aqueous phase is taken up with methylene chloride. The organic phase is washed with water, dried over magnesium sulphate and evaporated under reduced pressure. The residue (2.9 g) is dissolved in hot ethyl acetate (15 cc); ethyl ether (30 cc) is then added, and the precipitate is filtered off and chromatographed on silica gel using a toluene/methanol/diethylamine (90:5:5 by volume) mixture. 4-{[2-(4-Aminophenyl)-4-quinolyl]oxyacetyl}morpholine (1.05 g), m.p. 174° C., is thereby isolated.
Reaction SMILES: [CH3:1][C@H:2]1[C@:7]2([OH:30])[C@:8]34[O:28][C@H:27]5[C@@:16]6([C@@H:23]([OH:29])[C:24]([O:26]5)=[O:25])[C@H:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:18][C@H:12]([C@@:13]36[C@@H:14]([OH:15])[C@@H:6]2[O:5][C:3]1=[O:4])[O:11][C:9]4=[O:10].[C:31]([O-])([O-])=O.[K+].[K+].IC>C(#N)C>[CH3:1][C@H:2]1[C@:7]2([OH:30])[C:8]34[O:28][CH:27]5[C@@:16]6([C@@H:23]([O:29][CH3:31])[C:24]([O:26]5)=[O:25])[C@H:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:18][C@H:12]([C@:13]36[C@H:14]([OH:15])[CH:6]2[O:5][C:3]1=[O:4])[O:11][C:9]4=[O:10]
Reactant: O=C([O-])[O-]
Reactant: C[C@@H]1C(=O)O[C@H]2[C@H](O)[C@@]34[C@H]5C[C@@H](C(C)(C)C)[C@]36[C@@H](OC(=O)[C@@H]6O)O[C@@]4(C(=O)O5)[C@@]12O
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CO[C@H]1C(=O)OC2OC34C(=O)O[C@@H]5C[C@@H](C(C)(C)C)[C@@]21[C@]53[C@H](O)C1OC(=O)[C@@H](C)[C@@]14O
Yield: 54.6 %

Procedure:
To a suspension of ginkgolide B (0.030 g, 0.071 mmol) and K2CO3 (0.030 g, 0.212 mmol) in acetonitrile (0.5 mL) was added iodomethane (0.020 g, 0.141 mmol). The reaction mixture was heated under reflux for 30 min. This reaction resulted in a mixture of 10-methoxy-ginkgolide B and 1-methoxy ginkgolide B in a ratio of 4 to 1. 10-Methoxy-ginkgolide B was separated using an HPLC semi-preparative C18 column (7.8 mm×30 cmL) with a mobile phase of MeOH/H2O (40:60) at a flow of 2 mL/min to give the final product as a white solid (0.017 g, 56%). 1H NMR (400 MHz, CD3OD): δ1.14 (s, tert-butyl), 1.24 (d, J=7.1, CH3), 1.90 (dd, J=14.2, 4.6, 8-H), 2.06 (td, J=13.9, 4.3, 7α-H), 2.25 (dd, J=13.6, 4.6, 7β-H), 3.05 (q, J=7.1, 14-H), 3.80 (s, OCH3), 4.24 (d, J=7.4, 1-H), 4.57 (d, J=7.4, 2-H), 4.93 (s, 10-H), 5.43 (d, J=4.1, 6-H), 6.10 (s, 12-H). 13C NMR (75 MHz, CD3OD): δ7.6, 7.0, 29.6 (3 C), 32.9, 37.6, 41.8, 48.8, 68.6, 70.5, 71.5, 74.4, 80.4, 82.2, 84.8, 90.9, 98.2, 110.3, 171.1, 173.0, 175.4. [Hu, L., Chen, Z., Xie, Y., Jiang, Y., & Zhen, H. (2000) Bioorg. Med. Chem. 8, 1515-1521]
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH:22][C:23]3[CH:42]=[CH:41][C:26]([CH2:27][N:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)=[CH:25][CH:24]=3)[C:14]3[C:19](=[O:20])[NH:18][N:17]=[CH:16][C:15]=3[N:21]=2)=[CH:7][CH:6]=1)=[O:4].[ClH:43]>O1CCOCC1>[ClH:43].[O:20]=[C:19]1[NH:18][N:17]=[CH:16][C:15]2[N:21]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=3)[N:12]=[C:13]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([CH2:27][N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[CH:41][CH:42]=3)[C:14]1=2
Reactant: COC(=O)c1ccc(-c2nc(Nc3ccc(CN4CCN(C(=O)OC(C)(C)C)CC4)cc3)c3c(=O)[nH]ncc3n2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2nc(Nc3ccc(CN4CCNCC4)cc3)c3c(=O)[nH]ncc3n2)cc1

Procedure:
Tert-butyl 4-(4-(2-(4-(methoxycarbonyl)phenyl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)benzyl)piperazine-1-carboxylate (0.1 g, 0.175 mmol) was dissolved in dioxane.HCl (5 mL) and stirred at room temperature for 1.5 hours. The solid obtained was filtered and the residue washed with EtOAc and dried to give the desired product (40 mg).