Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]N(C)C=O.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:30][C:31](=[O:42])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH3:41].CI>O>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[N:30]([CH3:1])[C:31](=[O:42])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH3:41]
Reactant: COc1ccccc1COC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1ccccc1COC(=O)N(C)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (11 mg), and 2-methoxybenzyl N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (66 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of methyl iodide (77 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (50 mg, yield 75%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[N:6]=[CH:5]2.[NH2:17][CH:18]([CH3:29])[CH:19]([C:21]1[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[OH:20].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)CCC.C1(C)C=CC=CC=1.[Cu]I>[CH3:28][O:27][C:24]1[N:23]=[CH:22][C:21]([CH:19]([O:20][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:6]=[CH:5]3)[CH:18]([NH2:17])[CH3:29])=[CH:26][CH:25]=1
Reactant: COc1ccc(C(O)C(C)N)cn1
Reactant: Ic1ccc2c(cnn2-c2cccnc2)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCCC#N
Product: COc1ccc(C(Oc2ccc3c(cnn3-c3cccnc3)c2)C(C)N)cn1
Temperature: 130 °C
Reaction time: 20 h

Procedure:
5-Iodo-1-(3-pyridinyl)indazole (750 mg, 2.3 mmole), 2-Amino-1-[6-methoxypyridin-3-yl]propan-1-ol (410 mg, 2.2 mmol), copper(I)iodide (42 mg, 0.22 mmol) and caesium carbonate (1.45 g, 4.5 mmole) were suspended in butyronitrile (2.4 mL) and toluene (4.8 mL). The reaction vessel was capped and the mixture was stirred at 130° C. for 20 hours. Then the solvent was removed i.vac., and the product purified by chromatography on silica gel. Yield 254 mg (3 0%) as a racemic mixture of two diastereomeres.
Reaction SMILES: [CH3:1][C:2]1[C:30]([CH3:31])=[CH:29][C:5]2[N:6]([C:19](=[O:28])[CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[NH:12][N:13]=3)[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38]Cl>CN(C)C=O.C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[C:30]([CH3:31])=[CH:29][C:5]2[N:6]([C:19](=[O:28])[CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[N:12]([CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])[N:13]=3)[C:4]=2[CH:3]=1
Reactant: CCCN(CCC)CC(=O)N1c2cc(C)c(C)cc2-n2c(n[nH]c2=O)-c2cccnc21
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: CCCN(CCC)CC(=O)N1c2cc(C)c(C)cc2-n2c(nn(CCCN(C)C)c2=O)-c2cccnc21
Reaction time: 22 h

Procedure:
In the manner given in Example 25, to 6,7-dimethyl-9-[(dipropylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a]-[1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react at about 95° C. for 40 minutes and after cooling 3-(dimethylamino)propylchloride in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in example 21 to give 6,7-dimethyl-2,9-dihydro-2-[3-(dimethylamino)-propyl]-9-[(dipropylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepine-3-one.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[Cl-].[CH:13](=[N+:20]([CH3:22])[CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>>[CH3:21][N:20]([CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)[CH3:22]
Reactant: Oc1ccc2ccccc2c1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: C[N+](C)=Cc1ccccc1
Agent: [Cl-]
Product: COc1ccc(C(=O)Oc2ccc3ccccc3c2C(c2ccccc2)N(C)C)cc1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 and 6 from 2-naphthol, benzylidene-dimethyl-ammonium chloride and 4-methoxybenzoyl chloride. The structure was demonstrated by means of ESI-MS: mass calculated 411.51 g/mol, mass found M+H=412.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:26])[CH:24]=O.C(O)(=O)C(O)=O.[CH2:33]([O:35][P:36]([CH2:41][CH2:42][NH2:43])(=[O:40])[O:37][CH2:38][CH3:39])[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C=O)C>[CH2:38]([O:37][P:36]([CH2:41][CH2:42][NH:43][CH2:24][C:23]([CH3:26])=[CH:22][CH2:21][C:4]1[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])=[C:6]2[C:10](=[C:11]([CH3:12])[C:3]=1[O:2][CH3:1])[CH2:9][O:8][C:7]2=[O:13])(=[O:40])[O:35][CH2:33][CH3:34])[CH3:39]
Reactant: CCOP(=O)(CCN)OCC
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)C=O)C(=O)OC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOP(=O)(CCNCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Reaction time: 48 h
Yield: 96.5 %

Procedure:
To a solution of 4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal (84 mg, 0.22 mmol), (2-amino-ethyl)-phosphonic acid diethyl ester oxalate (91 mg, 0.33 mmol), and sodium triacetoxyborohydride (93 mg, 0.44 mmol) in DMF (1.5 mL) was added acetic acid (60 μL, 1.0 mmol) at room temperature. The solution was stirred for 2 days when it was quenched by addition of saturated aqueous sodium bicarbonate solution and EtOAc. The organic layer was separated and concentrated under reduced pressure. The residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 115 mg (96%) of the product as an oil. 1H NMR (300 MHz, CDCl3) δ 0.04 (s, 9H), 1.16-1.27 (m, 2H), 1.34 (t, 6H, J=7 Hz), 1.94 (s, 3H), 2.18 (s, 3H), 2.20-2.31 (m, 2H), 3.13-3.31 (m, 2H), 3.48 (d, 2H, J=7 Hz), 3.54 (s, 2H), 3.78 (s, 3H), 4.14 (pent, 4H, J=7 Hz), 4.30-4.37 (m, 2H), 5.13 (s, 2H), 5.65 (t, 1H, J=7 Hz), 6.23 (br s, 2H) ppm; 31P (121.4 MHz, CDCl3) δ 27.8 ppm; MS (m/z) 542.3 [M+H]+, 564.2 [M+Na]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]=[CH:12]2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]=[CH:12]2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc2cnccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc2cnccc12
Reaction time: 72 h
Yield: 45.6 %

Procedure:
Methanesulfonyl chloride (3.2 ml, 42 mmol) was added to a solution of 5-aminoisoquinoline (5.0 g, 35 mmol) in pyridine (40 ml) and the mixture was allowed to stand for 72 h. The reaction mixture was then poured into aqueous citric acid (10%, 400 ml) and extracted with EtOAc (2×230 ml). The organic layer was evaporated to give a residue which was purified on silica gel, eluting with CH2C2/MeOH to afford the subtitle compound as a solid (3.55 g, 46%). Rf 0.03 (CH2Cl2/ether 4/1, v/v). 1H NMR (D6-DMSO) δ: 3.07 (3H, s), 7.68 (1H, t), 7.75 (1H, d), 8.03 (1H, d), 8.10 (1H, d), 8.54 (1H, d), 9.32 (1H, s), 9.79 (1H, bs).
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][NH:4][N:3]=1.[CH3:10][C:11]([CH3:17])=[CH:12][C:13]([O:15][CH3:16])=[O:14].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:10][C:11]([N:4]1[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[C:2]([CH3:1])=[N:3]1)([CH3:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C=C(C)C
Reactant: Cc1n[nH]cc1[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)CC(C)(C)n1cc([N+](=O)[O-])c(C)n1
Yield: 6.8 %

Procedure:
A solution of 3-methyl-4-nitro-1H-pyrazole (1.00 g, 7.87 mmol), methyl 3-methylbut-2-enoate (2.20 g, 18.9 mmol), and DBU (3.10 g, 20.5 mmol) in DMF (5.0 mL) was stirred overnight. The mixture was purified by reverse phase Combiflash to afford the title compound (130 mg, 7%) as yellow oil. LC-MS (ESI): m/z=242 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[C:5]([F:15])=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1)=[C:2]=[O:3].C([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][NH:22]1)=O)C>C(N(CC)CC)C.O1CCOCC1>[F:15][C:5]1[C:4]([N:1]2[C:19](=[O:18])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][N:22]3[C:2]2=[O:3])=[CH:14][C:8]2[NH:9][C:10](=[O:13])[CH2:11][O:12][C:7]=2[CH:6]=1
Reactant: CCOC(=O)N1CCCCN1
Reactant: O=C=Nc1cc2c(cc1F)OCC(=O)N2
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1COc2cc(F)c(-n3c(=O)n4n(c3=O)CCCC4)cc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A mixture composed of 6-isocyanato-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (2.14 g), 1-ethoxycarbonylhexahydropyridazine (1.62 g) and dioxane (30 ml) is treated with a few drops of triethylamine, stirred at an ambient temperature for 2 hours, and left overnight. The reaction mixture is made free from dioxane by evaporation in vacuo, mixed with methanol (30 ml) containing a catalytic amount of sodium, and refluxed for 2 hours. After removal of methanol by evaporation in vacuo, the resultant solid is collected, and washed with water to obtain an end product 2-[7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl]-hexahydro-1H-(1,2,4)-triazolo (1,2-a) pyridazine-1,3-dione (2.45 g).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1)[CH3:16]>>[CH2:15]([O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:12]([C:9]2[NH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:11][CH:10]=2)=[O:14])[CH:21]=1)[CH3:16]
Reactant: O=C(O)c1cnc(-c2ccccc2)[nH]1
Reactant: CCOC(=O)Cc1cccc(N)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cnc(-c3ccccc3)[nH]2)c1

Procedure:
2-Phenyl-1H-imidazole-5-carboxylic acid (105 mg, 0.56 mmol) was coupled with ethyl ester (6) (100 mg, 0.56 mmol) following Method C to give the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH2:35][CH2:36][OH:37])[N:12]=[C:13]3[C:22]4[C:17](=[C:18]([O:23][CH2:24][C:25]5[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=5[CH3:33])[CH:19]=[CH:20][CH:21]=4)[C:16](=[O:34])[C:15]=1[C:14]=23.ClC1C=CC2N(CCO)N=C3C4C(=CC=CC=4OCC4C(C)=CC(C)=CC=4C)C(=O)C=1C=23>>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH2:35][CH2:36][O:37][S:2]([CH3:1])(=[O:4])=[O:3])[N:12]=[C:13]3[C:22]4[C:17](=[C:18]([O:23][CH2:24][C:25]5[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=5[CH3:33])[CH:19]=[CH:20][CH:21]=4)[C:16](=[O:34])[C:15]=1[C:14]=23
Reactant: Cc1cc(C)c(COc2cccc3c2C(=O)c2c(Cl)ccc4c2c-3nn4CCO)c(C)c1
Reactant: CS(=O)(=O)Cl
Agent: Cc1cc(C)c(COc2cccc3c2-c2nn(CCO)c4ccc(Cl)c(c24)C3=O)c(C)c1
Product: Cc1cc(C)c(COc2cccc3c2C(=O)c2c(Cl)ccc4c2c-3nn4CCOS(C)(=O)=O)c(C)c1

Procedure:
Starting with methanesulfonyl chloride and the mixture of regioisomers of 5-chloro-2-(2-hydroxyethyl)7- [(2,4,6-trimethylphenyl)methoxy]anthra- [1, 9-cd]pyrazol-6(2H)-one II and 5-chloro-2-(2-hydroxyethyl)10- [(2,4,6-trimethylphenyl)methoxy]anthra- [1, 9-cd] pyrazol-6(2 H)-one III, using the procedure of example 3, the title compound was prepared.
Reaction SMILES: N[C@H]1C[C@@H](N2C=NC3C2=NC([Cl:33])=NC=3NCC(C2C=CC(O)=CC=2)C2C=CC(O)=CC=2)[C@H](O)[C@@H]1O.C(OC(=O)[NH:42][C@H:43]1[CH2:47][C@@H:46]([N:48]2[CH:56]=[N:55][C:54]3[C:49]2=[N:50][C:51]([C:72](=[O:92])[NH:73][CH2:74][CH2:75][NH:76][C:77]([NH:79][CH:80]2[CH2:85][CH2:84][N:83]([C:86]4[CH:91]=[CH:90][CH:89]=[CH:88][N:87]=4)[CH2:82][CH2:81]2)=[O:78])=[N:52][C:53]=3[NH:57][CH2:58][CH:59]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C@H:45]([OH:93])[C@@H:44]1[OH:94])(C)(C)C>>[ClH:33].[ClH:33].[N:83]1([C:86]2[CH:91]=[CH:90][CH:89]=[CH:88][N:87]=2)[CH2:84][CH2:85][CH:80]([NH:79][C:77](=[O:78])[NH:76][CH2:75][CH2:74][NH:73][C:72]([C:51]2[N:50]=[C:49]3[C:54]([N:55]=[CH:56][N:48]3[C@@H:46]3[CH2:47][C@H:43]([NH2:42])[C@@H:44]([OH:94])[C@H:45]3[OH:93])=[C:53]([NH:57][CH2:58][CH:59]([C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)[N:52]=2)=[O:92])[CH2:81][CH2:82]1
Reactant: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O
Product: Cl
Product: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to (1S,2R,3S,5R)-3-Amino-5-{6-[2,2-bis-(4-hydroxy-phenyl)-ethylamino]-2-chloro-purin-9-yl}-cyclopentane-1,2-diol (example 7 step 2) by replacing N-((1S,2R,3S,4R)-4-{6-[2,2-Bis-(4-hydroxy-phenyl)-ethylamino]-2-chloro-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide hydrochloride with (1S,2R,3S,4R)-4-(6-(2,2-Diphenyl-ethylamino)-2-{2-[3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-ureido]-ethylcarbamoyl}-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-carbamic acid tert-butyl ester (Example 12).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:16][CH2:17][CH2:18][CH:19]=C)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1.BrC1C(NCCCC=C)=CC=CN=1.CC([O:38]C(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[O:38]=[C:19]1[CH2:18][CH2:17][CH2:16][N:8]([C:9]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:15])[C:7]2[CH:6]=[CH:5][CH:4]=[N:3][C:2]1=2
Reactant: C=CCCCN(C(=O)OC(C)(C)C)c1cccnc1Br
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: C=CCCCNc1cccnc1Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(=O)c2ncccc21
Temperature: 25 °C

Procedure:
tert-butyl (2-bromopyridin-3-yl)(pent-4-en-1-yl)carbamate. To a solution of 2-bromo-N-(pent-4-en-1-yl)pyridin-3-amine (1 eq.) and DCM (0.2 M) is added (Boc)2O (1.5 eq.). The solution is stirred at room temperature until judged complete by TLC. The solution is concentrated in vacuo and purified by column chromatography to give the title compound.
Reaction SMILES: Br[C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:14][CH3:15])[CH:3]=1.C([Li])CCC.[CH3:21][S:22]SC.Cl>C1(C)C=CC=CC=1.O>[CH3:15][O:14][C:4]1[CH:3]=[C:2]([S:22][CH3:21])[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH2:7][C:6]=2[CH:5]=1
Reactant: COc1cc(Br)c2c(c1)CCN(C)CC2
Reactant: CSSC
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(c(SC)c1)CCN(C)CC2

Procedure:
A solution of 6-bromo-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2.7 g, 0.01 m) in toluene (30 ml) is added to a solution of n-butyl lithium (0.044 m) in toluene (15 ml) stirred at -78°. The mixture is stirred for thirty minutes, treated with a solution of methyl disulfide (8.2 g, 0.087 m) in toluene (10 ml), stirred for fifteen minutes and poured into water (125 ml). The mixture is acidified with 10% hydrochloric acid and the aqueous phase is washed with ether, made alkaline with aqueous sodium hydroxide and extracted with ethyl acetate. The ethyl acetate extract is washed, dried with sodium sulfate and concentrated in vacuo to give 8-methoxy-3-methyl-6-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:17]([CH3:19])[CH3:18].O>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([O:9][CH:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: CC(C)Br
Reactant: Cc1nc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(Br)ccc1OC(C)C
Temperature: 100 °C
Yield: 84.7 %

Procedure:
6-Bromo-2-methylpyridin-3-ol (10.5 g, 55.9 mmol) was dissolved in DMF (100 mL). K2CO3 (19.3 g, 139.6 mmol) and 2-bromopropane (13.1 ml, 139.6 mmol) were added to the solution and the mixture was heated at 100° C. overnight. The mixture was poured into a mixture of water and EtOAc (200 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried (Na2SO4) and concentrated. The crude oil was purified by column chromatography (0-20% ethyl acetate/heptanes) to give 6-bromo-3-isopropoxy-2-methylpyridine (10.9 g, 85) as a yellow oil. 1H-NMR (300 MHz, CDCl3) 1.42 (d, 6H), 2.48 (s, 3H), 4.65 (m, 1H), 7.20 (d, 1H), 8.04 (d, 1H).
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.O>ClCCl.CC1C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>[CH3:7][C:2]([O:1][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][O:9]1)([CH3:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: C1=COCCC1
Reactant: COC(=O)C(C)(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(C)(C)OC1CCCCO1
Reaction time: 1.5 h
Yield: 84.5 %

Procedure:
To a mixture of methyl 2-hydroxy-2-methylpropanoate (5.04 g, 42.7 mmol) and 3,4-dihydro-2H-pyran (5.85 ml, 64.0 mmol) in dichloromethane (40 ml) was added pyridine 4-methylbenzenesulfonate (0.536 g, 2.13 mmol) and the reaction mixture was stirred for 1.5 hours. The reaction mixture was poured into water and extracted with Et2O. The organic layers were dried over Na2SO4 filtered, and concentrated in vacuo to give a crude oil. The crude residue was purified by silica gel chromatography (hexane/ethyl acetate, 100:0 to 17:3) to afford methyl 2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propanoate (7.30 g, 36.1 mmol, 85% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 (s, 3H) 1.36-1.55 (m, 7H) 1.57-1.81 (m, 2H) 3.32-3.42 (m, 1H) 3.62 (s, 3H) 3.72-3.85 (m, 1H) 4.65-4.75 (m, 1H).
Reaction SMILES: C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[F:17][CH:18]([CH:24]([OH:27])[CH2:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20].[C:28](Cl)(=[O:32])[C:29]([CH3:31])=[CH2:30].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1COCC1>[F:17][CH:18]([CH:24]([O:27][C:28](=[O:32])[C:29]([CH3:31])=[CH2:30])[CH2:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: C=C(C)C(=O)Cl
Reactant: CCOC(=O)C(F)C(O)CC
Agent: CN(C)c1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC(CC)C(F)C(=O)OCC
Reaction time: 2 h
Yield: 71.9 %

Procedure:
Under a nitrogen atmosphere, 50 mL of dehydrated THF, 4.63 g (45.8 mmol) of triethylamine and 466 mg (3.82 mmol) of dimethylaminopyridine were added to 6.27 g (38.2 mmol) of the ethyl 2-fluoro-3-hydroxypentanoate at a room temperature. Thereafter, 4.39 g (42.0 mmol) of methacrylic acid chloride was added dropwise over 10 min, and then the mixture was stirred for 2 hrs. After disappearance of the raw material was confirmed by thin layer chromatography (TLC), an aqueous sodium bicarbonate solution was added to stop the reaction. Thereafter, ethyl acetate was added to the reaction liquid and extraction was carried out three times. The organic layer thus obtained was washed with water and saturated brine each once, and dried by adding anhydrous sodium sulfate. Thereafter, the product obtained by distilling off the solvent under a reduced pressure was purified by column chromatography to give 6.38 g (yield: 60%) of ethyl 2-fluoro-3-(methacryloyloxy)pentanoate represented by the following formula.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([N:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(Br)ccc1OC2)c1ccc(F)cc1F
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc3c(c2)-c2sc(C(=O)N(C)c4ccc(F)cc4F)cc2CO3)CC1

Procedure:
Following Example 70 and General Procedure D, 8-bromo-N-(2,4-difluorophenyl)-N-methyl-4H-thieno[3,2-c]chromene-2-carboxamide 160bp and N-methylpiperazine were reacted to give 128bp. 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 1H), 6.94-7.00 (m, 2H), 6.85 (m, 1H), 6.75-6.82 (m, 2H), 6.68 (s, 1H), 5.03 (s, 2H), 3.69 (m, 2H), 3.46 (m, 2H), 3.39 (s, 3H), 3.30 (m, 2H), 3.07 (m, 2H), 2.90 (s, 3H). LCMS (ESI) m/z: 456.2.
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:14]3[CH:17]=[CH:18][C:19]([O:23][CH3:24])=[C:20]([O:21][CH3:22])[C:13]=3[CH2:12][CH:11]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10]=2[CH2:9]1)C1C=CC=CC=1.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.[Cl:47]C(OC(Cl)C)=O>ClCCCl>[ClH:47].[CH3:22][O:21][C:20]1[C:13]2[CH2:12][CH:11]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:10]3[CH2:9][NH:8][CH2:16][C:15]=3[C:14]=2[CH:17]=[CH:18][C:19]=1[O:23][CH3:24]
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)C1=C2CN(Cc2ccccc2)C1
Reactant: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCCl
Product: COc1ccc2c(c1OC)CC(c1ccccc1)C1=C2CNC1
Product: Cl
Yield: 75 %

Procedure:
To a solution of 1.0 g (2.52 mmol) of 2-benzyl-6,7-dimethoxy-4-phenyl-2,3,4,5-tetrahydro-1H-benz[e]isoindole, from Step 5, in 22 mL of 1,2-dichloroethane was added 0.11 g (0.05 mmol) of 1,8-bis(dimethylamino)naphthalene and 0 33 mL (3.15 mmol) of 1-chloroethyl chloroformate at 0° C. The solution was heated to reflux for 2 h and the solvent removed in vacuo. The residue was filtered through silica gel, eluting with 25% ethyl acetate in hexanes. After concentration under reduced pressure, methanol (20 mL) was added and the solution was heated to reflux for 30 minutes before the solvent was removed in vacuo. The product was crystallized from ethanol/diethyl ether to give 0.46 g (75% yield) of 6,7-dimethoxy-4-phenyl-2,3,4,5-tetrahydro 1H-benz[e]isoindole hydrochloride as a white solid. MS DCI: (M+H)+ 308. 1H NMR (d6DMSO) delta 3.05-3.25 (m, 2H), 3.55 (s, 3H), 3.80 (s, 3H), 3.88 (m, 1H), 4.0-4.15 (m, 2H), 4.25-4.45 (m, 2H), 6.91 (m, 1H), 7.15-7.3 (m, 3H), 7.4-7.6 (m, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[N:4][C:3]1=[O:10].[Br:11][CH2:12][CH2:13][CH2:14][OH:15]>C(#N)C>[Br-:11].[OH:15][CH2:14][CH2:13][CH2:12][NH+:4]1[C:5]([CH3:9])=[CH:6][CH:7]([CH3:8])[N:2]([CH3:1])[C:3]1=[O:10]
Reactant: OCCCBr
Reactant: Cc1cc(C)n(C)c(=O)n1
Solvent: CC#N
Product: CC1=CC(C)N(C)C(=O)[NH+]1CCCO
Product: [Br-]

Procedure:
A mixture of 10.0 g (0.072 mol) of 1,4,6-trimethylpyrimidin-2(1H)-one and 20.6 g (0.144 mol) of 3-bromopropanol was heated under reflux in acetonitrile for 16 hours under an inert gas atmosphere. After cooling, a pale pink-colored solid precipitated out, which was filtered off with suction (starting material). The filtrate was admixed with chloroform, then the same amount of diethyl ether was added. The product separated out in the form of an oil.