Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](Cl)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:17][NH2:18].C([O-])([O-])=O.[K+].[K+]>CCO>[CH2:1]([O:8][C:9]1[C:10]([NH:17][NH2:18])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: Clc1ncccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NNc1ncccc1OCc1ccccc1
Temperature: 90 °C
Yield: 68.5 %

Procedure:
3-(Benzyloxy)-2-chloropyridine (22.3 g, 101 mmol) was dissolved in EtOH (300 ml) and hydrazine monohydrate (10.2 ml, 203 mmol) added. The reaction was heated to reflux at 90° C. for 90 minutes. Hydrazine monohydrate (50 ml) was added and the reaction was heated at reflux overnight. K2CO3 (10 g) was added and the mixture was heated at refluxed for 4 hours. The mixture was concentrated to a residue and dissolved in n-BuOH (120 ml) and hydrazine monohydrate (40 ml) was added. The mixture was heated at reflux for 6 days. The reaction was cooled, diluted with water and extracted with EtOAc. The organics were concentrated to an oil that was dissolved in CH2Cl2 and decanted away from the solids. The organics were concentrated and dried on high vacuum overnight. The residue solidified on high vacuum. The crude product (24.47 g) was triturated in water and the solids filtered to give 3-(benzyloxy)-2-hydrazinylpyridine (14.9 g, 68% yield) as a solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:42][CH3:43])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[CH:15][N:16]=1)[CH:8]=[C:7]2[O:17][CH:18]1[CH2:36][CH:35]2[N:20]([C:21](=[O:41])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]3[C:32]([C:38]([OH:40])=O)([NH:33][C:34]2=[O:37])[CH2:31]3)[CH2:19]1.C(C1N=C(C2C=C(OC3CC4N(C(=O)CCCCCCC=CC5C(C([NH:85][S:86]([CH:89]6[CH2:91][CH2:90]6)(=[O:88])=[O:87])=O)(NC4=O)C5)C3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[Br:1][C:2]1[C:3]([O:42][CH3:43])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[CH:15][N:16]=1)[CH:8]=[C:7]2[O:17][CH:18]1[CH2:36][CH:35]2[N:20]([C:21](=[O:41])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]3[C:32]([C:38]([NH:85][S:86]([CH:89]4[CH2:91][CH2:90]4)(=[O:88])=[O:87])=[O:40])([NH:33][C:34]2=[O:37])[CH2:31]3)[CH2:19]1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nccs3)nc2c1Br
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nccs3)nc2c1Br

Procedure:
The title compound was prepared from 18-[8-bromo-7-methoxy-2-(thiazol-2-yl)-quinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (41) following the procedure reported for synthesis of N-[[18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl](cyclopropyl)sulfonamide 11: m/z=773 (M+H)+. 1H NMR (CDCl3): 0.90-0.98 (m, 1H), 1.05-2.0 (m, 2H), 1.27-1.58 (m, 9H), 1.80-1.97 (m, 3H), 2.18-2.24 (m, 1H), 2.29-2.38 (m, 1H), 2.48-2.62 (m, 2H), 2.69-2.73 (m, 2H), 2.88-2.94 (m, 1H), 4.01 (d, J=11.8 Hz, 1H), 4.08 (s, 3H), 4.12 (dd, J=11.5 Hz, J=3.6 Hz, 1H), 4.61 (t, J=7.9 Hz, 1H), 5.00 (t, J=9.5 Hz, 1H), 5.47-5.60 (m, 1H), 5.70-5.77 (m, 1H), 6.69 (br s, 1H), 7.24 (d, J=9.2 Hz, 1H), 7.55 (d, J=3.2 Hz, 1H), 7.59 (s, 1H), 7.98 (d, J=3.2 Hz, 1H), 8.05 (d, J=9.2 Hz, 1H), 8.20 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11][S:12][C:13](=[O:15])[CH3:14])[CH2:10][CH2:9]O[CH2:7][CH2:6]1)=[O:4].[CH3:16]OC(C1(CI)CCCCC1)=O>>[CH3:1][O:2][C:3]([C:5]1([CH2:11][S:12][C:13](=[O:15])[CH3:14])[CH2:10][CH2:9][CH2:16][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(CI)CCCCC1
Reactant: COC(=O)C1(CSC(C)=O)CCOCC1
Product: COC(=O)C1(CSC(C)=O)CCCCC1
Yield: 92 %

Procedure:
Prepared according to the method for the preparation of 4-acetylsulfanylmethyltetrahydropyran-4-carboxylic acid methyl ester, from 1-iodomethylcyclohexanecarboxylic acid methyl ester (20 g), to yield the title compound as a brown gum (15 g, 92%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10])([O-])=O.[CH2:11]([N:18]([C:42]1[CH:47]=[C:46](Cl)[N:45]=[CH:44][N:43]=1)[C:19]([N:21]([C:30]1[C:35]([Cl:36])=[C:34]([O:37][CH3:38])[CH:33]=[C:32]([O:39][CH3:40])[C:31]=1[Cl:41])COCC[Si](C)(C)C)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]([C:42]1[N:43]=[CH:44][N:45]=[C:46]([NH:1][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:10][C:34](=[O:37])[CH:33]=[CH2:32])[CH:47]=1)[C:19]([NH:21][C:30]1[C:31]([Cl:41])=[C:32]([O:39][CH3:40])[CH:33]=[C:34]([O:37][CH3:38])[C:35]=1[Cl:36])=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(Cc2ccccc2)c2cc(Cl)ncn2)c1Cl
Product: C=CC(=O)Nc1ccccc1Nc1cc(N(Cc2ccccc2)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Yield: 20 %

Procedure:
The compound was synthesized following the approach outlined in Procedure 2G (Example 123), substituting 2-nitro-phenylamine and 1-benzyl-1-(6-chloro-pyrimidin-4-yl)-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-urea (preparation shown below) in step (d) to afford the title compound (26 mg, yield: 20% over five steps). 1H NMR (300 MHz, DMSO-d6) δ 12.27 (s, 1H), 9.68 (s, 1H), 8.90 (s, 1H), 8.39 (s, 1H), 7.69 (d, 1H), 7.33-7.19 (m, 6H), 6.92 (s, 1H), 6.45 (dd, 1H), 6.24 (d, 1H), 6.18 (s, 1H), 5.74 (d, 1H), 5.07 (s, 2H), 3.95 (s, 6H); MS (ESI): 593 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:23])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24]I.[H-].[Na+].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([O:23][CH3:24])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)CCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.218 g (0.68 mmol) of 1-t-butoxy carbonyl-4-(3-phenyl-1-hydroxypropyl)piperidine (Example 239) and 0.3 mL of methyl iodide in 2 mL of DMF was added 0.066 g (1.5 mmol)of NaH (60% dispersion in mineral oil) and the mixture was stirred for 16 h at rt. To the reaction was added 5 mL of water and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate, 4:1) to give 1-t-butoxy carbonyl-4-(3-phenyl-1-(RS)-methoxypropyl)piperidine. Removal of the BOC protecting group was achieved as described in Example 233, Step 6 to give the title compound.
Reaction SMILES: [C:1]([P:5]([C:7]([CH3:10])([CH3:9])[CH3:8])Cl)([CH3:4])([CH3:3])[CH3:2].ClCCl.[OH2:14]>>[C:1]([PH:5](=[O:14])[C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: O
Solvent: ClCCl
Product: CC(C)(C)[PH](=O)C(C)(C)C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a flask were added 1.0 g of di(tert-butyl)chlorophosphine and 5 ml of dichloromethane under nitrogen. After slow addition of 0.25 g of water, the mixture was stirred at 22 C for 30 minutes and the solvent was removed leaving a solid. After purification by sublimation, 0.9 g of a white solid was obtained.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][NH2:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.ON1C2C=CC=CC=2N=N1.[C:33]([C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](O)=[O:39])#[N:34].C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:33]([C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([NH:20][O:19][CH:16]1[CH2:17][CH2:18][N:13]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[CH2:14][CH2:15]1)=[O:39])#[N:34]
Reactant: NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cccc(C(=O)NOC2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 35.9 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (160 mg, 0.84 mmol) was added to a solution of O-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yl)hydroxylamine (238 mg, 0.70 mmol), 1-hydroxybenzotriazole (114 mg, 0.84 mmol), 3-cyanobenzoic acid (103 mg, 0.70 mmol) and N,N-diisopropylethylamine (271 mg, 2.10 mmol) in N,N-dimethylformamide (6 ml). The reaction mixture was stirred at room temperature for 17 hours and quenched with H2O (10 ml) and aqueous 1 N HCl solution (pH=3). The aqueous phase was extracted with CH2Cl2 (20 ml×3) and the combined organic phase was washed with aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane: 33/67) to give 3-cyano-N-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yloxy)benzamide (118 mg, 36%) as a white solid: LCMS: 470 [M+1]+. 1H NMR (DMSO-d6) δ: 1.77 (s, 2H), 1.92 (s, 2H), 3.02 (s, 2H), 3.12 (s, 2H), 4.03 (s, 1H), 7.67 (m, 3H), 8.01 (m, 5H), 11.7 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:24]=[CH:25][C:26]3[O:30][C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:28][C:27]=3[CH:37]=2)[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:23]4[CH:24]=[CH:25][C:26]5[O:30][C:29]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)=[N:28][C:27]=5[CH:37]=4)[O:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(-c2ccc3oc(-c4ccccc4)nc3c2)n1
Product: c1ccc(-c2nc3cc(-c4nc(COc5ccc(CCCn6ccnc6)cc5)co4)ccc3o2)cc1
Yield: 53 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 5-(4-chloromethyl-2-oxazolyl)-2-phenylbenzoxazole to give 5-[4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-oxazolyl]-2-phenylbenzoxazole. The yield was 53%. Recrystallization from ethyl acetate-hexane gave pale yellow prisms, mp 166-167° C.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[N:13]=[N:14][CH:15]=[CH:16][C:17]=2[N:18]2[CH2:23][CH2:22][CH:21]([C:24](C)(C)[O:25][SiH2]C(C)(C)C)[CH2:20][CH2:19]2)[CH2:9]1)=O)(C)(C)C.[ClH:33].CO>>[ClH:33].[NH:8]1[CH2:9][CH:10]([C:12]2[N:13]=[N:14][CH:15]=[CH:16][C:17]=2[N:18]2[CH2:19][CH2:20][CH:21]([CH2:24][OH:25])[CH2:22][CH2:23]2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(c2nnccc2N2CCC(C(C)(C)O[SiH2]C(C)(C)C)CC2)C1
Agent: Cl
Solvent: CO
Product: OCC1CCN(c2ccnnc2C2CNC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A mixture of 3-{4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-piperidin-1-yl]-pyridazin-3-yl}-azetidine-1-carboxylic acid tert-butyl ester (63) (730 mg, 1.58 mmol) in 4 M HCl/MeOH solution (20 mL) was stirred at RT for 30 min. Then the solvent was evaporated at 40° C. to give [1-(3-azetidin-3-yl-pyridazin-4-yl)-piperidin-4-yl]-methanol hydrochloride (64) (387 mg, 1.56 mmol, 98% yield) as a yellow solid.
Reaction SMILES: [Cl-].[Li+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([Mg]Br)=[CH:16][CH:15]=1>C1COCC1>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12])=[CH:16][CH:15]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: BrCCCCCCCCBr
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(CCCCCCCCBr)cc1
Reaction time: 0.5 h

Procedure:
Lithium chloride (0.15 g, 3.5 mmol) and cupric chloride (0.3 g, 2.2 mmol) were added to THF (100 ml) and stirred for 1 hour 30 minutes. 1,8-Dibromooctane (37 g, 137 mmol) was then added. While keeping the temperature between 0° C. and 5° C., 4-methylphenyl magnesium bromide in THF (prepared from magnesium (2.3 g, 95 mmol) and 4-methylphenyl bromide (15.4 g, 90 mmol) in THF (150 ml)) was added over 1 hour, allowing the temperature to reach room temperature overnight. The reaction mixture was poured over concentrated hydrochloric acid/ice mixture and the product was extracted into ether. The ether was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated to give an oil, which was distilled under vacuum to give 8-(4-methylphenyl)octylbromide as an oil, bp 128° at 0.2mm.
Reaction SMILES: [OH:1][C:2]1[C:19]2[CH2:18][C@@:17]([OH:24])([C:20](=[O:23])[CH2:21][OH:22])[CH2:16][C@H:15]([O:25][C@@H:26]3[O:40][C@@H:39]([CH3:41])[C@H:29]4[O:30][C@H:31]5[N:36]([C@H:28]4[CH2:27]3)[CH2:35][CH2:34][O:33][C@@H:32]5[O:37][CH3:38])[C:14]=2[C:13]([OH:42])=[C:12]2[C:3]=1[C:4](=[O:46])[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([O:44][CH3:45])[C:10]=1[C:11]2=[O:43].[O:47]1[CH:52]=[CH:51][CH2:50][CH2:49][CH:48]1[CH2:53][O:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>ClCCl.CO>[O:23]=[C:20]([C@@:17]1([OH:24])[CH2:16][C@H:15]([O:25][C@@H:26]2[O:40][C@@H:39]([CH3:41])[C@H:29]3[O:30][C@H:31]4[N:36]([C@H:28]3[CH2:27]2)[CH2:35][CH2:34][O:33][C@@H:32]4[O:37][CH3:38])[C:14]2[C:19](=[C:2]([OH:1])[C:3]3[C:4](=[O:46])[C:5]4[C:10]([C:11](=[O:43])[C:12]=3[C:13]=2[OH:42])=[C:9]([O:44][CH3:45])[CH:8]=[CH:7][CH:6]=4)[CH2:18]1)[CH2:21][O:22][CH:52]1[O:47][CH:48]([CH2:53][O:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH2:49][CH2:50][CH2:51]1
Reactant: CCOC(=O)COCC1CCC=CO1
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)COCC1CCCC(OCC(=O)[C@]2(O)Cc3c(O)c4c(c(O)c3[C@@H](O[C@H]3C[C@H]5[C@H](O[C@@H]6[C@@H](OC)OCCN65)[C@H](C)O3)C2)C(=O)c2c(OC)cccc2C4=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
To a solution of (8S,10S)-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5] [1,3] oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione (50 mg, 0.078 mmol) [PNU-159682, formula IIA, prepared as reported in WO 9802446] in 4 ml of dry dichloromethane under argon atmosphere, ethyl (3,4-dihydro-2H-pyran-2-ylmethoxy)acetate from step 1 (118.5 mg, 0.592 mmol) and anhydrous p-toluenesulfonic acid (22.3 mg, 0.12 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours, until no starting material was detectable (TLC analysis, MeOH:CH2Cl2=0.3:9.7). Sodium bicarbonate 10% aqueous solution was then added to the reaction mixture and the aqueous phase was extracted with dichloromethane (4×20 ml).The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. The residue was purified by flash column chromatography (MeOH:CH2Cl2=0.3:9.7) on silica gel (230-400 mesh), affording 41 mg (red wax, yield 62%) of 48, as a mixture of four diastereoisomers. MS (ESI): 842 [M+H]+. Retention time=7.47, 7.83 min (method 2).
Reaction SMILES: C([C:3](C)=[O:4])C.[C:6]([O:11][C:12]1([CH2:22]C)C2CC3CC(C[CH:13]1C3)C2)(=[O:10])[C:7](C)=C.N(C(C)(C)C#N)=NC(C)(C)C#N>CO>[CH3:13][CH:12]([O:11][C:6]([CH3:7])=[O:10])[CH2:22][O:4][CH3:3]
Reactant: CCC(C)=O
Reactant: C=C(C)C(=O)OC1(CC)C2CC3CC(C2)CC1C3
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CO
Product: COCC(C)OC(C)=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A monomer solution was prepared by placing 4800 g of methyl ethyl ketone (hereinafter inscribed as “MEK”) in a tank kept at a nitrogen atmosphere, and dissolving 2080 g of 5-acryloyloxy-2,6-norbornanecarbolactone (hereinafter inscribed as “NLA”) as a repeat unit (B) having a polar group for enhancing adhesion to a semiconductor substrate {hereinafter (B) on a head of the compounds in the examples has the same meaning as this} and 2480 g of 2-ethyl-2-adamantyl methacrylate (hereinafter inscribed as “EAM”) as a repeat unit (A) which is decomposed by an acid to become alkali soluble (hereinafter (A) on a head in the compounds in the examples has the same meaning as this). A polymerization initiator was prepared by placing 700 g of MEK and 80 g of azobisisobutyronitrile (hereinafter inscribed as “AIBN”) in another container kept at a nitrogen atmosphere and dissolving. Into a polymerization tank kept at the nitrogen atmosphere, 3500 g of MEK was put and the temperature was raised to 80° C. with stirring. Subsequently, the monomer solution and the polymerization initiator solution kept at the temperature of 25 to 30° C. were fed into the polymerization tank kept at 80° C. over 4 hours, respectively. After the completion of feed, the polymerized solution was matured for 2 hours with keeping the polymerization temperature at 80° C., then cooled to room temperature and taken out. Polymer was precipitated from the resulting polymerized solution by dropping in 70 kg of aqueous methanol and filtrated. The resultant wet cake was washed with 70 kg of methanol, filtrated subsequently dissolved in MEK again, and passed through a filter 40QSH supplied from Cuno Incorporated to remove a trace amount of metals. Then, the solvent was replaced by PGMEA with removing MEK by heating under reduced pressure to prepare PGMEA solution containing 15% polymer. The features of the resultant polymer, the content of high polymer and the evaluation results of storage stability of PGMEA solution are shown in Table 1.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl-].[N:21]1([CH:27]2[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].CCN(CC)CC>CC#N>[N:21]1([CH:27]2[CH2:28][CH2:29][CH:30]([NH:33][C:2]3[C:3]4[C:10]5[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:14][C:9]=5[S:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH2:31][CH2:32]2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: CCOC(=O)c1ccc2sc3ncnc(Cl)c3c2c1
Reactant: NC1CCC(N2CCOCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2sc3ncnc(NC4CCC(N5CCOCC5)CC4)c3c2c1
Yield: 66.8 %

Procedure:
A solution of ethyl 4-chlorobenzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylate (500 mg, 1.7 mmol, 1.00 equiv), 4-(morpholin-4-yl)cyclohexan-1-amine chloride (1.1 g, 4.25 mmol, 2.5 equiv) and potassium carbonate (2.3 g, 17 mmol, 10.17 equiv) in CH3CN (100 mL) was Et3N (2 mL) at room temperature under nitrogen. The resulting solution was heated to reflux overnight. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1) to give the desired ethyl 3-[[4-(morpholin-4-yl)cyclohexyl]amino]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5,10,12-hexaene-12-carboxylate (500 mg, 66%) as a yellow solid. LCMS: (ES, m/z) 441 [M+H]+. 1H-NMR (300 MHz, CD3OD): δ 1.44-1.53 (4H, m), 1.57-1.65 (3H, m), 2.24-2.29 (2H, m), 2.25-2.33 (3H, m), 2.56-2.67 (4H, m), 3.45-3.75 (4H, m), 4.31-4.43 (1H, m), 4.45-4.50 (2H, m), 8.07-8.16 (2H, m), 8.49 (1H, s), 8.78 (1H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](/[C:7](/[CH2:24][CH3:25])=[CH:8]/[CH2:9][CH2:10][C:11]([CH2:22][CH3:23])([CH2:20][CH3:21])[O:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[S:5][CH:6]=1.C([Li])CCC.CN(C)[CH:33]=[O:34].[Cl-].[NH4+]>C1COCC1>[CH2:24](/[C:7](/[C:4]1[S:5][CH:6]=[C:2]([CH:33]=[O:34])[CH:3]=1)=[CH:8]\[CH2:9][CH2:10][C:11]([CH2:22][CH3:23])([O:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[CH2:20][CH3:21])[CH3:25]
Reactant: CN(C)C=O
Reactant: CC/C(=C\CCC(CC)(CC)O[Si](CC)(CC)CC)c1cc(Br)cs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC/C(=C\CCC(CC)(CC)O[Si](CC)(CC)CC)c1cc(C=O)cs1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
11 g (24.7 mmol) of [(E)-5-(4-bromo-2-thienyl)-1,1-diethylhept-4-enyloxy]triethylsilane are dissolved in 100 mL of anhydrous THF and the mixture is cooled to −78° C. 10.9 mL (27 mmol) of 2.5 M butyllithium are added slowly and the mixture is stirred for 15 minutes. 2.1 mL (27 mmol) of dimethylformamide are then added and the medium is stirred for 30 minutes and then poured into aqueous ammonium chloride solution. After extraction with ethyl acetate and chromatography on silica gel (eluent: 9 heptane/1 ethyl acetate), the product is obtained in the form of a colourless oil (m=4 g; Y=41%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([F:35])=[CH:11][C:12]([F:34])=[C:13]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:27])=[C:22](F)[C:23]=3[Cl:25])[C:18](=[O:28])[C:17]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16]2)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:36]=[N+:37]=[N-:38].[Na+].CN(C)C=O>C(OCC)(=O)C>[N:36]([C:22]1[C:23]([Cl:25])=[C:24]2[C:19]([C:18](=[O:28])[C:17]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16][N:15]2[C:13]2[CH:14]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:10]([F:35])=[CH:11][C:12]=2[F:34])=[CH:20][C:21]=1[F:27])=[N+:37]=[N-:38]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(N=[N+]=[N-])c(F)cc2c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
Ethyl 1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (1,545 mg) and sodium azide (230 mg) were added to N,N-dimethylformamide (20 ml), and the mixture was stirred overnight at 60° C. After the reaction mixture was cooled back to room temperature, ethyl acetate (100 ml) was added to the reaction mixture, and the resultant mixture was washed 3 times with water (100 ml). After an organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (1,280 mg) as an amorphous substance.