Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3]Br.[CH2:5]([O:7][C:8](=[O:18])[C:9]1[CH:17]=[C:15]([OH:16])[C:13]([OH:14])=[C:11]([OH:12])[CH:10]=1)[CH3:6].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:5]([O:7][C:8]([C:9]1[CH:10]=[C:11]([OH:12])[C:13]2[O:14][CH2:3][CH2:2][O:16][C:15]=2[CH:17]=1)=[O:18])[CH3:6]
Reactant: BrCCBr
Reactant: CCOC(=O)c1cc(O)c(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(O)c2c(c1)OCCO2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 0.2 ml of 1,2-dibromoethane in 4 ml of dimethylformamide is added dropwise, four times at 2 hour intervals, to a solution, stirred at 100° C., of 2 g of gallic acid ethyl ester and 6.5 g of caesium carbonate in 80 ml of dimethylformamide. After being stirred for a further 2 hours at 100° C. the reaction mixture is concentrated by evaporation and the residue is partitioned between diethyl ether and water. The organic phases are dried over sodium sulfate and concentrated by evaporation. The title compound is obtained from the residue by FC (50 g of silica gel, methylene chloride-methanol=8:2): Rf (methylene chloride/methanol=8:2)=0.39.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][N:12](S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[C:5]([CH2:33][OH:34])[N:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(S)C=CC=CC=1>C(#N)C>[OH:34][CH2:33][C:5]1[CH:6]=[C:7]([O:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]=[C:3]([CH2:2][OH:1])[N:4]=1
Reactant: CCOC(=O)CCCN(CCOc1cc(CO)nc(CO)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)CCCNCCOc1cc(CO)nc(CO)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 74.7 %

Procedure:
To a solution of 390 mg of ethyl 4-[[2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)ethyl]-(2-nitro-benzenesulfonyl)-amino]-butanoate in 10 ml of acetonitrile, under argon, was added 766 mg of caesium carbonate and 160 μl of thiophenol. The mixture was stirred for 17 hours at room temperature and then filtered through a sinter of porosity 4. The cake was washed with EtOAc and the filtrate was concentrated under reduced pressure and purified on a Mega BE-SCX, 2GM 12ML cartridge (Varian), using washing with MeOH and detachment of the expected product with a 2N solution of ammonia in MeOH. The fractions containing the desired product were combined and concentrated under reduced pressure. 183 mg of ethyl 4-[2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethylamino]-butanoate were obtained. LC/MS (B): tr=0.68 min; [M+H]+: m/z 313.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][O:9][C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][CH:13]1[CH2:18][CH:17]([CH3:19])[CH2:16]C(O)C1.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1>[C:5]([O:4][CH:1]1[CH2:16][CH:17]([CH3:19])[CH2:18][CH:13]([CH2:12][CH2:11][C:10]([O:9][CH3:8])([CH3:22])[CH3:21])[CH2:2]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: COC(C)(C)CCC1CC(C)CC(O)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(C)(C)CCC1CC(C)CC(OC(C)=O)C1

Procedure:
Acetic anhydride (1.4 mL, 0.014 mol), 3-(3-methoxy-3-methylbut-1-yl)-5-methylcyclohexan-1-ol (2.0 g, 0.0093 mol), toluene (3.0 mL) and sodium acetate (0.05 g) were combined and heated at reflux for 16 hours. Workup provided 1-acetoxy-3(3-methoxy-3-methylbut-1-yl)-5-methylcyclohexane, bp0.5 175-177~C. (1.61 g) as a mixture of diastereoisomers (ratio 92.3:3.2:4.5); NMR(CDCl3)δ 0.6(q,1H), 0.9(d,3H), 1.0-1.3(m,3H), 1.2(s,6H), 1.4-1.6(m,4H), 1.6-2.0(m,4H), 2.1(s,3H), 3.2(s,3H), 5.1(m,1H); IR(neat) 2960, 2925, 1740, 1460, 1380, 1250, 1085, 1015 cm-1 ; MS(m/e) 43, 73, 93, 108, 149, 164, 181, 241, 242.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:40][CH2:41][CH3:42])[C:18]2[C:27]3[CH:26]=[C:25]([O:28][CH2:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][C:33]4=[O:37])[CH:24]=[CH:23][C:22]=3[N+:21]([O-])=[CH:20][C:19]=2[N:39]=1)[CH3:13].[OH-].[NH4+:44]>ClCCl>[NH2:44][C:20]1[C:19]2[N:39]=[C:16]([CH2:15][O:14][CH2:12][CH3:13])[N:17]([CH2:40][CH2:41][CH3:42])[C:18]=2[C:27]2[CH:26]=[C:25]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][C:33]3=[O:37])[CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: CCCn1c(COCC)nc2c[n+]([O-])c3ccc(OCCCN4CCCC4=O)cc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OCCCN4CCCC4=O)cc3c21
Reaction time: 16 h

Procedure:
p-Toluenesulfonyl chloride (0.700 g, 3.66 mmol) was added to a stirred mixture of 1-(3-{[2-(ethoxymethyl)-5-oxido-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}propyl)pyrrolidin-2-one (1.56 g, 3.66 mmol), ammonium hydroxide (24 mL), and dichloromethane (36 mL) at room temperature. After 16 hours, the layers were separated and the aqueous layer was extracted with dichloromethane (3×50 mL). The organic layers were combined, washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Recrystallization from acetonitrile afforded 0.759 g of 1-(3-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}propyl)pyrrolidin-2-one as off-white needles, mp 188.5-190° C.
Reaction SMILES: [I-].[Br:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]([C:15]1[CH:20]=[CH:19][N+:18]([CH3:21])=[CH:17][CH:16]=1)([CH3:14])[CH3:13].CO.[BH4-].[Na+]>C(Cl)Cl>[Br:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]([C:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH:16]=1)([CH3:14])[CH3:13]
Reactant: C[n+]1ccc(C(C)(C)c2ccc([N+](=O)[O-])cc2Br)cc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CC=C(C(C)(C)c2ccc([N+](=O)[O-])cc2Br)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[1-(2-Bromo-4-nitro-phenyl)-1-methyl-ethyl]-1-methyl-pyridiniumiodide was mixed with MeOH (400 ml) and CH2Cl2 (200 ml), then treated with NaBH4 (2.5 g) in portions. After stirring at RT for 2 h, the mixture was extracted with CH2Cl2 (300 mL×3). The CH2Cl2 layer was washed with brine, dried over Na2SO4 and concentrated in vacuo, to provide the desired compound.
Reaction SMILES: [C:1]([C:3]([NH2:8])([CH3:7])[CH:4]([CH3:6])[CH3:5])#[N:2].[CH2:9]([O:12][C:13]1[C:21]([O:22][CH3:23])=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][C:14]=1[O:24][CH3:25])[C:10]#[CH:11]>>[C:1]([C:3]([NH:8][C:17](=[O:18])[C:16]1[CH:15]=[C:14]([O:24][CH3:25])[C:13]([O:12][CH2:9][C:10]#[CH:11])=[C:21]([O:22][CH3:23])[CH:20]=1)([CH3:7])[CH:4]([CH3:6])[CH3:5])#[N:2]
Reactant: CC(C)C(C)(N)C#N
Reactant: C#CCOc1c(OC)cc(C(=O)Cl)cc1OC
Product: C#CCOc1c(OC)cc(C(=O)NC(C)(C#N)C(C)C)cc1OC

Procedure:
According to the same method as that of Production Example 1, 1-cyano-1,2-dimethylpropylamine was used in place of 2,2-dimethylpropylamine, 4-(2-propynyloxy)-3,5-dimethoxybenzoyl chloride was used in place of 4-(2-propynyloxy)-3-methoxybenzoyl chloride to obtain N-(1-cyano-1,2-dimethylpropyl)-4-(2-propynyloxy)-3,5-dimethoxybenzamide (hereinafter, described as the compound 19 of the present invention) represented by the formula:
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH:6]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12].Cl.N1(S([N:32]=[N+:33]=[N-])(=O)=O)C=CN=C1.S(=O)(=O)(O)[O-].[K+]>CO.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].O>[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]([NH:6][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:13]([OH:15])=[O:14])=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=NS(=O)(=O)n1ccnc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)O
Agent: [Cu+2]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCCN=[N+]=[N-])C(=O)O
Temperature: 25 °C
Reaction time: 23 h
Yield: 86 %

Procedure:
Sodium bicarbonate (0.65 g, 7.74 mmol) was added to a mixture of Boc-Lys-OH (Compound tk39) (1.0 g, 4.06 mmol) and copper sulfate pentahydrate (20 mg, 0.081 mmol) in methanol (15 mL)-water (3 mL) at room temperature, followed by addition of 1H-imidazole-1-sulfonyl azide hydrochloride synthesized by the method described in the literature (Org. Lett., 2007, 9, 3797) (1.02 g, 4.87 mmol). Sodium bicarbonate (0.65 g, 7.74 mmol) was added to the reaction mixture, followed by stirring at room temperature for 23 hours. The reaction mixture was cooled in an ice bath, followed by addition of a saturated aqueous potassium bisulfate solution (10 mL). The resulting mixture was filtered through celite and washed with ethyl acetate, and the filtrate was then concentrated under reduced pressure. The resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (S)-6-azido-2-((tert-butoxycarbonyl)amino)hexanoic acid (Compound tk48) (948.7 mg, 86%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]([O:21][CH3:22])=[CH:8][C:4]=1[C:5]([NH2:7])=[O:6].[CH3:23]N(C=NC=[N+](C)C)C.[Cl-].C(O)(=O)C.C([O-])(=O)C.[Na+]>O1CCOCC1>[OH:6][C:5]1[C:4]2[C:3](=[CH:11][C:10]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:9]([O:21][CH3:22])[CH:8]=2)[N:2]=[CH:23][N:7]=1
Reactant: COc1cc(C(N)=O)c(N)cc1OCCCN1CCCC1
Reactant: CN(C)C=NC=[N+](C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1cc2c(O)ncnc2cc1OCCCN1CCCC1
Yield: 92.6 %

Procedure:
A mixture of 2-amino-5-methoxy-4-(3-(pyrrolidin-1-yl)propoxy)benzamide hydrochloride (5.92 g, 16.2 mmol) and Gold's reagent (3.5 g, 21.4 mmol) in dioxane (50 ml) was heated at reflux for 5 hours. Acetic acid (0.7 ml) and sodium acetate (1.33 g) were added to the reaction mixture which was heated at reflux for a further 5 hours. The mixture was allowed to cool and the volatiles were removed by evaporation. The residue was dissolved in water, adjusted to pH8 with 2M aqueous sodium hydroxide solution and purified on a Diaion (trademark of Mitsubishi) HP20SS resin column eluting with methanol (gradient 0–50%) in water. The fractions containing product were concentrated by evaporation and then freeze dried to give 4-hydroxy-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (4.55 g, 83%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].C1(C)C=CC(S(O[CH2:27][C:28]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH:29]=2)(=O)=O)=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:28]1([CH2:27][N:9]2[CH2:8][CH2:7][CH:6]([C:4](=[O:5])[C:3]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:2]=3[F:1])[CH2:11][CH2:10]2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2=Cc3ccccc32)cc1
Reactant: O=C(c1ccc(F)cc1F)C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1F)C1CCN(CC2=Cc3ccccc32)CC1

Procedure:
0.0019 mole of 4-(2,4-difluorobenzoyl)piperidine, 0.0019 mole of benzocyclobuten-1-ylmethyl para-toluenesulfonate and 0.04 mole of triethylamine dissolved in 50 ml of toluene are mixed and then brought to reflux for 18 hours. The reaction medium is then extracted with 1N hydrochloric acid and the aqueous phase is alkalinized and extracted with dichloromethane. The oil obtained is purified on a silica column using a mixture of cyclohexane and acetone (93:7 V/V) as eluent.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH:13]1[CH2:16][CH:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:8][C:7]1[C:2]([N:13]2[CH2:16][CH:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:14]2)=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CN(c2ncc(C(F)(F)F)cc2Cl)C1
Temperature: 150 °C
Yield: 34.8 %

Procedure:
2,3-Dichloro-5-(trifluoromethyl)pyridine (1.50 g, 6.94 mmol), tert-butyl azetidin-3-ylcarbamate (1.67 g, 9.72 mmol) and K2CO3 (2.88 g, 20.83 mmol) were dissolved in dry DMF (13 mL) under nitrogen atmosphere. The reaction mixture was heated in a microwave reactor at 150° C. for 15 mins. The reaction mixture was filtered and diluted with EtOAc, washed with water, dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography (ISOLUTE SI (20 g), eluated with DCM, DCM/MeOH (99:1)) affording the title compound (0.85 g, 34.8%). 1H NMR (500 MHz, CDCl3): δ 1.48 (s, 9H), 4.10-4.14 (m, 2H), 4.57 (bs, 1H), 4.65 (t, 2H), 5.00 (bs, 1H), 7.61 (s, 1H), 8.28 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 28.56, 41.67, 60.34, 80.45, 115.51, 117.44 (q, JC-F=33.2 Hz), 123.83 (m, JC-F=271.4 Hz), 135.06, 143.75, 155.18, 157.35; Mass Spectrum: M−H+ 350.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:32]2[CH:33]=[CH:34][C:35]([C:38]#[N:39])=[N:36][CH:37]=2)O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:37]=[N:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(C#N)nc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxa borolan-2-yl)-pyridine-2-carbonitrile following a procedure analogous to that described in Example 28. LC (method 10): tR=1.70 min; Mass spectrum (ESI+): m/z=407 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:43])[C:5]([CH3:42])([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:25]=[CH:26][CH:27]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:18]3[O:19][C:20]([CH3:21])=[C:16]([CH2:15][CH2:14][O:13][C:10]4[CH:11]=[CH:12][C:7]([CH2:6][C:5]([CH3:42])([O:35][C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:4]([OH:43])=[O:3])=[CH:8][CH:9]=4)[N:17]=3)[CH:23]=2)=[CH:29][CH:30]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(-c3cccc(-c4ccc(F)cc4)c3)oc2C)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1oc(-c2cccc(-c3ccc(F)cc3)c2)nc1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Temperature: 55 °C
Reaction time: 18 h

Procedure:
3-(4-{2-[2-(4′-Fluorobiphenyl-3-yl)-5-methyloxazol-4-yl]ethoxy}phenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (3.6 mmol) in MeOH (7 mL) was treated with 2N NaOH (7 mL) and warmed to 55° C. After 18 h, the mixture was concentrated under reduced pressure and then acidified with 5N HCl to pH=1. The solution was extracted with EtOAc and then the organic phases dried (Na2SO4), filtered and concentrated to a white solid. 1H NMR (400 MHz, CDCl3) δ 8.18, (s, 1H), (d, J=7.6 Hz, 1H), 7.62–7.58 (m, 3H),7.48 (t, J=7.6 Hz, 1H), 7.24–7.03 (m, 7H), 6.90 (t, J=8.4 Hz, 2H), 6.83 (t, J=8.4 Hz, 2H), 4.22 (t, J=6.8 Hz, 2H), 3.25 (d, J=14.0 Hz, 1H), 3.15 (d, J=14.0 Hz, 1H), 3.01 (t, J=6.8 Hz, 2H), 2.40 (s, 3H), 1.42 (s, 3H); MS (EI) 552.3 (M+H)+, 550.3 (M−H)−.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16]([NH:18][C:19]2[S:20][CH:21]=[C:22]([CH2:24][CH:25]=O)[N:23]=2)=[O:17])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27]([CH:32]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:29][CH2:30][CH3:31])=[O:28]>>[CH2:30]([O:29][C:27](=[O:28])[CH:32]=[CH:25][CH2:24][C:22]1[N:23]=[C:19]([NH:18][C:16]([NH:15][C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:7])=[O:17])[S:20][CH:21]=1)[CH3:31]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(NC(=O)Nc2nc(CC=O)cs2)c(C(=O)C2CCCC2)c1
Product: CCOC(=O)C=CCc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Yield: 41.9 %

Procedure:
4-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-but-2-enoic acid ethyl ester (50 mg, 42%) was prepared from 1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[4-(2-oxo-ethyl)-thiazol-2-yl]-urea (0.10 g, 0.27 mmol) and (carbethoxymethylene)-triphenylphosphorane (0.09 g, 0.27 mmol) following the general procedure X.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2.O[NH:13]S(O)(=O)=O.[OH-].[Na+]>C(O)=O>[CH:3]12[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]([CH2:8]3)[C:2](=[O:11])[NH:13]1)[CH2:4]2
Reactant: O=S(=O)(O)NO
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: O=C1NC2CC3CC(C2)CC1C3
Temperature: 25 °C
Yield: 97.3 %

Procedure:
To a solution of 2-adamantanone (2.00 g) in formic acid (10 ml) was added dropwise a suspension of hydroxyamine-O-sulfonic acid (2.26 g) in formic acid (7 ml) under stirring at ambient temperature. The mixture was heated at reflux temperature for 3.5 hours. The reaction mixture was allowed to cool to room temperature, alkalined with 1N sodium hydroxide aqueous solution and extracted with chloroform twice. The combined extracts were washed with water and dried over sodium sulfate. Removal of the solvent gave 2-azatricyclo[4.3.1.14,8 ]undecan-3-one (2.14 g), which was used in a following reaction step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Br:12]Br>C(Cl)(Cl)Cl.CC(O)=O>[Br:12][C:7]1[CH:6]=[CH:5][C:4]([OH:8])=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cccc(O)c1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1c(Br)ccc(O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3-methyl-2-nitro-phenol (20 g, 0.13 mol) in CHCl3 (20 mL) was added a solution of Br2 (6.4 mL) in HOAc (15 mL) dropwise at 0° C. and the mixture was stirred at 0° C. for 3 h. Ice was added and the mixture was extracted with CHCl3. After drying over Na2SO4, CHCl3 was removed to give 4-bromo-3-methyl-2-nitro-phenol (30 g) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[C:7]=1[NH2:13].CO[C:16](=N)[C:17]([Cl:20])([Cl:19])[Cl:18]>C(O)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[N:13]=[C:16]([C:17]([Cl:20])([Cl:19])[Cl:18])[NH:12][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: COCCOc1cccc(N)c1N
Solvent: CC(=O)O
Product: COCCOc1cccc2[nH]c(C(Cl)(Cl)Cl)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.33 g (7.30 mmol) 3-(2-Methoxy-ethoxy)-benzene-1,2-diamine were dissolved in 35 mL acetic acid. 1.25 mL (10.22 mmol) 2,2,2-trichloro-acetimidic acid methyl ester were added and the resulting mixture was stirred for 2 h at room temperature. The mixture was concentrated under reduced pressure and the residue was co-distilled twice with 20 mL toluene to give crude 4-(2-Methoxy-ethoxy)-2-trichloromethyl-1H-benzoimidazole as a brown solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14](COCC[Si](C)(C)C)[C:15]=3[CH2:16][NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:10][C:5]=2[C:4](=[O:34])[NH:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH3:1][C:2]1([CH3:35])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][NH:14][C:15]=3[CH2:16][NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:10][C:5]=2[C:4](=[O:34])[NH:3]1
Reactant: CC1(C)NC(=O)c2sc(-c3cnn(COCC[Si](C)(C)C)c3CNCCc3ccccc3)cc2N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)NC(=O)c2sc(-c3cn[nH]c3CNCCc3ccccc3)cc2N1
Temperature: 60 °C
Reaction time: 8 h
Yield: 26.3 %

Procedure:
A mixture of 4-(2,2-dimethyl-4-oxo-1,2,3,4-tetrahydrothieno[3,2-d]pyrimidin-6-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carbaldehyde (122 mg, 0.30 mmol), 2-phenylethanamine (0.151 mL, 1.20 mmol) and THF (5 mL) was stirred at room temperature overnight. Then, sodium borohydride (0.023 g, 0.60 mmol) and MeOH (2 mL) were added. After 30 min, the mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, NH, 95:5 hexane/EtOAc to EtOAc then to 80:20 EtOAc/MeOH) to afford 2,2-dimethyl-6-(5-{[(2-phenylethyl)amino]methyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (140 mg). 2,2-Dimethyl -6-(5-{[(2-phenylethyl)amino]methyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (140 mg) was dissolved with N,N,N,N-tetrabutylammonium fluoride (1.0 M in THF, 3.0 mL, 3.00 mmol) and the mixture was stirred at 60° C. overnight. The mixture was filtered, and the filtrate was poured into saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, NH, 95:5 hexane/EtOAc to EtOAc then to 80:20 EtOAc/MeOH) to afford the title compound (27.5 mg, 24%) as a colorless oil:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:14])[O:9][CH2:10][C:11](=O)[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C(COC)OC>[Cl:1][C:2]1[C:7]2[C:8](=[O:14])[O:9][CH2:10][C:11](=[S:24])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1COC(=O)c2c(Cl)cccc2N1
Solvent: COCCOC
Product: O=C1OCC(=S)Nc2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 162.5 %

Procedure:
6-Chloro-4,1-benzoxazepin-2,5-dione (10.6 g, 50 mmole) in dimethoxyethane (250 ml) was treated with Lawesson's reagent (12.1 g, 30 mmole) and the mixture stirred at room temperature for 24 hours. The solution was filtered and evaporated. The residue in ethyl acetate was washed with sodium bicarbonate solution and dried (Na2SO4). The solution was diluted with hexane and filtered through silica. The filtrate was evaporated to give the product (11.1 g, 97%), m.p. 177°-180° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH:11]=[C:10](I)[CH:9]1[CH2:8][N:7]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:6]2)=[O:4].[S:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]12[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH:11]=[C:10]([C:30]3[CH:31]=[CH:32][S:28][CH:29]=3)[CH:9]1[CH2:8][N:7]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:6]2)=[O:4]
Reactant: OB(O)c1ccsc1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(c1ccsc1)=CCC2c1ccccc1
Yield: 90.9 %

Procedure:
By carrying out the reaction as in Stage C of Example 45, but from 1.2 g of methyl(3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate in 30 cm3 of toluene, from 150 mg of tetrakis(triphenylphosphine)palladium, from 0.35 g of 3-thienylboronic acid in 15 cm3 of methanol and from 28 cm3 of a 2N aqueous sodium carbonate solution at reflux for three hours, 0.99 g (93%) of methyl(3aRS,4SR,7aRS)-2-benzyl-4-phenyl-7-(3-thienyl)-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate was obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and ethyl acetate (85/15 by volume), in the form of a yellow oil, the characteristic of which was as follows: