Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:20](=[O:22])[CH3:21])[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1.Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[CH:4]=[C:5]([C:20](=[O:22])[CH3:21])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)=[CH:8][C:7]=2[CH:19]=1
Reactant: COc1ccc(-c2cc3cc(OC)cc(C(C)=O)c3o2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Temperature: 200 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A mixture of 122 (0.37 g, 1.3 mmol) and Pyridine HCl (10 g) was heated to 200° C. After 1 hr, the reaction was cooled, diluted with water and extracted with EtOAc. The EtOAc layer was dried over MgSO4, concentrated and the product was purified by column chromatography (50% EtOAc/Hex) to give 123 as a solid (0.25 g, 74%): Mp=274-276° C.;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][CH:8]=2)=[N:3][CH:2]=1.[OH-].[Na+].[ClH:19]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([Cl:19])=[O:12])=[CH:9][CH:8]=2)=[N:3][CH:2]=1
Reactant: COC(=O)c1ccc(-c2ccncn2)cc1
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Cl)c1ccc(-c2ccncn2)cc1

Procedure:
Methyl 4-(4-pyrimidinyl)benzoate (0.41 g, 1.9 mmol) was stirred at room temperature in ethanol (20 mL) and 2N NaOH(aq) (20 mL) for 1 hour. 2N HCl(aq) was added until a precipitate formed. The resulting suspension was concentrated in vacuo and azeotroped with toluene. Thionyl chloride (100 mL) and DMF (1 drop) were added and the reaction mixture refluxed for 1 hour. The reaction mixture was concentrated in vacuo and azeotroped twice with dichloromethane to yield 4-(4-pyrimidinyl)benzoyl chloride. The acid chloride was suspended in dichloromethane (100 mL) and 1-(6-bromonaphth-2-ylsulphonyl)piperazine hydrochloride (0.545 g, 1.5 mmol) added as a solid in two portions followed by triethylamine (2.2 mL, 15 mmol). The reaction mixture was stirred overnight at room temperature then concentrated in vacuo. The resulting solid was separated between ethyl acetate (100 mL) and water (2×100 mL). The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo to yield a black oil which was subjected to chromatography (SiO2: 40%, 50%, 60% Ethyl acetate/Hexane) to yield 1(6-bromonaphth-2-ylsulphonyl)4-[4-(4-pyrimidinyl)benzoyl]piperazine as a white solid; 1H NMR (250 MHz, DMSO-d6) δ=2.94 to 3.18 ppm (m,4H), δ=3.40 to 3.83 ppm (m,4H), δ=7.49 ppm (d,2H), δ=7.83 ppm (m,2H), δ=8.10 ppm (dd,1H), δ=8.14 to 8.23 ppm (m,4H), δ=8.43 ppm (d,1H), δ=8.49 ppm (s,1H), δ=8.89 ppm (d,1H), δ=9.26 ppm (s,1H); MS (M+H)+ 536.
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Br[C:14]1[S:18][C:17]([S:19]([N:22]2[CH:26]=[CH:25][CH:24]=[CH:23]2)(=[O:21])=[O:20])=[CH:16][CH:15]=1>>[S:1]1[C:5]([C:14]2[S:18][C:17]([S:19]([N:22]3[CH:26]=[CH:25][CH:24]=[CH:23]3)(=[O:20])=[O:21])=[CH:16][CH:15]=2)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Reactant: OB(O)c1cc2ccccc2s1
Product: O=S(=O)(c1ccc(-c2cc3ccccc3s2)s1)n1cccc1
Yield: 68 %

Procedure:
N-[5-(benzo[b]thien-2-yl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 32C from benzo[b]thiophene-2-boronic acid (426 mg, 2.39 mmol) and N-(5-bromothiophene-2-sulfonyl)pyrrole (700 mg, 2.39 mmol). Purification by column chromatography using 2% ethyl acetate/hexanes gave the pure sulfonamide in 68% yield as a brownish-red solid.
Reaction SMILES: [CH3:1][C@@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][CH2:11][CH2:12]O.Br>ClCCl>[BrH:10].[Br:10][CH2:11][CH2:12][NH:9][C@H:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCCBr
Reactant: C[C@@H](N)c1ccccc1
Agent: Br
Solvent: ClCCl
Product: C[C@@H](NCCBr)c1ccccc1
Temperature: 51 °C
Reaction time: 50 h
Yield: 108.6 %

Procedure:
76.61 g (630 mmole) of (R)-(+)-α-methylbenzylamine was dissolved in 77 ml of dichloromethane and 94.8 g (760 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51° C. for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 286.4 ml (2500 mmole) of 48% aqueous hydrobromic acid solution was added thereto and then allowed to react at 126° C. for 30 minutes under refluxing. The reaction solution was then distilled for 2 hours under normal pressure at constant temperature and 250 ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 350 ml of isopropyl alcohol with refluxing for 30 minutes, and this solution was cooled to 10.C and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 50 ml of ethyl acetate, and then dried to obtain 127.5 g of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[N+:18]([O-])=O>[Pt].C(O)C>[CH3:1][CH:2]([CH3:21])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[NH2:18]
Reactant: CC(C)CNc1c([N+](=O)[O-])c2nnnn2c2ccccc12
Agent: [Pt]
Solvent: CCO
Product: CC(C)CNc1c(N)c2nnnn2c2ccccc12
Yield: 39 %

Procedure:
N-(2-Methylpropyl)-4-nitrotetrazolo[1,5-a]quinolin-5-amine (1.0 g, 3.5 mmole, Example 15), ethanol (100 mL) and Pt/C were placed in a Paar apparatus. The mixture was hydrogenated at 50 psi (3.44×105 Pa). The reaction mixture was filtered to remove the catalyst then concentrated under vacuum. The residue was recrystallized from ethyl acetate to provide 0.35 g of N5 -(2-methylpropyl)tetrazolo[1,5-a]quinoline-4,5-diamine as off white needles, m.p. 148°-150° C. Analysis: Calculated for C13H16N6 : % C, 60.92; % H, 6.29; % N, 32.79; Found: % C, 60.94; % H, 6.25; % N, 32.93.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[C:4]([CH3:23])[CH:3]=1.[CH3:24][N:25]([CH3:36])[CH2:26][CH2:27][O:28][C:29]1[N:30]=[CH:31][C:32]([SH:35])=[N:33][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu](I)I>[CH3:24][N:25]([CH3:36])[CH2:26][CH2:27][O:28][C:29]1[N:30]=[CH:31][C:32]([S:35][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([C:9]3[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[S:12][CH:13]=3)=[C:4]([CH3:23])[CH:3]=2)=[N:33][CH:34]=1
Reactant: Cc1cc(I)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Reactant: CN(C)CCOc1cnc(S)cn1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Sc2cnc(OCCN(C)C)cn2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 100 °C
Yield: 46.1 %

Procedure:
A mixture of N-(4-(4-iodo-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (0.51 g, 1.2 mmol), 5-(2-(dimethylamino)ethoxy)pyrazine-2-thiol (28-4, 0.96 g, 4.8 mmol), copper iodide (73.0 mg, 0.38 mmol), and potassium carbonate (0.64 g, 4.6 mmol) in 5.0 mL of DMF was heated at 100° C. for 16 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (MeOH:CH2Cl2=1:10 as eluant) to give N-(4-(4-{5-(2-(dimethylamino)ethoxy)pyrazin-2-ylthio}-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (28, 0.28 g) as light yellow solids in 47% yield: 1H NMR (500 MHz, CD3OD) δ 8.75 (s, 2 H), 8.14 (d, J=1.1 Hz, 1 H), 8.04 (s, 1 H), 7.97 (d, J=5.9 Hz, 2 H), 7.18 (s, 2 H), 7.00 (s, 1 H), 4.58 (s, 3 H), 4.46 (t, J=5.5 Hz, 2 H), 2.81 (t, J=5.4 Hz, 2 H), 2.37 (s, 6 H), 2.10 (s, 6 H). ESI-MS: m/z 507.1 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:31]1([CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])[CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH:40][CH2:39][CH2:38][CH2:37][CH2:36][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Reactant: NCCCCN1CCCC1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)NCCCCN4CCCC4)c3)C(C)(C)C2=O)cc1

Procedure:
This compound may be prepared as obtained in stage c) of Example 9, but starting with 100 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9, 2 mL of dioxane and 40.2 mg of 4-pyrrolidin-1-ylbutan-1-amine. After chromatography on a column of silica, eluting with a mixture of dichloromethane/methanol/28% aqueous ammonia (95/4/1 by volume), 60.2 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]-methyl}pyridin-2-yl)-3-(4-pyrrolidin-1-ylbutyl)urea are obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:22][C:23]1([CH3:29])[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>>[CH3:22][C:23]1([CH3:29])[NH:24][CH2:25][CH2:26][N:27]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)[CH2:28]1
Reactant: CC1(C)CNCCN1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ncc(F)nc34)cc21
Product: CC1(C)CN(c2cnc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)CCN1
Temperature: 60 °C
Yield: 67 %

Procedure:
Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 57 mg, 0.202 mmol) and 2,2-dimethylpiperazine (46.1 mg, 0.404 mmol, Chem-Impex International, Wood Dale, Ill.), heating at 60° C. for 1 h. Purification by filtration provided 2-(3-(3,3-dimethylpiperazin-1-yl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (67% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (s, 6H) 2.87 (t, J=6.85 Hz, 2H) 2.92-2.99 (m, 2H) 3.44 (td, J=6.85, 2.15 Hz, 2H) 3.61 (s, 2H) 3.74 (t, J=4.69 Hz, 2H) 6.94 (br. s., 1H) 7.14 (d, J=2.15 Hz, 1H) 7.39 (t, J=7.82 Hz, 1H) 7.66 (d, J=6.85 Hz, 1H) 7.89 (d, J=6.46 Hz, 1H) 8.87 (s, 1H) 11.77 (br. s., 1H). MS (ESI, pos. ion) m/z: 377.1 (M+1).
Reaction SMILES: [C:1]([C@@H:3]([NH:27][C:28]([C:30]1([NH:36]C(=O)OC(C)(C)C)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)#[N:2]>C(O)=O>[NH2:36][C:30]1([C:28]([NH:27][C@H:3]([C:1]#[N:2])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:12]=[CH:13][C:14]([S:17]([N:20]4[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]4)(=[O:18])=[O:19])=[CH:15][CH:16]=3)=[CH:9][CH:10]=2)=[O:29])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: CN1CCN(S(=O)(=O)c2ccc(-c3ccc(C[C@@H](C#N)NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)cc3)cc2)CC1
Solvent: O=CO
Product: CN1CCN(S(=O)(=O)c2ccc(-c3ccc(C[C@@H](C#N)NC(=O)C4(N)CCOCC4)cc3)cc2)CC1
Yield: 20.6 %

Procedure:
(S)-tert-Butyl 4-(1-cyano-2-(4′-(4-methylpiperazin-1-ylsulfonyl)biphenyl-4-yl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 29, step (ii), 250 mg) in formic acid (2 mL) was heated at 50° C. for 20 min. Volatiles were removed under reduced pressure and then azeotroped with methanol. The product was purified by reversed phase HPLC using methanol in 0.1% aqueous TFA as eluent. The residue was converted to the free base by elution through a PL-HCO3 MP cartridge in dichloromethane/methanol to afford the titled compound (43 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[NH:3][CH:2]=1.C(Cl)(=O)C([Cl:15])=O>>[Cl:15][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][N:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=c1[nH]cnc2ccccc12
Product: Clc1ncnc2ccccc12

Procedure:
The process for the preparation of Erlotinib disclosed in WO 96/30347 is shown in Scheme-1. The starting material Ethyl-3,4-dihydroxy benzoate of formula (2) is reacted with 2-bromo ethylmethyl ether in presence of a base to obtain bis-O-alkylated compound of formula (3), which is nitrated on ortho position with nitric acid in acetic acid medium to get 2-Nitro-4,5-bis(2-methoxyethoxy)benzo ate of formula (4). The nitro compound of formula (4) on hydrogenation using platinum oxide hydrate gives the amino compound of formula (5), which further reacted with ammonium formate and formamide to get 4-quinazolone compound of formula (6). The 4-quinazolone derivative is reacted with oxalyl chloride to get 4-chloro quinazoline derivative of formula (7), which on condensation with 3-ethynylaniline gives a residue containing Erlotinib base of formula (1). The residue thus obtained is purified by flash chromatography on silica to get Erlotinib base. Then the base is converted to its hydrochloride salt.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH:7]2[N:9]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]([C:20]#[N:21])=[CH:12][CH:11]=3)[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[CH3:22][CH:8]1[C:2](=[O:1])[CH2:3][CH:4]2[N:9]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]([C:20]#[N:21])=[CH:12][CH:11]=3)[CH:7]1[CH2:6][CH2:5]2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#Cc1ccc(N2C3CCC2CC(=O)C3)c2ccccc12
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1C(=O)CC2CCC1N2c1ccc(C#N)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
To 156AF03-217 (552 mg, 2 mmol) in THF (20 mL) under argon atmosphere at −78° C. was added dropwise lithium bis(trimethylsilyl)amide (2.6 mL, 2.6 mmol, 1 M in THF). After 30 min at −78° C., iodomethane (2.0 mL) was added over 1 min and the reaction was allowed to warm to rt overnight. Partitioning of the reaction mixture between ethyl acetate (2×500 mL) and water (500 mL), drying of the combined organic phases over Na2SO4, filtration, removing of volatiles in vacuo and purification by preparative TLC (ethyl acetate/n-heptane 1:4, 5× eluted) afforded the title compound (115 mg, 20%) as a thick oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([O:29][Si:30]([CH2:34][CH3:35])([CH2:32][CH3:33])[CH3:31])[C:9]([CH3:28])([CH3:27])[C:10](=[O:26])[CH:11]([CH3:25])[CH:12]([OH:24])[CH:13]([CH3:23])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.[Si:45](OS(C(F)(F)F)(=O)=O)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([O:29][Si:30]([CH2:34][CH3:35])([CH2:32][CH3:33])[CH3:31])[C:9]([CH3:27])([CH3:28])[C:10](=[O:26])[CH:11]([CH3:25])[CH:12]([O:24][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH:13]([CH3:23])[CH2:14][O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC[Si](C)(CC)OC(CC(=O)OC(C)(C)C)C(C)(C)C(=O)C(C)C(O)C(C)COCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC[Si](C)(CC)OC(CC(=O)OC(C)(C)C)C(C)(C)C(=O)C(C)C(O[Si](C)(C)C(C)(C)C)C(C)COCc1ccccc1
Reaction time: 2 h
Yield: 111.5 %

Procedure:
To a solution of 71a (4.1 mg, 7.6 μmol) and 2,6-lutidine (10.0 μL, 43.5 mmol) in CH2Cl2 (0.2 mL) at −78° C. was added TBSOTf (10.0 μL, 85.8 mmol). After 2 h, more, 6-lutidine (10.0 μL, 43.5 mmol) and TBSOTf (10.0 μL, 85.8 mmol) were added. After 6 h, the mixture was diluted with sat aq NaHCO3. The aqueous layer was extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (gradient hexane to hexane/EtOAc 91:9) to give 36 (5.4 mg, 82%) as a clear oil. Spectroscopic data agreed well with the reported values.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]([CH3:25])[C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:17]2[C:18]([CH3:25])=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=2[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(C)c1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 71.6 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (2.40 g), 2,6-dimethyl-4-nitrophenol (1.50 g) and triphenylphosphine (3.06 g) in dichloromethane (60 ml) was added dropwise diethyl azodicarboxylate (1.80 ml) in an ice bath and the mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=5/1 as an eluant to give the desired compound (2.25 g, yield 71%) as a colorless solid.
Reaction SMILES: [CH3:1][S:2][CH2:3]Cl.[Na].[OH:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1.[I-].[Na+]>C(COC)OC>[CH3:1][S:2][CH2:3][O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: CSCCl
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: COCCOC
Product: COC(=O)c1ccc(COCSC)cc1
Yield: 75 %

Procedure:
4-(Methyloxycarbonyl)benzyl methylthiomethyl ether was prepared by the reaction of chloromethyl methyl sulphide with the sodium salt of methyl 4-hydroxymethylbenzoate (see G. D. Brindell, L. D. Lillwitz, J. P. Wuskell and A. P. Dunlop, Ind. Eng. Chem. Prod. Res. Dev. 15, 83(1976) in dimethoxyethane in the presence of sodium iodide as described for analogous reactions in E. J. Corey and M. C. Bock, Tetrahedron Letters 38 3269 (1975); yield 75%, b.p. 110°-120° C./0.01 mmHg. 1H NMR (CDCl3): δ2.17 (SMe) 3.92 (OMe), 4.67 (CH2), 4.70 (CH2), 7.2-8.2 (Ph).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:5]=[C:4]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[N:3]=1.C(O)(=[O:31])C>O>[O:31]=[C:2]1[NH:3][C:4]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[N:5][C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:7]1[CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: CC(=O)O
Reactant: CCCC(C(=O)OC)c1c(Cl)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Solvent: O
Product: CCCC(C(=O)OC)c1c(-c2ccc(C)cc2)nc(N2CCCCC2)[nH]c1=O
Temperature: 150 °C

Procedure:
A mixture of methyl 2-(4-chloro-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)pentanoate in acetic acid and water (4/1 v/v; 30 mL/mmol) is stirred at 150° C. until completion. The reaction mixture is concentrated under reduced pressure, dissolved in dichloromethane and purified by flash chromatography on silica gel using a linear gradient of ethyl acetate in heptane.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:13]=[O:14]>[OH-].[Na+]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:13][OH:14]
Reactant: Cc1ccc2nccc(O)c2c1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2ncc(CO)c(O)c2c1

Procedure:
4-Hydroxy-6-methylquinoline was reacted with formaldehyde in aqueous sodium hydroxide at 40°-45° for 60 hours to give the novel compound 4-hydroxy-3-hydroxymethyl-6-methylquinoline, m.p. 188°-189° (dec.).
Reaction SMILES: [CH:1]1([C:4]([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][C:6]#[CH:7])[CH2:3][CH2:2]1.[CH2:17]([SnH:21]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20].N(C(C)(C)C#N)=NC(C)(C)C#N>>[CH:1]1([C:4]([O:12][Si:13]([CH3:16])([CH3:14])[CH3:15])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5]/[CH:6]=[CH:7]/[Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:2][CH2:3]1
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCC(CCCC)(O[Si](C)(C)C)C1CC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCC(C/C=C/[Sn](CCCC)(CCCC)CCCC)(O[Si](C)(C)C)C1CC1
Temperature: 85 °C

Procedure:
A stirred mixture of 23.8 g of 4-cyclopropyl-4-trimethylsiloxy-1-octyne (Example 10), 28 ml of tri-n-butyltin hydride, and 50 mg of azobisisobutyronitrile under nitrogen is heated to 85° C. After the resulting exothermic reaction subsides the mixture is heated at 130° C. for 1 hour. The crude product is evaporatively distilled to give a liquid, p.m.r. spectrum (C D Cl3):δ0.10 (trimethylsiloxy group), 2.33 (doublet, =CHCH2), and 6.02 (vinyl hydrogens).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[CH2:8](O)[CH2:9][OH:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]2[O:10][CH2:9][CH2:8][O:7]2)=[CH:2]1
Reactant: OCCO
Reactant: O=Cc1ccoc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: c1cc(C2OCCO2)co1

Procedure:
As depicted in Scheme 13 above, a mixture of furan-3-carbaldehyde (1.20 mol), ethylene glycol (1.32 mol), p-toluenesulfonic acid (4.6 grams, 0.024 mol) and benzene (100 ml) is heated to reflux for 19 hours in a 500 ml round-bottomed flask fitted with a Dean-Stark trap, while water are removed from the mixture by azeotropic distillation. Once water ceases to condense, the reaction mixture is washed with saturated sodium bicarbonate (NaHCO3, 200 ml). The combined organic phase is washed with water (100 ml) and saturated sodium chloride (NaCl, 100 ml), dried over MgSO4, and then concentrated a rotary evaporator. The residual paste is purified by distillation at 80° C. and 10 Torr (1333 pascals).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:1][CH2:2][CH2:3][O:4][C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(OCCN)cc1
Reactant: O=C(O)c1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCNC(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
Methyl 4-(2-aminoethoxy)benzoate (19.5 g) and 14 g of p-fluorobenzoic acid were dissolved in 300 ml of N,N-dimethylformamide and 20.6 g of N,N'-dicyclohexylcarbodiimide was added thereto little by little with stirring at room temperature. The mixture was stirred for 8 hours, the resulting N,N'-dicyclohexylurea was removed by filtration, the filtrate was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% hydrochloric acid, saturated potassium carbonate solution, and water. This was dried with anhydrous magnesium sulphate, concentrated in vacuo, the residue was crystallised with n-hexane, and the resulting 25.4 g of crystals were recrystallised from ethyl acetate/n-hexane to give 21.3 g (yield: 67%) of crystalline product. M.p. 105°-107° C.