Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [B]1OC2C(=CC=CC=2)O1.[CH2:10]([O:12][C:13]#[CH:14])[CH3:11].CCCCCC.Br[C:22]1[C:23]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[N:24][C:25]([Cl:28])=[N:26][CH:27]=1.[OH-].[Na+]>C1COCC1.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.CCOC(C)=O>[C:30]([NH:29][C:23]1[C:22](/[CH:14]=[CH:13]/[O:12][CH2:10][CH3:11])=[CH:27][N:26]=[C:25]([Cl:28])[N:24]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: C#COCC
Reactant: CC(C)(C)Nc1nc(Cl)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [B]1Oc2ccccc2O1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCO/C=C/c1cnc(Cl)nc1NC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
Catecholborane (7.8 g, 65.4 mmol) in THF (50 mL) was added dropwise to a solution of 40% ethoxyacetylene in hexane (12.8 mL, 72.5 mmol) under nitrogen at 0-5° C. The mixture was stirred for 2 hours at room temperature then heated at 70° C. for 2 hours. The mixture was then cooled to room temperature and a solution of 5-bromo-N-tert-butyl-2-chloropyrimidin-4-amine (10 g, 37.8 mmol) (see Preparation 60) in THF (50 mL) was added. The solution was degassed with argon for about 25 minutes followed by the addition of Pd(PPh3)4 (1.3 g, 1.13 mmol) and powdered sodium hydroxide (4.53 g, 113 mmol). The mixture was heated at 70° C. for 16 hours and then cooled to room temperature. EtOAc (200 mL) was added and the mixture was filtered through a Celite™ pad. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (gradient of hexane:EtOAc 93:7 to 90:10) to afford the title compound as a yellow oil in 55% yield, 5.3 g.
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[N:9]=[CH:8][C:7]=1[O:14][CH2:15][C:16]1[C:17]([C:22]([OH:24])=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=1.O=S(Cl)Cl.[CH3:29]O>>[CH:2]([C:6]1[CH:11]=[C:10]([O:12][CH3:13])[N:9]=[CH:8][C:7]=1[O:14][CH2:15][C:16]1[C:17]([C:22]([O:24][CH3:29])=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:3]
Reactant: CO
Reactant: COc1cc(C2OCCO2)c(OCc2cccnc2C(=O)O)cn1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ncccc1COc1cnc(OC)cc1C=O

Procedure:
To 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinic acid (55 mg, 0.17 mmol, 1 equiv) in MeOH (15 mL) was added SOCl2 (5.0 mL). The mixture was heated to reflux O/N, concentrated, and neutralized to pH 8-9 with NaHCO3(sat.) solution. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give methyl 3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinate (51.5 mg, quantitative yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 8.67 (dd, J=4.6, 1.5 Hz, 1H), 8.14 (dd, J=8.0, 1.5 Hz, 1H), 8.03 (s, 1H), 7.51 (dd, J=8.0, 4.6 Hz, 1H), 7.06 (s, 1H), 5.60 (s, 2H), 3.95 (s, 3H), 3.85 (s, 3H). LRMS (M+H+) m/z 303.1.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:25])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]2[N:15]=[C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]3[CH:23]=2)=[CH:8][C:7]=1O)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O1CCCC1.O>[CH3:22][C:20]1[CH:19]=[CH:18][N:17]2[CH:23]=[C:14]([CH2:13][CH2:12][C:9]3[CH:10]=[CH:11][C:6]4[N:5]=[C:4]([NH:3][CH2:1][CH3:2])[O:25][C:7]=4[CH:8]=3)[N:15]=[C:16]2[CH:21]=1
Reactant: CCNC(=O)Nc1ccc(CCc2cn3ccc(C)cc3n2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCNc1nc2ccc(CCc3cn4ccc(C)cc4n3)cc2o1
Reaction time: 1 h
Yield: 8.5 %

Procedure:
A mixture of 2-[2-{4-(3-ethylureido)-3-hydroxyphenyl}ethyl]-7-methylimidazo[1,2-a]pyridine (17.5 g) and polyphosphate ester (170 g) was stirred at 110° to 120° C. for one hour. The reaction mixture was dissolved in a mixture of ethyl acetate, tetrahydrofuran and water and the resultant solution was adjusted to pH 8.0 with potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. The crude product obtained by concentration was purified by alumina column chromatography eluting with chloroform. The eluted fraction containing the desired product was evaporated to give 6-[2-(7-methylimidazo[1,2-a]pyridin-2-yl)ethyl]-2-ethylaminobenzoxazole (1.41 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[N:9]=[C:10]([CH3:27])[C:11]2[CH:17]=[C:16]([C:18]#[C:19][Si](C)(C)C)[C:15](=[O:24])[N:14]([CH2:25][CH3:26])[C:12]=2[N:13]=1>CO>[NH2:7][C:8]1[N:9]=[C:10]([CH3:27])[C:11]2[CH:17]=[C:16]([C:18]#[CH:19])[C:15](=[O:24])[N:14]([CH2:25][CH3:26])[C:12]=2[N:13]=1
Reactant: CCn1c(=O)c(C#C[Si](C)(C)C)cc2c(C)nc(N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc2c(C)nc(N)nc2n(CC)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium carbonate (1.00 g, 7.28 mmol) was added to a flask charged with 2-amino-8-ethyl-4-methyl-6-((trimethylsilyl)ethynyl)pyrido[2,3-d]pyrimidin-7(8H)-one (1.09 g, 3.64 mmol) in anhydrous methanol (15 mL). The reaction was stirred at room temperature under nitrogen for 16 h. The reaction was concentrated to one half volume and the yellow precipitate collected by vacuum filtration to afford 2-amino-8-ethyl-6-ethynyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one.
Reaction SMILES: [CH:1]12[O:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2]2.Cl[CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.BrBr.C([O-])([O-])=O.[K+].[K+]>>[N:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][CH2:19][CH2:18][N:7]2[CH2:6][CH:5]3[O:9][CH:1]([CH2:2][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]3)[CH2:8]2)=[CH:23][CH:24]=1
Reactant: ClCCCCc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CC2CN(CCCCc3ccncc3)CC(C1)O2
Yield: 45.5 %

Procedure:
tert-Butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.35 g, 5.9 mmol, see Preparation A and Preparation C(iii) above) was mixed with 4-(4-chlorobutyl)pyridine (1.35 g, 7.37 mmol, see Example 10(i) above), Br2 (0.094 g, 0.59 mmol) and K2CO3 (3.26 g, 23.6 mmol). The mixture was refluxed under argon for 3 days. The reaction mixture was filtered, evaporated and purified by chromatography (DCM, 2-5% MeOH) giving 0.97 g (44%) of the sub-title compound.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C@H:5]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]([CH3:9])[CH3:8].[OH-].[Na+]>C1COCC1.CO>[C:14]([O:13][C:11]([NH:10][C@H:6]([CH:7]([CH3:9])[CH3:8])[C@@H:5]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21])[CH2:4][C:3]([OH:26])=[O:2])=[O:12])([CH3:15])([CH3:16])[CH3:17]
Reactant: COC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)[C@H](CC(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 47 (500 mg, 1.28 mmol) in 25 mL of THF/MeOH (1:1), cooled to 0° C., 1N NaOH solution (25 mL) was added. The reaction was stirred at 0° C. for 2 h and then overnight at rt. The reaction mixture was concentrated and diluted with H2O (20 mL), cooled to 0° C., acidified to pH 2 with 1N KHSO4 solution, and extracted with EtOAc (3×20 mL). The combined organic layers were washed with NaCl (50 mL, sat), dried (Na2SO4), filtered and evaporated. The resulting acid 48 was obtained as a colorless oil (1.76 g, 86%) and used directly in the next step. 1H-NMR (500 MHz, CDCl3): 0.06 (s, 6H), 0.84-0.95 (m, 15H), 1.43 (s, 9H), 2.01-2.11 (m, 1H), 2.53 (m, 1H), 2.64 (m, 1H), 3.53-3.58 (m, 1H), 4.10-4.14 (m, 1H), 3.65 (s, 3H), 4.17-4.19 (m, 1H), 4.51-4.54 and 6.29-6.31 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:18][C:19]#[N:20].C(O)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:18][C:19]#[N:20])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:6][CH:7]=1
Reactant: N#CCCl
Reactant: O=C1CCCCC1c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: N#CCC1(c2ccc(Cl)cc2)CCCCC1=O
Temperature: 22.5 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-(4-chlorophenyl)-cyclohexanone (100 g, 0.48 mol) in N,N-dimethylformamide (0.5 L) was added slowly to a mixture of sodium hydride (13.8 g, 0.78 mol) in N,N-dimethylformamide (0.2 L), the temperature being kept below 40° C. The reaction mixture was stirred at 20-25° C. for 1.5 h when a precipitate was formed. The mixture was diluted with N,N-dimethylformamide (0.2 L), and thereafter, a solution of chloroacetonitrile (43.0 g, 0.57 mol) in N,N-dimethylformamide (0.1 L) was slowly added with cooling over 0.5 h, the temperature being kept below 25° C. The mixture was stirred for 18 h, and then, ethanol (50 mL) was slowly added. The mixture was stirred for 0.5 h and then poured onto ice-water.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:15]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>O1CCCC1>[CH2:23]([N:14]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:15][CH:17]1[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(C1CCNCC1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CN(Cc2ccccc2)CC2CCNCC2)cc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 96.8 %

Procedure:
To a suspension of lithium aluminum hydride (min. 80%, 1.50 g, 40.0 mmol) in tetrahydrofuran (50 ml) was added dropwise a solution of N,N-dibenzylpiperidine-4-carboxamide (EXAMPLE 4, Step 2, 3.08 g, 10.0 mmol) in tetrahydrofuran (50 ml) at 0° C. over 15 min. The mixture was stirred at 0° C. for 30 min and at 40° C. for 4 h. After cooling to 0° C., water (3.3 ml), 15% NaOH aqueous solution (3.3 ml), and then water (10 ml) were carefully added dropwise. The resulting mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to give 2.85 g (97%) of the title compound as a pale yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:29]CC)=[O:28])=[CH:23][CH:22]=3)=[O:19])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[OH-].[Na+]>CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=3)=[O:19])[CH2:12][CH2:13]2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1ccc(NC(=O)NCCCN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCCCN1CCN(Cc2ccc(Cl)cc2)CC1)Nc1ccc(C(=O)O)cc1
Yield: 146.7 %

Procedure:
A solution of 1-{3-[4-(4-chlorobenzyl)piperazin-1-yl]-propyl}-3-(4-ethoxycarbonylphenyl)urea hydrochloride (2.59 g; 5.6 mmole) in methanol (75 ml) was refluxed for 8 hours with aqueous sodium hydroxide (1N; 10 ml). The reaction mixture was concentrated in vacuo, and the residue was dissolved in water. After filtration, the solution was acidified with hydrochloric acid, and the precipitated solid was collected and washed with methanol to provide the title compound (1.92 g; 80% yield) as colorless crystals, m.p. 244°-246° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.C[NH:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1>C1COCC1>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)=[O:16])[CH2:6][CH2:5]2
Reactant: CNCCc1ccccn1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCc1ccccn1)O2
Reaction time: 1 h

Procedure:
A solution of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (500 mg, 2.0 mmol) in 10 mL THF was treated with 356 mg CDI (2.2 mmol). After 1 h, 366 mg 2-(2-methylaminoethyl)pyridine (3.0 mmol) in 10 mL THF was added over 1 h and stirred overnight. The solution was concentrated, dissolved into 70 mL CH2Cl2, extracted once with 1.0 M NaHCO3. The aqueous phase was then back extracted 2×25 mL CH2Cl2 and the combined organics washed with 2×25 mL saturated NaCl and dried over Na2SO4. The solution was concentrated and purified by flash chromatography to give 6-hydroxy-2,5,7,8-tetramethyl-N-(2-(pyridin-2-yl)ethyl)chroman-2-carboxamide.
Reaction SMILES: C(OC([N:6]1[CH:15]=[C:14]([CH:16]=[O:17])[C:13]2[C:8](=[CH:9][C:10]([O:24][CH3:25])=[C:11]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:12]=2)[CH:7]1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1)=O)C.[OH-].[K+]>CO>[CH:19]1([O:18][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][C:10]=2[O:24][CH3:25])[CH:7]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[NH:6][CH:15]=[C:14]3[CH:16]=[O:17])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCOC(=O)N1C=C(C=O)c2cc(OC3CCCC3)c(OC)cc2C1Cc1cccc(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(CC2NC=C(C=O)c3cc(OC4CCCC4)c(OC)cc32)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.7 %

Procedure:
To a stirred solution of 6-cyclopentyloxy-4-formyl-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (386 mg, 0.83 mmol) in methanol (15 mL) was added powdered potassium hydroxide (465 mg, 8.30 mmol). The reaction mixture was stirred at room temperature for 15 hrs. The solvent was evaporated and the residue was diluted with ethyl acetate (20 mL) and water (20 mL). The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 6-cyclopentyloxy-7-methoxy-1-(3-methoxy-benzyl)-1,2-dihydro-isoquinoline-4-carbaldehyde (280 mg, 86% yield) as a yellow oil. The crude product was used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1)=[O:5].[C:16]1([CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[O:13]=[C:11]1[NH:10][C:9]2[CH:14]=[CH:15][C:6]([C:4](=[O:5])[CH2:3][CH2:2][N:26]3[CH2:27][CH2:28][N:23]([CH2:22][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:24][CH2:25]3)=[CH:7][C:8]=2[O:12]1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(CCCl)c1ccc2[nH]c(=O)oc2c1
Product: O=C(CCN1CCN(Cc2ccccc2)CC1)c1ccc2[nH]c(=O)oc2c1
Yield: 66.9 %

Procedure:
Using 0.6 g of 3-chloro-1-(2,3-dihydro-2-oxobenzoxazol-6-yl)-1-propanone and 0.47 g of 1-(phenylmethyl)piperazine, 0.65 g of the title compound was obtained as colorless crystals, m.p. >300° C., in the same manner as in Example 6.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH2:7][S:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si](C(C)(C)C)(C)C)=[CH:11][CH:10]=1)[C:3]([O:5]C)=[O:4].[OH-].[K+]>O>[CH3:1][C:2]([CH3:23])([CH2:7][S:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)CSc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)(CSc1ccc(O)cc1)C(=O)O
Temperature: 25 °C
Yield: 82.2 %

Procedure:
Methyl 2,2-dimethyl-3-(4'-tert-butyldimethylsilyloxyphenylthio)propionate (7.09 g, 20 mmol) was added to KOH (6.73 g, 120 mmol) in 40 mL of H2O and the mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature, diluted with 40 mL of H2O and extracted with ether. The aqueous layer was separated, acidified to pH=2 and extracted with ether (3×100 mL). The combined ether layers were dried over anhydrous MgSO4, filtered and evaporated to give 3.72 g (82%) of 2,2-dimethyl-3-(4'-hydroxyphenylthio)propionic acid as a white solid. 1H NMR (CD3COCD3) δ1.25 (s, 6H), 3.11 (s, 2H), 6.80 (d, 2H, J=8.4 Hz), 7.31 (d, 2H, J=8.7 Hz), 8.6 (br s, 1H, --OH); 13C NMR (CD3COCD3) δ25.13, 44.53, 47.63, 117.21, 127.46, 134.67, 158.18, 178.41.
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:19][O:20]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.ClCCl>[CH2:1]([C:13]1[CH:14]=[CH:15][C:16]([CH:19]=[O:20])=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COC(Cl)Cl
Reactant: CCCCCCCCCCCCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To 70 mL of dehydrated dichloromethane, 24.68 g (100 mmol) of n-dodecylbenzene was added and 36.82 g (189 mmol) of titanium tetrachloride was gradually added in drops. The reaction system kept below 10° C. in an ice bath and 13.16 9 (114 mmol) of 1,1-dichloromethl methy ether added in drops thereto were stirred together below 10° C. for 30 minutes and further stirred at a room temperature for 45 minutes. The resultant reaction mixture was added to 500 mL of ice water. It was extracted four times with 200 mL of dichloromethane and dried overnight on sodium sulfate. The solvent was removed by the use of an evaporator and purified by column chromatography (silica gel, benzene:hexene =1:1). Consequently, 11.22 g (40.2 mmol) of a light yellow slightly viscous liquid was obtained. The yield was 40%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14](I)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:22][CH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([CH2:23][OH:22])[CH:25]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=C(I)c2ccccc2)CC1
Reactant: OCc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2cccc(CO)c2)CC1
Temperature: 90 °C
Yield: 29.5 %

Procedure:
To a mixture of 4-(1-iodo-1-phenyl-methylene)-piperidine-1-carboxylic acid tert-butyl ester (0.132 g, 0.33 mmol) and 3-hydroxymethylphenylboronic acid (0.050 g 0.33 mmol) in DME (3 mL) was added 2M sodium carbonate (0.65 mL, 1.30 mmol). The reaction vessel was then flushed with Ar for 10 minutes, Pd2 dba3 (0.015 g, 0.016 mmol) was added, the vessel was sealed and the mixture was heated at 90° C. for 16 h. The cooled mixture was filtered (0.45 μm syringe filter) and the filtrate was evaporated. The residue was purified by preparative HPLC to give the title compound (0.037 g, 71%) as a white solid:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[N:10]=[CH:9][N:8]=1)=[O:5].[H][H]>CO.C(Cl)Cl.CC(O)=O.[Pt]>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][C:11]2[N:10]=[CH:9][N:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:12]=2)=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ncn1
Agent: [Pt]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: COCC(=O)Nc1cc(Oc2ccc(N)cc2)ncn1

Procedure:
A solution of 2-methoxy-N-(6-(4-nitrophenoxy)pyrimidin-4-yl)acetamide (730 mg, 2.53 mmol) in a mixture of MeOH and DCM (1:1 v/v, 80 mL) containing AcOH (5 drops) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, RT, 10% Pt/C, full hydrogen mode) and was then evaporated in vacuo. The residue was partitioned between DCM (100 mL) and saturated aq NaHCO3 solution (25 mL). The organic layer was separated and washed with brine (25 mL) and then dried (MgSO4). Evaporation of the volatiles in vacuo gave the title compound, Intermediate N1, (560 mg, 66%, estimated 82% purity); Rt 0.93 min (Method 2); m/z 275 (M+H)+ (ES+). This material was used directly in the next step without further purification.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([NH2:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:40][CH:33]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Reactant: NC1CCCCCC1
Solvent: O
Solvent: CCO
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NC4CCCCCC4)ncnc32)[C@]1(C)F
Yield: 67.4 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.55 g, 1.10 mmol) in ethanol (about 5 ml) was added cycloheptylamine (about 1.80 ml, 14.2 mmol) and refluxed for about 30 minutes. Completion of the reaction mixture monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compound (0.4 g) as a colorless solid. Yield: 62%; 1H-NMR: 1H NMR (300 MHz, CDCl3): δ 8.38 (s, 1H), 8.04 (d, 2H), 7.97 (s, 1H), 7.60-7.55 (m, 1H), 7.47-7.42 (m, 2H), 6.52 (d, 1H, J=22.2 Hz), 5.81 (bs, 1H), 4.83-4.77 (m, 2H), 4.48-4.41 (m, 1H), 2.15 (s, 3H), 1.89-1.88 (s, 3H), 1.62-1.11 (m, 16H); ES Mass: [M+1]+ 540 (60%), [M+Na] 562 (100%); IR cm−: 3430, 2924, 2853, 2348, 1753, 1725, 1617, 1451, 1274, 1060, 950, 711. HPLC: 92%.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]([O:15][CH2:16][CH2:17][CH3:18])=S)=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.[CH2:19]([NH2:22])[CH2:20][CH3:21]>>[I:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:12]=[C:13]([O:15][CH2:16][CH2:17][CH3:18])[N:22]([CH2:19][CH2:20][CH3:21])[C:7]2=[O:9]
Reactant: CCCN
Reactant: CCCOC(=S)Nc1ccc(I)cc1C(=O)OC
Product: CCCOc1nc2ccc(I)cc2c(=O)n1CCC
Reaction time: 48 h

Procedure:
To the remaining 320 mL solution of methyl 5-iodo-2-[(propoxythioxomethyl)amino]benzoate from Step C above was added 10.86 mL (0.132 mol) of propylamine. The reaction solution was heated at reflux overnight, concentrated to 1/3 volume under reduced pressure, and treated with 75 mL water added dropwise at room temperature. Following refrigeration at 0-5° C. overnight, an additional 25 mL H2O was added and cooling was continued for an additional 48 h. Filtration of the ensuing mixture provided 15.68 g of the title compound, 1H NMR (300 MHz, CDCl3): δ0.96 (t,3H); 1.06 (t,3H); 1.64-1.79 (m,2H); 1.81-1.92 (m,2H); 4.05 (t,2H); 4.43 (t,2H); 7.19 (d,1H); 7.85 (dd,1H); 8.49 (d,1H), m.p. 49-53° C.