Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16](Cl)[N:15]=1.C(N(CC)CC)C>C(#N)C>[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH:12][CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:15]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: NCc1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Clc1nc(NCc2cccc3ccccc23)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 64 h
Yield: 97.4 %

Procedure:
1-Naphthylmethanamine (5.4 g, 19.7 mmol) was added to a stirred solution of 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (3.5 g, 22.3 mmol) (Preparation 19) and triethylamine (4 g, 39.6 mmol) in acetonitrile (150 ml) at room temperature. The reaction mixture was stirred at room temperature for 64 hours. The solvent was removed under reduced pressure, ethyl acetate (100 ml) was added and then the solvent was removed under reduced pressure again. The residue was purified by column chromatography on silica gel eluting with pentane: ethyl acetate (1:1 by volume) increasing in polarity to neat ethyl acetate. The solvent was removed under reduced pressure to give the title compound (7.56 g) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2].[CH2:32]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[C:33]#[CH:34].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:15]=[C:16]([C:34]#[C:33][CH2:32][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:19]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2]
Reactant: C#CCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCCC3CCCCC3)c2)cc1C
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCCC3CCCCC3)c2)cc1C

Procedure:
The title product was prepared from {4-[3-Bromo-5-(2-cyclohexyl-ethoxy)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (300 mg; 0.59 mmol) and 4-prop-2-ynyl-morpholine (222.0 mg; 1.77 mmol) applying the procedure described for {4-[3-[2-(4-Chlorophenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 200 mg (30%). HPLC-MS: m/z: 551.8 (M)+; Rt: 2.35 min
Reaction SMILES: Br[CH:2]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:17]([O:21][C:22](=[O:33])[C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28](=[O:32])[C@H:29]([CH3:31])[NH2:30])([CH3:20])([CH3:19])[CH3:18].C(OCC)C>C1(C)C=CC=CC=1>[C:17]([O:21][C:22](=[O:33])[C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28](=[O:32])[C@H:29]([CH3:31])[NH:30][CH:2]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])([CH3:19])([CH3:18])[CH3:20]
Reactant: CC(C)(C)OC(=O)C(Br)C(=O)OC(C)(C)C
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C[C@H](NC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 14 h

Procedure:
Di-t-butyl bromomalonate (15.9 g.) was added to a stirred solution of L-alanyl-L-proline t-butyl ester (26 g.) in toluene (30 ml.) which was cooled to 0° C., and the mixture was allowed to warm up to laboratory temperature during 2 hours and was stirred at that temperature for 14 hours. Diethyl ether (300 ml.) was added, the mixture was filtered to remove unreacted L-alanyl-L-proline t-butyl ester as the hydrobromide salt thereof, andthe filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (400 ml.) and the mixture was washed successively twice with aqueous 0.5N-citric acid solution (100 ml. each time), once with water (100 ml.) and once with saturated aqueous sodium chloride solution (100 ml.), dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue was purified by chromatography on a silica gel column using a 9:1 v/v mixture of dichloromethane and ethyl acetate as eluant, and there was thus obtained as an oil N-[di-t-butoxycarbonylmethyl]-L-alanyl-L-proline t-butyl ester.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH:20]1([CH2:26][NH:27][CH2:28][CH:29]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH2:36])[CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(OCC)(=O)C.C(OC(C)C)(C)C>>[CH:20]1([CH2:26][NH:27][CH2:28][CH:29]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH:36][C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:30]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: NCCN1CCC(CNCC2CCCCC2)C1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCC(CNCC3CCCCC3)C2)c2ccccc21
Yield: 19 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[[(cyclohexyl)methylamino]methyl]-pyrrolidin-1-yl]ethanamine in a yield of 19% of theory. Colourless crystals, m.p. 166°-167° C. (ethyl acetate/methanol 1/1 v/v).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Si:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:13])[CH:3]=1.CC1CCCN(C)C1(C)C.[Li].CN([CH:28]=[O:29])C>C1COCC1>[Cl:1][C:2]1[C:3]([CH:28]=[O:29])=[C:4]([F:13])[C:5]([Si:9]([CH3:10])([CH3:12])[CH3:11])=[C:6]([F:8])[CH:7]=1
Reactant: C[Si](C)(C)c1c(F)cc(Cl)cc1F
Reactant: CN(C)C=O
Agent: CC1CCCN(C)C1(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: C[Si](C)(C)c1c(F)cc(Cl)c(C=O)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
A solution of 1-chloro-3,5-difluoro-4-trimethylsilylbenzene (1.5 g, 6.8 mmol) in THF (10 mL) was added to a solution of lithium tetramethylpiperdine (14 mmol) in THF (15 mL) at −75° C. The solution was stirred for 2 hours then DMF (1.5 g, 20 mmol) was added and the solution allowed to warm to ambient temperature. The reaction was quenched with a saturated solution of ammonium chloride (25 mL) and extracted with ethyl ether (2×25 mL) and the combined extracts dried (sodium sulfate) and concentrated. The residue was purified by chromatography (hexanes) to give 6-chloro-2,4-difluoro-3-trimethylsilylbenzaldehyde (1.4 g, 5.6 mmol): LC/MS (m/z=248).
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[CH:17]=[CH:16][C:8]([CH2:9][C@H:10]2[CH2:14][O:13][C:12](=[O:15])[NH:11]2)=[CH:7][CH:6]=1)[NH2:4].C(O[CH:21](OCC)[CH2:22][CH2:23][C:24]#[N:25])C>O>[C:24]([CH2:23][CH2:22][CH:21]=[N:4][NH:3][C:5]1[CH:17]=[CH:16][C:8]([CH2:9][C@H:10]2[CH2:14][O:13][C:12](=[O:15])[NH:11]2)=[CH:7][CH:6]=1)#[N:25]
Reactant: NNc1ccc(C[C@H]2COC(=O)N2)cc1
Reactant: CCOC(CCC#N)OCC
Agent: Cl
Solvent: O
Product: N#CCCC=NNc1ccc(C[C@H]2COC(=O)N2)cc1
Reaction time: 2 h
Yield: 93.2 %

Procedure:
1M aqu. HCl (4.0 ml) was added to a solution of the product from step (a) (2.4 g) in water (35 ml). 3-Cyanopropanal diethylacetal (Aldrich, 1.7 g) was added at room temperature and the mixture stirred for 2 hours. Further acetal (0.20 g) was added and the mixture stirred for another 20 minutes. The aqueous phase was decanted from the resulting gum and extracted with ethyl acetate. The extracts were combined with the gum and evaporated in vacuo to give the desired product (2.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][CH:8]=[N+:9]([O-])[C:10]=2[CH:11]=1.C1(C)C=CC(S(Cl)(=O)=[O:20])=CC=1.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[NH:9]2)=[N:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [O-][n+]1cccc2ncc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=c1ccc2ncc(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of 0.50 g of 3-bromo-1,5-naphthyridin-5-oxide in 10 mL of chloroform, 0.51 g of p-toluenesulfonyl chloride, 1.04 g of potassium carbonate and 3 mL of water were added, and the mixture was stirred at room temperature overnight. Thereto were added water and chloroform, and the solid was filtered off to obtain 0.39 g of 7-bromo-1,5-naphthyridin-2(1H)-one as a white solid.
Reaction SMILES: [CH3:1][C:2]1([C:15]([O:17]CC)=[O:16])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[OH-].[Li+].Cl>C1COCC1.CO>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C:2]([CH3:1])([C:15]([OH:17])=[O:16])[CH2:3]1)=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(C)(C(=O)O)C1
Reaction time: 15 h
Yield: 98 %

Procedure:
To a solution of 1-tert-butyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylate (15 g, 55.3 mmol) in THF (87 mL) and MeOH (87 mL) was added lithium hydroxide(2M in water) (172 mL, 345 mmol) at RT and stirred at same temperature for 15 h. The reaction mixture was cooled in an ice-bath, and adjusted to pH ˜4 by adding 1N HCl solution. The aqueous layer was extracted with ethylacetate (3×200 mL) and the combined organic extracts was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated to give desired 1-(tert-butoxycarbonyl)-3-methylpiperidine-3-carboxylic acid (13.45 g, 54.2 mmol, 98% yield) as a white solid. This material was directly used for next step with out any further purification. Anal. Calcd. for C12H21NO4 m/z 243.3, found: 242.2 (M−H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.31 (s, 1 H) 3.68-3.52 (m, 1 H), 3.32-3.02 (m, 4 H), 1.89-1.82 (m, 1 H), 1.54-1.43 (m, 11 H) 1.06 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[C:4]([CH3:23])[CH:3]=1.C(N(CC)CC)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:33]=1[N:42]=[C:43]=[O:44]>C(Cl)Cl>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:33]=1[NH:42][C:43]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[C:4]([CH3:23])[CH:3]=1)=[O:44]
Reactant: Cc1cc(N)ccc1C1CN=C2c3ccccc3NC(=O)N2C1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)ccc1C1CN=C2c3ccccc3NC(=O)N2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a mixture of 3-(4-amino-2-methylphenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (92 mg, 0.30 mmol) and triethylamine (0.125 mL, 0.90 mmol) in 2.5 mL CH2Cl2 at rt was added 2-fluoro-5-(trifluoromethyl)phenyl isocyanate (0.065 mL, 0.45 mmol) and the reaction stirred at rt. After 2.5 hours the reaction was quenched with 0.3 mL MeOH, and then stored overnight in the refrigerator. The reaction mixture was filtered and rinsed with EtOAc to give the title compound as an off-white solid (130 mg, 84%). 1H NMR (DMSO-d6) δ: 10.69 (s, 1H), 9.09 (s, 1H), 8.87 (d, J=2.9 Hz, 1H), 8.63 (dd, J=7.5, 2.2 Hz, 1H), 7.99 (dd, J=7.9, 1.2 Hz, 1H), 7.33-7.53 (m, 4H), 7.24-7.29 (m, 1H), 7.13-7.17 (m, 1H), 7.00-7.10 (m, 2H), 4.15-4.23 (m, 1H), 3.64-3.73 (m, 1H), 3.46-3.56 (m, 2H), 3.07-3.15 (m, 1H), 2.33 (s, 3H)
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[BH4-].[Na+]>CO.O>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: N#Cc1ccc(N2CCC(=O)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(N2CCC(O)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
240 mg (1.2 mmol) of 4-(4-oxo-piperidin-1-yl)-benzonitrile (reference example 116) was dissolved in 5 ml of methanol, 23 mg (0.6 mmol) of NaBH4 was added and stirred 3 h at room temperature. A few drops of water were added, methanol evaporated then 20 ml of water were added and extracted with DCM (3×), dried with Na2SO4, filtered and evaporated to give 230 mg (95% yield) of the title compound. 1H NMR (CDCl3): d 7.47 (d, 2H), 6.85 (d, 2H), 3.93 (bs, H), 3.70 (m, 2H), 3.11 (m, 2H), 1.95 (m, 2H), 1.62 (m, 2H). MS (ion spray) m/z 202 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:14](=O)[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([Br:21])[CH:16]=2)=[CH:10][C:11]=1[O:12][CH3:13])[C:6](O)=[O:7].O.[NH2:24][NH2:25]>C(O)C>[Br:21][C:17]1[CH:16]=[C:15]([C:14]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=3)[C:6](=[O:7])[NH:25][N:24]=2)[CH:20]=[CH:19][N:18]=1
Reactant: NN
Reactant: COc1cc(C(=O)O)c(C(=O)c2ccnc(Br)c2)cc1OC
Solvent: O
Solvent: CCO
Product: COc1cc2c(-c3ccnc(Br)c3)n[nH]c(=O)c2cc1OC

Procedure:
3,4-Dimethoxy-6-(2-bromoisonicotinoyl)benzoic acid (15.2 g) and hydrazine monohydrate (15 ml) are added to ethanol (30 ml), and the mixture is heated under reflux for one hour. The reaction mixture is cooled with ice, and the precipitates are collected by filtration to give 2-bromo-4-(6,7-dimethoxyphthalazin-1(2H)-on-4-yl)pyridine (14.1 g).
Reaction SMILES: [ClH:1].[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Cl:15][C:16]1[CH:29]=[CH:28][C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][N:36]([CH2:39][CH2:40]Cl)[CH2:35][CH2:34]3)[C:18]=2[CH:17]=1.[OH-].[Na+]>CS(C)=O.O>[ClH:15].[ClH:1].[ClH:15].[Cl:15][C:16]1[CH:29]=[CH:28][C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:30][CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][N:36]([CH2:39][CH2:40][O:14][C:11]4[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][CH2:4][NH:3][CH3:2])=[CH:13][CH:12]=4)[CH2:37][CH2:38]3)[C:18]=2[CH:17]=1
Reactant: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Reactant: CNCCCOc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CNCCCOc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1
Reaction time: 4 h
Yield: 33.3 %

Procedure:
A solution of 4-(3-methylaminopropoxy)phenol hydrochloride (4.7 g) and 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-(2-chloroethyl)piperazine (10.7 g) (as its dihydrochloride) in dimethylsulfoxide (125 ml) was stirred under nitrogen during the addition of sodium hydroxide (3.46 g) in water (5 ml). The reaction was then stirred at 55° for 4 hours and then was diluted with water (500 ml). The oil which separated was extracted into ethyl acetate and hydrogen chloride was bubbled into the solution previously dried over potassium carbonate to precipitate the crude product as its trihydrochloride salt (4.3 g). Crystallization of the salt from acetonitrile-methanol yielded 1.9 g of 3-[[4-[2-[4-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-1-piperazinyl]ethoxy]phenyl]oxy]-N-methylpropanamine trihydrochloride, mp 223°-226°.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:52]([O-])(=[S:54])[CH3:53].[K+]>C(Cl)(Cl)(Cl)Cl>[CH3:25][C:2]1([CH3:1])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=3)[CH:8]=[CH:7][C:6]=2[CH:5]([C:52](=[S:54])[CH3:53])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3)cc1
Reactant: CC([O-])=S
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3C(C)=S)cc1

Procedure:
To a solution of 543 mg (1.64 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (obtainable from Compound M by coupling with ethyl-4-iodobenzoate) in 20 ml of CCl4 was added 320 mg (1.81 mmol) of N-bromosuccinimide and 26 mg (0.11 mmol) of benzoyl peroxide. The mixture was refluxed for 3 hours under argon atmosphere, cooled, filtered through celite and concentrated in vacuo to a dark brown syrup. The syrup was taken up in 20 ml of dry THF and 780 mg (6.9 mmol) of potassium thioacetate was added. The mixture was refluxed for 4 hours under argon atmosphere, concentrated in vacuo and purified by chromatography (silica, 10% EtOAc-hexane) to yield the title compound as a pale yellow solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:28])([CH3:27])[C@@H:14](O)[C:15]([O:17][CH2:18][CH2:19][O:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2].[P:29](Cl)(OC1C=CC=CC=1)([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:28])([CH3:27])[C@@H:14]([PH:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30])[C:15]([O:17][CH2:18][CH2:19][O:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OCCOC(=O)C(C)C
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@H](C(=O)OCCOC(=O)C(C)C)[PH](=O)Oc1ccccc1
Yield: 91 %

Procedure:
Following the general procedure for phosphorylation of Description 23, (2-methylpropanoyloxy)ethyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-hydroxy-butanoate (29) (1.0 g, 2.4 mmol) dissolved in 20 mL of anhydrous dichloromethane (DCM) was reacted with 1.46 mL (1.9 g, 7.0 mmol) of diphenyl chlorophosphate [(PhO)2POCl] in the presence of 4-(N,N-dimethylamino)pyridine (DMAP) (0.17 g, 1.4 mmol) and triethylamine (TEA) (0.97 mL, 0.71 g, 7.0 mmol). The reaction was monitored by TLC. After aqueous work-up, the crude material was further purified by silica gel column chromatography using ethyl acetate (EtOAc) as eluent to provide 1.2 g (80% yield) of the title compound (49a) as a colorless oil. Rf=0.55 (EtOAc). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.06-1.15 (m, 12H), 1.40-1.46 (2d, J=5.6, 5.6 Hz, 3H), 1.85 (s, 3H), 2.01-2.08 (m, 2H), 2.45-2.55 (m, 1H), 3.13-3.17 (m, 2H), 3.28-3.33 (m, 2H), 3.97-4.04 (m, 2H), 4.84-4.88 (2d, J=7.2, 7.6 Hz, 1H), 6.32-6.36 (br. m, 1H), 6.88-6.93 (m, 1H), 7.18-7.26 (m, 6H), 7.31-7.38 (m, 4H) ppm. MS (ESI) m/z 658.25 (M+H)+. The analytical data was consistent with proposed structure.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[C:8]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[C:25]([Br:26])=[CH:24][C:23]([C:27](=[O:29])[CH3:28])=[C:22]([OH:30])[C:21]=2[CH2:31][CH2:32][CH3:33])[C:7]=1[CH2:34][CH2:35][CH3:36].[OH-].[Na+]>CO.C(OCC)(=O)C>[C:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:37])=[O:2])=[C:7]([CH2:34][CH2:35][CH3:36])[C:8]=1[O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:25]([Br:26])=[CH:24][C:23]([C:27](=[O:29])[CH3:28])=[C:22]([OH:30])[C:21]=1[CH2:31][CH2:32][CH3:33])(=[O:14])[CH3:13]
Reactant: CCCc1c(O)c(C(C)=O)cc(Br)c1OCCCOc1c(C(C)=O)ccc(OCC(=O)OC)c1CCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1c(O)c(C(C)=O)cc(Br)c1OCCCOc1c(C(C)=O)ccc(OCC(=O)O)c1CCC
Reaction time: 16 h
Yield: 47.8 %

Procedure:
To a solution of 2.1 g (0.0037 mol) of [4-acetyl-3-[3-(4-acetyl-6-bromo-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]acetic acid methyl ester in 50 ml of methanol was added 50 ml (0.05 mol) of 1N sodium hydroxide. The mixture was stirred at 25° for 16 hours and acidified to pH 4. The gummy precipitate was dissolved in ethyl acetate and washed with sodium choloride solution. The gummy solid obtained on concentration of the ethyl acetate was purified by C18 reverse phase column chromatography, eluting with 60% to 75% of methanol in water to yield 1.0 g, melting point 129°-130° (48% yield) of [4-acetyl-3-[3-(4-acetyl-6-bromo-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]acetic acid.
Reaction SMILES: Br[CH2:2][C:3]([O:11][CH3:12])=[CH:4][C:5](=[O:10])[C:6]([Cl:9])([Cl:8])[Cl:7].[C:13]([O-:16])(=[O:15])[CH3:14].[K+].C(O)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[C:13]([O:16][CH2:2][C:3]([O:11][CH3:12])=[CH:4][C:5](=[O:10])[C:6]([Cl:9])([Cl:8])[Cl:7])(=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: COC(=CC(=O)C(Cl)(Cl)Cl)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=CC(=O)C(Cl)(Cl)Cl)COC(C)=O

Procedure:
29.6 g (0.1 mol) of 5-bromo-1,1,1-trichloro-4-methoxypent-3-en-2-one, 17 g of potassium acetate, 5 g of tetrabutylammonium bromide and 8 g of acetic acid were stirred at 40° C. in 300 ml of acetonitrile for 16 h. The mixture was concentrated under reduced pressure, and the water was added to the residue. The product was extracted with ethyl acetate, the organic phase was washed with water and the solvent was removed completely under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]([OH:13])[CH3:12])=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]([O:13][S:28]([CH3:27])(=[O:30])=[O:29])[CH3:12])=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)c1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
To a solution of 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-ethanol (500 mg) in dichloromethane (20 mL) at 0° C. was added triethylamine (0.28 mL) and then methanesulphonyl chloride (0.14 mL) and the reaction stirred at room temperature for 16 h. The reaction was quenched with water (20 mL) and extracted into dichloromethane (2×20 mL). The combined organic layers were washed with aqueous brine solution (2×20 mL), dried (MgSO4) and reduced in vacuo to give methanesulfonic acid 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-ethyl ester as a yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CCOC(=O)Cc1ccc(I)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(Br)cc2)cc1
Yield: 71 %

Procedure:
In accordance with Example 11-(1), but using ethyl 4-iodophenylacetate instead of 4-bromobenzyl bromide, and (4-bromophenyl)boronic acid instead of [3-(hydroxymethyl)phenyl]boronic acid, ethyl (4′-bromobiphenyl-4-yl)acetate (yield 71%) was afforded as a white solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:4]2[N:5]([CH:19]=[CH:20][N:21]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:8]=1.C([O-])(=O)C.[Na+].[I:29]Cl>C(O)(=O)C>[I:29][C:19]1[N:5]2[CH:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[CH:8]=[C:3]([C:2]([F:1])([F:22])[F:23])[C:4]2=[N:21][CH:20]=1
Reactant: ClI
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3nccn3c2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3ncc(I)n3c2)cc1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a solution of 8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (1.36 g, 4.1 mmol) in 5 mL of acetic acid was added sodium acetate (0.51 g, 6.2 mmol) and a solution of iodine monochloride (2M, 2.5 mL, 5.0 mmol)-slightly exothermic. The reaction mixture was stirred for 30 min at 23° C., precipitate formed, then partitioned between 60 mL of water and 60 mL of EtOAc. The organic layer was washed with sat. NaHCO3, water, aq. sodium thiosulfate, water, then dried over Na2SO4, filtered and concentrated to give 1.36 g (72%) of an off-white solid. MS (ISP) 457.3 [(M+H)+].