Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]([C@H:18]2[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:26]([S:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])=[O:29])[CH3:27]>>[CH:1]1([N:7]([C@H:18]2[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:34]3[CH2:33][CH2:32][N:31]([S:28]([CH2:26][CH3:27])(=[O:29])=[O:30])[CH2:36][CH2:35]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(C=O)s2)C2CCCCC2)CC1
Agent: Cl
Product: CCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)[C@H]3CC[C@H](C)CC3)s2)CC1

Procedure:
Prepared in 60% (307 mg) yield as described in general procedure (B) from trans-1-cyclohexyl-3-(5-formyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-urea (349 mg, 1.0 mmol) and 1-ethanesulfonyl-piperazine hydrochloride (215 mg, 1.0 mmol).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)[CH2:10][C:9]2([CH3:27])[CH3:26])=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH3:26][C:9]1([CH3:27])[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)[CH2:10]1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(F)(F)F)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CC(c2cccc(C(F)(F)F)c2)Nc2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 12 h
Yield: 94.9 %

Procedure:
A mixture of 4,4-dimethyl-2-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.0 g, 7.96 mmol), lithium hydroxide hydrate (3.34 g, 79.6 mmol), water (10 mL) in methanol (10 mL) and tetrahydrofuran (20 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 mol/L aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 4,4-dimethyl-2-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2.64 g, 95%) as a white solid which was used for next step without further purification: MS (ESI) M+1=350.4.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[C:6]([S:19]([NH:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])(=[O:21])=[O:20])([C:9]([C:12]([C:15]([F:18])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C(OCCOCCO)CCC>O>[C:6]([S:19]([N:22]([CH2:23][CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])[CH2:3][CH2:2][C:1]([OH:5])=[O:4])(=[O:20])=[O:21])([C:9]([C:12]([C:15]([F:16])([F:17])[F:18])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7]
Reactant: CN(C)CCCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C=CC(=O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CCCCOCCOCCO
Solvent: O
Product: CN(C)CCCN(CCC(=O)O)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 125 °C

Procedure:
An acrylic acid Michael addition reaction was then run according to the general procedure given in U.S. Pat. No. 5,144,069 (Stern et al.). 50 g (0.12 mole) of the purified C4F9SO2N(H)C3H6N(CH3)2, 16.4 g (0.23 mole) of acrylic acid and 0.2 g of phenothiazine (free radical polymerization inhibitor) were added to a 250-mL three-neck flask equipped with an air stirrer and thermometer. The resulting mixture was heated to 125° C. and was allowed to react for 6 hours. After this reaction period, a positive solubility check of the product in water of pH 7 indicated that the Michael addition reaction was essentially complete. While still mixing, a solvent blend of 18 g of diethylene glycol monobutyl ether and 42 g of deionized water was added and the mixture was allowed to cool to room temperature. The water solubility test was run again with the same positive result, showing good conversion to the desired Michael addition product, C4F9SO2N(C2H4COOH)C3H6 (CH3)2.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.C(=S)=S>>[Br:10][C:11]1[S:12][C:13]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:14][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Brc1cccs1
Solvent: S=C=S
Product: O=C(c1ccccc1)c1ccc(Br)s1
Reaction time: 2.5 h
Yield: 96.2 %

Procedure:
To a mixture of benzoyl chloride (2.81 g, 20.0 mmol) and 2-bromothiophene (3.42 g, 21.0 mmol) in carbon disulfide (120 mL) aluminum chloride (5.34 g, 40.0 mmol), was added in portions over 10 min with vigorous magnetic stirring. The reaction was next allowed to stir for 2.5 h before being quenched with 100 mL 1 M HCl(aq). The organics were separated, the aqueous layer extracted with carbon disulfide (3×50 mL), and the combined organics washed with water (3×100 mL) and dried over MgSO4. After filtration, the organics were concentrated in vacuo and the residue chromatographed on a silica gel column (hexane:ether=9:1) to yield 5.14 g (96%) of yellow crystals. mp 41-43° C.; 1H NMR (CDCl3): δ 7.84 (d, 2H, 3J=8.0 Hz), 7.62 (t, 1H, 3J=7.2 Hz), 7.52 (t, 2H, 3J=7.5 Hz), 7.40 (d, 2H, 3J=3.5 Hz), 7.15 (d, 2H, 3J=4.0 Hz).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]1[N:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.Br[C:18]1[C:19]([NH2:24])=[N:20][CH:21]=[CH:22][CH:23]=1>COCCOC.O.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>[F:7][C:8]1[N:13]=[CH:12][C:11]([C:18]2[C:19]([NH2:24])=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: Nc1ncccc1Br
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: O
Solvent: COCCOC
Product: Nc1ncccc1-c1ccc(F)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A mixture of sodium carbonate (5.79 g), tetrakis(triphenylphosphine)palladium(0) (0.631 g), 6-fluoropyridin-3-ylboronic acid (5 g) and 3-bromopyridin-2-amine (4.72 g) in DME (75 mL) and water (15 mL) was stirred at 80° C. overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane, then. NH silica gel, eluted with EtOAc in hexane) to give the title compound (4.53 g) as a colorless solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[CH:9]=2)[CH:4]=1.[C:22]1([C:28]2[C:32]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][NH:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][O:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]=[C:3]([CH2:2][N:30]1[CH:31]=[C:32]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:28]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:29]1)[CH:12]=[CH:11]2
Reactant: CCOC(=O)CCc1c[nH]nc1-c1ccccc1
Reactant: Fc1ccccc1COc1ccc2cc(CCl)ccc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc3cc(OCc4ccccc4F)ccc3c2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
2-Chloromethyl-6-(2-fluorobenzyloxy)naphthalene (540 mg) and ethyl 3-(3-phenyl-1H-pyrazol-4-yl]propionate (390 mg) were dissolved in N,N-dimethylformamide (10 ml). Sodium hydride (60%, oily, 70 mg) was added to the solution at 0° C., which was stirred at room temperature for two hours. The reaction mixture was poured into saturated aqueous sodium chloride solution, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[6-(2-fluorobenzyloxy)-2-naphthylmethyl]-3-phenyl-1H-pyrazole-4-yl]propionate (0.58 g, yield: 72%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:39])=[C:4]([N:8]([CH2:17][C:18]2[CH:38]=[CH:37][C:21]([O:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:36])=[C:27]([CH:35]=3)[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:20][CH:19]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:5]=[CH:6][CH:7]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>N1C=CC=CC=1>[CH3:2][CH3:7].[Cl:36][C:26]1[CH:25]=[CH:24][C:23]([O:22][C:21]2[CH:37]=[CH:38][C:18]([CH2:17][N:8]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:41]([CH3:40])(=[O:43])=[O:42])[C:3]=3[CH3:39])=[CH:19][CH:20]=2)=[CH:35][C:27]=1[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)COc1cc(Oc2ccc(CN(Cc3ccccc3F)c3cccc(N)c3C)cc2)ccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC
Product: CCOC(=O)COc1cc(Oc2ccc(CN(Cc3ccccc3F)c3cccc(NS(C)(=O)=O)c3C)cc2)ccc1Cl
Reaction time: 1 h

Procedure:
The product from Example 306C in anhydrous pyridine (1.5 mL) was cooled at 0° C. and treated with methane sulfonyl chloride (0.042 mL, 0.54 mmoles) at 0° C. for 1 hour, then room temperature for 1 hour. The reaction mixture concentrated in vacuo, residue dissolved in dichloromethane, filtered and filtrate concentrated in vacuo to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13]O)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(NC(C)C)(C)C.CS(Cl)(=O)=O.[C:28]1([SH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[C:9]([O:8][C:6]([NH:5][C@H:4]([C:3]([O:2][CH3:1])=[O:15])[CH2:13][S:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: Sc1ccccc1
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CSc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 0° C. solution of N-(tert-butoxycarbonyl)-L-serine methyl ester (30 g, 137 mmol) and diisopropylamine (58 mL, 330 mmol) in dichloromethane (250 mL) was treated with methanesulfonyl chloride (11.65 mL, 151 mmol), stirred for 20 minutes, treated with thiophenol (15.5 mL, 151 mmol), warmed to room temperature, stirred for 30 minutes, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)) m/e 310 (M−H)−.
Reaction SMILES: [CH2:1]([C@:3]1([OH:23])[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH2:16][CH:15]=[C:14]([O:21]C)[CH2:13][C:12]=1[CH2:11][CH2:10]3)[CH3:2].Cl>O.CO>[CH2:1]([C@:3]1([OH:23])[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@]1(O)CC[C@H]2[C@@H]3CCC4=C(CC=C(OC)C4)[C@H]3CC[C@@]21C
Agent: Cl
Solvent: CO
Solvent: O
Product: CC[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Yield: 47.1 %

Procedure:
Stir dl-17α-ethyl-3-methoxyestra-2,5(10)-dien-17-ol (1.4 g) with concentrated hydrochloric acid (2.4 ml) in water (1.6 ml) and methanol (36 ml) for two hours. Add water, extract with ether and wash, dry and evaporate the ethereal solution. Recrystallize the product from ethyl acetate-ether to obtain the title compound (0.63 g), m.p. 173°-174.5°; ultraviolet absorption maximum at 240 mμ (ε17,500).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].O.[Na+].Cl[C:19]([F:24])([F:23])C([O-])=O>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][CH:19]([F:24])[F:23])[CH:3]=1
Reactant: Oc1cc(F)cc(Br)c1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cc(Br)cc(OC(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-bromo-5-fluorophenol (0.5 g, 2.6 mmol) in DMF (4.5 mL) was added K2CO3 (0.9 g, 6.54 mmol) and stirred at 25° C. for 10 min. Water (0.5 mL) was added to the above mixture followed by addition of 2-Chloro-2,2-difluoroacetic acid sodium salt (0.6 g, 3.93 mmol) and stirring was continued at 100° C. for 3 h. The reaction mixture was cooled to 25° C. and diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by column chromatography (using silica gel and 2% ethyl acetate in Hexane as eluent) to afford the desired compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.2-6.9 (2H, m), 6.8-6.7 (1H, d), 6.7-6.2 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]([N:9]([CH:16]([CH3:18])[CH3:17])[C:10](=O)[C:11]([F:14])([F:13])[F:12])[C:7]#N)=[CH:4][CH:3]=1.ClC(=C)[C:23]#[N:24].[C:26](OCC)(=O)C.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[N:9]([CH:16]([CH3:17])[CH3:18])[C:10]([C:11]([F:12])([F:13])[F:14])=[CH:26][C:7]=2[C:23]#[N:24])=[CH:19][CH:20]=1
Reactant: C=C(Cl)C#N
Reactant: CCOC(C)=O
Reactant: CC(C)N(C(=O)C(F)(F)F)C(C#N)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)n1c(C(F)(F)F)cc(C#N)c1-c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 20.8 %

Procedure:
A solution of N-(p-chloro-α-cyanobenzyl)-2,2,2-tri-fluoro-N-isopropylacetamide (6.1 g, 0.02 mol) in toluene is treated at room temperature with tetrafluoroboric acid diethyl etherate (4.2 g as is, 3.6 g real, 0.022 mol) under a nitrogen atmosphere, heated to 60° C., treated with 2-chloroacrylonitrile (2.62 g, 0.03 mol) over 15-20 minutes, held at 60° C. for 3 hours, cooled to room temperature and treated with ethyl acetate and water. The phases are separated and the organic phase is washed with water and concentrated to give a brown gum residue. Flash column chromatography of the residue on silica gel packed and eluted with 15% ethyl acetate in heptane gives the title product as a brown oil, 1.3 g (20.8% yield), identified by 1H and 19F NMR and mass spectral analyses.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[C:9]([O:15][CH2:16][O:17][P@@:18]([CH2:27][O:28][CH:29]([CH3:41])[CH2:30][N:31]1[CH:39]=[N:38][C:37]2[C:32]1=[N:33][CH:34]=[N:35][C:36]=2[NH2:40])([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].N.[OH2:43]>>[C:1]([OH:8])(=[O:7])[C@@H:2]([C@H:3]([C:4]([OH:6])=[O:5])[OH:14])[OH:43].[C:9]([O:15][CH2:16][O:17][P@@:18]([CH2:27][O:28][C@H:29]([CH3:41])[CH2:30][N:31]1[CH:39]=[N:38][C:37]2[C:32]1=[N:33][CH:34]=[N:35][C:36]=2[NH2:40])([O:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:19])(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(Cn1cnc2c(N)ncnc21)OC[P@](=O)(OCOC(=O)C(C)(C)C)Oc1ccccc1
Reactant: O
Reactant: O=C(O)/C=C/C(=O)O
Agent: N
Product: C[C@H](Cn1cnc2c(N)ncnc21)OC[P@](=O)(OCOC(=O)C(C)(C)C)Oc1ccccc1
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reaction time: 0.5 h

Procedure:
In a round bottom flask, fumaric acid salt of ((R)-((1-(6-amino-9H-purin-9-yl)propan-2-yloxy)methyl)(phenoxy)phosphoryloxy)methyl pivalate (50 g), water (500 ml) and liquid ammonia (50 ml) at 23-25° C. The reaction mass was stirred for 30 minutes and extracted with dichloromethane (500 ml). The organic layer was collected and distilled under vacuum. To the residue, 135 ml water and 27 ml acetonitrile was added. The contents were stirred at 23-25° C. for 15 minutes. L-tartaric acid (4.25 g) was added and stirred at 55-60° C. The material was filtered, washed with acetonitrile and dried at 40-45° C. to obtain ((R)—(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yloxy)methyl)(phenoxy)phosphoryloxy)methyl pivalate L-tartarate. (Yield—10 g, 80% diastereomeric purity). The solid was purified with water and acetonitrile to obtain ((R)—(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yloxy)methyl)(phenoxy)phosphoryloxy)methyl pivalate L-tartarate (Yield—7 g, 95% diastereomeric purity).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.S(=O)(O)[O-].[Na+].[N+:15]([CH2:18][CH3:19])([O-:17])=[O:16].[OH-].[Na+]>O>[N+:15]([CH:18]([CH3:19])[CH:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1)[OH:8])([O-:17])=[O:16]
Reactant: Cc1ccc(C=O)cc1
Reactant: CC[N+](=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C(O)C(C)[N+](=O)[O-])cc1

Procedure:
The procedure of Example 1 was followed for the reaction of 120 g of p-tolualdehyde and 114 g of sodium bisulfite with 150 g of 1-nitroethane and 80 g of sodium hydroxide. Water was the solvent. The final product was a yellow liquid weighing 103 g: ir (film) 2.85 (m), 3.4 (m), 6.5 (s), 7.2 (m), 7.35 (m), 9.5 (m), 12.15 (m) microns; nmr (CDCl3) 7.12 (4H, s), 5.0 to 4.5 (2H, m), 2.95 (1H, s), 2.3 (3H, s), 1.4 and 1.2 (3H, doublet and doublets) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:22][C:23]1[C:28](B(O)O)=[CH:27][CH:26]=[CH:25][N:24]=1.[O:32]1[CH2:37][CH2:36][CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH2:33]1>>[O:32]1[CH2:37][CH2:36][CH:35]=[C:34]([C:12]2[N:11]=[CH:10][C:9]3[O:8][C:5]4[C:4]([C@@:15]5([CH2:19][S:18][C:17]([NH2:20])=[N:16]5)[C:14]=3[CH:13]=2)=[CH:3][C:2]([C:28]2[C:23]([F:22])=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:7][CH:6]=4)[CH2:33]1
Reactant: OB(O)c1cccnc1F
Reactant: NC1=N[C@@]2(CS1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Product: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1cnc(C3=CCCOC3)cc12

Procedure:
The titled compound was synthesized by steps analogous to those described in method BB12 above, but using (S)-7-bromo-3-chloro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazol]-2′-amine (prepared as described in Method BB26 but using 7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one), 2-fluoropyridin-3-ylboronic acid and 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][N:7]([CH3:14])[CH2:6][CH:5]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[CH:17]=1.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>O=[V].Cl.Cl.Cl.C(Cl)Cl>[OH:1][C:2]1[C:3]2=[C:4]3[CH:5]([CH2:15][C:16]4[CH:17]=[C:18]([OH:24])[C:19]([O:22][CH3:23])=[CH:20][C:21]=42)[CH2:6][N:7]([CH3:14])[CH2:8][C:9]3=[CH:10][C:11]=1[O:12][CH3:13].[F:25][C:26]([F:31])([F:30])[C:27]([O-:29])=[O:28]
Reactant: COc1ccc(CC2CN(C)Cc3cc(OC)c(O)cc32)cc1O
Reactant: O=C(O)C(F)(F)F
Agent: O=[V]
Agent: Cl
Solvent: ClCCl
Product: COc1cc2c(cc1O)CC1CN(C)Cc3cc(OC)c(O)c-2c31
Product: O=C([O-])C(F)(F)F

Procedure:
1 g. (3 mMol) (±)-6-Hydroxy-7-methoxy-4-(3-hydroxy-4-methoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline is dissolved, with ice cooling, in 25 ml. trifluoroacetic acid and mixed at -10° C. with a solution of 0.42 ml. (0.77 g., 4.5 mMol) vanadium oxytrichloride in 5 ml. anhydrous methylene chloride within the course of 1 minute. The reaction mixture is allowed to react for 3 hours at -10° C., then concentrated in a vacuum to about one third of its volume and the concentrate partitioned between methylene chloride and water. Usual work up and crystallisation from acetone/diethyl ether gives (±)-5,6,6a,7-Tetrahydro-1,9-dihydroxy-2,10-dimethoxy-5-methyl-4H-dibenz(de,g)isoquinoline in the form of its trifluoroacetate; m.p. 208°-215° C.; yield 60-70% of theory. Hydrochloride: m.p. >300° C. (decomp.), after recrystallisation from methanol/chloroform.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
To a solution of m-bromoiodobenzene (25.0 g. 881.1 mmol) in diisopropylamine (500 ml), there were added bis(triphenylphosphine)palladium dichloride (1.24 g. 1.80 mmol) and copper (I) iodide (1.24 g, 2.03 mmol). The solution was degassed via a rapid stream of argon, and trimethylsilylacetylene (9.51 g, 97.0 mmol) was added over a period of 15 min. The reaction mixture was stirred at room temperature until G.C. analysis indicated the disappearance of starting material (2 h). The reaction mixture was cooled to room temperature and filtered to remove salts. The filtrate was concentrated in vacuo, and the oily residue was taken up in dichloromethane. The solution was washed with an aqueous 5% HCl solution (2×200 ml), water (2×200 ml) and brine (1×200 ml). The combined organic layers were dried (MgSO4) and the solvent removed in vacuo yielding the crude product as a yellow oil. The liquid chromatographed from silica gel in pentane. Elution with pentane gave the product (1b) (20.59 g, 91 %) as a clear liquid: bp 81°-82° C., 1H NMR (200 MHz, CDCl3) c 0.30 (s), 7.23(m).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:3]1.C[Si]([NH-])(C)C.[Na+].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[S:31])[CH:25]=[CH:26][C:27]=1[Cl:28]>C(Cl)(Cl)Cl.C1COCC1>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([N:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH:4]3[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]3)[CH2:10][CH2:11]2)=[S:31])[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: CN1CCCC(CN2CCNCC2)C1
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)[NH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1CCCC(CN2CCN(C(=S)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-[(1-methylpiperidin-3-yl)methyl]piperazine (400 mg) in chloroform (10 ml) was added a 2M solution of sodium(trimethylsilyl)amide in THF (2.2 ml). The resulting solution was stirred at room temperature for 10 minutes. 3,4-Dichlorophenylisothiocyanate (0.44 ml) was added and mixture stirred at room temperature for 1 hour. The reaction was quench with water (1 ml) then concentrated in vacuo before being separated between ethyl acetate (100 ml) and saturated sodium bicarbonate solution (100 ml). The ethyl acetate layer was separated, dried over magnesium sulphate, filtered then concentrated in vacuo onto silica gel (1.0 g). The resulting powder was purified by column chromatography on silica gel (50 g) using a gradient of 100% dichloromethane through to 10% methanolic ammonia in dichloromethane to give the title compound (726 mg).