Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O-])(C)C.[K+].[N:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[S:9][C:8]=1[NH:16][C:17]1[C:22]([S:23][CH2:24][CH2:25][C:26](OC)=O)=[CH:21][CH:20]=[CH:19][N:18]=1.FC1C=C[C:34]([C:35]#[N:36])=[CH:33][CH:32]=1.C(OCC)(=O)C>CS(C)=O>[N:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[S:9][C:8]=1[NH:16][C:17]1[C:22]([S:23][C:24]2[CH:32]=[CH:33][C:34]([C:35]#[N:36])=[CH:26][CH:25]=2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: COC(=O)CCSc1cccnc1Nc1nc2cccnc2s1
Reactant: N#Cc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(Sc2cccnc2Nc2nc3cccnc3s2)cc1
Reaction time: 0.25 h
Yield: 32.5 %

Procedure:
Added potassium 2-methylpropan-2-olate (0.097 g, 0.87 mmol) to a solution of methyl 3-(2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)propanoate (100 mg, 0.289 mmol) in DMSO (1 mL). Stirred 15 minutes, added 4-fluorobenzonitrile (0.105 g, 0.866 mmol) and stirred overnight. Partitioned between ethyl acetate and water. Washed the organic layer with water, brine, dried, and concentrated. Purified by MPLC eluting with 3:2 hexane:ethyl acetate to afford the title compound (0.034 g, 33% yield) as a white powder: 1H NMR (CDCl3) δ 7.10-7.15 (m, 3H), 7.32 (dd, 1H), 7.52 (d, 2H), 7.87 (d, 1H), 7.96 (d, 1H), 8.42 (d, 1H), 8.58 (d, 1H), 9.10 (bs, 1H).
Reaction SMILES: [F-:1].[K+].[N+]([C:6]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:7]=1[C:8]([NH:10][C@H:11]([CH3:15])[C:12]([OH:14])=[O:13])=[O:9])([O-])=O.C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[F:1][C:6]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:7]=1[C:8]([NH:10][C@H:11]([CH3:15])[C:12]([OH:14])=[O:13])=[O:9]
Reactant: [F-]
Reactant: C[C@@H](NC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H](NC(=O)c1ccc([N+](=O)[O-])cc1F)C(=O)O
Temperature: 175 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
A mixture of spray-dried KF (307 mg, 5.3 mmol), intermediate 12 (150 mg, 0.53 mmol) and catalytic amount of 18-crown-6 in dry DMSO (4 mL) was stirred at 170-180° C. for 30 min. Work-up of the reaction mixture as described in example 1 gave the product as a pale brown color solid (92 mg, 68%), mp 146-150° C. 1H NMR (400 MHz, DMSO-d6): δ 8.90 (1H, d, J=4.0 Hz), 8.21 (1H, d, J=9.6 Hz), 8.15 (1H, d, J=8.0 Hz), 7.84 (1H, t, J=6.8 Hz), 4.36-4.40 (1H, m), 1.38 (3H, d, J=6.4 Hz); LC-MS (negative ion mode): m/z 255 (M−H)−.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([Br:13])[CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH3:14]I>CN(C=O)C>[CH3:14][N:9]1[C:10]2[C:6](=[CH:5][C:4]([CH3:3])=[CH:12][C:11]=2[Br:13])[CH:7]=[CH:8]1
Reactant: Cc1cc(Br)c2[nH]ccc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)c2c(ccn2C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a suspension of sodium hydride (60%, 0.91 g, 22.9 mmol) in DMF (70 mL) was added a solution of 5-methyl-7-bromoindole (4.0 g, 19.05 mmol) in DMF (10 mL). The mixture was stirred at room temperature for 1 h, and then methyl iodide (1.78 mL, 28.6 mmol) was added with cooling in an ice-water-bath. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water and extracted with ethyl acetate. The extract was washed with water and brine, dried (sodium sulfate) and concentrated to give a crude product (4.1 g, 96%), which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 2.38 (s, 3H), 4.12 (s, 3H), 6.36 (d, J=3.12 Hz, 1H), 6.95 (d, J=3.13 Hz, 1H), 7.18 (d, J=1.56 Hz, 1H), 7.31 (dd, J1=0.79 Hz, J2=1.56 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:5]=[CH:6][C:7]=1[F:8]>C(O)C>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]([C:23]#[N:24])=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(F)c(Cl)c1
Solvent: CCO
Product: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(F)c(Cl)c1
Reaction time: 2 h
Yield: 91.4 %

Procedure:
A mixture of 5.360 g (15.6 mmol) 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-3-quinolinecarbonitrile, 250 ml ethanol, and 17.67 g (78.2 mmol) SnCl2 dihydrate was heated to reflux under N2. Removed heat at 1.5 hours and added ice water. Made basic with sodium bicarbonate. Stirred for 2 hours extracted with chloroform. Added brine to the separatory funnel to help separate layers. Stirred organic layer with Darco and dried with sodium sulfate. Filtered, stripped solvent and dried in vacuo, giving 4.460 g of yellow-brown solid: mass spectrum (electrospray m/e): M+H=312.9, 315.0.
Reaction SMILES: S([O-])([O-])=O.[Na+:5].[Na+].C(=O)(O)[O-].[Na+].O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[S:23](Cl)(=[O:25])=[O:24]>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[S:23]([O-:25])=[O:24].[Na+:5]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)[O-])c1
Reaction time: 2 h

Procedure:
321 ml. (4.7 moles) of chlorosulfonic acid and 79 g. (0.5 moles) of 4-chloro-nitrobenzene are stirred at 130° C. for 6 hours. The reaction mixture is then cooled to a temperature below 10° C. and is poured onto 750 ml. of icy water. The mixture is filtered at room temperature and the substance collected on the filter is washed solid-free with about 2 litres of water. The crude 2-chloro-5-nitrobenzene sulfonyl chloride obtained is subjected to the subsequent reaction steps without purification. 118 g. (0.935 moles) of anhydrous sodium sulfite and 20 g. of sodium bicarbonate are dissolved in 250 ml. of water, and to the solution obtained a mixture of the crude 2-chloro-5-nitrobenzene sulfonyl chloride and 20 g. of sodium bicarbonate is added at a temperature of 23° to 25° C., in one hour. The reaction mixture is stirred for two hours at a temperature of 23° to 25° C., and, after the addition of 200 ml. of toluene, for further 15 minutes. The mixture is stirred at 25° C. and the substance filtered off is washed with 100 ml. of toluene. The sodium 2-chloro-5-nitrobenzene sulfinate obtained is dissolved in 400 ml. of water at 40° C., and the solution is admixed with 200 ml. of toluene. The insoluble part is filtered off and the toluene phase is separated from the filtrate. The aqueous phase is cooled to 10° C., acidified with 100 ml. of concentrated aqueous hydrochloric acid solution and the precipitated crystals are stirred, filtered off at 10° C. and dried. 61 g. of 2-chloro-5-nitrobenzene sulfinic acid are obtained. Yield: 55% of theoretical related to 4-chloro-nitrobenzene.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:13][CH2:12]3)[N:9]=[CH:10][C:5]2=[C:4]([N:22]2[CH2:28][CH:27]3[O:29][CH:24]([CH2:25][CH2:26]3)[CH2:23]2)[N:3]=1.[NH2:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH:27]12[O:29][CH:24]([CH2:25][CH2:26]1)[CH2:23][N:22]([C:4]1[N:3]=[C:2]([C:34]3[CH:35]=[CH:36][C:31]([NH2:30])=[CH:32][CH:33]=3)[N:7]=[C:6]3[N:8]([CH:11]4[CH2:12][CH2:13][N:14]([CH2:17][C:18]([F:19])([F:20])[F:21])[CH2:15][CH2:16]4)[N:9]=[CH:10][C:5]=13)[CH2:28]2
Reactant: FC(F)(F)CN1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(Cl)nc32)CC1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(CC(F)(F)F)CC4)c3n2)cc1
Temperature: 120 °C

Procedure:
A mixture of 3-(6-chloro-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (0.55 g, 1.3 mmol), 4-aminophenylboronic acid pinacol ester (0.42 g, 1.9 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.15 g, 10 mol %) in toluene/ethanol (1:1, 10 mL) and 2 M aqueous sodium carbonate solution (2 mL) was heated in a 10-20 mL Smith process vial in the microwave reactor for one hour at 120° C. The cooled mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude residue was purified via reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 95% acetonitrile over 30 minutes. After the concentration of fractions under reduced pressure, 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline was obtained as a maroon oil that solidified upon standing. MS (ES+): 488.4 (M+H)+
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C([O-])([O-])=O.[K+].[K+].[Br:15][CH2:16][C:17](Br)=[O:18].O>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:17](=[O:18])[CH2:16][Br:15])[CH3:3]
Reactant: O=C(Br)CBr
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)CBr
Yield: 37.5 %

Procedure:
To a mixture of glycine ethyl ester hydrochloride (2.0 g, 14.3 mmol) and K2CO3 (2.1 g, 15.2 mmol) in CH2Cl2 (35 ml) cooled at 0-5° C. bromoacetyl bromide (1.36 ml, 15.6 mmol) was added dropwise. The suspension was stirred at room temperature and after 3 h H2O (20 ml) was added. The phases were separated and the organic one was washed with a saturated solution of NaHCO3 (20 ml) and H2O (20 ml) and dried over Na2SO4. The solvent was evaporated obtaining 39 as white solid (1.2 g, 40%). ESI+MS: calcd for C6H10BrNO3: 224.06; found: 224.0 and 226.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH:12]1([CH2:18][O:19][C:20]2[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=2[O:22][CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][N:27]2[CH2:26][CH2:25][CH:24]([CH2:23][O:22][C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=3[O:19][CH2:18][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:29][CH2:28]2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)cc1C=O
Reactant: c1ccc(OCC2CCNCC2)c(OCC2CCCCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ncc(Cl)cc1CN1CCC(COc2ccccc2OCC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
150 mg of 5-chloro-2-methoxy-3-pyridinecarboxaldehyde and 291 mg of 4-[2-(cyclohexylmethyloxy)phenoxymethyl]piperidine were dissolved in 5 ml of 1,2-dichloroethane. To the mixture were added 0.06 ml of acetic acid and 214 mg of sodium triacetoxyborohydride, followed by stirring at room temperature overnight. An aqueous saturated sodium bicarbonate was added to the reaction solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to give 285 mg of the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[CH:10]=[C:6]2[N:5]=[C:4]([CH3:18])[CH:3]=1.[I:19]N1C(=O)CCC1=O>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:10]([I:19])=[C:6]2[N:5]=[C:4]([CH3:18])[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(Cl)n2nc(-c3ccccc3Cl)cc2n1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(Cl)n2nc(-c3ccccc3Cl)c(I)c2n1
Reaction time: 1.5 h

Procedure:
To a solution of 7-chloro-2-(2-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine (I-1A-3g; 370 mg, 1.33 mmol) in 5:1 methylene chloride/chloroform (9 ml) cooled in an ice bath was added N-iodosuccinimide (449 mg, 2.0 mmol), portionwise, to give a heterogeneous mixture. After 1.5 hours, the ice bath was removed and the reaction was stirred an additional 2.5 hours to give a homogenous, pink solution. The reaction was extracted from aqueous NaHCO3 with methylene chloride. The combined extracts were washed with saturated aqueous Na2S2O4 and brine, dried (MgSO4), and then concentrated, in vacuo, to afford product I-1A-3h as a tan solid (535 mg, quantitative): +ESI MS (M+1) 403.9; 1H NMR (400 MHz, CD2Cl2) δ 7.57–7.40 (m, 4H), 6.99 (s, 1H), 2.66 (s, 3H).
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][O:9][C:8]([NH:12][C@H:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][CH2:14]3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:11]3[CH2:10][O:9][C:8]([NH:12][C@H:13]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH2:15][CH2:14]4)=[N:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Fc1ccc(-c2cccc3c2COC(N[C@@H]2CCc4ccccc42)=N3)cc1
Temperature: 80 °C
Yield: 91.5 %

Procedure:
A stirred mixture of (5-bromo-4H-benzo[d][1,3]oxazin-2-yl) -(R)-indan-1-yl-amine (Example 10) (171.6 mg, 0.5 mmol), 4-fluorophenyl-boronic acid (84 mg, 0.6 mmol), 1M sodium carbonate solution (1.25 ml, 1.25 mmol), tetarkis(triphenylphosphine)palladium (17.3 mg, 0.015 mmol) in 1,2-dimethoxy-ethane (2.5 ml) was heated at 80° C. for 17 h. The reaction mixture was poured into water (20 ml), extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with water (20 ml) and brine (20 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography (ethyl acetate/heptane) on silica gel yielded the title compound as white foam (164 mg, 92%). MS (ISP) m/e=359.1 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH3:12])=[CH:5]2.[CH3:13][CH:14](C)[CH2:15]CC1NC2C(C=1)=CC=CC=2>>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][CH:14]([CH3:15])[CH3:13])=[CH:5]2
Reactant: CC(C)CCc1cc2ccccc2[nH]1
Reactant: CCc1cc2cc(N)ccc2[nH]1
Product: CC(C)CCc1cc2cc(N)ccc2[nH]1

Procedure:
Refer to 41a) using 2-(3-methyl-n-butyl) indole.
Reaction SMILES: O.S.[Na].[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1
Agent: S
Agent: [Na]
Solvent: O
Solvent: CCO
Product: Nc1ccc(OCc2ccccc2)cc1

Procedure:
Sodium hydrogen sulphide monohydrate (40 g) was added to a solution of 4-benzyloxynitrobenzene (25 g) in ethanol (800 ml) and the reaction mixture heated under reflux for four hours. The solvent was removed and the residue was treated with water and extracted into ether. The ether extract was dried and evaporated to give 4-benzyloxyaniline which was purified by extraction with hexane.
Reaction SMILES: CC([OH:4])C.CC1(C)O[C@H](CN2C=CC(N[C:18](=[O:38])[C@@H:19]([N:24]3[CH2:28][C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])=[CH:26][C:25]3=[O:37])[CH2:20][CH:21]([CH3:23])[CH3:22])=N2)CO1.Cl.C(OC)(C)(C)C>O>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[O:29][C:27]1[CH2:28][N:24]([C@@H:19]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:18]([OH:38])=[O:4])[C:25](=[O:37])[CH:26]=1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Reactant: CC(C)O
Agent: Cl
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a 200-L glass-lined reactor was charged with 42.7 kg of 2-propanol and 13.6 kg (27.0 mol) of ((S)-2-[4-(2-Chlorophenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide. The suspension was stirred at 25-30° C. until the solids dissolved. After adjusting the batch temperature to <15° C., 59.5 kg of 2.0N hydrochloric acid was added over 3.5 h while maintaining a batch temperature of 9-17° C. The mixture was warmed to 18 to 23° C. and stirred for 5.5 h. HPLC analysis at 2 h indicated the reaction was complete. The reaction mixture was transferred into a 500 L glass-lined reactor and diluted with 28.6 kg of purified water and 166.1 kg of methyl tert-butyl ether. The aqueous phase was separated and the organic phase was washed with 1.0N sodium hydroxide solution, 10.7 wt % sodium chloride solution, and 1.0 wt % sodium chloride solution subsequently. The organic phase was transferred into a 200 L glass-line reactor. Solvents were removed by distillation in vacuo at 10-26° C. to a volume of ca. 27 L. The resulting oil was diluted with 107.6 kg of ethanol and solvents were removed by distillation in vacuo at 12-30° C. to afford 19.85 kg (10.04 kg corrected by wt %, 80.4% of yield) of (S)-2-[4-(2-Chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl-1H-pyrazol-3-yl]-amide in ethanol. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.3 Hz, 3 H), 0.94 (d, J=6.3 Hz, 3 H), 1.33-1.50 (m, 1 H), 1.49-1.67 (m, 1 H), 1.68-1.85 (m, 1 H), 3.16-3.32 (m, 2 H), 3.70-3.93 (m, 2 H), 4.09 (m, J=13.6, 3.6 Hz, 1H), 4.21 (d, J=18.4 Hz, 1H), 4.61 (d, J=18.4 Hz, 1 H), 4.71 (t, J=5.6 Hz, 1 H), 4.79 (s, 1 H), 4.88 (dd, J=10.6, 4.8 Hz, 1 H), 4.94 (d, J=5.1 Hz, 1 H), 6.41 (d, J=1.5 Hz, 1 H), 7.37 (t, J=7.5 Hz, 1 H), 7.46 (t, J=7.5 Hz, 1 H), 7.50-7.56 (m, 2 H), 7.65 (d, J=7.5 Hz, 1 H), 10.78 (s, 1 H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[SH:7])(=[O:3])[CH3:2].I[CH2:22][CH2:23][C:24]([OH:26])=[O:25].C(N(CC)CC)C.Cl>ClCCl>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[S:7][CH2:22][CH2:23][C:24]([OH:26])=[O:25])(=[O:3])[CH3:2]
Reactant: O=C(O)CCI
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](S)[C@H]1OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](SCCC(=O)O)[C@H]1OC(C)=O
Reaction time: 16 h
Yield: 87 %

Procedure:
A solution of 2,3,4-tri-O-acetyl-1-thio-β-L-fucopyranose (1.49 g, 4.87 mmol) and freshly crystallized 3-iodopropionic acid (0.97 g, 4.86 mmol) in dichloromethane (20 ml) containing triethylamine (1.35 ml) is kept for 16 hours at room temperature. Hydrochloric acid (2.5 N, 20 ml) and dichloromethane (10 ml) are added and the solution is washed with water, dried, and evaporated in vacuo to a residue that is put on a column of silica gel and eluted with chloroform-methanol-water, 92.5:7.5:0.75 (v/v/v). Compound 23 is isolated in 87% yield (1.6 g), and used, without further purification, for the preparation of 24.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[B-](F)(F)(F)[F:31].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CN(C=O)C>[F:31][CH:13]1[C:14](=[O:17])[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1
Reactant: F[B-](F)(F)F
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: C[Si](C)(C)Cl
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1F
Temperature: 80 °C

Procedure:
To a solution of 10.0 g (43 mmol) of benzyl-4-oxo-1-piperidinecarboxylate in 25 mL of DMF was added 14.3 mL (103 mmol) of triethylamine and then 6.53 mL (52 mmol) of TMSCl. The reaction was heated at 80° C. overnight, cooled to room temperature, and then dumped into hexanes in a separatory funnel. The mixture was partitioned with saturated aqueous NaHCO3, separated, washed with brine, dried over MgSO4 and concentrated by rotary evaporation. The residue was dissolved in 500 mL of CH3CN and treated with 16.7 g (47 mmol) of Selectfluor. After 90 min the reaction was concentrated to about half the original volume, partitioned between EtOAc and brine, separated, dried over MgSO4, filtered, and concentrated by rotary evaporation. The residue was loaded onto a silica gel column and eluted with EtOAc/hexanes to provide 2-2 as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:11]2[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:11]3[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1C
Product: Cc1sc2nc(-n3ccnc3C)nc(NCc3ccc4c(c3)OCO4)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6-dimethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6-dimethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Br)C.[CH3:22][C:23]1([CH3:31])[C:25]([CH3:27])([CH3:26])[CH:24]1[C:28](Cl)=[O:29]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:28]([CH:24]1[C:25]([CH3:27])([CH3:26])[C:23]1([CH3:31])[CH3:22])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3ccc(OCc4ccccc4)cc23)C1(C)C
Yield: 26.8 %

Procedure:
A mixture of 5-benzyloxyindole (1.2 g, 5.6 mmol), ethylmagnesium bromide (1.0 M solution in THF, 6.1 mL, 6.1 mmol), zinc chloride (1.0 M solution in Et2O, 6.1 mL, 6.1 mmol) and the product of Example 1A (5.6 mmol) in 25 mL of dichloromethane was processed as described in Example 1B to provide the title compound (0.53 g, 1.5 mmol, 27% yield). MS (DCI/NH3) m/z 348 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])([OH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.O>CN(C)C=O>[OH:8][C:3]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])([CH2:4][CH2:5][CH2:6][CH3:7])[CH2:2][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: c1c[nH]cn1
Reactant: CCCCC(O)(CCl)c1ccc(Cl)cc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(O)(Cn1ccnc1)c1ccc(Cl)cc1Cl
Yield: 94.4 %

Procedure:
A mixture of 40 g (0.14 m) of 1-chloro-2-(2,4-dichlorophenyl)hexan-2-ol and 38.6 g (0.57 m) of imidazole in 10 ml of dimethyl formamide is heated at 160° for one hour. The reaction mixture is cooled, poured into 300 ml of water and extracted with ether. The combined ether extracts are washed with water, then saturated sodium chloride solution and dried over MgSO4. Solvent is evaporated to give 42 g of a gummy brown solid, mp 78°-80°.