Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([O:7][CH2:8][CH2:9][Cl:10])=[O:6].[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.O>CN(C=O)C>[Si:14]([O:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([O:7][CH2:8][CH2:9][Cl:10])=[O:6])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: O=C(OCCCl)c1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)OCCCl)c1

Procedure:
A solution of 10 g (50 mmol) the ester from step (a), t-butyldimethylsilyl chloride (8.25 g, 55 mmol) and imidazole (4.76 g, 70 mmol) in 100 mL of DMF was stirred under argon for 1 h. The solution was poured into 100 mL of water and extracted with ether (3×50 mL). The combined ether solutions were extracted with 20 mL of water. The organic layer was dried and evaporated giving 18 g of an oil which was purified by column chromatography using 0-2% ethyl acetate in hexane yielding 14.4 g of the product as a colorless oil (91%); 1H NMR (CDCl3) δ0.218 (s,6H), 0.995 (s,9H), 3.81 (t,2H), 4.56 (t,2H), 7.05-7.65 (m,4H). ##STR13##
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]=[C:16](S(C)(=O)=O)[N:15]=1>O1CCCC1>[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([F:22])([F:21])[F:23])[N:17]=[C:16]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:15]=1
Reactant: CS(=O)(=O)c1nc(Cl)cc(C(F)(F)F)n1
Reactant: OC1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(Cl)nc(OC2CCCC2)n1
Temperature: -78 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
To a stirred solution of cyclopentanol (0.61 mL, 6.75 mmol) in tetrahydrofuran (24 mL) at 0° C. was added potassium tert-butoxide (0.76 g, 6.75 mmol). The resulting yellow solution was added dropwise to a stirred solution of 4-chloro-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine (1.76 g, 6.75 mmol) in tetrahydrofuran (24 mL) at −78° C. over 15 minutes. The reaction was then stirred at −78° C. for 2 h then allowed to warm to rt. After stirring for 15 h at room temperature, the reaction was quenched with water (20 mL) and diluted with ethyl acetate (200 mL). The aqueous layer was extracted with ethyl acetate (2×74 mL). The combined organic extract was washed with saturated sodium chloride (2×20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent to afford the title compound (0.60 g, 33%) as a colorless oil. MW=266.65. 1H NMR (CDCl3, 500 MHz) δ 7.26 (s, 1H), 5.48 (sept, J=3.0 Hz, 1H), 2.08-1.76 (m, 6H), 1.75-1.58 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][N:5]([CH2:7][CH2:8]O)[CH3:6].S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][N:5]([CH2:7][CH2:8][Cl:16])[CH3:6]
Reactant: CN(CCO)Cc1ccccc1F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CN(CCCl)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(N-(2-fluorobenzyl)-N-methylamino)-ethanol (Step B, 7.51 g, 41 mmol) in dry toluene (50 ml) was added thionyl chloride (16 ml). The reaction mixture was stirred at room temperature for 16 hours and concentrated. The crude mixture was diluted with chloroform and washed with aq NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to provide the title compound which was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:32])[CH2:15][CH:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[O:30][CH3:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:4])([CH3:3])[CH3:2].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:7][C:6]=1[NH:13][C:14](=[O:32])[CH2:15][CH:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[O:30][CH3:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(CN)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Reactant: CS(=O)(=O)Cl
Product: CCCCCC(CC(=O)Nc1cc(CNS(C)(=O)=O)ccc1C(C)(C)C)c1ccc(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 11, but using N-[2-t-butyl-5-(aminomethyl)phenyl]-3-(2,4-dimethoxy-phenyl)octanamide (prepared as described in Preparation 26A) and methanesulfonyl chloride in similar relative proportions, the title compound was obtained as a foam-like substance.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][N:6]=[CH:5]2.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][N:6]=[CH:5]2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cc2ncncc2cc1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4cncnc4cc3C)c2cc1OC
Temperature: 150 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
6-Hydroxy-7-methyl-quinazoline (38 mg), 4-chloro-6,7-dimethoxyquinoline (159 mg), and 4-dimethylaminopyridine (87 mg) were suspended in o-dichlorobenzene (2 ml), and the suspension was stirred at 150° C. overnight. The reaction solution was cooled to room temperature, water was then added to the solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (71 mg, yield 86%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C.ClCCl>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[CH:7][C:2]=1[CH3:1]
Reactant: COc1ccccc1C
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Methylanisole (2.5 ml) in acetic acid (140 ml) and dichloromethane (150 ml) was cooled to 15° C. Concentrated nitric acid (20 ml) was added slowly keeping the temperature of the reaction below 40° C. The reaction was stirred at ambient temperature for 30 minutes and cooled to 0° C. before adding fuming nitric acid (50 ml) dropwise. The reaction mixture was allowed to warm to ambient temperature slowly and stirred for a further 4 days. The reaction mixture was poured onto ice water (600 ml) and the organic layer was washed with water (2×40 ml) and saturated sodium hydrogencarbonate (2×40 ml), dried over magnesium sulfate and concentrated. The residual deep red solid was subjected to flash silica chromatography on silica eluting with isohexane/ethyl acetate (9:1) to (7:3) to yield 1-methoxy-2-methyl-4-nitrobenzene (2.70 g) as an off white solid. LC-MS (Method J): RT 3.74 minutes, 168.27 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)#[CH:2].Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C(N(CC)CC)C>C(#N)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>[S:13]1[CH:14]=[CH:15][N:16]=[C:12]1[C:8]1[CH:7]=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:1]#[CH:2]
Reactant: Brc1nccs1
Reactant: C#Cc1ccc(OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#Cc1ccc(OC)cc1-c1nccs1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
The alkyne of the current example, 2-(2-thiazolyl)-4-methoxyphenylacetylene was prepared by adding to a degassed solution of 4 mmol of 4-ethynylanisole, 4 mmol of 2-bromothiazole, and 1 ml of triethylamine in 10 ml of acetonitrile, 140 mg (0.2 mmol) of PdCl2(PPh3)2 and 19 mg(0.1 mmol) of CuI. The mixture was degassed and stirred for 5 minutes at RT and heated to 90° C. for 12 hours. The reaction mixture was concentrated in vacuo and purified by silica column to afford 0.61 g of brown liquid in a 70% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12](=[O:33])[N:13]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[S:23][C:24]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:25][N:26]=4)[CH:17]=3)[N:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C=O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:10]=[CH:11][C:12](=[O:33])[N:13]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[S:23][C:24]([CH:27]5[CH2:32][CH2:31][N:30]([CH3:36])[CH2:29][CH2:28]5)=[CH:25][N:26]=4)[CH:17]=3)[N:14]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=c1ccc(-c2cc(F)cc(F)c2)nn1Cc1cccc(-c2ncc(C3CCNCC3)s2)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Product: CN1CCC(c2cnc(-c3cccc(Cn4nc(-c5cc(F)cc(F)c5)ccc4=O)c3)s2)CC1

Procedure:
Analogously to Example 28.5, 6-(3,5-difluorophenyl)-2-[3-(5-piperidin-4-ylthiazol-2-yl)benzyl]-2H-pyridazin-3-one is reacted with formaldehyde and sodium triacetoxyborohydride to give 6-(3,5-difluorophenyl)-2-{3-[5-(1-methylpiperidin-4-yl)thiazol-2-yl]benzyl}-2H-pyridazin-3-one (“A92”), ESI 479.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1.[CH3:19][N:20]=[C:21]=[O:22]>>[CH3:19][NH:20][C:21]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1)=[O:22]
Reactant: CN=C=O
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Product: CNC(=O)NC1CCN(CCc2c[nH]c3ccccc23)CC1

Procedure:
Following the procedure of Example 1 3-[2-(4-aminopiperidyl) ethyl]indole is reacted with methyl isocyanate to give the title compound which is converted to the hydrochloride.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH2:15][OH:16])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])C.O.[Li+].[OH-]>C1COCC1>[OH:16][CH2:15][C:12]1[CH:13]=[CH:14][C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[S:10][C:9]=2[CH:11]=1
Reactant: CCOC(=O)c1cc2ccc(CO)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2ccc(CO)cc2s1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
6-Hydroxymethyl-benzo[b]thiophene-2-carboxylic acid ethyl ester (2.4 g, 9.6 mmol, 1 eq) was dissolved in THF (10 mL, 4 vol) and water added (10 mL) along with LiOH (0.69 g, 28.8 mmol). The reaction mixture was stirred at 50° C. for 3 h and then concentrated to dryness and taken onto the next step without purification.
Reaction SMILES: Cl[C:2]1[C:3]2[C:4](=[N:14][N:15]([CH3:17])[CH:16]=2)[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[Na].[CH2:19]([OH:21])[CH3:20]>>[CH2:19]([O:21][C:2]1[C:3]2[C:4](=[N:14][N:15]([CH3:17])[CH:16]=2)[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)[CH3:20]
Reactant: Cn1cc2c(Cl)cc(-c3ccccc3)nc2n1
Reactant: CCO
Agent: [Na]
Product: CCOc1cc(-c2ccccc2)nc2nn(C)cc12

Procedure:
8.5 g. of 4-chloro-2-methyl-6-phenyl-2H-pyrazolo[3,4-b]pyridine (0.035 mol.) are added to a solution of 0.9 g. of sodium (0.038 mol.) in 100 ml. of absolute ethanol. The mixture is heated at 150° in an autoclave for 5 hours. After cooling, the crystallized 4-ethoxy-2-methyl-6-phenyl2H-pyrazolo[3,4-b]pyridine is filtered off, washed with alcohol and then with water, yield: 6.2 g.; m.p. 170°-171°. An additional crop of 2.4 g. is obtained by evaporation of the mother liquor, total yield: 8.6 g. (97%). Recrystallization from ethanol gives a product of the melting point 171°-172°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[N:12]([S:15]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[O:26][CH:27]=[N:28][N:29]=1)(=[O:17])=[O:16])=[C:13]=[O:14]>O1CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:13]([NH:12][S:15](=[O:17])(=[O:16])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[O:26][CH:27]=[N:28][N:29]=2)=[O:14])[N:7]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: O=C=NS(=O)(=O)Oc1ccccc1-c1nnco1
Solvent: C1CCOC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Oc2ccccc2-c2nnco2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.9 %

Procedure:
To a suspension of 6 g of 2-amino-4,6-dimethoxypyrimidine in 25 ml of tetrahydrofuran was added a solution of 8 g of the isocyanate prepared in Example 3 dissolved in 25 ml of tetrahydrofuran. After an initial exotherm, the solution was stirred at 25° C. for 16 hours, to yield a precipitate. The mixture was filtered, and the solid was recrystallized from acetonitrile to yield 1.5 g of the title compound; m.p. 161°-164° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][C@@H:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].O=[C:22]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24].C([BH3-])#N.[Na+]>C(O)C>[CH2:26]([O:25][C:23]([C@@H:22]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][C@@H:12]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])[CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: C[C@H](N)C(=O)N1C[C@@H](Cc2ccccc2)C[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1C[C@@H](Cc2ccccc2)C[C@H]1C(=O)O

Procedure:
A solution of 1-(L-alanyl)-4-(S)-(phenylmethyl)-L-proline and ethyl 2-oxo-4-phenylbutyrate in ethanol is stored at room temperature with powdered molecular sieves. Over the course of several hours, sodium cyanoborohydride is added and the reaction mixture is filtered and concentrated under reduced pressure. The residue is purified by absorption on ion exchange resin to yield 1-[N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-4-(S)-(phenylmethyl)-L-proline.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:32]=[CH:31][C:24]([C:25]([O:27]CC=C)=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[OH:33])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:31][CH:32]=5)=[CH:18]4)=[CH:13][C:12]=3[O:33][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CCOC(=O)CCCCBr
Reactant: C=CCOC(=O)c1ccc(-c2ccc3cc(O)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Product: CCOC(=O)CCCCOc1cc2ccc(-c3ccc(C(=O)O)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Yield: 65.4 %

Procedure:
Following the procedure of Example 12(a), but reacting 2 g (4.5 mmol) of allyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 1.4 g (6.7 mmol) of ethyl 5-bromovalerate, 1.55 g (59%) of the expected compound was obtained, which compound had a melting point of 117°-8° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[CH3:21][C:22]1[CH:23]=[CH:24][C:25]2[S:29][C:28]([S:30](Cl)(=[O:32])=[O:31])=[CH:27][C:26]=2[CH:34]=1>>[CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:30]([C:28]1[S:29][C:25]3[CH:24]=[CH:23][C:22]([CH3:21])=[CH:34][C:26]=3[CH:27]=1)(=[O:31])=[O:32])[CH:7]=[CH:6]2
Reactant: Cc1ccc2sc(S(=O)(=O)Cl)cc2c1
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2cc3cc(C)ccc3s2)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.6 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 5-methyl-1-benzothiophene-2-sulfonyl chloride (27 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (8 mg, 27%) as a white solid. MS (ESI+) for C21H22N2O3S2 m/z 415 (M+H)+.
Reaction SMILES: [CH3:1][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[Cl:27][C:28]1[CH:29]=[C:30]([C:35](=O)[CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:31]=[CH:32][C:33]=1[Cl:34].O>C1C=CC=CC=1>[Cl:27][C:28]1[CH:29]=[C:30]([C:35](=[CH2:1])[CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:31]=[CH:32][C:33]=1[Cl:34]
Reactant: COC(=O)CCC(=O)c1ccc(Cl)c(Cl)c1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: C=C(CCC(=O)OC)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.8 %

Procedure:
1.75 g (49.0 mmole) of methyltriphenylphosphonium bormide and 5.50 g (49.0 mmole) of potassium t-butoxide were suspended in 200 ml of dried benzene, and the mixture was stirred at room temperature for 6 hours under a nitrogen atmosphere. At the end of this time, 8.50 g of methyl 4-(3,4-dichlorophenyl)-4-oxobutanoate [prepared as described in step (a) above] were dissolved in 40 ml of benzene, and the resulting solution was added to the reaction mixture. The mixture was then stirred for 1 hour. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of hexane and diethyl either ranging from 19:1 to 23:2 by volume as the eluent, to give 4.20 g of the title compound as a pale orange oil.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[N:5]=[C:4]([S:16][CH3:17])[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([CH3:28])[CH:20]=1>>[CH2:12]([CH:11]([NH:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][C:21]=2[CH3:28])[N:3]=[C:4]([S:16][CH3:17])[N:5]=1)[CH2:14][CH3:15])[CH3:13]
Reactant: CCC(CC)Nc1nc(SC)nc(Cl)c1C=O
Reactant: Cc1cc(F)ccc1B(O)O
Product: CCC(CC)Nc1nc(SC)nc(-c2ccc(F)cc2C)c1C=O

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-(1-ethyl-propylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 4-fluoro-2-methyl-phenylboronic acid to give the title compound 4-(1-ethyl-propylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 0.92 (m, 6H), 1.54-1.71 (m, 4H), 2.21 (s, 3H), 2.53 (s, 3H), 4.28 (m, 1H), 6.63-7.05 (m, 2H), 7.21 (m, 1H), 9.05 (br s, 1H), 10.50 (s, 1H). LC MS (m/e)=348 (MH+).
Reaction SMILES: [NH:1]1[CH2:9][C@H:7]([OH:8])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C([O-])([O-])=O.[Na+].[Na+].[C:16](ON1C(=O)CCC1=O)([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17]>C1COCC1.O.C1COCC1.O>[N:1]1([C:16]([O:18][CH2:19][CH:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:17])[CH2:9][C@H:7]([OH:8])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of H-trans-Hyp-OH (122.5 g, 362 mmol) in THF/H2O (100 mL/200 mL) is added 2N Na2CO3 (250 mL), along with addition of a suspension of Fmoc-OSu in THF (700 mL). The mixture is stirred at room temperature overnight. The mixture is diluted with H2O (2700 mL) and extracted with ether/petroleum ether (500 mL/500 mL) The aqueous layer is acidified by 6N HCl and then extracted with ethyl acetate (1×1000 mL, 1×500 mL). The combined extract is washed with brine once and dried over Na2SO4. After removal of most of solvent, the residue is treated with ethyl ether (200 mL). The white solid is filtered and dried under vacuum. Yield: 125.8 g (356 mmol, 98%)
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)[S:13][C:6]=12.[Cl-].[NH4+]>O.C(O)C.[Fe]>[F:1][C:2]1[CH:30]=[C:29]([CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[CH:18][N:19]=3)[S:13][C:6]=12)[NH2:31]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CN5CCOCC5)cn4)sc23)c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCOCC5)cn4)sc23)c(F)c1
Temperature: 80 °C
Yield: 33.7 %

Procedure:
A mixture of the nitro compound 358 (432 mg, 0.926 mmol), iron powder (440 mg, 7.87 mmol), and ammonium chloride (42.6 mg, 0.796 mmol) in a mixture of water (3.00 mL) and ethanol (6 mL) was heated to 80° C. for 30 min. The reaction mixture was then filtered while hot through a pad of Celite. The filtrate was concentrated and the residue was purified using Biotage (eluent 0-20% EtOAc/MeOH, 10 g SNAP column) to afford the amine 359 (136 mg, 0.312 mmol, 33.6% yield) as a white solid. MS: 437 (MH)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][CH:7]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:34][CH2:35][CH2:36][CH2:37][C:38]#[CH:39]>C(N(CC)CC)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>[Cl:34][CH2:35][CH2:36][CH2:37][C:38]#[C:39][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([F:14])([F:13])[F:1])=[CH:7][CH:8]=1
Reactant: C#CCCCCl
Reactant: O=C(Nc1ccc(I)cc1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C#CCCCCl)cc1)C(F)(F)F
Temperature: 55 °C

Procedure:
A mixture of 2,2,2-trifluoro-N-(4-iodophenyl)acetamide (3.2 g, 10 mmol, prepared according to Melissaris, A. P. and Litt, M. H. J Org Chem 1994, 59, 5818-5821), dichlorobis(triphenylphosphine)palladium(II) (0.14 g, 0.2 mmol), triphenylphosphine (19 mg, 0.07 mmol), and copper (I) iodide (0.019 g, 0.1 mmol) in triethylamine (50 mL) was degassed under Argon for 10 minutes while stirring in a 55° C. oil bath. The mixture was then treated with 5-chloropentyne (1.1 mL, 10 mmol). After four hours of heating, the mixture was allowed to cool to room temperature and was then filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated under reduced pressure to provide the crude title compound, which was carried forward without further purification. ES/MS calcd. for C14H14ClF3NO+: 290.1, found m/z=290.1 (M+H)+
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH2:23][CH3:24].Cl>C(#N)C>[C:22]([CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:12][CH2:13][CH3:14])=[O:11])(=[O:25])[CH2:23][CH3:24]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)CC)C(=O)OCC
Reaction time: 0.25 h
Yield: 93.5 %

Procedure:
To magnesium chloride (2.96 g, 31.2 mmol) was added dry acetonitrile (5 mL) and the mixture was then cooled in ice and treated with diethyl malonate (5 g, 31.2 mmol). Once the mixture was cold, triethylamine (8.6 mL, 62.5 mmol) was added and the resulting suspension was stirred for 15 mins. Propionyl chloride (2.71 mL, 31.2 mmol) was added dropwise and the mixture was stirred at 0° C. for 1.5 h and at ambient temperature for 5 h. The mixture was cooled in an ice-bath and treated with aqueous hydrochloric acid (2M, 10 mL) and the product extracted with ether. The organic phase was washed with water then brine, dried and evaporated to afford 6.31 g of a yellow oil. This was dissolved in ether and washed with aqueous hydrochloric acid (2M) then brine, dried and evaporated to afford 5.93 g of the title compound.