Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3](=O)[CH:4]([S:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[CH3:1][N:2]([CH3:20])[C:3]1[C:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=2[S:11][C:4]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1ccc(SC(C(=O)N(C)C)c2ccccc2)cc1
Solvent: CCO
Product: Cc1ccc2sc(-c3ccccc3)c(N(C)C)c2c1
Reaction time: 5 h

Procedure:
Proceed as in Example 31 starting from the N,N-dimethyl-α-(4-methylphenylthio)-α-phenylacetamide (colourless crystals in cyclohexane, mp 99°-102°). The duration of reaction is 5 hours. 61% of theory of colourless needles, mp 89°-92° (ethanol).
Reaction SMILES: Br[CH2:2][CH:3]1[O:15][C:14]2[C:5](=[C:6]3[C:11](=[C:12]([CH3:16])[CH:13]=2)[NH:10][C:9](=[O:17])[CH:8]=[CH:7]3)[CH2:4]1.[N-:18]=[N+:19]=[N-:20].[Na+].CN(C)C=O>C(Cl)(Cl)Cl>[N:18]([CH2:2][CH:3]1[O:15][C:14]2[C:5](=[C:6]3[C:11](=[C:12]([CH3:16])[CH:13]=2)[NH:10][C:9](=[O:17])[CH:8]=[CH:7]3)[CH2:4]1)=[N+:19]=[N-:20]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)CC(CBr)O2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)CC(CN=[N+]=[N-])O2
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 96.3 %

Procedure:
2-Bromomethyl-5-methyl-1,2-dihydrofuro-[3,2-f]quinoline7-one (4.90 g, 16.7 mmol) and sodium azide (7.5 g, 115 mmol) were added to dimethylformamide (150 ml), and the mixture was stirred in a bath of 100° C. for 1.5 hours, followed by cooling and condensing. The residue was combined with chloroform, and washed with water. The washed material was dried and condensed. The resultant residue was recrystallized from chloroform--n-hexane. As a result, 4.12 g of 2-azidomethyl-5-methyl-1,2-dihydrofuro-[3,2-f]quinoline-7-one was obtained as brown prisms (96.6%).
Reaction SMILES: [CH:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH2:23][NH2:24]>C(O)C>[CH:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:23][NH2:24])=[O:17])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)CN1CCN(Cc2ccc(C(C)C)cc2)CC1
Reactant: NN
Solvent: CCO
Product: CC(C)c1ccc(CN2CCN(CC(=O)NN)CC2)cc1

Procedure:
Synthesized according to General Procedure C: 6{19} (7.15 g, 23.5 mmol, 1 equiv.), anhydrous hydrazine (2.2 mL, 70.4 mmol, 3 equiv.), ethanol (47.4 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{19} (6.19 g, 91%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 8.17 (br s, 1H), 7.19 (d, 2H, J=8.0 Hz), 7.15 (d, 2H, J=8.0 Hz), 3.81 (br s, 2H), 3.46 (s, 2H), 3.05 (s, 2H), 2.87 (sept, 1H, J=7.0 Hz), 2.51 (br s, 4H), 2.44 (br s, 4H), 1.22 (d, 6H, J=7.0 Hz). 13C-NMR (125 MHz, CDCl3): δ 170.4, 147.6, 134.9, 129.0, 126.1, 62.5, 60.5, 53.5, 52.8, 33.6, 23.9.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([CH3:10])[C:5]([O:7]CC)=O.[C:12](#[N:14])[CH3:13]>C1COCC1>[F:11][C:4]([F:3])([CH3:10])[C:5](=[O:7])[CH2:13][C:12]#[N:14]
Reactant: CCOC(=O)C(C)(F)F
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(F)(F)C(=O)CC#N
Temperature: 75 °C
Reaction time: 8 h

Procedure:
In a round bottomed flask flushed with argon, a suspension of sodium hydride 60% in mineral oil (1.30 g, 34 mmoles) was rinsed twice with hexane, and suspended in 20 mL of dry THF. The solution was heated to 75° C., and ethyl difluoropropionate (3.00 g, 22 mmoles) and acetonitrile (1.78 mL) in 5 ml of dry THF was added dropwise over 30 minutes. The temperature of the reaction was lowered to 65° C. and stirred overnight. The mixture was then concentrated to an oil and partitioned between water and ether, and extracted twice to remove any mineral oil and other impurities. The aqueous layer was acidified to pH=1 with 10% HCl, and the solution extracted twice. These extracts were dried over magnesium sulfate, filtered and concentrated to a crude oil. The crude product was purified using silica gel chromatography using a gradient of 10-40% ethyl acetate/hexane to afford 4,4-difluoro-3-oxo-pentanenitrile 1H (300 MHz, CDCl3) δ 3.95 (s, 2H), 1.86 (m, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[CH:10]=[N:9][CH:8]=[N:7][C:6]=2[N:5]([C@@H:12]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:14]([OH:19])[CH2:13]2)[CH:4]=1)[CH3:2].C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.[C:35]([O:39][C:40](=[O:46])[NH:41][S:42](Cl)(=[O:44])=[O:43])([CH3:38])([CH3:37])[CH3:36]>C(C#N)(C)=O>[C:35]([O:39][C:40](=[O:46])[NH:41][S:42]([O:18][CH2:17][C@@H:15]1[C@@H:14]([OH:19])[CH2:13][C@H:12]([N:5]2[C:6]3[N:7]=[CH:8][N:9]=[CH:10][C:11]=3[C:3]([CH2:1][CH3:2])=[CH:4]2)[O:16]1)(=[O:44])=[O:43])([CH3:38])([CH3:36])[CH3:37]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c2ncncc12
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Agent: CC(=O)C#N
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](COS(=O)(=O)NC(=O)OC(C)(C)C)O2)c2ncncc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
To a solution of (2R,3S,5R)-5-(5-ethyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol (0.0560 g, 0.213 mmol) and 2,6-di-tert-butyl-4-methylpyridine in AcCN (4 mL) at 0° C. was added tert-butyl(chlorosulfonyl)carbamate (0.0573 g, 0.266 mmol), the solution was warmed to room temperature and stirred for 1 hour. The reaction was quenched with 7N ammonia in methanol (2 mL) and concentrated. The residue was purified by flash chromatography (0 to 10% MeOH/DCM) to give the title compound as a white solid (39 mg, 29%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([NH:17][C:18]([CH:20]3[CH2:25][CH2:24][N:23](C(OCC4C=CC=CC=4)=O)[CH2:22][CH2:21]3)=[O:19])=[C:11]2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[C+4].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-]>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([NH:17][C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[O:19])=[C:11]2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2c(NC(=O)C3CCN(C(=O)OCc4ccccc4)CC3)ccnc21
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)n1ccc2c(NC(=O)C3CCNCC3)ccnc21
Yield: 83.4 %

Procedure:
N-(1-tert-Butoxycarbonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-benzyloxycarbonyl-4-piperidinecarboxamide (2 g) was dissolved in methanol (30 ml) and 10% palladium carbon hydroxide (0.5 g) was added for hydrogenation (normal pressure). After the completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 1.2 g of N-(1-tert-butoxycarbonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-piperidinecarboxamide.
Reaction SMILES: O[CH:2]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[OH2:22].[OH-].[Li+:24]>>[OH:22][CH:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O-:15])=[O:14].[Li+:24]
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)O
Reactant: O
Agent: [Li+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCC(O)C(=O)[O-]

Procedure:
A lithium hydroxystearate grease thickener was prepared by saponification of a mixture containing about 8% by weight of 12-hydroxystearic acid and 9% by weight of the glyceride thereof, with lithium hydroxide monohydrate (2.5%) in a mineral oil vehicle (about 76%) at about 177° C. and final pressure of about 110 psig in a closed contactor. All percentages were percentages by weight of the total weight of the thickener.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][CH:3]=1.[Mg].[B:11](OC)([O:14]C)[O:12]C>CCOCC>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([B:11]([OH:14])[OH:12])=[CH:3][CH:4]=1)[CH3:9]
Reactant: COB(OC)OC
Reactant: CCc1ccc(Br)cc1
Agent: [Mg]
Solvent: CCOCC
Product: CCc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41 %

Procedure:
A solution of 1-bromo-4-ethyl benzene (2.0 g, 11 mmol) in dry ether (5 ml) was added to magnesium turnings (311 mg, 13 mmol), which had been suspended in dry ether, by dropwise addition. After addition was complete, the suspension was refluxed for a period of 15 min, by which time nearly all of the magnesium had reacted. The solution was then added to trimethyl borate (1.12 g, 11 mmol), previously dissolved in ether (5 ml) at −78° C., warmed to room temperature and stirred for 90 min. The reaction was quenched by the addition of 10% aqueous HCl (2 ml) and the solution was extracted with ether. The combined ether extract was extracted with 1 M NaOH (2×20 ml), the aqueous extracts were acidified with dilute HCl to pH 2 and extracted with ether (2×25 ml). The resulting combined ether extract was washed once with water (10 ml), dried and evaporated to produce a white solid (676 mg, 38% yield), m.p. 138-140° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][C:9]([C:12](=O)[CH3:13])=[CH:10][N:11]=2)[CH:2]=1.Cl.[NH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][C:9]([C:12](=[N:16][OH:17])[CH3:13])=[CH:10][N:11]=2)[CH:2]=1
Reactant: CC(=O)c1cnc(-c2cccnc2)s1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=NO)c1cnc(-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 1-[2-(3-pyridyl)thiazol-5-yl]ethanone (0.8 g, 3.76 mmol) in 50 ml EtOH was treated with hydroxylamine hydrochloride (0.277 g, 3.95 mmol) and potassium carbonate (0.551 g, 3.95 mmol), and stirred at ambient temperature, monitored by LCMS and TLC, which indicated a ca. 1:1 mixture of isomer formation. After 3 hours, the mixture was concentrated in vacuo to approximately 10 ml. Addition of saturated ammonium chloride gave Isomer A of the title product as a beige precipitate which was filtered, and washed successively with water, isopropanol, and tertiary-butyl methyl ether (yield 156 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16]([NH:20][C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])=[N:17][C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2.CN(C)C=O.[H-].[Na+].[CH:37](I)([CH3:39])[CH3:38]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16]([N:20]([CH:37]([CH3:39])[CH3:38])[C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])=[N:17][C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2.[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16](=[N:20][C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])[N:17]([CH:37]([CH3:39])[CH3:38])[C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)-c1cc(Nc3c(C)cc(C)cc3C)nc(=O)n1CC2
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc2c(cc1OC)-c1cc(=Nc3c(C)cc(C)cc3C)n(C(C)C)c(=O)n1CC2
Product: COc1cc2c(cc1OC)-c1cc(N(c3c(C)cc(C)cc3C)C(C)C)nc(=O)n1CC2
Temperature: 25 °C

Procedure:
9,10-Dimethoxy-2-(2,4,6-trimethylanilino)-6,7-dihydro-4H-pyrimido(6,1-a)isoquinolin-4one (5.85 g) and dimethylformamide (30 ml) are added to oil-free sodium hydride (1.5 g). The mixture is heated for 5 minutes to 110° C. and then cooled to room temperature. Isopropyl iodide (2.55 g) is added and the whole is heated to 110° C. for 40 hours. After cooling, methanol is added to the reaction mixture and the solvents are removed under reduced pressure. The residue is extracted with chloroform, the extract washed with water, dried over sodium sulfate and evaporated to dryness. The residue is chromatographed to give the bases (a) m.p. 182°-183° C. and (b) m.p. 178°-179° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3ccncc3)nc(NCc3ccc(F)cc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-4-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(4-fluorobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1>C(OCC)(=O)C.[Pd]>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]2([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CCCCC=CC1(c2cc(OC)cc(OC)c2)CCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCC1(c2cc(OC)cc(OC)c2)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 1-(3,5-dimethoxyphenyl)-1-(hex-1-enyl)-cyclopentane (1 equiv.) in ethyl acetate (0.11M) was added 10% Pd/C (17%, w/w) and the resulting suspension was stirred vigorously under an hydrogen atmosphere, overnight at room temperature. The catalyst was removed by filtration through celite and the filtrate was evaporated under reduced pressure to afford the crude product. Purification through a short column of silica gel using 5% diethyl ether-petroleum ether yielded the title compound in 95% yield.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Br[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]12([C:29](O)=[O:30])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2>>[CH3:1][C:2]1[N:3]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)/[C:4](=[N:8]/[C:29]([C:19]23[CH2:28][CH:23]4[CH2:22][CH:21]([CH2:27][CH:25]([CH2:24]4)[CH2:26]2)[CH2:20]3)=[O:30])/[S:5][C:6]=1[CH3:7]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1nc(N)sc1C
Reactant: BrCCOc1ccccc1
Product: Cc1s/c(=N\C(=O)C23CC4CC(CC(C4)C2)C3)n(CCOc2ccccc2)c1C

Procedure:
4,5-Dimethylthiazol-2-ylamine, (2-bromoethoxy)benzene and 1-adamantane carboxylic acid were processed according to the method of Example 47 to afford the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 1.57-1.77 (m, 6 H) 1.83 (d, J=2.50 Hz, 6 H) 1.93-2.03 (m, 3 H) 2.16 (s, 3 H) 2.26 (s, 3 H) 4.34 (t, J=5.30 Hz, 2 H) 4.46 (t, J=5.30 Hz, 2 H) 6.83-7.03 (m, 3 H) 7.23-7.36 (m, 2 H); MS (ESI) m/z 411 (M=H)+.
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH:34]=[C:33]1[C:41]([OH:43])=O.Cl.[C:45]([O:49][C:50](=[O:60])[C:51]1[CH:56]=[CH:55][C:54]([C@H:57]([NH2:59])[CH3:58])=[CH:53][CH:52]=1)([CH3:48])([CH3:47])[CH3:46]>O.C(Cl)Cl>[O:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH:34]=[C:33]1[C:41]([NH:59][C@@H:57]([C:54]1[CH:55]=[CH:56][C:51]([C:50]([O:49][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:60])=[CH:52][CH:53]=1)[CH3:58])=[O:43]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: C[C@@H](N)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1cc2ccccc2o1)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 2-dram vial was added triethylamine (0.10 mL, 0.72 mmol), HATU (0.068 g, 0.18 mmol), benzofuran-2-carboxylic acid (0.029 g, 0.18 mmol), and DCM (2 mL). The solution was stirred at rt for 30 min then transferred to another 2-dram vial containing solid tert-butyl-4-[(1R)-1-aminoethyl]benzoate hydrochloride. The mixture was stirred at rt for 16 h. To the reaction was then added DCM (3 mL) and water (1 mL). After separation, the aqueous layer was extracted with DCM (2×3 mL). The combined organic phases were concentrated to dryness to give crude tert-butyl 4-{(1R)-1-[(1-benzofuran-2-ylcarbonyl)amino]ethyl}benzoate as a brown solid. LC-MS: (FA) ES+ 366.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([N:19]=[C:20]=[S:21])(=O)C1C=CC=CC=1>CC(C)=O>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:20]([NH2:19])=[S:21])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CC(C)=O
Product: NC(=S)Nc1ccc2[nH]ccc2c1
Temperature: 25 °C

Procedure:
A solution of 5-aminoindole (8 g, 60.6 mmol) in acetone (150 mL) was reacted with benzoylisothiocyanate (9.88 g, 60 mmol) at RT for about 4 h. The resulting solid was filtered and treated with 2 N NaOH in THF (120 mL). The mixture was refluxed for about 6 h and allowed to warm to RT. The solvent was evaporated off under vacuum. The residue was diluted with water (20 mL) and neutralized to pH 7 with 1 N HCl. The resulting solid was filtered and dried under vacuum to afford 5-indolylthiourea (55-2). 5-Indolyl thiourea (0.01 mol) and ethyl bromopyruvate (0.011 mol) were dissolved in 3 mL ethanol and held at reflux for 2 h. The reaction was cooled, the crystalline ethyl 2-(1H-indol-5-ylamino)thiazole-4-carboxylate (55-3) was collected by filtration and washed with ethanol. Refluxing the mixture of ethyl esters with the NaOH-ethanol solution gave 2-(1H-indol-5-ylamino)thiazole-4-carboxylic acid (55-4) which was used directly in next steps. To a mixture of the crude acid (2.5 mmol), EDCI (2.9 mmol), HOBt (2.6 mmol) and NMM (5.3 mmol) in CH2Cl2 (30 mL) was added HNCH3OCH3HCl salt (2.6 mmol) and stirring continued at RT for overnight. The reaction mixture was diluted with CH2Cl2 (20 mL) and sequentially washed with water, satd. NaHCO3, brine and dried over MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 2-(1H-indol-5-ylamino)-N-methoxy-N-methylthiazole-4-carboxamide (55-5) (45.6% yield for overall 5 steps). At −78° C., to a solution of 5-bromo-1,2,3-trimethoxybenzene (1.235 g, 5.0 mmol) in 30 mL THF was charged n-BuLi in hexane (2.5 N, 2.4 mL, 6 mmol) under Ar2 protection and stirred for 10 min Weinreb amide (1 mmol) in 10 mL THF was added to lithium reagent and allowed to stir at RT for 2 h. The reaction mixture was quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 55 (51.7% yield). 1H NMR (300 MHz, CDCl3) δ 8.29 (br, 1H), 7.68 (d, 1H), 7.46 (s, 2H), 7.39 (s, 1H), 7.36 (s, 1H), 7.28-7.26 (m, 1H), 7.15-7.12 (m, 1H), 6.55 (m, 1H), 3.93 (s, 3H), 3.89 (s, 6H). MS (ESI) m/z 432.1 (M+Na)+, 408.0 (M−H)−.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([N+:15]([O-])=O)[CH:13]=2)[CH2:8][C@H:7]1[CH3:20])=[O:5]>[Pd].CO>[CH3:21][N:2]([CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([NH2:15])[CH:13]=2)[CH2:8][C@H:7]1[CH3:20])=[O:5])[CH3:1]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN(C)C)[C@H](C)C2
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N)N(C(=O)CN(C)C)[C@H](C)C2
Temperature: 25 °C
Yield: 92.6 %

Procedure:
10% palladium on carbon (0.25 g, 8.52 mmol) was placed under N2 atm. MeOH (10 mL) was added, followed by a solution of N,N-dimethyl-2-[(2R)-2-methyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-2-oxoethanamine (2.92 g, 9.96 mmol) in MeOH (190 mL). The slurry was purged with N2, then was placed under H2 atm via a rubber balloon and maintained at rt for 2 days. The resulting mixture was filtered through a pad of Celite and the filtrate was concentrated. The oily residue was taken up into Et2O and concentrated again to obtain (2R)-1-[(dimethylamino)acetyl]-2-methyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine as a beige solid (2.43 g, 93%). 1H NMR (400 MHz, DMSO-d8) δ ppm 1.17 (d, J=5.86 Hz, 3H), 2.26 (s, 6H), 2.44 (d, J=14.83 Hz, 1H), 3.02 (d, J=14.28 Hz, 1H), 3.10-3.27 (m, 1H), 3.36 (d, J=14.28 Hz, 1H), 3.72 (s, 3H), 4.52-4.77 (m, 3H), 6.72 (s, 1H), 7.48 (s, 1H); ESIMS (M+H)+=264.23.
Reaction SMILES: [SH:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.[CH3:7][C:8](=[O:11])[C:9]#[CH:10]>C(O)C>[SH:1][C:2]1(/[CH:10]=[CH:9]/[C:8](=[O:11])[CH3:7])[N:6]=[CH:5][CH2:4][S:3]1
Reactant: SC1=NCCS1
Reactant: C#CC(C)=O
Solvent: CCO
Product: CC(=O)/C=C/C1(S)N=CCS1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-mercaptothiazoline (3.7 g., 0.03 mole) in aqueous ethanol (35 ml) at 35° C., a solution of 3-butyn-2-one (2.0 g., 0.03 mole) in ethanol (10 ml) was added dropwise over 10 minutes. The resulting solution was refluxed for 2 hours and stirred at ambient temperature for 18 hours. The volatiles were removed in vacuo and the residue was extracted into ethyl acetate and washed thoroughly with water. After drying (MgSO4), the solution was concentrated to an amber oil consisting of the cis and trans isomers. Purification and isolation of the isomers was accomplished via column chromatography on silica gel using hexanes/ethyl acetate (4:1), yielding 2.7 g cis-isomer as a white solid, mp 69°-72° C. IR.(nujol) uc=o 1660 cm-1. The trans-isomer was recovered as an amber oil, 0.2 g IR (neat) uc=o 1660 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][N:10]=[N:9]1.[N:17]1([CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:28]3[C:29](=[O:32])[O:30][CH2:31][C:27]=3[CH:26]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([N:20]2[CH2:21][CH2:22][N:17]([CH2:23][CH2:24][C:25]3[CH:34]=[CH:33][C:28]4[C:29](=[O:32])[O:30][CH2:31][C:27]=4[CH:26]=3)[CH2:18][CH2:19]2)=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][N:10]=[N:9]1
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Reactant: O=C(O)Cc1ccc(-n2cnnn2)c(F)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C1OCc2cc(CCN3CCN(C(=O)Cc4ccc(-n5cnnn5)c(F)c4)CC3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [3-fluoro-4-(1H-tetrazol-1-yl)phenyl]acetic acid (0.68 mmol) in 10 mL of anhydrous DCM was added 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one (191 mg, 0.68 mmol), EDC (200 mg, 1.01 mmol), HOBt (136 mg, 1.01 mmol), TEA (341 mg, 3.38 mmol) was stirred at ambient temperature overnight. The mixture was added DCM, washed with brine, the organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified via prep-TLC to give the title compound. 1H-NMR (400 MHz, CDCl3) δ ppm 8.84 (s, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.31˜737 (m, 3H), 7.11˜7.19 (m, 2H), 5.29 (s, 2H), 3.59 (s, 2H), 3.49˜3.52 (m, 2H), 3.37˜3.4 (m, 2H), 2.89˜2.93 (m, 2H), 2.64˜2.68 (m, 2H), 2.4˜2.45 (m, 4H).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][SiH:6]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:5][CH2:4]1.[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:18]Br.C(OP(OCC)OCC)C>[Cu](I)I.C1COCC1>[F:14][C:15]1[CH:16]=[C:17]([CH2:18][CH2:2][C@H:3]2[CH2:8][CH2:7][Si@H:6]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:5][CH2:4]2)[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: Fc1ccc(CBr)cc1F
Reactant: CC(C)CC[SiH]1CCC(CBr)CC1
Agent: I[Cu]I
Agent: CCOP(OCC)OCC
Solvent: C1CCOC1
Product: CC(C)CC[Si@H]1CC[C@H](CCc2ccc(F)c(F)c2)CC1

Procedure:
65 ml of a Grignard's reagent (1.0M THF solution) prepared from 4-bromomethyl-1-isopentyl-1-silacyclohexane was dripped into a mixture of 10.4 g (50.2 mmol) of 3,4-difluorobenzylbromide, 200 mg of copper iodide (I), 400 mg of triethylphosphite and 100 ml of THF. After a conventional after treatment, they were separated by means of chromatography to obtain 11.7 g of the target product (yield 75%).