Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[S:13])[NH:8]3.Br[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C(N(CC)CC)C.O>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])=[N:8]3
Reactant: Cc1nc2cccc3[nH]c(=S)c1n23
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc2cccc3nc(SCCCCN4C(=O)c5ccccc5C4=O)c1n23
Temperature: 100 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
A mixture of 5.68 g (30 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]indene-2-thione, 8.47 g (30 mmol) of N-(4-bromobutyl)phthalimide and 6.27 ml (45 mmol) of triethylamine in 150 ml of DMF was stirred for 2 hours at 100° C. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate. The extract solution was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized from chloroform-ethanol to give 7.39 g of the desired compound (63.1%, pale brown solid)
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]#[N:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH3:22][CH2:23][O:24][C:25]([CH2:27]Br)=[O:26]>CCOCC>[CH2:23]([O:24][C:25](=[O:26])[CH2:27][C:13]1([C:15]#[N:16])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: N#CC1c2ccccc2Oc2ccccc21
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOC(=O)CC1(C#N)c2ccccc2Oc2ccccc21
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
9H-Xanthene-9-carbonitrile [27] (1.0 g, 4.825 mmol) was dissolved in anhydrous Et2O and cooled in an icebath. n-Butyl lithium (1.93 mL, 6.75 mmol. 2.5M soln. in hexanes) was added dropwise over 10 min. with continuos stirring. Stirring was continued for 30 min. at the same temperature and then brought to room temperature. The reaction mixture was heated at reflux (1 hr), cooled in an icebath and ethyl bromo acetate (0.75 mL, 6.755 mmol) was added dropwise via syringe. The resulting mixture was heated at reflux (4 h) cooled and filtered. The residue was washed with ether (25 mL). Water (25 mL) was added to the filterate and the organic layer was separated. The aqueous layer was once again extracted with ether (25 mL). The combined ether extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure to give an oil which was purified by mplc using pet. ether: EtOAc (9:1) as eluent to give 0.9 g (64%) of the product as a colorless oil. 1H NMR (CDCl3)d: 1.04-1.08 (t, J=7.5 Hz, CH3), 3.01 (s, 2H, CH2), 3.90-3.99 (q, 2H, CH2), 7.14-7.69 (m, 8H, Ar—H). 13C NMR (CDCl3)d: 13.54, 39.06, 48.47, 60.85, 116.88, 118.90, 119.75, 123.81, 127.34, 129.83, 150.30, 166.98.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH2:14][C:15]23[CH2:24][CH:19]4[CH2:20][CH:21]([CH2:23][C:17]([CH2:25][OH:26])([CH2:18]4)[CH2:16]2)[CH2:22]3)=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[Si:31]([O:26][CH2:25][C:17]12[CH2:23][CH:21]3[CH2:20][CH:19]([CH2:24][C:15]([CH2:14][O:13][C:3]4[C:2]([Cl:1])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:12])[CH:4]=4)([CH2:22]3)[CH2:16]1)[CH2:18]2)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32]
Reactant: COC(=O)c1cc(Cl)c(OCC23CC4CC(CC(CO)(C4)C2)C3)cc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(OCC23CC4CC(C2)CC(CO[Si](C)(C)C(C)(C)C)(C4)C3)cc1F
Yield: 102 %

Procedure:
A solution of methyl 5-chloro-2-fluoro-4-((3-(hydroxymethyl)-adamantan-1-yl)methoxy)benzoate (0.83 g, 2.17 mmol), tert-butylchlorodimethylsilane (0.36 g, 2.39 mmol), and imidazole (0.74 g, 10.90 mmol) in anhydrous dimethylformamide (12 mL) was stirred at ambient temperature under nitrogen for 16 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (50 mL), saturated ammonium chloride (2×50 mL) and brine (2×50 mL); dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (8:1 hexanes:ethyl acetate) to provide the title compound (1.10 g, quant): 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J=7.6 Hz, 1H), 6.62 (d, J=12.1 Hz, 1H), 3.87 (s, 3H), 3.58 (s, 2H), 3.17 (s, 2H), 2.13-2.05 (m, 2H), 1.69-1.58 (m, 6H), 1.49-1.36 (m, 6H), 0.87 (s, 9H), −0.01 (s, 6H); MS (ES+) m/z 497.1, 499.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])O)[CH2:3]1.N.[Li]>>[CH3:16][C:11]1[CH2:12][CH:13]=[CH:14][CH2:15][C:10]=1[CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:2]([CH3:1])[CH2:3]1
Reactant: Cc1ccccc1C(O)CC1CCN(C)C1
Agent: N
Agent: [Li]
Product: CC1=C(CCC2CCN(C)C2)CC=CC1

Procedure:
A sample of 1-methyl-α-(2-methylphenyl)-3-pyrrolidine-ethanol (23 g, 0.105 moles) is subjected to Birch reduction in 500 ml liquid ammonia which 7 g (1 mole) of lithium to give a quantitative yield of 3-(3,6-dihydro-2-methylphenethyl)-N-methylpyrrolidine.
Reaction SMILES: Br.[NH2:2][C:3]1[C:4]([Br:16])=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH3:14])([CH3:13])[C:7](=[O:15])[NH:6]2.[NH:17]1[CH2:21][CH2:20][N:19]=[C:18]1S(O)(=O)=O.Br>C(O)C(C)C>[Br:16][C:4]1[C:3]([NH:2][C:18]2[NH:19][CH2:20][CH2:21][N:17]=2)=[CH:12][CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:15])[C:8]([CH3:13])([CH3:14])[NH:9]2
Reactant: O=S(=O)(O)C1=NCCN1
Reactant: CC1(C)Nc2ccc(N)c(Br)c2NC1=O
Agent: Br
Solvent: CC(C)CO
Product: CC1(C)Nc2ccc(NC3=NCCN3)c(Br)c2NC1=O

Procedure:
A mixture of 6-amino-5-bromo-1,2-dihydro-2,2-dimethyl-3-(4H) - quinoxalinone hydrobromide (479 mg, 1 mmol) and 2-imidazoline-2-sulfonic acid (224 mg, 1.5 mmol) in isobutanol (5 ml) is heated at reflux until the starting hydrobromide material is consumed. The solvent is removed in vacuo and the residue chromatographed on silica gel with CHCl3 : CH3OH saturated with NH3 (g) elution to yield the title compound.
Reaction SMILES: [H-].[Na+].[Br-].[CH3:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=1)[CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7].[C:34]12([CH2:44][CH2:45][C:46]3[N:50]([CH3:51])[C:49]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=4[CH3:58])=[N:48][C:47]=3[CH:59]=O)[CH2:43][CH:38]3[CH2:39][CH:40]([CH2:42][CH:36]([CH2:37]3)[CH2:35]1)[CH2:41]2.O>C1COCC1.C(OCC)(=O)C>[CH3:4][O:5][C:6](=[O:7])[C:8]1[CH:33]=[CH:32][CH:31]=[C:10]([CH:11]=[CH:59][C:47]2[N:48]=[C:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[CH3:58])[N:50]([CH3:51])[C:46]=2[CH2:45][CH2:44][C:34]23[CH2:43][CH:38]4[CH2:37][CH:36]([CH2:42][CH:40]([CH2:39]4)[CH2:41]2)[CH2:35]3)[CH:9]=1
Reactant: Cc1ccccc1-c1nc(C=O)c(CCC23CC4CC(CC(C4)C2)C3)n1C
Reactant: COC(=O)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(C=Cc2nc(-c3ccccc3C)n(C)c2CCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% dispersion in oil) (122 mg, 3.05 mmol) was added to an ice cooled suspension of 3-methoxycarbonyl-benzyl-triphenylphosphonium bromide (1.25 g, 2.54 mmol) in THF (5 ml). The yellow suspension was stirred at room temperature for 10 min, cooled to 0° C. and the solution of the product of step b (7686 mg, 2.12 mmol) in THF (5 ml) was added. The suspension was allowed to warm to room temperature and stirred for 72 h. Water (2 ml), then ethyl acetate (40 ml) were added. The organic phase was washed with water (30 ml), brine (30 ml), dried (MgSO4) and the solvent was evaporated. The crude product was purified by flash column chromatography (silica, hexane/ethyl acetate 5:2) to afford the product as 2:1 mixture of trans/cis isomers (778 mg, 74%).
Reaction SMILES: [Br:1]Br.[BrH:3].[CH3:4][CH:5]1[NH:11][CH2:10][CH2:9][C:8](=[O:12])[CH2:7][CH2:6]1>C(O)(=O)C>[BrH:1].[Br:3][CH:7]1[CH2:6][CH:5]([CH3:4])[NH:11][CH2:10][CH2:9][C:8]1=[O:12].[BrH:1].[Br:1][CH:9]1[C:8](=[O:12])[CH2:7][CH2:6][CH:5]([CH3:4])[NH:11][CH2:10]1
Reactant: BrBr
Reactant: CC1CCC(=O)CCN1
Agent: Br
Solvent: CC(=O)O
Product: CC1CC(Br)C(=O)CCN1
Product: CC1CCC(=O)C(Br)CN1
Temperature: 25 °C

Procedure:
9.8 mL bromine was added to 30 g 7-methyl-azepan-4-one hydrobromide in 180 mL acetic acid. The reaction was stirred over night at RT. The reaction was evaporated to yield 33 g of the desired product as isomere mixture. Rf: 0.4 (DCM/MeOH=20/1), (M+H)+=206
Reaction SMILES: FC(F)(F)C(O)=O.O.C(OC([N:16]1[CH2:19][CH2:18][C@H:17]1[CH2:20][O:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:29]=[C:30]([CH2:34][C@H:35]([OH:43])[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:31]=[CH:32][CH:33]=2)[CH:25]=[N:26][CH:27]=1)=O)(C)(C)C>C(Cl)Cl>[NH:16]1[CH2:19][CH2:18][C@H:17]1[CH2:20][O:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:29]=[C:30]([CH2:34][C@H:35]([OH:43])[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:31]=[CH:32][CH:33]=2)[CH:25]=[N:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cccc(C[C@H](O)Cc3ccccc3)c2)c1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O[C@H](Cc1ccccc1)Cc1cccc(-c2cncc(OC[C@@H]3CCN3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
Trifluoroacetic acid (1.6 mL) and water (0.16 mL) were added to CH2Cl2 (8.0 mL). This mixture was added to 1-[3-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]phenyl]-3-phenyl-2(R)-propanol (381 mg, 0.80 mmol) in a 25 mL round-bottom flask with magnetic stirrer under N2. After stirring at room temperature overnight, the solution was concentrated in vacuo, the residue was diluted with water, and the solution was basified with saturated aqueous NaHCO3 solution and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the crude product (250 mg) was purified by preparative HPLC (column: SunFire Prep C18, 150×19, 5 μm particle size; UV detection at 254 nm; flow 20 mL/min; mobile phase: A, water with 0.05% TFA; B, methanol; 40-70% B in A in 6 min). The product-containing eluate was partially concentrated under reduced pressure to remove MeOH. The residual solution was basified with saturated aqueous NaHCO3 solution and extracted with EtOAc (3×50 mL). The combined organic phases were washed with brine and dried over Na2SO4. Concentration gave the free amine (130 mg, 43%) as a white solid. LC-MS (ESI) m/z 375 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]([O:32][CH3:33])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:14]4[C:15](=[O:26])[N:16]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:13]=4[C:12]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)=[C:9]3[C:10]=2[CH:11]=1.C([Sn](CCCC)(CCCC)[C:39]1[CH:44]=[N:43][CH:42]=[CH:41][N:40]=1)CCC.C(OCC)C>C1(C)C=CC=CC=1.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>[C:22]([N:16]1[C:15](=[O:26])[C:14]2[N:8]3[CH2:7][CH2:6][C:5]4[CH:4]=[C:3]([O:32][CH3:33])[C:2]([C:39]5[CH:44]=[N:43][CH:42]=[CH:41][N:40]=5)=[CH:11][C:10]=4[C:9]3=[C:12]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[C:13]=2[CH2:21][O:20][CH2:19][CH2:18][CH2:17]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: COc1cc2c(cc1Br)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCOC3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1-c1cnccn1)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCOC3

Procedure:
A solution of 60 mg of 7k and 125 mg of 2-tributylstannyl pyrazine and 13 mg of Pd(PPh3)4 was heated in 2 ml of degassed toluene, under N2 atmosphere for 16 hr. The reaction mixture was concentrated and the crude material was chromatographed over silica gel, using a gradient of toluene/ethyl acetate as eluent. The material thus isolated was treated with diethyl ether, to provide 13 mg of crystalline 7m; Mp 267-268° C.; MS-ESI: [M+1] 529.3.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2>O1CCOCC1.C(O)(=O)C>[CH3:1][N:2]([CH2:4][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([Cl:6])[CH:8]=2)[NH:12][CH:11]=1)[CH3:3]
Reactant: C=O
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: CNC
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CN(C)Cc1c[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Aqueous dimethylamine (8.0 mL, 63.7 mmol) and aqueous formaldehyde (4.8 mL, 64.0 mL) were combined in dioxane (50 mL) and acetic acid (50 mL). 5-Chloro-1H-indole (9.5 g, 62.5 mmol) in dioxane (30 mL) was added dropwise to the mixture, which was then was stirred at room temperature for 18 hours. The mixture was concentrated to approximately 50 mL by rotary evaporation, diluted with water (≈500 mL), and extracted with ether (~200 mL). The aqueous phase was separated, cooled, made basic with sodium hydroxide, and extracted into methylene chloride. The methylene chloride phase was separated, washed with water and then brine, dried over potassium carbonate, filtered, and evaporated. Crystallization from a mixture of acetone and diisopropyl ether gave 3-(dimethylaminomethyl)-5-chloro-1H-indole (10.6 g, 50.5 mmol) as white crystals, m.p. 148°-150° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[Cl:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][N:11]=1.[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[Cl:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:4]2[N:3]=[C:2]([NH:24][C:23]3[CH:25]=[CH:26][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH:7]=[CH:6][CH:5]=2)[N:11]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Fc1cccc(F)n1
Reactant: Clc1n[nH]c2ccccc12
Product: Clc1ccc(Nc2cccc(-n3nc(Cl)c4ccccc43)n2)cc1

Procedure:
Was prepared according to Method C from 2,6-difluoropyridine, 3-chloroindazole and 4-chloroaniline. LC-ESI-HRMS of [M+H]+ shows 355.0528 Da. Calc. 355.051727 Da, dev. 3 ppm.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][NH:39][C:40]1[CH:41]=[N:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][CH2:38][NH:39][C:40]2[CH:41]=[N:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: COc1ccc(NCCN)cn1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(NCCNC(=O)c2ccc(OC/C=C(\C)CCC=C(C)C)cc2)cn1
Reaction time: 1 h
Yield: 25.9 %

Procedure:
4-geranyloxybenzoic acid(3.48 g) was dissolved in chloroform(50 ml) and triethylamine(3.52 ml), and then diphenylphosphinic chloride(2.42 ml) was added thereto while being cooled with ice. After being stirred for 1 hour, the mixture, with 3-(2-aminoethylamino)-6-methoxypyridine(2.12 g) added thereto, was stirred for 3 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexan/ethyl acetate, thereby yielding 1.39 g of the aimed compound.
Reaction SMILES: C1N[C@H:5]([CH2:7][OH:8])[C@@H:4]([OH:9])[C@H:3]([OH:10])[C@H:2]1[OH:11].ClC(OCC1C=CC=CC=1)=[O:14].[C:23](=[O:26])(O)[O-].[Na+]>>[CH2:23]([OH:26])[C@@H:7]([C@H:5]([C@@H:4]([C@@H:3]([CH2:2][OH:11])[OH:10])[OH:9])[OH:14])[OH:8]
Reactant: O=C([O-])O
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC[C@H]1NC[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Na+]
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-deoxynojirimycin (100 g, 0.61 mol) in saturated aqueous sodium bicarbonate (1000 ml), benzyl chloroformate (95%, 121 g, 0.67 mol) was added dropwise at room temperature. After stirring at room temperature for 18 hr, the solution was extracted once with methylene chloride (300 ml) to remove any unreacted benzyl chloroformate. The aqueous layer was then extracted several times with ethyl acetate to give a total of 2.5-3 liters of the extract. The organic layer was then dried (Na2SO4), filtered and concentrated to give (2) a white solid (98 57 g, 54%), mp 101°-2° C., Anal calcd. for C14H19NO6C, 56.56, H, 6.44, N, 4.71 Found C, 56.33, H, 6.38, N, 4.58., 1H NMR (CD3OD) 7.2-7.4 (m, 5H), 5.15 (s, 2H), 4.23 (br m, 1H), 4.05 (br d., J=8 Hz, 1H), 3.87 (dd, J=6, 4 Hz, 1H), 3.78-3.85 (m, 2H), 3.70-3.78 (m, 2H), 3.45 (br d, J=8 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12](Cl)=[N:11][CH:10]=1.CC(=O)CC.[IH:39].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([I:39])=[N:11][CH:10]=1
Reactant: I
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: Cc1ccccc1-c1cc(I)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 93.6 %

Procedure:
To a solution of 1.00 g (2.05 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-chloro-N-methyl-4-o-tolyl-nicotinamide in 10 ml 2-butanone 1.1 g (7.2 mmol) sodium iodide and 0.28 ml (2.1 mmol) hydroiodic acid (57% in water) were added at room temperature. The mixture was heated at 80° C. for 2 h. After cooling to room temperature the mixture was diluted with ethyl acetate and treated with saturated aqueous sodium bicarbonate solution. The layers were separated, the organic layer washed with water, dried with magnesium sulfate and concentrated to give 1.5 g of crude product. Flash column chromatography gave 1.11 g (93.6%) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[Br:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[S:28](Cl)(=[O:30])=[O:29]>CN(C)C1C=CN=CC=1.ClCCl>[Br:17][C:18]1[CH:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:21]=[CH:20][C:19]=1[S:28]([NH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Br
Reactant: COC(=O)c1sccc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 24 %

Procedure:
To a cooled (0° C.) solution of methyl 3-aminothiophene-2-carboxylate (534.0 mg; 3.4 mmol), 4-dimethylaminopyridine (94.3 mg; 0.77 mmol) and pyridine (2.5 mL; 30.9 mmol) in anhydrous dichloromethane (60 mL) was added 2-bromo-4-(trifluoromethyl)benzene-1-sulfonyl chloride (1.0 g; 3.09 mmol) portion-wise. After addition was complete the reaction mixture was stirred at 0° C. for 20 minutes, gradually allowed to war to room temperature, stirred for 16 hours, and then washed with aqueous hydrochloric acid (50 mL; 2N). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 30% v/v over 400 mL gradient elution) to give the title product as a white solid (330 mg).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH2:29][C:30]([CH2:32][Si](C)(C)C)=[CH2:31])(=O)C.P(OC(C)C)(OC(C)C)OC(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:15]1[CH2:32][C:30](=[CH2:29])[CH2:31][C@H:16]1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc(Cl)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: C=C(COC(C)=O)C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)OP(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: C=C1C[C@@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)[C@H](c2ccc(Cl)cc2)C1
Temperature: 25 °C
Yield: 39.1 %

Procedure:
An oven-dried 250 mL round bottom flask equipped with a magnetic stir bar and a septum was charged with 4.705 g (13.7 mmol) of the product of Step A, 0.185 g (0.82 mmol) of palladium acetate, and 27 mL anhydrous tetrahydrofuran. The reaction mixture was freed of air by alternate cycles of degassing in vacuo and flushing with nitrogen using an external manifold attached through tubing to a needle inserted through the septum of the flask. To the brick red suspension was then added 3.80 mL (3.334 g, 17.9 mmol) 2-[(trimethylsilyl)methyl]-2-propen-1-yl acetate followed by 1.02 mL (0.860 g, 4.13 mmol) of triisopropyl phosphite. The reaction mixture was heated to reflux and stirred under nitrogen for 3 h at which point TLC analysis (15% ethyl acetate-hexanes) revealed consumption of the starting material and production of two new products. The reaction mixture was cooled to room temperature, transferred to a separatory funnel and partitioned between water and diethyl ether. The organic layer was washed with water, brine, dried (MgSO4), filtered and evaporated in vacuo. The product mixture was purified on a Biotage Flash 40i chromatography apparatus (90 g Flash 40M silica gel cartridge) eluted with 10% ethyl acetate-hexanes which afforded a less polar and a more polar product. Evaporation of the fractions containing the more polar product and drying in vacuo afforded 2.12 g of the title compound.
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9](=[O:14])[CH2:10][CH2:11][O:12][CH3:13])([CH3:7])[CH2:3][C:4](=O)[CH3:5].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[H][H]>[Pt]=O.CO>[CH3:1][C:2]([NH:8][C:9](=[O:14])[CH2:10][CH2:11][O:12][CH3:13])([CH3:7])[CH2:3][CH:4]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH3:5]
Reactant: [H][H]
Reactant: COCCC(=O)NC(C)(C)CC(C)=O
Reactant: C1CCNC1
Agent: O=[Pt]
Solvent: CO
Product: COCCC(=O)NC(C)(C)CC(C)N1CCCC1

Procedure:
Following the procedure of Example 1, 20.1 grams (0.1 mole) of N-(1,1-dimethyl-3-oxobutyl)-3-methoxypropionamide is reacted with 10 grams (0.14 mole) of pyrrolidine in the presence of 0.3 gram of platinum oxide and 100 ml. of methanol. When hydrogen uptake has ceased, the methanol is stripped and the product, N-(1,1-dimethyl-3-pyrrolidylbutyl)-3-methoxypropionamide, is isolated as described in Example 1.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][C:18]=2[Cl:26])=[CH:13][S:12][C:11]=1[N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37])=[O:9])C.Cl>O>[Cl:26][C:18]1[CH:19]=[C:20]([CH:23]([CH3:25])[CH3:24])[CH:21]=[CH:22][C:17]=1[CH:16]=[CH:15][C:14]1[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:27]2[C:35](=[O:36])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]2=[O:37])[S:12][CH:13]=1
Reactant: CCOC(=O)c1c(C=Cc2ccc(C(C)C)cc2Cl)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1ccc(C=Cc2csc(N3C(=O)c4ccccc4C3=O)c2C(=O)O)c(Cl)c1

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 4-[2-(2-Chloro-4-isopropylphenyl)vinyl]-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 31, Part C). The mixture is heated to reflux for 90 minutes, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.