Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([CH3:42])[C:6](=[O:41])[CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C@H:21]2[CH2:38][C@@:36]3([CH3:37])[C@@H:32]([CH2:33][CH2:34][C:35]3=[O:39])[C@H:31]3[C@H:22]2[C:23]2[CH:24]=[CH:25][C:26]([OH:40])=[CH:27][C:28]=2[CH2:29][CH2:30]3)=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH3:4]>CO>[CH2:1]([N:5]([CH3:42])[C:6](=[O:41])[CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C@H:21]2[CH2:38][C@@:36]3([CH3:37])[C@@H:32]([CH2:33][CH2:34][C@@H:35]3[OH:39])[C@H:31]3[C@H:22]2[C:23]2[CH:24]=[CH:25][C:26]([OH:40])=[CH:27][C:28]=2[CH2:29][CH2:30]3)=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C)C(=O)CSCCCCCOc1ccc([C@H]2C[C@]3(C)C(=O)CC[C@H]3[C@@H]3CCc4cc(O)ccc4[C@H]32)cc1
Solvent: CO
Product: CCCCN(C)C(=O)CSCCCCCOc1ccc([C@H]2C[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]3CCc4cc(O)ccc4[C@H]32)cc1

Procedure:
One reduces the N-butyl-(5-(4-(3-hydroxy-17-oxo-estra-1,3,5(10)-trien-11beta-yl)-phenoxy)-pentylthio)-N-methyl acetamide obtained in Example 76 using sodium borohydride in methanol. In this way one obtains the expected product. [alpha]D =-32.5° (c=0.1% CHCl3).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:24])=[C:5]([C:25]([NH:27][CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32]CC)=[O:31])=[O:26])[N:4]=1)#[N:2].O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:24])=[C:5]([C:25]([NH:27][CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([OH:32])=[O:31])=[O:26])[N:4]=1)#[N:2]
Reactant: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3cccc4ccccc34)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3cccc4ccccc34)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Ethyl 3-(1-cyano-4-hydroxy-7-(naphthalen-1-yloxy)isoquinoline-3-carboxamido)-2,2-dimethylpropanoate (16 mg, 0.03 mmol) was dissolved in MeOH (4 mL) and 2 N NaOH (4 mL). After stirring for 5 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 13 mg. MS: (−) m/z 454.03 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:36])[C:9](=O)[CH2:10][CH:11]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.CSC.CO>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:36])[CH2:9][CH2:10][CH:11]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CN(C(=O)CC(CCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCC(CCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1
Yield: 48.6 %

Procedure:
N-(4-Chlorophenyl)-beta-(3,4-Dichlorophenyl)-N-methyl-4-(phenylmethyl)-1-piperidinepentanamide (0.38 g) in THF (30 mL) was treated with BH3 :DMS (0.4 mL; 10M) and heated at reflux temperature for 18 hours. The cooled reaction mixture was then treated with MeOH (2.0 mL) and the solvent evaporated under reduced pressure. The residue was dissolved in EtOH (20 mL), treated with potassium carbonate and heated at reflux temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and partitioned between CH2Cl2 (20 mL) and saturated NaHCO3 solution (20 mL). The organic portion was separated and the aqueous rextracted with CH2Cl2 (2×20 mL). The combined organic was dried over MgSO4, filtered and evaporated to give an oil. Silica gel chromatography eluting with 5% MeOH:CH2Cl2 gave the title compound (0.18 g). Mass spectrum (CI): 529.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5]>C(O)C.[Pd]>[NH2:10][C:7]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: [Pd]
Solvent: CCO
Product: N#Cc1cc(N)ccc1F
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
To a suspension of 2-fluoro-5-nitrobenzonitrile (5.20 g) in ethanol (150 mL) was added 5% Pd/C (1.00 g). The reaction was placed on a hydrogenator (50 psi) for 10 minutes. The reaction mixture was filtered through celite and the filtrate evaporated to give 4.25 g of 5-amino-2-fluorobenzonitrile. 1H NMR (CDCl3) δ 3.75 (bs, 2H, NH2), 6.83 (m, 2H, aromatic H), 6.99 (m, 1H, aromatic H). GC mass spectrum z (rel. intensity) 137 (M+H, 100).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C([NH:14][NH:15][C:16]([NH2:18])=[O:17])(=O)C.[ClH:19]>C(O)C>[ClH:19].[NH:15]([C:16]1[O:17][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:18]=1)[NH2:14]
Reactant: CC(=O)NNC(N)=O
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Solvent: CCO
Product: NNc1nc(-c2ccccc2)co1

Procedure:
A solution of α-bromoacetophenone (19.9 g) and acetylsemicarbazide (10.7 g) in ethanol (300 ml), containing 1N hydrochloric acid (1 ml), was refluxed for thirty hours. The solvent was removed in vacuo and the residue was crystallized from ether-ethanol to give 2-hydrazino-4-phenyloxazole hydrochloride. This salt was suspended in an aqueous solution of 10% ammonium hydroxide to give 2-hydrazino-4-phenyloxazole, m.p. 158°-160° C.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][Si:16]([CH2:19]Cl)([CH3:18])[CH3:17]>C(#N)C>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)CCl
Solvent: CC#N
Product: C[Si](C)(C)CNC(c1ccccc1)c1ccccc1
Yield: 29.8 %

Procedure:
A mixture of benzhydrylamine (25 g, 136.4 mmol) and trimethylsilylmethyl chloride (8.39 g, 68.4 mmol) in acetonitrile (105 ml) was refluxed overnight. Then the mixture was concentrated under vacuum at 70° C. with a rotary evaporator to remove all volatiles. The white residue was mixed with n-heptane (150 ml) and filtered over a glass filter. The salt residue was washed with n-heptane (2×25 ml). The combined heptane filtrates were concentrated under vacuum to give the crude product as a clear, slightly yellow oil (23 g; >100%). Purification by chromatography on silica gel (700 ml) eluting with n-heptane (2000 ml), followed by n-heptane:ethyl acetate (10:1) gave pure diphenyl-N-((trimethylsilyl)methyl)methanamine (5.5 g, 20.4 mmol; 30%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:21]4[S:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][C:17]=4[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[K+]>CO>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:21]4[S:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][C:17]=4[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc2cccc(-c3ccc(N4CCOCC4)cc3)c2s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc2cccc(-c3ccc(N4CCOCC4)cc3)c2s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 111.7 %

Procedure:
A solution of 330 mg (0.77 mmol) of methyl 7-[4-(4-morpholinyl)phenyl]-1-benzothiophene-2-carboxylate (Example 19A) in 6 ml of a 1:1 mixture of methanol and 2N potassium hydroxide solution is stirred at room temperature for 2 h and at 50° C. for 1 h. The reaction mixture is concentrated in vacuo and, after addition of water, acidified with conc. hydrochloric acid. The resulting precipitate is filtered off with suction, washed twice with water and dried under high vacuum. 292 mg of crude product are obtained and reacted without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[NH:11]([CH2:15][CH2:16][OH:17])[CH2:12][CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][N:11]([CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])[CH2:15][CH2:16][OH:17]
Reactant: OCCNCCO
Reactant: N#Cc1cccc(CBr)c1
Product: N#Cc1cccc(CN(CCO)CCO)c1

Procedure:
The title compound was prepared following the general procedure 10, starting from 3-(bromomethyl)benzonitrile and diethanolamine. It was obtained as a colorless oil (820 mg, 73%). LC/MS (Method B): 219.1 (M−H)−, 221.1 (M+H)+.
Reaction SMILES: C(OC(C)(C)C)(=[O:4])NN.[C:10]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22](Cl)=[O:23])=[CH:19][CH:20]=2)[C:15]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[N:14]1)(=[O:12])[CH3:11]>N1C=CC=CC=1>[C:10]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([OH:4])=[O:23])=[CH:19][CH:20]=2)[C:15]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[N:14]1)(=[O:12])[CH3:11]
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Reactant: CC(C)(C)OC(=O)NN
Solvent: c1ccncc1
Product: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution containing tert-butyl carbazate (0.79 g, 0.006 mol) in pyridine (30 mL) was added 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (1.7 g, 0.005 mol). The reaction mixture was allowed to stir at ambient temperature for 18 hours. Solvent was removed and water was added to the mixture. The reaction was extracted with ethyl acetate. Some 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carboxylic acid was isolated. The reaction mixture was treated with an equivalent of tert-butyl carbazate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in dichloromethane and allowed to stir overnight. The reaction was extracted with ethyl acetate. The product was taken up in a solution of 0.3% ammonia in methanol (˜50 mL) and allowed to stir overnight. The reaction mixture was extracted with dichloromethane, dried with magnesium sulfate, and concentrated. The material was purified by silica gel chromatography using 2% methanol in dichloromethane. The product was taken up in ethanol and gaseous hydrochloric acid was bubbled into solution. A solid precipitated out and was collected by filtration. This material was dried to provide the title compound (0.91g, 56% yield). ES-MS (m/z) 271 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:23][CH3:24].N1C=CC=CC=1.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36][C:37](Cl)=[O:38]>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:37](=[O:38])[CH2:36][C:32]4[S:31][CH:35]=[CH:34][CH:33]=4)=[C:3]([O:23][CH3:24])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1NC(=O)Cc1cccs1
Reaction time: 8 h
Yield: 32.3 %

Procedure:
5-(4-Amino-3-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (31 mg, 0.096 mmol) was dissolved in dichloromethane (1 mL). Pyridine (1 mL) was added followed by 2-(2-thienyl)ethanoyl chloride (14 uL, 0.113 mmol). After stirring overnight, another 14 uL of 2-(2-thienyl)ethanoyl chloride was added and the reaction mixture was stirred overnight. The solvent was removed and the residue was purified by preparative thin layer chromatography eluting with dichlormethane/methanol (95:5) to give N1-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-2-(2-thienyl)acetamide (14 mg, 0.031 mmol). 1H NMR (DMSO-d6) δ 1.89 (m, 6H), 2.25 (m, 2H), 3.82 (s, 3H), 3.99 (s, 2H), 5.19 (bs, 2H), 5.21 (m, 1H), 6.93 (s, 1H), 6.94 (s, 1H), 7.06 (m, 3H), 7.31 (m, 1H), 8.02 (s, 1H), 8.32 (s, 1H), 8.42 (d, J=8.22 Hz, 1H). LC/MS MH+=448.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]([CH3:17])=[CH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9]>C(Cl)Cl>[CH3:5][C:6]1([CH3:17])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:8](=[O:9])[CH2:7]1
Reactant: CC(C)=CC(=O)Nc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CC(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
To a 500 mL round bottom flask containing AlCl3 (5.22 g, 0.039 mol) was added dry CH2Cl2 (40 mL). Then a solution of N-(3,3-dimethylacryloyl) aniline (Compound 37, 4.45 g, 0.025 mol) in CH2Cl2 (50 mL) was added slowly. The reaction mixture was stirred at room temperature for overnight followed by the addition of ice-cubes. This mixture was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with NaCl (sat.), dried over MgSO4 and concentrated to give a brownish oil. Purification of this oil by column chromatography (10% ethyl acetate in hexane) gave the title compound as a light yellow solid (2.31 g, 52%). 1H NMR d 1.34 (s, 6H), 2.51 (s, 2H), 6.85 (d, J=7.8 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.03-7.08 (m, 1H), 7.16-7.23 (m, 1H), 9.01 (b, 1H).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][CH2:8][C:9]2[C:10]3[C:15]([CH:16]=[C:17]4[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]4)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23](Br)[C:24]#[CH:25].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH:1]1([CH2:6][N:7]([CH2:25][C:24]#[CH:23])[CH2:8][C:9]2[C:10]3[C:15]([CH:16]=[C:17]4[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]4)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CCBr
Reactant: c1ccc2c(CNCC3CCCC3)c3ccccc3cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C#CCN(Cc1c2ccccc2cc2ccccc12)CC1CCCC1
Yield: 88.4 %

Procedure:
A mixture of 63.5 g of N-cyclopentylmethyl-9-anthracenemethylamine, 50 g of propargyl bromide, 200 ml of methylene chloride and 200 ml of 10% aqueous, potassium carbonate solution is stirred vigorously under nitrogen for two hours. The layers are separated and the aqueous layer is extracted once with methylene chloride. Removal of the solvent from the dried extract gives 63.5 g of N-cyclopentylmethyl-N-propargyl-9-anthracenemethylamine as an oil; nmr spectrum: τ 2.3-3.0 (m, 9); 5.5 (s, 2) 6.8 (d, 2.5Hz, 2); 7.5 (m, 2); 7.7 (t, 2.5Hz, 1) and 7.5-9.2 (m, 9). This product is cyclized by heating under reflux in 200 ml toluene for 1.25 hours. Removal of the solvent and crystallization of the residue from 150 ml of isopropyl alcohol gives 44.4 g of 2-cyclopentylmethyl-1,2,3,5-tetrahydro-5,9b-o-benzenobenz[e]isoindole, identical by infrared and nmr spectroscopy with the sample prepared by acylation of 1,2,3,5-tetrahydro-5,9b-o-benzenobenz[e]isoindole with cyclopentanecarbonyl chloride followed by reduction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:5]=[CH:4][C:3]=1[OH:17].Cl[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:5]=[CH:4][C:3]=1[O:17][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: CC1(C)OB(c2ccc(O)c(F)c2)OC1(C)C
Reactant: ClCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)OB(c2ccc(OCc3ccccn3)c(F)c2)OC1(C)C

Procedure:
2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1 equivalent), 2-(chloromethyl)pyridine (1.1 equivalent), K2CO3 (3 equivalents), and KI (0.1 equivalents) are refluxed in acetone overnight. The mixture is cooled, filtered, the filtrate is concentrated and purified by column chromatography.
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1Br.C(=O)([O-])[O-].[K+].[K+]>C(O)CC.O>[CH:15]1[C:16]2[N:2]=[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]3[CH2:9][O:10][C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: Nc1cccc[n+]1COc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCCO
Product: C1=CC2=Nc3ccccc3OCN2C=C1

Procedure:
A mixture of 9.5 g of 2-amino-1-[(o-bromophenoxy)-methyl]pyridinium chloride, 8.3 g of potassium carbonate, 0.4 g of copper-bronze in 150 ml of n-propanol and 25 ml of water under N2, is heated under reflux for 12 hours while stirring. The mixture is filtered hot and the deep yellow filtrate is concentrated to dyrness. The residue is dissolved in 400 ml of ether, the ether solution is washed, dried and the solvent removed to give about 6.4 g of the crude yellow product. This is recrystallized from cyclohexane to give about 3.6 9 of the title product, mp about 125°-127°.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([CH2:12][CH2:13][CH3:14])[CH2:6][C:7]([O:9]CC)=O)([O-])=O.C([O-])=O.[NH4+].[CH:19]([Si:22]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[N:23]1[C:27]2=[N:28][CH:29]=[C:30]([CH:32]=O)[CH:31]=[C:26]2[CH:25]=[CH:24]1)([CH3:21])[CH3:20]>CO.CCOCC.[Pd]>[CH2:12]([CH:5]1[CH2:4][N:1]([CH2:32][C:30]2[CH:31]=[C:26]3[CH:25]=[CH:24][N:23]([Si:22]([CH:19]([CH3:21])[CH3:20])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[C:27]3=[N:28][CH:29]=2)[C:7](=[O:9])[CH2:6]1)[CH2:13][CH3:14]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C=O)cnc21
Reactant: CCCC(CC(=O)OCC)C[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CO
Product: CCCC1CC(=O)N(Cc2cnc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
Ethyl 3-(nitromethyl)hexanoate (0.52 g, 1.1 eq, 2.55 mmol) is dissolved in absolute methanol (8 ml). Then 10% Pd/C (0.2 g) and ammonium formate (1 g) are added under vigorous stirring. After 15 min, the mixture is diluted with ether (100 ml) and filtered. The solid on the filter is washed with ether (2×50 ml). A solution of aldehyde x255 (0.7 g, 1 eq, 2.3 mmol) in methanol (5 ml) is added immediately. The combined solution is evaporated in the vacuum of a rotary evaporator. The residue is dissolved in methanol (10 ml), CH(OMe)3 (0.5 ml) is added, and the obtained solution is stirred at room temperature for 16 h. An excess of NaBH4 (1 g in several small portions) is then added to the reaction solution under vigorous stirring for 20 min. The reaction mixture is evaporated in the vacuum of a rotary evaporator. The residue is partitioned between ethyl acetate and water. The organic phase is separated, dried with anhydrous sodium sulfate, and evaporated. The residue is dissolved in acetonitrile (10 ml), and the solution is refluxed for 24 h to complete the cyclization. The solvent is distilled off. The residue is purified by chromatography on silicagel (CCl4/MeCN) to afford 4-propyl-1-{[1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}pyrrolidin-2-one x256.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.[CH:11]([Mg]Cl)=[CH2:12].[Cl-].[NH4+]>C(OCC)C>[CH:11]([C:6]1([OH:10])[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH2:9][CH2:8][CH2:7]1)=[CH2:12]
Reactant: C=C[Mg]Cl
Reactant: O=C1CCCc2sccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CC1(O)CCCc2sccc21
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
6,7-Dihydrobenzo[b]thiophen-4(5H)-one (8.48 g, 56 mmol) was dissolved in anhydrous diethyl ether (200 mL) and the solution was cooled to −30° C. Vinyl magnesium chloride (60 mL, 1.6 M solution in THF, 96 mmol) was added to the ketone portion-wise whilst maintaining the temperature at −30° C. Upon completion of the addition, the reaction was stirred at −30° C. for 30 min and then allowed to warm to 25° C. Stirring was continued overnight and the solution was then treated with saturated ammonium chloride solution. The product was extracted into dichloromethane and this was back extracted with water and saturated brine. The dichloromethane solution was dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a crude, yellow oil (10.1 g, 100%). This compound was used directly in the next step without further purification.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[CH2:13]([O:15][C:16]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=[O:17])[CH3:14].C(I)C=C>C1COCC1.CCCCCC.CN(P(N(C)C)(N(C)C)=O)C>[CH2:13]([O:15][C:16]([C:18]1([CH2:3][CH:1]=[CH2:2])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:20][CH2:19]1)=[O:17])[CH3:14]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C=CCI
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 100.9 %

Procedure:
In a 250-mL RBF was weighed 6.1 g (60 mmol) of diisopropylamine and dissolved in THF. This solution was cooled to −78° C. To this was added 24 mL of 2.5 M (60 mmol) of butyllithium in hexane and stirred for 15 min, warmed up to 0° C. for 20 min, re-cooled to −78° C. To this was added piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (12.87 g, 50 mmol) in THF (10 mL). There was almost no color change. This was stirred at −78° C. for 45 min. Then, a mixture of 5 g of HMPA and 10.92 g of allyl iodide was added via cannula. The solution was still clear, very light in yellow. This mixture was stirred at −78° C. for 20 min, then, the dry ice bath was removed and the stirring was continued to allow the reaction mixture warm to r.t. over 40 min. The reaction mixture was poured into ice (˜50 g), sat'd NH4Cl aq. (50 mL) and ether (50 mL). The two layers were separated, the aqueous layer was extracted with ether (3×50 mL). The combined organic layers were washed with brine, dried (K2CO3), filtered, and concentrated in vacuo to obtain 15 g (100%) of the title compound as a yellow liquid,
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([OH:16])[C@H:9]([OH:15])[CH2:10][O:11]COC.CO[C:19](OC)([CH3:21])[CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[O:16][C:19]([CH3:21])([CH3:20])[O:15][C@@H:9]1[CH2:10][OH:11]
Reactant: COCOC[C@@H](O)[C@H](O)c1ccccc1Cl
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC1(C)O[C@H](c2ccccc2Cl)[C@@H](CO)O1
Temperature: 0 °C
Reaction time: 5 h
Yield: 32.3 %

Procedure:
To (1R,2R)-1-(2-chlorophenyl)-3-(methoxymethoxy)propane-1,2-diol (3.31 g, 13.4 mmol, Preparation example 3), Dichloromethane was added and cooled to 0° C. 2,2-Dimethoxypropane (3.3 ml, 26.8 mmol) and p-toluenesulfonic acid (2 g, 10.7 mmol) was added and stirred at room temperature for 5 hrs. The reaction mixture was quenched with H2O, extracted with DCM, and washed with H2O. The organic layer was dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated. The crude compound was purified by a silica gel column to produce the title compound (1.05 g, 30˜40%).