Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Cl)(C)C.[O:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:11][C:12]([CH3:24])([CH3:23])[C:13]([NH:15][C:16]1[CH:21]=CC=C(Br)[N:17]=1)=[O:14].C1(C)C=CC=CC=1.CN(C)C=O>C(O)(=O)C>[CH3:11][C:12]([CH3:24])([CH3:23])[C:13]([NH:15][C:16]1[CH:21]=[CH:7][CH:8]=[C:9]([CH:10]=[O:6])[N:17]=1)=[O:14]
Reactant: CC(C)(C)C(=O)Nc1cccc(Br)n1
Reactant: C1CCOC1
Agent: CC(C)[Mg]Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)Nc1cccc(C=O)n1
Temperature: 13 °C
Reaction time: 24 h

Procedure:
A solution of 2.1 M isopropylmagnesium chloride in tetrahydrofuran (555.3 g, 1.20 mol) was added over 1.5 hours to the crude solution of 2-(trimethylacetylamino)-6-bromopyridine in toluene (501.2 g of crude solution from previous step, 0.500 mol) maintaining the temperature below 3° C. The resulting mixture was aged at 5° C. for 24 hours. Dimethylformamide (112.3 g, 1.54 mol) was added over 20 min maintaining the temperature at 11-15° C. After 15 min, the solution was transferred into 1 L of 10% aqueous acetic acid and the biphasic mixture stirred for 30 min. The organic phase was separated and combined with 500 mL of 20 wt % aqueous sodium hydrogen sulfite. The biphasic mixture was stirred vigorously for 45 min. The aqueous layer was separated and treated with 500 mL of 20 wt % aqueous Na2CO3, then extracted with ethyl acetate (2×500 mL). The combined organic layers were concentrated to approximately 400 mL at 50° C., 600 mmHg. The concentrate was dried over 8 g of MgSO4 and filtered to give 363.7 g of yellow solution (25.65 wt % title aldehyde, 93.28 assay g).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:13])[C:11]=1[OH:12])[C:6]([OH:8])=[O:7])[CH3:2].CN(C=O)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([CH3:13])[C:11]([OH:12])=[C:3]([CH2:1][CH3:2])[CH:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCc1cc(C(=O)O)cc(C)c1O
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(C(=O)OCc2ccccc2)cc(C)c1O
Temperature: 50 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a solution of 3-ethyl-4-hydroxy-5-methyl-benzoic acid (80.3 g, 0.446 mol) is DMF (500 mL), KHCO3 (53.5 g, 0.535 mol) followed by benzylbromide (114.3 g, 0.668 mol) is added. The mixture is stirred at 50° C. for 18 h before it is cooled to rt, diluted with water (250 mL), and extracted with TBME (2×250 mL). The org. extracts are washed with water, and then concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 19:1 to 9:1 to give 3-ethyl-4-hydroxy-5-methyl-benzoic acid benzyl ester (108.5 g) as a beige solid; 1H NMR (CDCl3): δ 1.28 (t, J=7.5 Hz, 3 H), 2.30 (s, 3 H), 2.68 (q, J=7.8 Hz, 2 H), 5.24 (s, 1 H), 5.37 (s, 2 H), 7.33-7.45 (m, 3 H), 7.45-7.50 (m, 2 H), 7.77 (s, 1 H), 7.79 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:3]=1[O:4]/[C:5](=[CH:9]\[C:10]([O-:12])=[O:11])/[C:6]([O-:8])=[O:7].[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:3]=1[O:4]/[C:5](=[CH:9]\[C:10]([OH:12])=[O:11])/[C:6]([OH:8])=[O:7]
Reactant: COc1ccc(O/C(=C\C(=O)[O-])C(=O)[O-])c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(O/C(=C\C(=O)O)C(=O)O)c(Br)c1
Yield: 88.5 %

Procedure:
Diethyl, (2Z)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioate (29.9 g, 86.6 mmol) as prepared in Reference Example 2a was suspended in ethanol (55 ml) and a solution of sodium hydroxide (7.0 g, 0.175 mol) in water (55 ml) was added. The solution was refluxed for 1 h to give a clear orange solution. Most of the ethanol was removed in vacuo then 6 M HCl (50 ml) was added. The solid was filtered, washed with water and dried to give (2Z)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioic acid as a light orange solid (24.3 g, 88% yield).
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3](Cl)=[O:4].O1CCCC1.[CH2:13]([CH:15]([C:18]1[CH:19]=[C:20]([CH3:23])[NH:21]C=1)[CH2:16][CH3:17])[CH3:14].[CH3:24][NH2:25]>O>[CH2:13]([CH:15]([C:18]1[CH:19]=[C:20]([CH3:23])[NH:21][C:2]=1[C:3]([NH:25][CH3:24])=[O:4])[CH2:16][CH3:17])[CH3:14]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CN
Reactant: CCC(CC)c1c[nH]c(C)c1
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)c1cc(C)[nH]c1C(=O)NC
Temperature: 0 °C

Procedure:
Trichloroacetyl chloride (2.03 mL) was added to the tetrahydrofuran solution (36 mL) of the compound prepared in Example 3 (2.76 g), and the reaction mixture was stirred at 0° C. for an hour. The reaction mixture was dropped to an aqueous solution of 40% methylamine (36 mL) on ice bath, and stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed by a saturated aqueous solution of sodium chloride, and dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (high flash-SI, size 3 L (made in Yamazen corporation), n-hexane/ethyl acetate=60/40→35/65) to obtain a title compound (1.55 g) having the following physical data.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].CO>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:25][CH2:24][N:23]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[C:16]([F:29])([F:30])[F:15])[CH2:28][CH2:27]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: FC(F)(F)c1ccccc1N1CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCN(c2ccccc2C(F)(F)F)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(2-trifluoromethylphenyl)piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 70% overall yield. mp 123°-124°. FDMS m/e=419 (M+ of free base). α[D]589 =-7.01 (c=0.66, methanol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)[C:6]=12.[Li]CCCC.[Cl:33]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:33][C:2]1[CH:3]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)[C:6]=12
Reactant: CN1CCn2c(C(F)(F)F)cc(Br)c2C12CCN(C(=O)OC(C)(C)C)CC2
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCn2c(C(F)(F)F)cc(Cl)c2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a solution of tert-butyl 8-bromo-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (5.00 g, 11.1 mmol) in anhydrous THF (125 mL) at −78° C. was added nBuLi (8.84 mL of 2.5 M, 22.1 mmol) slowly. The reaction mixture was allowed to stir at −78 for 20 minutes before 1,1,1,2,2,2-hexachloroethane (5.36 g, 22.7 mmol) was added dropwise as a solution in THF (12 mL). The reaction mixture was allowed to slowly warm to room temperature and was stirred overnight. The reaction mixture was quenched with the addition of saturated aqueous ammonium chloride (100 mL). The volatiles were removed under reduced pressure to half volume. The remaining aqueous suspension was extracted with EtOAc (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a thick brown oil. The crude product was purified by silica gel column chromatography: 10-20% EtOAc/hexane gradient to provide tert-butyl 8-chloro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (2.40 g, 53%) as a yellow oil that crystallized upon standing. ESI-MS m/z calc. 407.2, found 407.9 (M+1)+; Retention time: 1.70 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 6.47 (s, 1H), 3.97 (t, J=5.5 Hz, 4H), 3.28 (s, 2H), 3.13 (s, 2H), 2.51-2.28 (m, 5H), 1.93 (d, J=13.7 Hz, 2H), 1.47 (d, J=9.5 Hz, 9H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)[NH2:4].C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20].[CH:26]([O:29]C(C)C)(C)[CH3:27]>C(Cl)Cl>[C:19]([O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:3](=[N:2][O:1][C:26](=[O:29])[CH3:27])[NH2:4])[CH:6]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=NO)c1cccc(O)c1
Reactant: CC(C)OC(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)ON=C(N)c1cccc(OC(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 10.2 g (67 mmol) of the product obtained in Step A above in 150 ml of CH2Cl2 there are added 28 ml (0.201 mol) of triethylamine. 13.9 ml (0.147 mol) of acetic anhydride are added dropwise and the solution is stirred overnight at ambient temperature. After washing 3 times with water and then with brine, the organic phase is dried over MgSO4 and evaporated. The solid obtained is taken up in isopropyl ether and then filtered and dried to yield the title compound.
Reaction SMILES: C(O[C:4](=[O:12])[CH:5]([Na])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[H-].[Na+].C(OCC)(=O)CC(OCC)=O.[CH2:26]([O:33][C:34]([N:36]1[CH2:38][CH2:37]1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.P(=O)(O)(O)O>O1CCCC1>[CH2:9]([O:8][C:6]([CH:5]1[CH2:38][CH2:37][N:36]([C:34]([O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:35])[C:4]1=[O:12])=[O:7])[CH3:10]
Reactant: O=C(OCc1ccccc1)N1CC1
Reactant: CCOC(=O)C([Na])C(=O)OCC
Agent: O=P(O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C1=O
Reaction time: 22 h

Procedure:
To a solution of sodiomalonic acid diethyl ester prepared from sodium hydride (704 mg), diethyl malonate (3 ml), and tetrahydrofuran (10 ml) is added aziridine-1-carboxylic acid benzyl ester (1.8 g). After 22 hours at room temperature, the mixture is neutralized with 10% phosphoric acid, washed with water, dried and concentrated to give 1-carbobenzoxy-2-oxopyrroidine-3-carboxylic acid ethyl ester (1.85 g). Oil. IR (CHCl3) ν: 1785, 1730 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:3]=12.O=S(Cl)Cl.[CH3:18][NH:19][CH3:20].C1COCC1.CCN(CC)CC>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:19]([CH3:20])[CH3:18])=[O:13])[S:10][C:3]=12
Reactant: O=C(O)c1cc2nccc(Cl)c2s1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CN(C)C(=O)c1cc2nccc(Cl)c2s1
Yield: 84 %

Procedure:
This material was prepared from 7-chlorothieno[3,2-b]pyridine-2-carboxylic acid (0.57 g, 2.67 mmole), SOCl2 (5 ml), 2.0 M N,N-dimethylamine in THF (1.60 ml, 3.20 mmole) and Et3N (0.447 ml, 3.20 mmole) in a manner as previously described for example 9d to give a brown solid (0.54 g, 84%). 1H NMR (300 MHz, CDCl3) δδδ1H, d, J=5.0 Hz), 7.74 (1H, s), 7.35 (1H, d, J=5.0 Hz), 3.28 (3H, s), 3.22 (3H, s); ESIMS (MH+): 240.95.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[CH:6][N:5]=[C:4]2[N:18]([CH2:21][CH3:22])[N:19]=[CH:20][C:3]=12.Cl.[NH2:24]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(O)(=O)C>[CH2:21]([N:18]1[C:4]2[N:5]=[CH:6][C:7]3[C:2](=[N:24][O:17][C:8]=3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])[C:3]=2[CH:20]=[N:19]1)[CH3:22]
Reactant: NO
Reactant: CCn1ncc2c(Cl)c(C(=O)c3ccccc3OC)cnc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCn1ncc2c3noc(-c4ccccc4OC)c3cnc21

Procedure:
Five grams of 4-chloro-1-ethyl-5-(2-methoxybenzoyl)-1H-pyrazolo[3,4-b]pyridine was refluxed for 2 hours in 500 ml of acetic acid containing 15 g of hydroxylamine hydrochloride and 1 g of p-toluenesulfonic acid monohydrate. At the end of this time the reaction mixture was poured into water and extracted with dichloromethane. The organic phase was washed well with water, dried, evaporated and chromatographed over 230-400 mesh silica gel. The appropriate fractions were combined and evaporated to give 2.95 g of product, mp 126°-127° C. The melting point was unchanged after recrystallization from ethyl acetate/pentane.
Reaction SMILES: [CH2:1]([S:5]([NH:8][C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[C:15]([C:17]1[CH:29]=[CH:28][C:20]([CH2:21][NH:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH2:25])=[CH:19][CH:18]=1)#[N:16].Cl.[NH2:31][OH:32].CN1CCOCC1>CO>[CH2:1]([S:5]([NH:8][C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4].[OH:32][NH:31][C:15]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][NH:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH2:25])=[CH:28][CH:29]=1)=[NH:16]
Reactant: C[C@H](N)C(=O)NCc1ccc(C#N)cc1
Reactant: NO
Agent: CCCCS(=O)(=O)N[C@H](CO)C(=O)O
Agent: Cl
Solvent: CO
Solvent: CN1CCOCC1
Product: C[C@H](N)C(=O)NCc1ccc(C(=N)NO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product in Example 7 (117 mg, 0.285 mmol) in 1.14 ml methanol was added hydroxylamine hydrochloride (33.7 mg, 0.485 mmol), followed by N-methylmorpholine (53 μl, 0.485 mmol). The reaction mixture was stirred overnight at ambient temperature and then at 50° C. for six hours. The reaction mixture was concentrated in vacuo. The crude product was taken to the next step (Example 9) without further purification. The product eluted at 6.5 minutes by reverse phase (C18) HPLC at 0.1% trifluoroacetic acid in 5-50% aqueous acetonitrile over 20 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=3)[C:9]2=[O:26])=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:15][CH:14]=3)[C:9]2=[O:26])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1ccc(N2CCN(c3ccc(Br)cc3)C2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(N2CCN(c3ccc(Br)cc3)C2=O)cc1
Reaction time: 2 h

Procedure:
12.7 g of 3-(4-bromophenyl)-1-[4-[2-(ethoxycarbonyl)-ethyl]-phenyl]-imidazolidin-2-one, 300 ml of tetrahydrofuran, 100 ml of water and 23.6 ml of 4N sodium hydroxide solution are stirred overnight at ambient temperature. The precipitate is suction filtered, suspended in 1 liter of water, acidified with concentrated hydrochloric acid and stirred for 2 hours. It is then suction filtered, washed with water and dried at 60° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.C([Li])(C)(C)C.[CH:19](N1CCOCC1)=[O:20]>C1COCC1.CCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:19]=[O:20])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: O=CN1CCOCC1
Reactant: FC(F)(F)Oc1cc(Br)ccc1I
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(Br)cc1OC(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 4-bromo-2-(trifluoro-methoxy)iodobenzene (9.93 g, 28 mmol) in THF (150 mL) at -78° C. was added tert-butyllithium (37 mL of a 1.5 M solution in pentane, 56 mmol) dropwise over a period of 20 min. The pale yellow solution was stirred at -78° C. for 1.5 h when N-formylmorpholine (6.5 mL; 58 mmol) was added. The resulting solution was stirred at -78° C. for 15 min and the cooling bath was removed. The mixture was stirred for an additional 1 h, when 0.25 M aqueous citric acid (100 mL) was added. The mixture was diluted with EtOAc (150 mL), the layers were separated, the organic phase was washed with brine (100 mL), dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified using pressurized silica gel column chromatography eluting with hexane to give 4-bromo-2-(trifluoro-methoxy)benzaldehyde as a colorless liquid (TLC Rf =0.45 (hexanes)).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:10]([OH:12])C.[OH-:13].[Na+]>>[C:10]([CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1]1)([OH:12])=[O:13]
Reactant: CCO
Reactant: [OH-]
Reactant: c1ccc2c(c1)CCN2
Agent: [Na+]
Product: O=C(O)C1Cc2ccccc2N1

Procedure:
31.5 g of the above indoline (86%) are obtained by saponification in 250 ml of normal sodium hydroxide solution and 150 ml of ethanol for 18 hours at room temperature of 43 g (0.224 mol) of the corresponding ethyl ester prepared according to E. J. COREY et al. (J. Amer. Chem. Soc. 1970 92, p. 2476).
Reaction SMILES: C1([SiH3])C=CC=CC=1.N1CCCC1.CO.[O:15]([C:22]1[CH:23]=[C:24]([C:28]2[CH2:29][CH2:30][CH2:31][N:32]=2)[CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[O:15]([C:22]1[CH:23]=[C:24]([C@@H:28]2[CH2:29][CH2:30][CH2:31][NH:32]2)[CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(Oc2cccc(C3=NCCC3)c2)cc1
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Solvent: C1CCNC1
Product: c1ccc(Oc2cccc([C@@H]3CCCN3)c2)cc1
Reaction time: 0.75 h
Yield: 48 %

Procedure:
To oven dried round bottom flask is added S,S-EBTHITiF2 (100 mgs, 0.3 mmol) and diluted with THF (5 mL). The flask is sealed and purged with argon. To the yellow solution is added phenylsilane (4.6 mL, 37.5 mmol), pyrrolidine (100 uL, 1.1 mmol), and anhydrous methanol (100 uL, 1.1 mmol). The resulting yellow mixture is stirred for 45 minutes until green color persisted. A solution of 5-(3-phenoxy-phenyl)-3,4-dihydro-2H-pyrrole (1.2 g, 5.05 mmol) in THF (2 mL) is added to the catalyst and the mixture is stirred for 8 hrs. The reaction is carefully quenched with 10% HCl (100 mL) until gas evolution subsided and the pH˜2. The mixture is diluted with EtOAc (100 mL) and the aqueous layer is removed, neutralized with 3M NaOH (50 mL) until basic and extracted with EtOAc (3×100 mL). The organics were combined, dried over Na2SO4, filtered and concentrated under reduced pressures. The solid residue is purified by silica gel column chromatography (100% EtOAc) to give (S)-2-(3-phenoxy-phenyl)-pyrrolidine as a yellow solid (580 mgs, 48%). LCMS m/z 240.1 (M+1).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:11])[CH2:8][CH2:9][CH2:10][C:3]1=2.C(N(CC)CC)C.[CH2:19]([N:21]=[C:22]=[S:23])[CH3:20]>O1CCCC1>[CH2:19]([NH:21][C:22]([NH:11][CH:7]1[C:4]2[CH:5]=[CH:6][S:2][C:3]=2[CH2:10][CH2:9][CH2:8]1)=[S:23])[CH3:20]
Reactant: NC1CCCc2sccc21
Reactant: CCN=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=S)NC1CCCc2sccc21
Temperature: 50 °C
Reaction time: 0.38 h

Procedure:
A sample of 9.48 grams of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride is stirred in 100 ml. of dry tetrahydrofuran, and 6.06 grams of triethylamine is added. After stirring for 15 to 30 minutes, 5.23 grams of ethyl isothiocyanate in 20 ml. of dry tetrahydrofuran is added dropwise, and the mixture is heated for 2 hours at 50° C. The mixture is cooled and filtered, and the filter cake is washed with hexane. The filtrate is evaporated to dryness and poured on ice. The oil is extracted with ether, and the extract is washed with 1 N sulfuric acid, water, and saturated sodium bicarbonate solution. The ether extract is dried and evaporated to dryness to afford an oil. This oil crystallizes in ether to afford 1-ethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)thiourea, melting point 106° C. to 112° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([N+:21]([O-])=O)=[C:16]([NH2:24])[CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H][H].[I:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([O:35][CH3:36])[C:30]=1[CH:37]=O>CO.[Pd]>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([CH3:20])[C:17]3[N:21]=[C:37]([C:30]4[C:31]([O:35][CH3:36])=[N:32][CH:33]=[CH:34][C:29]=4[I:28])[NH:24][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nccc(I)c1C=O
Reactant: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)cc(N)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1nccc(I)c1-c1nc2c(C)cc(N3CCC(NC(=O)OC(C)(C)C)CC3)cc2[nH]1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
[1-(3-Amino-5-methyl-4-nitro-phenyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (1.54 g, 4.4 mmol) was dissolved in methanol (100 ml). Palladium on carbon (0.3 g, 10% Pd) was added and the suspension stirred vigorously under a balloon pressure of hydrogen overnight. The mixture was filtered through a pad of celite (under argon) into a 3-neck flask, the celite rinsed with methanol and the filtrate cooled to 0° C. A solution of 4-Iodo-2-methoxy-pyridine-3-carbaldehyde (1.21 g, 4.6 mmol) in methanol (50 ml) was added slowly (during 2 hours). The mixture was stirred overnight under air at ambient temperature, then concentrated in vacuo. Flash column chromatography on silica (eluent hexanes-ethyl acetate -methanol 5-4-1 gave the title compound. (0.79 g, 32%). LCMS (M+H)+ m/z 564 (t=1.31 min.).
Reaction SMILES: [Cl-].[CH2:2]([CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][NH3+:22])[CH:17]=2)[O:12][CH2:11][CH:10]1[NH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC1C=CN=C(N)C=1C.[CH3:38][N:39]1[CH:43]=[C:42]([S:44](Cl)(=[O:46])=[O:45])[CH:41]=[N:40]1>C(Cl)Cl>[CH2:2]([CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][NH:22][S:44]([C:42]3[CH:41]=[N:40][N:39]([CH3:38])[CH:43]=3)(=[O:46])=[O:45])[CH:17]=2)[O:12][CH2:11][CH:10]1[NH:23][C:24](=[O:25])[O:26][CH2:27][CH3:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)NC1COc2ccc(OCC[NH3+])cc2C1Cc1ccccc1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Agent: Cc1ccnc(N)c1C
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)NC1COc2ccc(OCCNS(=O)(=O)c3cnn(C)c3)cc2C1Cc1ccccc1
Temperature: 25 °C
Yield: 92 %

Procedure:
100 mg (0.25 mmol) of 2-(4-benzyl-3-(ethoxycarbonylamino)chroman-6-yloxy)ethanaminium chloride were dissolved in 5 ml methylene dichloride. Then, 95 mg (0.79 mmol) dimethyl aminopyridine and 54 mg (0.30 mmol) 1-methyl-1H-pyrazole-4-sulfonyl chloride were added. The reaction mixture was stirred at room temperature over night. The mixture was concentrated in vacuo and the residue was dissolved in ethylacetate and water. The phases were separated. The organic phase was washed with saturated ammonium chloride solution (2×), dried over MgSO4 and concentrated (127 mg crude). The crude material was purified by column chromatography to give 118 mg (0.23 mmol, 93%) of the desired product.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([O:10]C)[C:3]=1[C:4]#[N:5].[BrH:12]>C(O)(=O)C>[Br:12][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[C:4]#[N:5]
Reactant: Br
Reactant: COc1ccnc(Cl)c1C#N
Solvent: CC(=O)O
Product: N#Cc1c(O)ccnc1Br
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-Chloro-4-methoxy-nicotinonitrile (M. Mittelbach et al., Arch. Pharm. (Weinheim Ger.), 1985, GE, 318, 6, 481-486) (6.92 g) was suspended in 70 mL of 30% HBr in acetic acid in a pressure vessel and heated with stirring at 100° C. for 2 h. The reaction was cooled to room temperature and filtered, washing well with H2O, and dried in vacuo overnight at 50° C. providing 4.85 g 2-bromo-4-hydroxy-nicotinonitrile as a white solid. Proton NMR(DMSO) indicated the product was a mixture of 69% bromo compound with 31% starting chloro analog.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[C:6]([C:8]1[S:9][C:10](SC)=[C:11]2[C:16](=[O:17])[CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13][C:12]=12)#[N:7]>>[C:6]([C:8]1[S:9][C:10]([CH:1]([CH3:3])[CH3:2])=[C:11]2[C:16](=[O:17])[CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13][C:12]=12)#[N:7]
Reactant: CSc1sc(C#N)c2c1C(=O)CC(C)(C)C2
Reactant: CC(C)[Mg]Cl
Product: CC(C)c1sc(C#N)c2c1C(=O)CC(C)(C)C2
Yield: 36 %

Procedure:
In the same way as described in Example 6, Step 1, using isopropylmagnesium chloride and 1-cyano-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the title compound (1.2 g, 36%) was isolated as a colourless solid. mp 59-60° C. Found: C, 68.08; H, 6.97; N, 5.48%. C14H17NOS requires: C, 67.98; H, 6.93; N, 5.66%. 1HNMR (360 MHz, CDCl3) δ 1.08 (6H, s), 1.32 (6H, d, J=6.7 Hz), 2.43 (2H, s), 2.85 (2H, s), 4.24 (1H, heptet, J=6.7 Hz).