Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([Cl:9])[N:6]=[C:5](Cl)[C:4]=1[Cl:11])#[N:2].[NH:12]1[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]1>>[C:1]([C:3]1[N:8]=[C:7]([Cl:9])[N:6]=[C:5]([N:12]2[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]2)[C:4]=1[Cl:11])#[N:2]
Reactant: N#Cc1nc(Cl)nc(Cl)c1Cl
Reactant: O=S1CCNCC1
Product: N#Cc1nc(Cl)nc(N2CCS(=O)CC2)c1Cl

Procedure:
5.8 gm (0.02 mol) of 6-cyano-2,5-dichloro-4-(1-oxido-thiomorpholino)-pyrimidine (m.p. 145°-147°C), obtained from 6-cyano-2,4,5-trichloro-pyrimidine and thiomorpholine-1-oxide, were slowly added to a solution of 19.4 gm (0.1 mol) of piperazine hexahydrate in 100 ml of dioxane, whereby a mild endothermic reaction was released and a solution was rapidly formed. After standing for a short time, the reaction mixture was evaporated almost to dryness in vacuo, and the residue was taken up in about 100 ml of water. The reaction product, which separated out as pale yellow precipitate, was suction-filtered off, washed with water and dried. Yield: 6.4 gm (94% of theory); m.p. 203°-205°C.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:46][C:47]1[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][C:48]=1[N+:54]([O-:56])=[O:55].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:51][C:50]1[CH:52]=[CH:53][C:47]([CH3:46])=[C:48]([N+:54]([O-:56])=[O:55])[CH:49]=1)=[O:11])([CH3:4])[CH3:5])#[N:2]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1[N+](=O)[O-]
Reaction time: 72 h
Yield: 63.3 %

Procedure:
3-(2-cyanopropan-2-yl)benzoic acid 3 (25 g, 132 mmol), TBTU (63 g, 98 mmol), DIPEA (396 mmol, 65.4 mL) and 4-methyl-3-nitroaniline (20.1 g, 132 mmol) were dissolved in DMF (500 mL) and stirred for 72 h. The reaction mixture was poured into citric acid solution (3%) and extracted twice with EtOAc. The combined organic layers were washed with water (5×), brine (2×), dried, and evaporated. Purification by chromatography (CH2Cl2) gave 3-(2-cyanopropan-2-yl)-N-(4-methyl-3-nitrophenyl)benzamide 4 (27 g, 63%). 1H-NMR (400 MHz, CDCl3) 1.78 (s, 6H), 2.60 (s, 3H), (d, J=8.5 Hz, 1H), 7.55 (t, J=7.6 Hz, 1H), 7.73 (m, 1H), 7.80 (m, 1H), 7.90 (m, 1H), 7.99 (m, 1H), 8.06 (br s, 1H), 8.28 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[O:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1>CCOC(C)=O>[I:8][C:5]1[CH:6]=[CH:7][C:2]([NH:17][CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)=[N:3][CH:4]=1
Reactant: NCCN1CCOCC1
Reactant: Clc1ccc(I)cn1
Solvent: CCOC(C)=O
Product: Ic1ccc(NCCN2CCOCC2)nc1
Reaction time: 0.5 h

Procedure:
2-Chloro-5-iodopyridine (2.21 g, 9.25 mmol) was dissolved in 2-morpholinoethanamine (10 mL) and placed in the microwave for 30 min. at about 180° C. The reaction mixture was diluted with 100 mL EtOAc, washed with 50 mL saturated, aqueous NaHCO3, and dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained. MS (ES+): 334 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C:11](=[O:13])[CH2:10][O:9][C:8]=2[CH:14]=1)([O-])=O.[H][H]>CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C:11](=[O:13])[CH2:10][O:9][C:8]=2[CH:14]=1
Reactant: O=C1COc2cc([N+](=O)[O-])ccc2N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1)OCC(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into 500 mL 3-necked round bottom flask was added a solution of 7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (12 g, 61.86 mmol) in DMF (150 mL). To the mixture was added Pd/C (5 g) followed by addition of hydrogen gas. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:1). A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The product was precipitated by the addition of H2O. A filtration was performed. The filter cake was washed 3 times with 300 mL of hexane. This resulted in 7.3 g (68%) of 7-amino-2H-benzo[b][1,4]oxazin-3(4H)-one as a yellow solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:9]=2)[N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:3]=1.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26].C(N(CC)CC)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:16][N:14]1[CH:15]=[C:11]([C:8]2[N:9]=[C:10]3[C:2]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[CH:3][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:5]3=[N:6][CH:7]=2)[CH:12]=[N:13]1
Reactant: C#C[Si](C)(C)C
Reactant: Cn1cc(-c2cnc3c(n2)c(I)cn3C(=O)OC(C)(C)C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1cc(-c2cnc3c(n2)c(C#C[Si](C)(C)C)cn3C(=O)OC(C)(C)C)cn1

Procedure:
2.4 Reaction of tert-butyl 7-iodo-2-(1-methyl-1H-pyrazol-4-yl)pyrrolo-[2,3-b]pyrazine-5-carboxylate with bis(triphenylphosphine)palladium dichloride, copper(I) iodide, trimethylsilylacetylene and triethylamine in THF analogously to Example 1.3 gives tert-butyl 2(1-methylpyrazol-4-yl)-7-(2-trimethylsilylethynyl)pyrrolo[2,3-b]pyrazine-5-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[Br:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([Br:23])[CH:25]=3)[CH2:35][CH2:34]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: Brc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(OC)c(OC)cc2nc1OC
Product: COc1cc2nc(NC(=O)N3CCN(c4cccc(Br)c4)CC3)c(OC)nc2cc1OC
Yield: 63 %

Procedure:
Ethyl N-(2,6,7-trimethoxyquinoxalin-3-yl)carbamate and 1-(3-bromophenyl) piperazine were reacted by the same way with the example 190 to obtain the titled compound (yield, 63%) H NMR (300 MHz, CDCl3) δ 3.28-3.30 (m, 4H), 3.78 (m, 4H), 3.97 (s, 3H), 3.99 (s, 3H), 4.13 (s, 3H), 6.86 (m, 1H), 7.01 (s, 1H), 7.06-7.07 (m, 1H), 7.13-7.16 (m, 2H), 7.22-7.28 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:54])[C@@H:9]([CH3:53])[C:10]([NH:12][C@H:13]([C:31]([N:33]1[C@H:37]([C:38](=[O:50])[NH:39][C@H:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:43][CH2:42][CH2:41]2)[CH2:36][Si:35]([CH3:52])([CH3:51])[CH2:34]1)=[O:32])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29]C)=[O:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]([CH3:54])[C@@H:9]([CH3:53])[C:10]([NH:12][C@H:13]([C:31]([N:33]1[C@H:37]([C:38](=[O:50])[NH:39][C@H:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:43][CH2:42][CH2:41]2)[CH2:36][Si:35]([CH3:51])([CH3:52])[CH2:34]1)=[O:32])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)=[O:11])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)c1ccc(-c2ccc(C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N3C[Si](C)(C)C[C@H]3C(=O)N[C@@H]3CCCc4ccccc43)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](C(=O)N[C@@H](Cc1ccc(-c2ccc(C(=O)O)cc2)cc1)C(=O)N1C[Si](C)(C)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4′-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3-((R)-3,3-dimethyl-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,3-azasilolidin-1-yl)-3-oxopropyl)-[1,1′-biphenyl]-4-carboxylate (40 mg, 0.053 mmol) in THF (1 mL) and MeOH (0.5 mL) was added LiOH solution (0.48 mL, 0.95 mmol). The resulting mixture was stirred at rt overnight and acidified (1N HCl) to pH 1. The resulting mixture was extracted with ethyl acetate (2×). The organic layer was separated, dried over MgSO4 and concentrated in vacuo to give the title compound. MS(ESI+) m/z 741.5 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>Cl>[F:13][C:12]([F:15])([F:14])[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[NH:16][C:17]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1cc(F)ccc1N
Reactant: FC(F)(F)c1cccc2c(Cl)ccnc12
Agent: Cl
Product: COC(=O)c1cc(F)ccc1Nc1ccnc2c(C(F)(F)F)cccc12
Reaction time: 8 h
Yield: 44.8 %

Procedure:
A solution of 16 g of 4-chloro-8-trifluoromethylquinoline, 11.62 g of methyl 2-amino-5-fluoro-benzoate and 70 ml of 2 N hydrochloric acid solution was heated to reflux and was allowed to stand overnight at room temperature. The mixture was iced and filtered and the product was empasted with a little water and was vacuum filtered. The recovered crystals were dissolved in methanol and triethylamine was added to the resulting solution until the pH was alkaline. The mixture was iced and filtered and the product was dried to obtain 11.2 g of methyl 2-(8-trifluoromethyl-4-quinolinylamino)-5-fluoro-benzoate melting at 166° C.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:11]=[CH:12][C:13]4S[CH2:18][CH2:17][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=4[CH:24]=3)=[CH:4][C:3]=2[O:2]1.ClC1C=CC=C(C(OO)=O)C=1.[S:36]([O-:40])([O-])(=[O:38])=S.[Na+].[Na+]>C1COCC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:11]=[CH:12][C:13]4[S:36](=[O:40])(=[O:38])[CH2:18][CH2:17][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=4[CH:24]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)C1=Cc2cc(-c3ccc4c(c3)OCO4)ccc2SCC1
Reactant: O=S([O-])([O-])=S
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1=Cc2cc(-c3ccc4c(c3)OCO4)ccc2S(=O)(=O)CC1
Reaction time: 2 h

Procedure:
To a solution of methyl 7-(3,4-methylenedioxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g) in THF (10 ml) was added at 0° C. 70% 3-chloroperbenzoic acid (1.22 g), and the mixture was stirred at 0° C. for 15 minutes and then at room temperature for 2 hours. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was stirred for a few minutes and extracted with dichloromethane. The organic layer was washed with sodium bicarbonate solution and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give solid, which was recrystallized from THF/isopropanol to give colorless crystals of methyl 7-(3,4-methylenedioxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (763.3 mg).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH2:10].[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][N:22]([C:25]2[S:26][C:27]([C:31](O)=[O:32])=[C:28]([CH3:30])[N:29]=2)[C:21](=[O:34])[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][N:22]([C:25]2[S:26][C:27]([C:31]([NH:10][CH:2]3[CH2:3][C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:1]3)=[O:32])=[C:28]([CH3:30])[N:29]=2)[C:21](=[O:34])[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC1Cc2ccccc2C1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NC1Cc2ccccc2C1
Yield: 27 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use 2,3-dihydro-1H-inden-2-amine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 27% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.61 (d, J=8.1 Hz, 1H), 8.51 (d, J=7.0 Hz, 1H), 7.50-7.31 (m, 5H), 7.20-7.09 (m, 4H), 6.38 (dd, J=8.1, 2.7 Hz, 1H), 6.22 (d, J=2.7 Hz, 1H), 5.15 (s, 2H), 4.66-4.58 (m, 1H), 3.24-3.11 (m, 2H), 2.95-2.84 (m, 2H), 2.52 (s, 3H); MS (ES+) m/z 458.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:18]([C:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](O)=[O:27])([CH3:22])[CH3:21])#[N:19].Cl.C(N=C=NCCCN(C)C)C.CO>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:18]([C:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([O:8][C:7]2[CH:16]=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:10]=1)=[O:27])([CH3:22])[CH3:21])#[N:19]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Reactant: Nc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc([N+](=O)[O-])cc3)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
To a solution of 3-(4-nitrophenoxy)aniline (4.69 g, 20.4 mmol) and 3-(1-cyano-1-methylethyl)benzoic acid (3.98 g, 21.0 mmol) produced in Example A7(ii) in pyridine (100 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.69 g, 24.5 mmol) and N,N-dimethylpyridine-4-amine (151 mg, 1.24 mmol), and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added methanol (50 mL) and the mixture was further stirred at the same temperature for 30 min. The solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate (200 mL), washed with dilute hydrochloric acid (150 mL×2) and saturated aqueous sodium hydrogencarbonate solution (150 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (8.10 g, 99%) as a yellow amorphous substance. The obtained compound was used in the next reaction without a further purification.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][CH:7]=1)([O-:5])=[O:4].O.[ClH:15].CC[O:18][CH2:19][CH3:20]>CS(C)=O.CCOCC>[ClH:15].[Cl:15][C:8]1[CH:7]=[CH:6][N:3]=[CH:20][C:19]=1[O:18][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=1
Reactant: CCOCC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(COc2cnccc2Cl)cc1

Procedure:
The starting material was prepared by reaction of 4-nitro-3-hydroxy pyridine-N-oxide with acetyl chloride under reflux for 1 hour. The crude product was purified by rapid chromatography on silica gel using CH2Cl2 /MeOH 7:3 v/v as eluant to give 4-chloro-3-hydroxypyridine-N-oxide. Reduction of this compound with Raney nickel and hydrogen at ambient temperature for 2 hours in MeOH gave 4-chloro-3-hydroxypyridine. This compound was reacted with NaH in DMSO at 50°, the reaction mixture cooled and treated with 4-nitrobenzyl bromide for 1 hour. The reaction mixture was worked up with water and ether and the product treated with HCl/ether to give 4-chloro-3-(4-nitrobenzyloxy)pyridine hydrochloride. Reaction of the free base with excess methyl iodide at ambient temperature for 24 hours gave 4-chloro-1-methyl-3-(4-nitrobenzyloxy)pyridinium iodide. n.m.r. in d6DMSO-4.3(s, 3H); 5.6(s, 2H); 7.7(d, 2H); 8.3(d, 2H); 8.4(d, 1H); 8.7(d, 1H); 9.15(s, 1H).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](O)=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].O.Cl>C1(C)C=CC=CC=1>[CH2:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([CH2:11][OH:12])[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC[C@H]1CC[C@H](CO)CC1
Temperature: 25 °C

Procedure:
55 g (0.30 mol) of trans-4-butylcyclohexane carboxylic acid was dispersed in 200 cm3 of toluene, and while stirring at room temperature, 250 cm3 (0.90 mol) of a 70% NaAlH2 (OC2H4OCH3)2 in toluene was added dropwise at a rate where the toluene refluxed quietly, after which it was stirred for 3 hours on a 90° C. hot water bath. The reactant was cooled to room temperature, cm3 of water and 300 cm3 of 15% HCl were added dropwise while stirring, the oily layer was taken off, the water layer was extracted with toluene and combined with the oily layer, and they were washed with 10% HC1 and water. The toluene was removed, and the remaining oily substance was distilled under reduced pressure (b. p. 100° C./2 mmHg) to obtain 37 g (0.22 mol) of trans-4-butylcyclohexylmethanol.
Reaction SMILES: [H-].[Na+].[S:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[CH:5]=[CH:4]1.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Cl.Cl>C1COCC1.C1(C)C=CC=CC=1>[CH:18]1[CH:19]=[CH:20][C:13]([Cl:12])=[C:14]([CH2:15][N:8]2[CH2:7][C:6]3[CH:5]=[CH:4][S:3][C:11]=3[CH2:10][CH2:9]2)[CH:17]=1
Reactant: c1cc2c(s1)CCNC2
Reactant: ClCc1ccccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Clc1ccccc1CN1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.42 g, 8.6 mmole) in THF (5.0 ml) is added a solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1.0 g, 7.2 mmole), prepared, for example, as described in Example 4B, in THF (10 ml). The mixture is stirred under a nitrogen atmosphere at room temperature for 30 minutes and o-chlorobenzyl chloride (1.74 g, 10.8 mmole) is added. After stirring at room temperature for 90 minutes, toluene (15 ml) is added and the mixture is heated to reflux for 15 to 20 hours. Disappearance of starting material is confirmed by TLC. The mixture is then cooled to room temperature and acidified with 40 ml 1N hydrochloric acid. The organic layer is separated. The aqueous layer is extracted with 50 ml of toluene. The aqueous layer is then separated and basified with dilute aqueous sodium hydroxide to pH 13-14. The product is extracted into methylene chloride (3×40 ml). The methylene chloride extracts are washed (1×50 ml water) and (1×50 ml salt solution) then dried over anhydrous magnesium sulfate and concentrated to give the desired product.
Reaction SMILES: [C:1]([C@@H:3]([NH:22][C:23]([C:25]1([NH:31]C(=O)OC(C)(C)C)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:21]=[CH:20][C:14]3[CH2:15][S:16](=[O:19])(=[O:18])[CH2:17][C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)#[N:2].C(O)=O>CO>[NH2:31][C:25]1([C:23]([NH:22][C@H:3]([C:1]#[N:2])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:21]=[CH:20][C:14]4[CH2:15][S:16](=[O:19])(=[O:18])[CH2:17][C:13]=4[CH:12]=3)=[CH:9][CH:10]=2)=[O:24])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc4c(c3)CS(=O)(=O)C4)cc2)CCOCC1
Solvent: O=CO
Solvent: CO
Product: N#C[C@H](Cc1ccc(-c2ccc3c(c2)CS(=O)(=O)C3)cc1)NC(=O)C1(N)CCOCC1
Temperature: 50 °C
Yield: 33.6 %

Procedure:
To tert-butyl [4-({(1S)-1-cyano-2-[4-(2,2-dioxido-1,3-dihydro-2-benzothiophen-5-yl)phenyl]ethyl}carbamoyl)tetrahydro-2H-pyran-4-yl]carbamate (Example 34, step (ii), 300 mg) was added formic acid (2 mL) and the mixture heated to 50° C. for 30 min. The mixture was allowed to cool to room temperature and then methanol (5 mL) was added and the mixture evaporated to give an oil. The crude mixture was purified by preparative HPLC (SunFire column) eluting with methanol/0.1% aqueous trifluoroacetic acid to afford a product which was then purified by chromatography on silica eluting with ethyl acetate to give the titled compound (82 mg).
Reaction SMILES: C(OC([N:8]1[C@@H:12]([C@@H:13]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:14]([N:30]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.O.C(=O)(O)[O-].[Na+]>Cl.O1CCOCC1>[NH2:8][C@@H:12]([C@@H:13]([O:45][CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C@@H:14]([N:30]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=1)[CH2:11][OH:10]
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@@H](OCc2ccccc2)[C@H](Cc2cccc(OCc3ccccc3)c2)N(Cc2ccccc2)Cc2ccccc2)COC1(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N[C@H](CO)[C@@H](OCc1ccccc1)[C@H](Cc1cccc(OCc2ccccc2)c1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
Dissolve 4-(R)-[1-(S)-benzyloxy-3-(3-benzyloxyphenyl)-2-(S)-dibenzylaminopropyl]-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (16.01 g, 22.0 mmol) in 4 M hydrogen chloride in 1,4-dioxane (130 mL) and stir for 30 minutes. Add water (65 mL) and stir for 18 hours. Slowly add sodium bicarbonate (50 g) and water (˜50 mL). Extract with ethyl acetate, wash with saturated aqueous sodium chloride, dry (magnesium sulfate), filter and concentrate to give the crude desired compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[NH:9][S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:24][PH:25]([O-])([O-:29])[O:26][CH2:27][CH3:28].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C@@H:8]([NH:9][S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[C:5]1[CH:6]=[CH:7][C:2]([P:25]([CH3:24])(=[O:29])[O:26][CH2:27][CH3:28])=[CH:3][CH:4]=1
Reactant: CCO[PH](C)([O-])[O-]
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccc(Br)cc1)c1ccc(F)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1ccc([C@H](N[S@@](=O)C(C)(C)C)c2ccc(F)cc2F)cc1
Reaction time: 8 h
Yield: 44 %

Procedure:
To (S)—N—((S)-(4-bromophenyl)(2,4-difluorophenyl)methyl)-2-methylpropane-2-sulfinamide, 21-b, (2 g, 5 mmol), ethyl methylphosphite (1.08 g, 10 mmol) and Et3N (1.25 g, 12.5 mmol) in THF (20 ml) was added PdCl2(dppf) (360 mg). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken into ethyl acetate and washed with brine. The organic layer was concentrated under vacuum and the residue was purified over silica gel (dichloromethane:methanol=50/1) to provide the product, 21-c, (950 mg, 44%).
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.CC1(C)O[C:17](=[O:18])[CH2:16][C:14](=[O:15])[O:13]1>O>[I:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:10][C:17](=[O:18])[C:16]([C:14]([OH:15])=[O:13])=[CH:7]2
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1cc(I)ccc1O
Solvent: O
Product: O=C(O)c1cc2cc(I)ccc2oc1=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
5-iodosalicylaldehyde (344.2 mg, 1.39 mmol) and Meldrum's acid (200 mg, 1.39 mmol) were combined in H2O (2 mL). The solution was stirred at 75° C. for 2 h. After cooling to room temperature, the precipitate was filtered and dried at suction to give 302.0 mg of 6-iodo-3-carboxy-coumarin in 69% yield.