Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:12][C@H:13]([OH:16])[CH2:14]Cl)([CH:6]1[CH2:11][CH2:10][CH:9]=[CH:8][CH2:7]1)=[O:5])[CH3:2].[NH3:17]>C(O)C>[CH2:1]([O:3][P:4]([CH2:12][C@@H:13]([OH:16])[CH2:14][NH2:17])([CH:6]1[CH2:11][CH2:10][CH:9]=[CH:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(C[C@H](O)CCl)C1CC=CCC1
Reactant: N
Solvent: CCO
Product: CCOP(=O)(C[C@@H](O)CN)C1CC=CCC1
Reaction time: 72 h

Procedure:
A solution of 2.0 g of 3-chloro-2(S)-hydroxy-propyl-(cyclohex-3-enyl)-phosphinic acid ethyl ester in 40 ml of ethanol is placed in an autoclave. 10.0 g of ammonia are introduced under pressure and the mixture is left to stand at room temperature for 72 hours, concentrated to dryness by evaporation, chromatographed on silica gel, stirred at 0° with ethyl acetate/diethyl ether and filtered with suction, yielding 3-amino-2(S)-hydroxy-propyl-(cyclohex-3-enyl)-phosphinic acid ethyl ester, [α]20D =-5.2±0.9 (c=1.07 in methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]([C:36]1[S:37][CH:38]=[CH:39][C:40]=1[S:41](Cl)(=[O:43])=[O:42])=[O:35]>>[CH3:32][O:33][C:34]([C:36]1[S:37][CH:38]=[CH:39][C:40]=1[S:41](=[O:43])(=[O:42])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:30][CH:31]=1)=[O:35]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccsc4C(=O)OC)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3-chlorosulfonyl-thiophene-2-carboxylic acid methyl ester. Purity (ELSD, based on MW=625.7)=92%.
Reaction SMILES: C(OC(Cl)=O)C(C)C.[C:9]([NH:16][C@H:17]([C:22]([OH:24])=O)[CH2:18][CH2:19][CH2:20][CH3:21])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].CN1CCOCC1.[CH2:32]([NH2:36])[CH2:33][CH2:34][CH3:35]>C1COCC1>[CH2:32]([NH:36][C:22](=[O:24])[C@H:17]([CH2:18][CH2:19][CH2:20][CH3:21])[NH:16][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCN
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCCNC(=O)[C@H](CCCC)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
One equivalent of isobutylchloroformate is added to a solution of N-Boc-L-norleucine and one equivalent of a base such as N-methylmorpholine in THF at 0□C. After two minutes, one equivalent of butylamine is added and the mixture allowed to warm to room temperature. After thirty minutes, the reaction mixture is passed through a bed of Celite and all volatiles are removed under reduced pressure to yield N-Boc-L-norleucine butylamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:19]=1)([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])C(OC)=O>CS(C)=O.O>[CH3:1][O:2][C:3](=[O:35])[CH:4]([NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:19]=1
Reactant: COC(=O)C(Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)(NC(=O)OC(C)(C)C)C(=O)OC
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Temperature: 150 °C

Procedure:
To a solution of the title E compound, 2-(3-benzyloxy-4-nitro-benzyl)-2-t-butoxycarbonylamino-malonic acid dimethyl ester (6.98 g, 14.3 mmol) in DMSO (68 mL) and water (1.46 mL) sodium chloride (0.85 g, 14.6 mmol) is added and the mixture is gradually heated to 150° C. for 1 h. The mixture is cooled to RT, diluted with water (300 mL) and extracted 3 times with EtOAc. The organic extracts are washed with water and brine, dried over anhydrous MgSO4, decolorized with charcoal, filtered and evaporated. The residue is purified by chromatography (silica gel column, 6×30 cm, on EtOAc-hexane 1:1) to give 3-(3-Benzyloxy-4-nitro-phenyl)-2-tert-butyloxycarbonylamino-propionic acid methyl ester as a crystalline solid: mp=104-105° C.
Reaction SMILES: C[C:2]1[C:25]2[CH2:24][CH2:23][CH2:22][C:21]=2[C:5]2[O:6][CH:7]([CH2:9][NH:10]C(=O)OCC3C=CC=CC=3)[CH2:8][C:4]=2[CH:3]=1>[Pd]>[O:6]1[CH:7]([CH2:9][NH2:10])[CH2:8][C:4]2[CH:3]=[CH:2][C:25]3[CH2:24][CH2:23][CH2:22][C:21]=3[C:5]1=2
Reactant: Cc1cc2c(c3c1CCC3)OC(CNC(=O)OCc1ccccc1)C2
Agent: [Pd]
Product: NCC1Cc2ccc3c(c2O1)CCC3
Yield: 82.3 %

Procedure:
Treatment of (+)-benzyl (5-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methylcarbamate (0.93 g, 2.74 mmol) with palladium on carbon (10%, 0.093 g) generally according to the procedure described for Example 2 afforded 0.427 g (65%) of (+)-1-(3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. [α]D25=+48.0 (c 10.0 in methanol); mp>220° C.; Anal. calcd. for C13H17NOHCl.0.1H2O: C, 64.64; H, 7.59; N, 5.80. Found: C, 64.63; H, 7.63; N, 5.76.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)(=O)[CH3:2].II.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C(O)C>[N:18]1[C:1]([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=2)=[CH:2][N:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=12
Reactant: Nc1ccccn1
Reactant: CCOC(=O)Cc1ccc(C(C)=O)cc1
Agent: II
Solvent: CCO
Product: CCOC(=O)Cc1ccc(-c2cn3ccccc3n2)cc1
Yield: 36.8 %

Procedure:
A mixture of 6 g of ethyl 4-acetylphenylacetate, 20 ml of ethanol, 7.5 g of iodine and 5.7 g of 2-aminopyridine is heated under reflux for 3 hours. The ethanol is distilled off under reduced pressure, and the residue is extracted with ethyl acetate. The extract is washed with water, dried, and concentrated to give a reddish brown oil. The oil is column chromatographed over silica gel with chloroform as eluent, and the colorless crystals obtained from the chloroform eluate are recrystallized from a mixture of benzene and petroleum ether to give 3.0 g of ethyl 4-(imidazo[1,2-a]pyridin-2-yl)phenylacetate melting at 92°-93°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[N:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13][C:12](=[O:21])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]2[CH2:11][C:12](=[O:21])[CH2:13][CH2:14][N:15]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)N1CCC(=O)C=C1Cc1ccc(Cl)c(Cl)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCC(=O)CC1Cc1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
Intermediate 9 (0.176 mol) in THF (880 ml) was stirred under a N2 flow, and cooled to −78° C. L-selectride (0.264 mol) was added dropwise at −78° C. The reaction mixture was stirred for 1 hour, then poured out into water. DIPE was added. The organic layer was separated, washed with an aqueous NaHCO3 solution, with an aqueous NaCl solution, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 90/10). The desired fractions were collected and the solvent was evaporated, yielding 20.2 g (34.8% ) of (±)-ethyl 2-[(3,4-dichlorophenyl)methyl]-4-oxo-1-piperidinecarboxylate (intermediate 10).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5].[C:19]([NH:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)(=[O:21])[CH3:20].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[B-][N+](C)(C)C>C(O)(=O)C.CO.C1(C)C=CC=CC=1>[C:19]([NH:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:1][C:2]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=2)=[O:5])=[CH:25][CH:24]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [B-][N+](C)(C)C
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(=O)Nc1ccc(CNc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reaction time: 18 h

Procedure:
To a small sample of 2-amino-5-chloro-N-(5-chloropyridin-2-yl)benzamide (0.01 g, 0.035 mmol) weighed out in a sealable vial toluene was added (200 μL), followed by 4-acetamidobenzaldehyde (0.006 g, 0.035 mmol) and pyridinium p-toluenesulfonate (catalytic amount). A few molecular sieves were added; then the vial was sealed and placed in a shaker at 75° C. After 18 h, the reaction mixture was treated with borane-trimethylamine complex (100 μL of a 1 M solution in acetic acid) and the vial was placed in the shaker at room temperature for an additional 5 h. The reaction mixture was then diluted with methanol and applied to a 0.5 g SCX column, washed with methanol and gravity-eluted with 1 N ammonia in methanol. The product fractions were combined and concentrated in vacuo to a residue which was triturated in acetonitrile to provide the title compound as a yellowish powder (0.015 g, 100%) in 98% purity by LC-MS (method A).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:25]([O:27]C)=[O:26])[CH2:9]2)=[O:7])[CH2:3]1.CC(C)([O-])C.[K+]>>[OH:1][CH:2]1[CH2:3][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:18][CH:19]=3)[CH2:11][CH:10]([C:25]([OH:27])=[O:26])[CH2:9]2)=[O:7])[CH2:5]1
Reactant: COC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1

Procedure:
700 mg (1.43 mmol) of the compound from Example 109A and 1.61 g (14.3 mmol) of potassium tert-butoxide were reacted according to the General Method 9A. Yield: 700 g (99% of theory, 84% pure)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]([NH:13][C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:24])[CH:20]=3)[N:15]=1)[CH2:10][CH2:9][CH2:8]2.[CH3:25][O:26][CH2:27][C:28](O)=[O:29]>>[CH3:25][O:26][CH2:27][C:28]([NH:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([NH:13][CH:11]1[C:12]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[O:2][CH3:1])[CH2:8][CH2:9][CH2:10]1)[CH:23]=[CH:22]2)=[O:29]
Reactant: COCC(=O)O
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CCC2
Product: COCC(=O)Nc1ccc2nc(NC3CCCc4cccc(OC)c43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6-diamine and methoxyacetic acid; MS: m/e=392.3 (M+H+).
Reaction SMILES: CN(C)C=O.Cl.[NH2:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([OH:15])=[C:10]([Cl:16])[CH:9]=1.[OH-].[K+].[F:19][C:20]([F:24])=[C:21]([F:23])[F:22]>O>[Cl:14][C:13]1[CH:12]=[C:11]([O:15][C:21]([F:23])([F:22])[CH:20]([F:24])[F:19])[C:10]([Cl:16])=[CH:9][C:8]=1[NH2:7]
Reactant: FC(F)=C(F)F
Reactant: Nc1cc(Cl)c(O)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Cl)c(OC(F)(F)C(F)F)cc1Cl
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A mixture of 100 ml dimethylformamide (DMF), 75 g (0.035 mole) 4-amino-2,5-dichlorophenol, hydrochloride, and 3.0 g (0.05 mole) KOH (pellets ground to powder) was placed in a 500 ml 3-necked round bottom flask fitted with a mechanical stirrer, thermometer and reflux condenser and was stirred for about 1 hour. It was then heated to 85° C. with stirring and 6.0 g (0.06 mole) of tetrafluoroethylene was bubbled in while heating at 85°-90° C. The addition took about 10 minutes. The reactor and contents were cooled in an ice water bath and 200 ml of water were added. The product was extracted with 200 ml methylene chloride and then again with 100 ml methylene chloride. The extracts were combined and the solvents removed by vacuum distillation. A residue (7 g) remained.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl-:8].[Cl-].[CH2:10]([C:14]1([Zr+2:19]C2(CCCC)C=CC=C2)[CH:18]=[CH:17][CH:16]=[CH:15]1)[CH2:11][CH2:12][CH3:13].C=C>CO>[CH3:13][CH2:12][CH2:11][CH2:10][C:14]1[CH:15]=[CH:16][CH2:17][C-:18]=1.[CH3:13][CH2:12][CH2:11][CH2:10][C:14]1[CH:15]=[CH:16][CH2:17][C-:18]=1.[Cl-:8].[Cl-:8].[Zr+4:19]
Reactant: CCCCC1([Zr+2]C2(CCCC)C=CC=C2)C=CC=C1
Agent: C=C
Agent: [Cl-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCC1=[C-]CC=C1
Product: [Zr+4]
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
To a 500 mL four-necked flask equipped with magnetic stirrer was charged 250 mL of toluene. The toluene was heated to 34° C. To this was added a toluene solution of 0.043 g (1.6 mmol) of polymethylaluminoxane composition based on aluminum atoms. Bis(n-butylcyclopentadienyl)zirconium dichloride ((nBu-Cp)2ZrCl2) was added to achieve an Al/Zr mole ratio of 5,000. While raising the temperature to 40° C., ethylene gas was blown in. After 10 minutes, the ethylene gas feed was halted and methanol was introduced to deactivate the catalyst. The polyethylene produced was filtered and dried. The polymerization activity was calculated to be 35×106 g-PE/mol-Zr·atm·hr.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[CH2:5][N:6]([CH3:8])[CH3:7].[Mg].[CH2:13]=[O:14]>O1CCCC1>[CH3:7][N:6]([CH2:5][C:4]1[CH:3]=[C:2]([CH:11]=[CH:10][CH:9]=1)[CH2:13][OH:14])[CH3:8]
Reactant: C=O
Reactant: CN(C)Cc1cccc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CN(C)Cc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78 %

Procedure:
3-Bromo-N,N-dimethylbenzylamine (21.4 g) was reacted with magnesium turnings (2.4 g) in dry tetrahydrofuran (75 ml). The mixture was cooled to 0° and gaseous formaldehyde (generated by heating 15 g paraformaldehyde in a stream of argon) was passed over the stirred solution. Tetrahydrofuran (25 ml) was added and the mixture was stirred at room temperature for 2.5 hours and acidified to pH 1. The mixture was extracted with aqueous 3N hydrochloric acid, and the aqueous extracts were made alkaline with aqueous sodium hydroxide and extracted with ether. The ether extracts were evaporated to give 3-(dimethylaminomethyl)benzyl alcohol (14.78 g, 78%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[C:16]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=1>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:22][C:19]2[CH:20]=[CH:21][C:16]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][CH:18]=2)[CH:8]=1
Reactant: COC(=O)CCc1cccc(CN)c1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc(-c3ccccc3)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and biphenyl-4-carbaldehyde using the method described in Example 1, Step A except the mine was formed in MeOH at reflux over 3 h. 1H NMR (400 MHz, CDCl3) δ 7.55 (m, 4H), 7.40 (m, 4H), 7.32 (m, 1H), 7.29-7.22 (m, 2H), 7.17 (m, 1H), 7.07 (d, 1H), 3.82 (s, 2H), 3.79 (s, 2H), 3.64 (s, 3H), 2.93 (t, 2H), 2.61 (t, 2H); MS 360 (M+1).
Reaction SMILES: [Na].C([O:4][C:5](=[O:8])[CH2:6][SH:7])C.Cl[C:10]([CH3:18])=[C:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:12]=O>C(O)C.C1COCC1.C(OCC)C>[CH2:14]([C:11]1[CH:12]=[C:6]([C:5]([OH:4])=[O:8])[S:7][C:10]=1[CH3:18])[CH:15]([CH3:17])[CH3:16]
Reactant: CCOC(=O)CS
Reactant: CC(Cl)=C(C=O)CC(C)C
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOCC
Product: Cc1sc(C(=O)O)cc1CC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.3 %

Procedure:
Sodium (10.7 g, 467 mmol) is dissolved in ethanol (500 mL) and the resulting solution is diluted with THF (100 mL) before mercapto-acetic acid ethyl ester (33.7 g, 280 mmol) dissolved in THF (70 mL) is slowly added at 5° C. The mixture is stirred at rt for 1 h before a solution of 3-chloro-2-isobutyl-but-2-enal (30 g, 187 mmol) in THF (100 mL) is slowly added at 8° C. The resulting yellow suspension is stirred at rt for 16 h. The reaction mixture is diluted with diethyl ether (500 mL) and is washed with dilute aq. NaOCl solution, followed by aq. 1N HCl and water. The organic extract is dried over MgSO4, filtered and evaporated. The remaining orange oil is dissolved in ethanol (150 mL) and 2N aq. LiOH (50 mL) is added. The mixture is stirred for 16 h at 50° C., acidified with 2 N aq. HCl and extracted with EA. The organic extract is dried over MgSO4, filtered and evaporated. The crude product is recrystallized from EA/heptane to give 4-isobutyl-5-methyl-thiophene-2-carboxylic acid (10.5 g) as colourless crystals; LC-MS: tR=0.92 min, [M+1+CH3CN]=240.16; 1H NMR (CDCl3): δ 7.59 (s, 1H), 2.40-2.37 (m, 5H), 1.84 (hept, J=7.0 Hz, 1H), 0.90 (d, J=7.0 Hz, 6H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9].[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:12]([O:11][P:10]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9])(=[O:17])[O:14][CH2:15][CH3:16])[CH3:13]
Reactant: Cc1ccc(I)c(C)c1
Reactant: CCOP(OCC)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CCOP(=O)(OCC)c1ccc(C)cc1C
Temperature: 25 °C
Yield: 84 %

Procedure:
4-Iodo-m-xylene (4.31 mmol), triethyl phosphite (6.03 mmol) and palladium acetate (0.43 mmol) were mixed together in acetonitrile (10 ml), in a microwave tube. The vessel was sealed and placed in a microwave to react at 160° C., for 45 minutes. After cooling to room temperature, acetonitrile was removed. The crude material was purified by silica gel chromatography (eluent: stepwise gradient of ethyl acetate (0-30%) in petroleum ether) to yield Intermediate I.1 as an oil (84%). Intermediate 1.1 was characterized by the following spectroscopic data: 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.32 (t, J=8.0 Hz, 6H), 2.35 (s, 3H), 2.53 (s, 3H), 4.07-4.14 (m, 4H), 7.07-7.08 (m, 2H), 7.77-7.83 (m, 1H); 31P NMR (CDCl3, 162 MHz) δ (ppm) 20.15 (s, 1P); and MS (ESI, EI+) m/z=243 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]([C:20]2[S:30][C:29]3[N:31]4[C:22](=[CH:23][N:24]=[C:25]4[CH:26]=[CH:27][CH:28]=3)[CH:21]=2)=[O:19])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32]>C(O)C>[ClH:32].[ClH:32].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]([C:20]2[S:30][C:29]3[N:31]4[C:22](=[CH:23][N:24]=[C:25]4[CH:26]=[CH:27][CH:28]=3)[CH:21]=2)=[O:19])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCNC(=O)C2=Cc3cnc4cccc(n34)S2)CC1
Agent: Cl
Solvent: CCO
Product: O=C(NCCCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To a solution of 10.12 g (22.87 mM) of N-[3-(1-tert-butoxycarbonyl-4-piperidyl)propan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide in 100 ml of ethanol was added 9.4 ml (114.33 mM) of 12N-hydrochloric acid and the mixture was stirred at room temperature for 1 hour. The resulting precipitate was recovered by filtration and rinsed with small amounts of ethanol and ether to provide 8.79 g (92.5%) of the title compound as orange-colored crystals.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12])#[N:2].Cl.[CH3:17][NH:18][OH:19].C(=O)([O-])[O-].[Na+].[Na+].[C:26]([C:33]([O:35][CH2:36][CH3:37])=[O:34])#[C:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(OCC)(=O)C.O.C(O)C>[CH2:36]([O:35][C:33]([C:26]1([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[O:19][N:18]([CH3:17])[C:1]([C:3]2[C:4]([N:10]([S:11]([CH3:14])(=[O:13])=[O:12])[CH3:15])=[CH:5][CH:6]=[CH:7][C:8]=2[F:9])=[N:2]1)=[O:34])[CH3:37]
Reactant: CN(c1cccc(F)c1C#N)S(C)(=O)=O
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: CNO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CC1(C(=O)OCC)N=C(c2c(F)cccc2N(C)S(C)(=O)=O)N(C)O1
Temperature: 80 °C
Reaction time: 4 h
Yield: 55.8 %

Procedure:
To a stirred suspension of N-(2-cyano-3-fluoro-phenyl)-N-methyl-methanesulfonamide (0.685 g, 3.0 mmol) and N-methylhydroxylamine hydrochloride (1.0 g, 12 mmol) in 1:1 water/ethanol (20 mL) was added sodium carbonate (0.936 g, 6 mmol) in small portions and the resulting mixture stirred at 80° C. for 4 h. The reaction mixture was concentrated and the residue re-dissolved into 1:1 water :ethanol (20 mL). To this solution was added diethyl acetylenedicarboxylate (0.64 mL, 4 mmol) and the mixture stirred for 1 h at room temperature. The reaction mixture was then taken up in ethyl acetate (100 mL), washed successively with water and brine (50 mL each), dried (MgSO4), filtered and concentrated to give a yellow oil. The crude product was purified on silica gel column (2:3 to 3:2 ethyl acetate/hexanes) to afford the title compound as a viscous yellow oil (0.7453 g, 56% yield). 1HNMR (500 MHz, CDCl3) δ: 7.52–7.48 (1H, m), 7.31 (1H, d, J=8.24 Hz), 7.18 (1H, t, J=8.55 Hz), 4.35–4.25 (2H, m), 4.18 (2H, q, J=7.02 Hz), 3.40 (1H, d, J=16.48 Hz), 3.21 (3H, s), 3.09 (1H, d, J=16.48 Hz), 3.09 (3H, s), 3.07 (3H, s), 1.33 (3H, t, J=7.02 Hz), 1.26 (3H, t, J=7.02 Hz). HRMS (ESI) calcd for C18H25FN3O7S (M+H): 446.1397; found: 446.1383.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)(=O)=O)=CC=1>>[F:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][CH2:30][CH2:29][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)=[CH:33][CH:34]=1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccc(F)cc2)cc1
Product: O=C(N[C@H]1CCN(CCCc2ccc(F)cc2)C1)C12CC3CC(CC(C3)C1)C2
Yield: 19.4 %

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (0.5 g) and 3-(4-fluorophenyl)propyl p-toluenesulfonate (0.92 g) were reacted under the same conditions as in Example 6 to give (S)-N-(1-(3-(4-fluorophenyl)propyl)pyrrolidin-3-yl)-1-adamantanecarboxamide (0.15 g), melting point 114-115° C.
Reaction SMILES: [C:1](=[NH: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.Cl.N[CH2:17][C:18]([O:20][C:21]([CH3:31])([CH3:30])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=[O:19].[Cl-].[Cl-].[Ca+2]>C(Cl)Cl>[C:2]1([C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:14][CH2:17][C:18]([O:20][C:21]([CH3:31])([CH3:30])[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[O:19])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(Cc1ccc(Cl)cc1)OC(=O)CN
Agent: Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(Cc1ccc(Cl)cc1)OC(=O)CN=C(c1ccccc1)c1ccccc1
Yield: 63 %

Procedure:
Benzophenone imine (0.8 g, 2.9 mmol) and finely ground 1-(4-chlorophenyl)-2-methyl-2-propyl glycinate hydrochloride and 10 ml of CH2Cl2 were stirred at room temperature over night with the exclusion of moisture (CaCl2 tube). The reaction mixture was filtered to remove NH4Cl, and evaporated to dryness. The residue was taken up in 10 ml of ether, washed with water and dried. Filtration and removal of the solvent were followed by flash chromatography on SiO2 saturated with NH3 (methanol/NH3) with hexane: ethyl acetate 97:3 as eluent to yield 0.8 g (63%) of 1-(4-chlorophenyl)-2-methyl-2-propyl N-(diphenylmethylene)glycinate. 1H NMR (CDCl3, 60 MHz) δppm 7.5(m, 10, arom), 4.2(s, 2, N-CH2), 3.1(s, 2, benzylic), 1.5(s, 6, C(CH3)2).