Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[CH3:14][C:15]([NH2:24])([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:16]>ClCCl.C(OCC)(=O)C>[CH3:16][C:15]([NH:24][C:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12])([CH3:14])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(N)Cc1ccccc1
Reactant: O=C(Cl)c1cnc2ccccc2n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-Quinoxaloyl chloride (207 mg, 1.07 mmol) in dichloromethane (1 mL) was added to a solution of phentermine (160 mg, 1.07 mmol) in dichloromethane (3 mL) cooled to 0° C. The reaction was allowed to warm to 25° C. After 5 min, the reaction mixture was diluted with ethyl acetate (40 mL) and washed with 1 M sodium hydroxide (2×40 mL). The organic layer was dried (anhydrous magnesium sulfate), filtered through silica gel, and rotary evaporated. This provided 51 mg (16%) of (108):
Reaction SMILES: [CH2:1]([S:4][C@:5]1([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)[CH2:9][N:8]([C:10](=[O:24])[C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:7]([C:25]([OH:27])=O)[CH2:6]1)[CH:2]=[CH2:3].[NH2:40][C@:41]1([C:47]([NH:49][S:50]([C:53]2([CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH:61]=[CH2:62])[CH2:55][CH2:54]2)(=[O:52])=[O:51])=[O:48])[CH2:43][C@H:42]1[CH:44]([F:46])[F:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:1]([S:4][C@:5]1([C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:32][CH:33]=2)[CH2:9][N:8]([C:10](=[O:24])[C@@H:11]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:7]([C:25](=[O:27])[NH:40][C@:41]2([C:47](=[O:48])[NH:49][S:50]([C:53]3([CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH:61]=[CH2:62])[CH2:54][CH2:55]3)(=[O:52])=[O:51])[CH2:43][C@H:42]2[CH:44]([F:46])[F:45])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCCCCCC1(S(=O)(=O)NC(=O)[C@@]2(N)C[C@H]2C(F)F)CC1
Reactant: C=CCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCCCCC1(S(=O)(=O)NC(=O)[C@@]2(NC(=O)[C@@H]3C[C@@](SCC=C)(c4ccc(-c5ccccc5)cc4)CN3C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C[C@H]2C(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a slurry of (2S,4R)-4-(allylthio)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylic acid (55.3 mg, 0.10 mmol), (1R,2R)-1-amino-2-(difluoromethyl)-N-(1-(hept-6-enyl)cyclopropylsulfonyl)cyclopropanecarboxamide (38.7 mg, 0.10 mmol) and HATU (57.0 mg, 0.150 mmol) in DCM (2 mL) was added N,N-Diisopropylethylamine (0.087 mL, 0.500 mmol). The formed solution was stirred at room temperature overnight. Diluted with DCM, washed with 1M HCl and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by Biotage column, eluted with gradient 5%˜30% Acetone-Hexane to afford the desired product tert-butyl (S)-1-((2S,4R)-4-(allylthio)-4-(biphenyl-4-yl)-2-((1R,2R)-2-(difluoromethyl)-1-(1-(hept-6-enyl)cyclopropylsulfonylcarbamoyl)cyclopropylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (65 mg, 0.073 mmol, 73% yield) as a white foam. 1H NMR (400 MHz, MeOD) ppm 0.81-0.88 (m, 2 H) 1.07 (s, 9 H) 1.21-1.61 (m, 17 H) 1.64-1.80 (m, 1 H) 1.81-2.12 (m, 6 H) 2.37 (t, J=11.42 Hz, 1 H) 2.91-3.05 (m, 3 H) 3.91 (dd, J=10.29, 6.53 Hz, 1 H) 3.98 (d, J=11.04 Hz, 1 H) 4.48 (d, J=9.79 Hz, 1 H) 4.86-5.13 (m, 5 H) 5.66-6.14 (m, 3 H) 7.36 (t, J=7.28 Hz, 1 H) 7.45 (t, J=7.53 Hz, 2 H) 7.52-7.76 (m, 6 H). LC-MS (retention time: 3.39 min, Method B), MS m/z 885 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH2:12](O)[CH2:13][OH:14].O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:14][CH2:13][CH2:12][O:6]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1F
Reactant: OCCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2OCCO2)cc1F
Yield: 92.5 %

Procedure:
A solution of 3-fluoro-4-methoxy-benzaldehyde (463 mg, 3 mmol), ethylene glycol (0.86 mL, 15 mmol) and PPTs (75 mg, 0.3 mmol) in toluene (15 mL) was heated at reflux with aceotropic removal of water for 6 hours. The solvent was evaporated and the residue was diluted with methylene chloride (20 mL), washed with water (2×10 mL) and dried (MgSO4). Concentration produced 2-(3-Fluoro-4-methoxy-phenyl)-[1,3]-dioxolane as a colorless oil (550 mg, 92%). 1H-NMR (CDCl3, 200.15 MHz): δ 7.24–7.15 (m, 2H), 6.92 (t, 1H, J=8.5), 5.71 (s, 1H), 4.10–3.98 (m, 4H), 3.86 (s, 3H).
Reaction SMILES: O.FC1C(F)=CC=CC=1C1C=C2C(=CC=1)NN=C2C(NCC1CCN(CC2OC=C([C:35]([OH:37])=[O:36])N=2)CC1)=O.Br[C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][N:43]=[C:42]2[C:48]([NH:50][CH2:51][CH:52]1[CH2:57][CH2:56][N:55]([CH2:58][C:59]2[O:63][C:62]([C:64]([O:66]CC)=[O:65])=[CH:61][CH:60]=2)[CH2:54][CH2:53]1)=[O:49].[CH3:69][O:70][C:71]1[CH:76]=[CH:75][N:74]=[CH:73][C:72]=1B(O)O>>[CH:35]([OH:37])=[O:36].[CH3:69][O:70][C:71]1[CH:76]=[CH:75][N:74]=[CH:73][C:72]=1[C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][N:43]=[C:42]2[C:48]([NH:50][CH2:51][CH:52]1[CH2:57][CH2:56][N:55]([CH2:58][C:59]2[O:63][C:62]([C:64]([OH:66])=[O:65])=[CH:61][CH:60]=2)[CH2:54][CH2:53]1)=[O:49]
Reactant: COc1ccncc1B(O)O
Reactant: O=C(O)c1coc(CN2CCC(CNC(=O)c3n[nH]c4ccc(-c5cccc(F)c5F)cc34)CC2)n1
Reactant: CCOC(=O)c1ccc(CN2CCC(CNC(=O)c3n[nH]c4ccc(Br)cc34)CC2)o1
Solvent: O
Product: COc1ccncc1-c1ccc2[nH]nc(C(=O)NCC3CCN(Cc4ccc(C(=O)O)o4)CC3)c2c1
Product: O=CO
Reaction time: 0.25 h

Procedure:
5-({4-[({[5-(4-Methoxypyridin-3-yl)-1H-indazol-3-yl]carbonyl}amino)methyl]piperidin-1-yl}methyl)furan-2-carboxylic acid formate 21 was prepared, according to the procedure described for compound 12, from compound 15 and (4-methoxypyridin-3-yl)boronic acid and using the following preparative HPLC parameters for the purification: channel A=CH3CN+0.1% formic acid; channel B=H2O+0.1% formic acid: flow=40 ml/min; gradient=2%-40% of eluent A in 15 minutes. Yield: 40 mg, 14%.
Reaction SMILES: [OH:1][CH:2]([CH2:24][OH:25])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[O:13][CH2:14][C:15](=[O:22])[C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([CH3:23])[CH:6]=1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][N:33]=2)[C:28]([CH:35]=O)=[CH:27]1.N1CCCCC1>C(O)C>[NH:26]1[C:34]2=[N:33][CH:32]=[CH:31][CH:30]=[C:29]2[C:28]([CH:35]=[C:14]2[O:13][C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:24][OH:25])=[CH:6][C:7]=3[CH3:23])=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]2=[O:22])=[CH:27]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc(OCC(O)CO)cc2C)OCC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2ccc(OCC(O)CO)cc2C)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 22.5 %

Procedure:
To a stirred solution of ethyl 2-{[4-(2,3-dihydroxypropoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.17 g, 0.50 mmol) which similarly prepared according to the procedure described in the Example 74, First step to Fourth step and 7-azaindole-3-carboxaldehyde (0.070 g, 0.50 mmol) in ethanol (5.0 mL), piperidine (0.10 mL, 1.0 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with diethyl ether then dried to afford the titled compound as solid (0.054 g, y. 23%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:12])[N:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:26])[O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:15][CH2:14]1.CCN(CC)CC.CN(C=O)C>O>[Cl:12][C:4]1[N:3]=[C:2]([N:13]2[CH2:14][CH2:15][CH:16]([NH:19][C:20](=[O:26])[O:21][CH2:22][CH:23]([CH3:24])[CH3:25])[CH2:17][CH2:18]2)[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: Clc1cc2ccccc2c(Cl)n1
Reactant: CC(C)COC(=O)NC1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)COC(=O)NC1CCN(c2nc(Cl)cc3ccccc23)CC1
Temperature: 160 °C

Procedure:
A mixture of 1,3-dichloroisoquinoline (0.16 g, 0.78 mmol), isobutyl piperidin-4-ylcarbamate (0.16 g, 0.78 mmol), Et3N (0.11 mL, 0.78 mmol), and DMF (0.5 mL) was sealed in a microwave vessel and heated by microwave irradiation at 160° C. for three minutes. The reaction was cooled to room temperature, diluted with water, and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to yield isobutyl 1-(3-chloroisoquinolin-1-yl)piperidin-4-ylcarbamate. LC/MS: m/z 362.2 (M+H)+ at 3.98 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [N:1]1([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl>[C@H:3]12[O:24][C@H:4]1[CH2:5][N:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2]2
Reactant: O=C(OCc1ccccc1)N1CC=CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1C[C@@H]2O[C@@H]2C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 81.5 %

Procedure:
To a solution of benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate (2.00 g, 9.80 mmol) in CH2Cl2 (10 mL) was added slowly 3-chloroperbenzoic acid (3.00 g, 14.80 mmol) at 0° C. The reaction mixture was stirred for 13 h at room temperature, then quenched with saturated sodium thiosulfate aqueous solution and extracted with EtOAc. The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 6:1 (v/v) PE/EtOAc) to give the title compound as colorless oil (1.75 g, 81.02%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-])=O)[CH2:9][C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.C(O)(=O)/C=C\C(O)=O.[Cl:33]C1C=C2N(C3C=CC=CC=3[N+]([O-])=O)CC3(CCNCC3)C2=CC=1.C(O)C.Cl>[Fe].O>[ClH:1].[ClH:33].[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:8]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)[C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9]1
Reactant: O=[N+]([O-])c1ccccc1N1CC2(CCNCC2)c2ccc(Cl)cc21
Agent: [Fe]
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Solvent: O
Product: Nc1ccccc1N1CC2(CCNCC2)c2ccc(Cl)cc21

Procedure:
A mixture of 2.1 g of 6-chloro-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine], free base of Example 33, 95 ml of 95% ethyl alcohol, 7.5 ml of water and 4.4 g of iron powder is acidified with 0.2 ml of concentrated hydrochloric acid and then refluxed under nitrogen for 10 minutes. Thereafter, the mixture is permitted to cool before being filtered through celite. The filtrate is concentrated under vacuum leaving an oily residue which is basified. The alkaline mixture is extracted with ether and then dried. The product is converted to a solid dihydrochloric acid salt which is recrystallized from a methyl alcohol-ether mixture to provide off-white prisms, mp 270°-273° C. (after darkening) of 1-(2-aminophenyl)-6-chlorospiro[indoline-3,4'-piperidine] dihydrochloride.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14]1)=[O:4].CCN(CC)CC.[C:31](OC(=O)C)(=[O:33])[CH3:32]>C(Cl)Cl>[CH3:1][C:2]([CH3:23])([CH3:22])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]1[C:31](=[O:33])[CH3:32])=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C1Cc2ccccc2N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccccc2CC1c1cc(Cl)ccc1NC(=O)C(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 3.38 g 2,2-dimethyl-N-[2-(2,3-dihydro-1H-indol-2-yl)-4-chlorophenyl]propanamide in 40 ml CH2Cl2 at 10° C. were added 12.7 ml Et3N and then dropwise 6.59 ml acetic anhydride. The resulting mixture was stirred twenty-four hours at room temperature. The reaction was quenched with water (30 ml). The organic phase was separated, washed with 5% HCl, water, 7.5% NaHCO3 and sat. NaCl (1×), and dried (MgSO4). Concentration, trituration with hexane and recrystallization from cyclohexane gave 2.10 g solid, m.p. 131°-134° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15].O1CCCCC1.[O:30]1[CH:35]=[CH:34][C:33](=[O:36])[CH:32]=[CH:31]1>C1COCC1>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([CH2:13][C:33]2([OH:36])[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: O=c1ccocc1
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: C1CCOCC1
Product: O=S(=O)(CC1(O)CCOCC1)c1ccc(Br)cc1
Reaction time: 0.25 h

Procedure:
A −10° C. solution of diisopropylamine (0.35 mL) in THF (5 mL) was treated with n-BuLi (1 mL, 2.5M solution in hexanes), stiired for 15 min then added via canula to a −78 C solution of 4-bromophenyl methyl sulfone (534 mg) in THF (5 mL). Stirred for 1 h, then treated with tetrahydropyran-4H-pyran-4-one (0.21 mL) and stirred for an additional 1 h. The reaction was quenched with aq. NH4Cl, diluted with water and extracted wth EtOAc (3×). The combined organics were washed with brine, dried (Na2SO4), filtered, concentrated and purified via silica gel chromatography eluting with 10% ethyl acetate/dichloromethane to give 640 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH2:10][C:11]#N)=[C:5]([N+:13]([O-])=O)[CH:4]=1.O1CCCC1>[C].[Pd].C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([CH:10]=[CH:11][NH:13]2)=[CH:7][C:8]=1[CH3:9]
Reactant: COc1cc([N+](=O)[O-])c(CC#N)cc1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCCCO
Product: COc1cc2[nH]ccc2cc1C
Temperature: 60 °C
Reaction time: 36 h
Yield: 69.3 %

Procedure:
To a solution of (4-methoxy-5-methyl-2-nitrophenyl)acetonitrile (0.24 g) in a mixed solvent of tetrahydrofuran (2 mL) and n-butanol (2 mL) was added palladium-carbon powder (0.043 g) under an argon atmosphere and this mixture was stirred at 60° C. under a hydrogen atmosphere for 36 hours. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.13 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].O1C[CH2:23][CH2:22][O:21][CH:20]1[CH2:25][CH2:26][CH:27]([C:29]1[S:33][C:32]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)=[N:31][C:30]=1[CH3:44])O.C(P(CCCC)CCCC)CCC.CN(C)[C:60](N=NC(N(C)C)=O)=[O:61]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:27]([C:29]3[S:33][C:32]([C:34]4[CH:35]=[CH:36][C:37]([C:40]([F:42])([F:41])[F:43])=[CH:38][CH:39]=4)=[N:31][C:30]=3[CH3:44])[CH2:26][CH2:25][CH:20]3[CH2:60][O:61][CH2:23][CH2:22][O:21]3)[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)CCC1OCCCO1
Reactant: CN(C)C(=O)N=NC(=O)N(C)C
Agent: CCCCP(CCCC)CCCC
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(CCC1COCCO1)Oc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with [rac]-3-[1,3]dioxan-2-yl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to obtain [rac]-(6-{3-dioxan-2-yl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-indol-1-yl)-acetic acid tert-butyl ester as yellow oil.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=C([Cl:35])C=2)=CSC=1C(OC)=O.C([O:47][CH2:48]C)(OCC)OCC.COC1C=CC(N)=CC=1>C(O)(=O)C>[Cl:35][C:21]1[CH:22]=[C:17]([C:16]2[C:10]3[N:9]=[CH:8][N:7]([C:1]4[CH:6]=[CH:5][C:4]([O:47][CH3:48])=[CH:3][CH:2]=4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2cccc(Cl)c2)c1N
Reactant: CCOC(OCC)OCC
Solvent: COc1ccc(N)cc1
Solvent: CC(=O)O
Product: COc1ccc(-n2cnc3c(-c4cccc(Cl)c4)csc3c2=O)cc1
Yield: 76 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(3-chlorophenyl)thiophene-2-carboxylate (80 mg, 0.3 mmol), triethyl orthoformate (0.66 ml), p-anisidine (68.5 mg, 0.56 mmol), and acetic acid (0.09 ml) were used to give 84 mg (0.23 mmol, 76% yield) of the title compound.
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[CH3:45][C:33]1[N:32]([CH2:31][C:28]2[CH:29]=[CH:30][C:25]([C:20]3[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:26][CH:27]=2)[C:40]2[C:35]([C:34]=1[CH3:44])=[CH:36][C:37]([C:41](=[O:42])[NH:11][C@@H:9]1[CH2:10][C@H:8]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:38][CH:39]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H]3C[C@H]3c3ccccc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using (1R,2S)-2-phenylcyclopropanamine hydrochloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 515 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]=O)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:18]([F:23])([F:22])C([O-])=O.[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]=[C:18]([F:23])[F:22])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@H](CC=O)NC(=O)OC(C)(C)C
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC=C(F)F)NC(=O)OC(C)(C)C
Temperature: 115 °C
Yield: 13.3 %

Procedure:
A solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (5.97 g, 25.8 mmol), sodium 2-chloro-2,2-difluoroacetate (11.8 g, 77.0 mmol), triphenylphosphine (20.3 g, 77.0 mmol), and N,N-dimethylformamide (50 mL) was charged to a 500 mL 3-necked flask and heated to 115° C. for 15 min. The resulting mixture was filtered through diatomaceous earth (Celite®) and concentrated under reduced pressure. The crude material was purified over SiO2 (5-40% ethyl acetate/hexanes gradient elution) to afford (S)-methyl 2-((tert-butoxycarbonyl)amino)-5,5-difluoropent-4-enoate (0.91 g, 3.43 mmol, 13% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 5.25-5.06 (br. s., 1H), 4.42 (br. s., 1H), 4.24-4.10 (m, 1H), 3.78 (s, 3H), 2.59 (dd, J=14.4, 6.7 Hz, 1H), 2.51-2.31 (m, 1H), 1.47 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6](=[O:18])[N:7]2[C:12]=1[C:11]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:10]=1[CH2:9][CH2:8]2.Cl[C:26](OC1C=CC=CC=1)=[O:27].[NH2:35][CH2:36][C:37]#[N:38].C(=O)([O-])[O-]>O1CCOCC1.N1C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:10]2[CH2:9][CH2:8][N:7]3[C:12](=[C:3]([CH2:2][O:1][C:26](=[O:27])[NH:38][CH2:37][C:36]#[N:35])[CH:4]=[C:5]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:6]3=[O:18])[C:11]=2[CH:13]=1
Reactant: O=c1c(-c2ccccc2)cc(CO)c2n1CCc1ccc(Cl)cc1-2
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N#CCN
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: N#CCNC(=O)OCc1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 0.676 g of 6,7-dihydro-1-(hydroxymethyl)-3-phenyl-10-chloro-4H-benzo[a]quinolizine-4-one in 18 ml of dioxane was treated with 0.6 ml of phenyl chloroformate and 0.42 ml of pyridine and stirred at room temperature for 3 hours. 1.03 g of aminoacetonitrile were then added and the mixture was stirred at 100° until carbonate was no longer present according to thin-layer chromatography. After evaporation, the residue was taken up in chloroform, washed twice with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. Chromatography over silica gel [elution agent toluene/dioxane (9:1)] gave [[(10-chloro-6,7-7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-yl)methyl]amino]acetonitrile of m.p. 181°-183° (from methanol) as as well as in a second fraction (10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-yl)methyl-(cyanomethyl)carbamate of m.p. 166°-167° (from toluene).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([NH:13][NH:14][C:15](=[O:17])[CH3:16])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O>C(#N)C.O>[C:1]1([S:7]([CH2:10][C:11]2[O:17][C:15]([CH3:16])=[N:14][N:13]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)NNC(=O)CS(=O)(=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: O
Product: Cc1nnc(CS(=O)(=O)c2ccccc2)o1
Yield: 68.7 %

Procedure:
To a stirred solution of 1.40 g (5.5 mmol) of acetic acid N′-(2-benzenesulfonyl-acetyl)-hydrazide in 50 mL of acetonitrile, 1.02 g (6.5 mmol, 1.2 eq) of phosphorus oxychloride were added, and the solution heated at reflux for 3 hours. The reaction mixture was diluted with water, extracted with EtOAc, the organic phase dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel with EtOAc yielded 0.90 g (70%) of 2-benzenesulfonylmethyl-5-methyl-[1,3,4]oxadiazole as a white solid, MS: 239 (MH+).
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)[O:6][C:5]([CH3:16])([CH3:15])[NH:4]1.[C:17]([CH2:19][C:20](O)=[O:21])#[N:18].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)[O:6][C:5]([CH3:16])([CH3:15])[N:4]1[C:20](=[O:21])[CH2:19][C:17]#[N:18]
Reactant: N#CCC(=O)O
Reactant: CC1(C)N[C@H](CF)[C@@H](c2ccc(I)cc2)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)O[C@H](c2ccc(I)cc2)[C@@H](CF)N1C(=O)CC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a mixture of (4S,5R)-4-(fluoromethyl)-5-(4-iodophenyl)-2,2-dimethyl-oxazolidine (3.5 g, 10.50 mmol), 2-cyanoacetic acid (1.34 g, 15.8 mmol) and O-(7-azabenzotriazol-1-yl)-N, N,N′,N′-tetramethyluronium hexafluorophosphate (6.11 g, 15.8 mmol) in dimethylformamide (21 mL) is added triethylamine (2.12 g, 21 mmol) and stirred at room temperature for overnight. The mixture is partitioned between ethylacetate and brine. The organic solution is separated, dried over MgSO4, filtered and evaporated to give a yellow residue, which is purified on silica gel column using heptane to neat ethylacetate to give the title compound (2.75 g): 1HNMR (DMSO-d6): 1.48 (s, 3H), 1.53 (s, 3H), 3.96-4.24 (m, 2H), 4.47-4.84 (m, 3H), 5.11 (d, 1H), 7.31 (d, 2H), 7.77 (d, 2H).