Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[O:15])=[N:11][N:10]=1.[CH:29]1([CH2:32]Br)[CH2:31][CH2:30]1.C(N(CC)CC)C>CC(N(C)C)=O>[CH:29]1([CH2:32][N:26]2[CH2:27][CH2:28][N:23]([C:20]3[N:19]=[CH:18][C:17]([NH:16][C:14]([C:12]4[O:13][C:9]([NH:8][C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])=[N:10][N:11]=4)=[O:15])=[CH:22][CH:21]=3)[CH2:24][CH2:25]2)[CH2:31][CH2:30]1
Reactant: BrCC1CC1
Reactant: O=C(Nc1ccc(N2CCNCC2)nc1)c1nnc(Nc2ccccc2F)o1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCN(CC3CC3)CC2)nc1)c1nnc(Nc2ccccc2F)o1
Temperature: 110 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
5-[(2-Fluorophenyl)amino]-N-(6-piperazin-1-ylpyridin-3-yl)-1,3,4-oxadiazole-2-carboxamide (Intermediate 41) (120 mg, 0.31 mmol) in DMA (2 mL) was placed in a microwave tube with cyclopropylmethyl bromide (88 mg, 0.62 mmol), and triethylamine (64 mg, 0.62 mmol). The mixture was heated with stirring in the microwave at 110° C. for 60 minutes then transferred directly onto a reverse phase HPLC column and eluted with a gradient of acetonitrile/water containing 0.2%/TFA to give the title compound (125 mg, 91%) as a solid; 1H NMR δ 10.65 (1H, s), 10.40 (1H, bs), 8.20 (1H, s), 7.65 (2H, m), 6.90 (2H, m), 6.80 (1H, m), 6.65 (1H, d), 4.00 (2H, d), 3.25 (2H, d), 2.80 (6H, m), 0.75 (1H, m), 0.30 (2H, m), 0.00 (2H, m); MS m/e MH+ 438.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2].[NH2:13][OH:14].Cl.C([O-])([O-])=O.[K+].[K+]>CCO.O>[F:12][C:5]1[CH:4]=[C:3]([C:1](=[NH:2])[NH:13][OH:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: NO
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1ccc(C(=O)O)c(F)c1
Yield: 64.2 %

Procedure:
To a solution of 4-Cyano-2-fluorobenzoic acid (1 g, 6.06 mmol) in EtOH (10.09 mL) was added NH2OH.HCl (0.884 g, 12.72 mmol) previously dissolved in water (5 mL) and aqueous solution K2CO3 (1.339 g, 9.69 mmol) in water (15 mL). Then 8-hydroxyquinone (0.011 g, 0.079 mmol) was added. The resulting solution was stirred at reflux for 4 h. EtOH was evaporated from the reaction mixture, then acidified to pH 3 with aqueous HCl (2 N) solution. The precipitate was filtered, washed with water and dried to yield 2-fluoro-4-(N-hydroxycarbamimidoyl)-benzoic acid (786.3 mg, 3.89 mmol, 64.2% yield) as yellowish solid. The crude was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm: 13.21 (m, 1 H), 10.01 (s, 1 H), 7.85 (t, J=7.95 Hz, 1 H), 7.44-7.69 (m, 2 H), 5.99 (br. s., 2 H).
Reaction SMILES: [F:1][C:2]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:3][CH2:4][CH2:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30].O>CS(C)=O>[CH2:30]([C:6]([CH2:5][CH2:4][CH2:3][C:2]([F:21])([F:1])[C:17]([F:18])([F:19])[F:20])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:29][CH2:28][CH2:27][CH:26]=[CH2:25]
Reactant: C=CCCCCBr
Reactant: CCOC(=O)C(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCC(CCCC(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A solution of diethyl 2-(4,4,5,5,5-pentafluoropentyl)malonate (4.0 g, 12.5 mmol) in dimethyl sulfoxide (30 ml) was cooled to 10° C. To this solution, 60% sodium hydride (600 mg, 15 mmol) was added, and the resulting mixture was stirred for 1 hour at room temperature. 6-Bromo-1-hexene (2.5 ml, 18.75 mmol) was slowly added dropwise to the reaction mixture, followed by stirring for 3 hours at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/9) to give diethyl 2-(5-hexenyl)-2-(4,4,5,5,5-pentafluoropentyl)malonate (3.86 g, Yield 77%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH:27]1([O:32][C:33]([O:35][CH:36](I)[CH3:37])=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH:36]([O:35][C:33]([O:32][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:34])[CH3:37])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CC(I)OC(=O)OC1CCCC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CC(OC(=O)OC1CCCC1)OC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 86.7 %

Procedure:
In the same manner as in Example 81, 187 mg of the title compound was prepared from 162 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 148 mg of 1-(cyclopentyloxycarbonyloxy)ethyl iodide.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:13].C(=O)([O-])[O-].[K+].[K+].[C:20]([O:24][C:25](=[O:49])[CH2:26][C@@:27]1([C:33]([NH:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)=[O:34])[C@H:31]([CH3:32])[CH2:30][NH:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C(OCC)(=O)C>CN(C)C=O>[C:20]([O:24][C:25](=[O:49])[CH2:26][C@@:27]1([C:33]([NH:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)=[O:34])[C@H:31]([CH3:32])[CH2:30][N:29]([CH2:2][C:3]2[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:13])[CH2:28]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: FC(F)(F)c1cccc(Cl)c1CBr
Reactant: C[C@@H]1CNC[C@]1(CC(=O)OC(C)(C)C)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(Cc2c(Cl)cccc2C(F)(F)F)C[C@]1(CC(=O)OC(C)(C)C)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 40 °C
Reaction time: 48 h
Yield: 63.8 %

Procedure:
2-(Bromomethyl)-1-chloro-3-(trifluoromethyl)benzene (443 mg, 1.62 mmol) and potassium carbonate (244 mg) were added to a solution of tert-butyl 4-[(3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidin-3-amido]piperidine-1-carboxylate obtained in Example 3b (345 mg, 0.811 mmol) in N,N-dimethylformamide (dehydrated) (10 mL), which was stirred at 45° C. for six hours and at 40° C. for two days. Ethyl acetate was added to the reaction liquid, which was washed with a 1N aqueous sodium hydroxide solution and brine. This was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to give the title compound (320 mg, yield: 63.8%).
Reaction SMILES: [CH3:1][Li].CI.[Li].Cl.[CH3:7][O:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][CH:14]2[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[CH2:17][CH2:16][N:15]2[CH3:23])=[CH:11][CH:10]=1>O>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH:14]2[C:19]([CH3:21])([CH3:20])[C:18]([CH3:1])([OH:22])[CH2:17][CH2:16][N:15]2[CH3:23])=[CH:24][CH:25]=1
Reactant: COc1ccc(CC2N(C)CCC(=O)C2(C)C)cc1
Reactant: [Li]C
Agent: Cl
Agent: [Li]
Solvent: O
Solvent: CI
Product: COc1ccc(CC2N(C)CCC(C)(O)C2(C)C)cc1
Reaction time: 1.5 h
Yield: 84 %

Procedure:
To a mechanically stirred and nitrogen flushed ethereal solution (200 ml) of methyl lithium (prepared in the usual manner from 43 g of methyl iodide and 4.8 g of lithium) there is added in small quantities 9 g of 2-(p-methoxybenzyl)-1,3,3-trimethyl-4-piperidone hydrochloride. During the addition, which takes some 1.5 hour, the mixture is cooled with water. It is stirred at room temperature for 16 hours and finally refluxed for 1 hour. Then the lithium compounds are hydrolysed by careful addition of water (cooling with ice) and the basic material is extracted from the mixture with the aid of 4 N hydrochloric acid. Basification of the aqueous solution followed by extraction with ether and processing of the ethereal solution as usual, gives crystals which after recrystallization from petroleum ether melt at 55°-65° C. Yield 84%. Evidently a mixture of epimeric piperidinols has been formed.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH2:12][C:13](Cl)=[N:14][OH:15])[CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.[C:17]([C:19]1[C:20]([NH2:26])=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=1)#[CH:18].C(N(CC)CC)C>O1CCCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=2)[CH2:12][C:13]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:26])=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=3)[O:15][N:14]=2)[CH2:3][CH2:2]1
Reactant: ON=C(Cl)Cc1cccc(OCC2CC2)c1
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3cccc(OCC4CC4)c3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (3-cyclopropylmethoxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.626 mmol) described in Manufacturing Example 66-1-4 and 3-ethynyl-pyridin-2,6-diamine (53.2 mg, 0.399 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (218 μL, 1.57 mmol). This mixture was stirred for 4 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1˜ethyl acetate) to obtain the title compound (117 mg, 56%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C1COCC1>[Cl:1][C:2]1[C:11](/[CH:12]=[N:22]/[S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: Cc1c(F)ccc2cc(C=O)c(Cl)nc12
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: Cc1c(F)ccc2cc(/C=N/[S@](=O)C(C)(C)C)c(Cl)nc12
Yield: 86.1 %

Procedure:
Following the procedure for Intermediate 22, 2-chloro-7-fluoro-8-methyl-quinoline-3-carbaldehyde (6.6 g, 29.5 mmol), titanium(IV) isopropoxide (17 g; 60 mmol), (R)-(−)-2-methyl-2-propanesulfinamide (3.6 g, 29.5 mmol) and THF (200 mL) gave the title compound (8.3 g, 86%) as a yellow solid. δH (CDCl3) 9.12 (1H, s), 8.73 (1H, s), 7.71 (1H, dd, J=6.0 Hz), 7.40 (1H, t, J=8.2 Hz), 2.69 (3H, s), 1.32 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]=[CH:18][C:17]2[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:22])[F:23])=[CH:21][CH:20]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Cl)cn1N
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Solvent: CO
Product: COC(=O)c1cc(Cl)cn1N=Cc1ccc(C(F)(F)F)cc1

Procedure:
Prepared according to the imine formation condition used in Example 18 step b) from 1-amino-4-chloro-1H-pyrrole-2-carboxylic acid methyl ester (prepared according to literature: Bioorg & Med. Chem. Lett. 2006, 16, 3937-3942) and 4-trifluoromethylbenzaldehyde in refluxing methanol for 12 h. 1H NMR (CDCl3, δ in ppm): 8.43 (s, 1H), 7.95 (d, 2H, J=8.4 Hz), 7.70 (d, 2H, J=7.9 Hz), 7.23 (d, 1H, J=1.6 Hz), 6.91 (d, 1H, J=2.2 Hz), 3.84 (s, 3H).
Reaction SMILES: [OH:1][C@H:2]([C@@H:18]([NH:26][C:27](=[O:47])[C@@H:28]([N:33]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]=2)[C:34]1=[O:46])[C@@H:29]([CH3:32])[CH2:30][CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][NH:5][C:6]([C@@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])=[O:7].[CH:48](=O)[C:49]1[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[OH:1][C@H:2]([C@@H:18]([NH:26][C:27](=[O:47])[C@@H:28]([N:33]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]=2)[C:34]1=[O:46])[C@@H:29]([CH3:32])[CH2:30][CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][N:4]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=1)[NH:5][C:6]([C@@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])=[O:7]
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NNC[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H]([C@@H](C)CC)N1CCN(Cc2cccc(C)n2)C1=O
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(OC)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H]([C@@H](C)CC)N1CCN(Cc2cccc(C)n2)C1=O
Yield: 58.3 %

Procedure:
A solution of Example 283A (50 mg, 0.45 mmol) in 1,2-dichloroethane (1 mL) and treated with p-anisaldehyde (16 mg, 1.5 equivalents), acetic acid (5 μL, 2 equivalents), and sodium triacetoxy borohydride (32 mg, 2 equivalents) at 25° C. for 16 hrs. The mixture was quenched with 10% NaHCO3 (2 mL) and CHCl3. The organic layer was separated, dried over sodium sulfate, filtered and the solvents were evaporated. The residue was purified using 5% methanol/CHCl3 to give 53 mg (90%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][C:11](=[O:12])[CH:18]2[CH2:19][CH2:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:17]2)[CH2:15][C:14]([OH:13])=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Reactant: c1ccc2c(c1)CCCN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CC(CC(=O)C1CCc2ccccc2N1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,4-Dichlorophenyl)glutaric anhydride (10 g, Example 1, Step C) in CH2Cl2 (300 mL) at 0° C. was treated sequentially with 1,2,3,4-tetrahydroquinoline (5.6 mL), triethylamine (6.3 mL) and N,N-dimethylaminopyridine (472 mg). The mixture was stirred at 0° C. for two hours then allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was diluted with CH2Cl2 (500 mL) and washed with 1N HCl (1×200 mL) and water (1×200 mL). The organic layers were dried over MgSO4, filtered and concentrated to afford the title compound (14.3 g).
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:12][C:13]([C:15]2([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[C:9]([OH:11])=O)=[CH:3][CH:2]=1.Cl.[NH:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.ON1C2N=CC=CC=2N=N1>CN(C=O)C>[C:1]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]([NH:12][C:13]([C:15]2([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:14])[C:9]([N:33]2[CH2:37][CH2:36][CH2:35][C@H:34]2[C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])=[O:11])=[CH:5][CH:6]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CCOC(=O)CC1(C(=O)N[C@@H](Cc2ccc(-c3ccccc3)cc2)C(=O)O)CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(C(=O)N[C@@H](Cc2ccc(-c3ccccc3)cc2)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 83.6 %

Procedure:
A solution of (S)-3-(biphenyl-4-yl)-2-(1-(2-ethoxy-2-oxoethyl)cyclopentanecarboxamido)propanoic acid (201.7 mg, 0.476 mmol), (S)-benzyl pyrrolidine-2-carboxylate hydrochloride (138 mg, 0.572 mmol), WSC.HCl (137 mg, 0.714 mmol), DIPEA (0.125 ml, 0.714 mmol) and 1-hydroxy-7-azabenzotriazole (97 mg, 0.714 mmol) in DMF (2 ml) was allowed to stir at room temperature under nitrogen for 14 hours. The reaction was quenched with H2O. The products were extracted with EtOAc. The organic layer was washed with NH4Claq, 0.1 M HCl (twice) and then brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (heptane/EtOAc=100:0 to 0:100) to give (S)-benzyl 1-((S)-3-(biphenyl-4-yl)-2-(1-(2-ethoxy-2-oxoethyl)cyclopentanecarboxamido)propanoyl)pyrrolidine-2-carboxylate (243 mg); Retention time=1.74 minutes (condition B); MS (m+1)=611.2; 1H NMR (400 MHz, CD3CN, mixture of rotamers) δ ppm 0.91-1.06 (m, 3H) 1.33-1.42 (m, 6H) 1.55-2.09 (m, 6H) 2.25-2.42 (m, 2H) 2.57-2.93 (m, 2H) 3.06-3.59 (m, 2H) 3.75-3.91 (m, 2H) 4.14-4.61 (m, 2H) 4.68-5.09 (m, 3H) 6.40-6.52 (m, 1H) 7.00-7.45 (m, 14H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].I[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:14]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[F:1])[C:7](=[O:12])[C:8]1=[O:11])[CH3:15]
Reactant: O=C1Nc2c(F)cccc2C1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(=O)c2cccc(F)c21

Procedure:
7-Fluoro-1H-indole-2,3-dione (prepared according to the method of Gassman as described in U.S. Pat. No. 4,188,325 (4.00 g, 24.2 mmol), iodoethane (3.87 ml, 48.5 mmol) and potassium carbonate (6.61 g, 48.5 mmol) in DMF (20 ml) are stirred at room temperature for 20 hours. The reaction mixture is diluted with cold water and the resulting precipitate filtered and dried to give the title compound as an orange solid. HPLC r.t. 4.48 min; MS for C10H8FNO2 m/z 193.9 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5].N12CCCN=C1CCCCC2.[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21]>C(#N)C>[NH2:1][C@@H:2]([CH2:3][CH2:4][O:5][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25])[C:6]([OH:8])=[O:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N[C@@H](CCO)C(=O)O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](C)(C)OCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of L-Homoserine (1 g, 8.4 mmol) in acetonitrile (10 ml) at 0° C. was added 1,8-Diazabicyclo[5.4.0]undec-7-ene (1.32 ml, 8.8 mmol). Tert-butyl-dimethyl-silyl chloride (1.33 g, 8.8 mmol) was then added portionwise over 5 minutes and the reaction mixture allowed to warm to room temperature and stirred for 16 hours. A white precipitate had formed which was filtered off and washed with acetonitrile before drying under vacuum. The title compound was isolated as a white solid (1.8 g, 92%). 1H NMR (300 MHz, DMSO), δ: 7.50 (1H, bs), 3.70 (1H, m), 3.35 (4H, bm), 1.95 (1H, m), 1.70 (1H, m), 0.90 (9H, s), 0.10 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[N:11]([C:13]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:14]=1[NH:15]C)=O.C(O)(=O)C.Br>O>[CH3:21][C:19]1[CH:20]=[C:13]2[C:14](=[CH:17][CH:18]=1)[N:15]=[C:6]1[NH:7][C:8]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]1=[N:11]2
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: CNc1ccc(C)cc1N=O
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc2nc3[nH]c4ccc(Cl)cc4c3nc2c1
Reaction time: 2 h

Procedure:
A solution of 1.68 g 5-chloroindol (0.01 mole) and 1.50 g 2-nitroso-N-methyl-p-toluidine (0.01 mole), 10 ml acetic acid is boiled under reflux for 1 hour. Finally hydrogen bromide is introduced and the mixture is boiled for further 2 hours. After cooling it is poured into water. The dried reaction product is recrystallized from acetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][NH2:19])=[N:15][CH:16]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:19][CH2:18][CH2:17][C:14]2[CH:13]=[CH:12][C:11]([C:10]([F:21])([F:9])[F:20])=[CH:16][N:15]=2)=[CH:4][CH:3]=1
Reactant: NCCc1ccc(C(F)(F)F)cn1
Reactant: Brc1ccc(I)cc1
Product: FC(F)(F)c1ccc(CCNc2ccc(Br)cc2)nc1

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (4-bromo-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 347.0 [M+H]+) was prepared from 1-bromo-4-iodo-benzene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:31])[CH3:9])=[CH:4][CH:3]=1.[CH3:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@:13]2([CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[O:12][C:11](=[O:31])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:37]4[CH:36]=[CH:35][N:34]=[C:33]([CH3:32])[CH:38]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCNS(C)(=O)=O)(c4ccc(F)cc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propyl)methanesulfonamide and 2-methylpyridine-4-boronic acid Example 1 Step 2. LC-MS Method 2 tR=0.964 min, m/z=525.21; 1H NMR (CDCl3) 1.31-1.43 (m, 1H), 1.50 (d, 3H), 1.62 (m, 2H), 1.07-2.09 (m, 2H), 2.13-2.47 (m, 3H), 2.83 (d, 6H), 3.01 (m, 3H), 4.35 (s, 1H), 5.66 (m, 1H) 7.07 (m, 2H), 7.14 (m, 2H), 7.29 (m, 5H), 7.44 (m, 2H), 7.65 (m, 1H), 7.73 (d, 1H), 8.78 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11](=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH3:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>COCCOC.O.[Pd]>[N:6]1[C:5]([C@H:8]([NH:10][C:11](=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH3:9])=[CH:4][CH:3]=[C:2]([C:31]2[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=2)[CH:7]=1
Reactant: OB(O)c1cccnc1
Reactant: CC(C)c1ccc(CC(=O)N[C@H](C)c2ccc(Br)cn2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)c1ccc(CC(=O)N[C@H](C)c2ccc(-c3cccnc3)cn2)cc1
Temperature: 100 °C

Procedure:
To a mixture of N-[(1R)-1-(5-bromopyridin-2-yl)ethyl]-2-(4-isopropylphenyl)acetamide (40 mg, 0.11 mmol), tetrakis(triphenyl)phosphine)palladium (0) (1.3 mg, 0.01 mmol), sodium carbonate (22 mg, 0.20 mmol) in DME/water (4:1, 3.0 ml) was added 3-pyridyl boronic acid (19 mg, 0.16 mmol). The reaction was heated for ten minutes in the Smith Personal microwave system at 100° C. and then washed with brine. Organics were extracted with EtOAc and dried over Na2SO4, filtered and concentrated in vacuo to give a red oily solid. Reverse phase prep HPLC chromatography afforded the mono-trifluoroacetate salt of N-[(1R)-1-(3,3′-bipyridin-6-yl)ethyl]-2-(4-isopropylphenyl)acetamide as an oil. 1H NMR (CD3OD, 400 MHz) δ 9.18 (s, 1H); 8.95 (s, 1H); 8.84 (d, J=4.80 Hz, 1H); 8.78 (dd, J=1.20 Hz and 6.40 Hz, 1H); 8.29 (dd, J=2.40 and 8.40 Hz, 1H); 8.06 (dd, J=5.20 and 8.20 Hz, 1H); 7.61 (d, J=8.40 Hz, 1H); 7.19 (m, 4H); 5.10 (q, J=6.80 Hz, 1H); 3.55 (s, 2H); 2.86 (m, 1H); 1.55 (d, J=7.20 Hz, 3H); 1.21 (d, J=6.80 Hz, 6H); HRMS (ES) exact mass calcd for C23, H25, N3O: 360.2071, Found: 360.2070.