Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].[Li][CH2:9][CH2:10][CH2:11][CH3:12].[CH:13]12[N:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]([CH2:18][CH2:19]1)[CH2:16][CH:15]([C:26]([O:28]C1CCCC=C1)=[O:27])[CH2:14]2.C[Si](Cl)(C)C.Cl>C1COCC1>[CH:12]1([C:15]2([C:26]([OH:28])=[O:27])[CH2:14][CH:13]3[N:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]([CH2:18][CH2:19]3)[CH2:16]2)[CH2:2][CH2:1][CH2:9][CH:10]=[CH:11]1
Reactant: CCOC(=O)N1C2CCC1CC(C(=O)OC1C=CCCC1)C2
Reactant: CC(C)NC(C)C
Reactant: [Li]CCCC
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)N1C2CCC1CC(C(=O)O)(C1C=CCCC1)C2
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of diisopropylamine (0.471 g, 4.65 mmol) in anhydrous THF (10.0 mL) was added n-BuLi (2.91 mL, 4.65 mmol, 1.6 N in THF) at 0° C. The mixture was stirred at the temperature for 15 minutes and cooled to −78° C., followed by addition of a solution of 3-cyclohex-2-en-1-yl 8-ethyl 8-azabicyclo[3.2.1]octane-3,8-dicarboxylate (1-5) (1.30 g, 4.23 mmol) in THF (5.0 mL). After stirring at −78° C. for 30 min, TMSCl (0.459 g, 4.23 mmol) was added and the resulting solution was stirred at −78° C. for 1 h. The mixture was allowed to warm to room, temperature and stirred at 80° C. overnight. After cooling to room temperature, 2 N aqueous solution of HCl (10 mL) was added to the mixture. The mixture was stirred continued for 5 minutes, then partitioned between Et2O (50 mL) and 2 N HCl aqueous solution. The organic phase was washed with water, brine, dried over Na2SO4 and concentrated to give a crude residue. Purification of the crude residue by flash chromatography over silica gel (gradient elution; 10%-50% ethyl acetate/hexanes as eluent) afforded (1-6) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:5]=[C:4]([Cl:16])[CH:3]=1.[C:17](=[O:19])=[O:18]>O1CCCC1.Cl.C(OCC)(=O)C>[Cl:16][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:5]=1)[C:17]([OH:19])=[O:18]
Reactant: O=C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
To “Rieke Mg” (0.21 mol; Rieke, R. D.; Bales, S. E.; Hudnall, P. M.; Burns, T. P.; Poindexter, G. S. Org. Synth. Collective Volume VI, 1988, 845.) in tetrahydrofuran (1000 mL) was added ether 13 (27.7 g, 0.10 mol). After the reaction mixture was stirred for 20 min at ambient temperature there was an exotherm observed. The exotherm subsided within 5 min, and the reaction mixture was cooled to 20° C. with an ice bath. After 15 min, the reaction mixture was cooled to −78° C. To the cool reaction mixture was added CO2 gas for 30 min. The reaction mixture was warmed to ambient temperature, then diluted with cold (0° C.) 10% aqueous HCl (150 mL) and ethyl acetate (400 mL). The aqueous phase was extracted with ethyl acetate (400 mL). The combined organic phases were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting solid was recrystallized from acetonitrile to provide 14 as fluffy white needles (19.3 g, 64%). 1H NMR (300 MHz, CDCl3) δ 7.70 (s, 1H), 7.43 (s, 1H), 7.08 (s, 1H), 0.99 (s, 9H), 0.23 (s, 6H). IR (KBr) 2957, 1697, 1578, 1434, 1297, 1266, 1115, 990, 871 cm−1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(O)[CH:10]([OH:22])[CH2:9]1)=O)(C)(C)C.C(N(S(F)(F)[F:29])CC)C.CO>C(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:11]2([F:29])[CH2:12][CH2:13][NH:8][CH2:9][CH:10]2[OH:22])=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(O)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: OC1CNCCC1(F)c1ccc(Cl)cc1
Temperature: -78 °C
Yield: 24 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-3,4-dihydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.213 g, 3.34 mmol) in methylene chloride (30 ml) at −78° C. was added diethylaminosulfur trifluoride (DAST, 3 ml). The resulting solution was stirred at −78° C. 4h. Methanol (20 ml) was added to quench excess DAST and the mixture was allowed to remain at −78° C. 5 min before warming to rt. The mixture was concentrated and purified by silica gel chromatography (80% hexanes/20% ethyl acetate gradient) to afford 4-(4-chloro-phenyl)-4-fluoro-piperidin-3-ol (262 mg, 24%).
Reaction SMILES: [Br:1][C:2]([F:18])([F:17])[C:3]([CH:6]1[CH2:10][CH:9]([C:11]([OH:13])=O)[CH2:8][CH:7]1[C:14]([OH:16])=O)([F:5])[F:4].[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[Br:1][C:2]([F:18])([F:17])[C:3]([CH:6]1[CH2:10][CH:9]([C:11]([NH:25][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:13])[CH2:8][CH:7]1[C:14]([NH:25][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:16])([F:4])[F:5]
Reactant: O=C(O)C1CC(C(=O)O)C(C(F)(F)C(F)(F)Br)C1
Reactant: NC1CCCCC1
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)C1CC(C(=O)NC2CCCCC2)C(C(F)(F)C(F)(F)Br)C1
Yield: 76 %

Procedure:
Into a glass flask were charged 3.00 g (8.90 mmol) of 4-(2-bromo-1,1,2,2-tetrafluoroethyl)cyclopentane-1,3-dicarboxylic acid, 8.83 g (89.0 mmol) of cyclohexylamine and 50 g of toluene, and the mixture was refluxed using a Dean and Stark apparatus for 10 hrs. Thereafter, the solvent was distilled off, and 100 mL of dichloromethane was added thereto. The organic layer washed with 50 mL of 1 M aqueous hydrochloric acid four times, with 50 mL of an aqueous sodium bicarbonate solution three times, and then with 50 mL of saturated brine once. After washing, the solvent of the organic layer was distilled off, and purification was carried out on column chromatography to obtain 3.38 g of 4-(2-bromo-1,1,2,2-tetrafluoroethyl)-N1,N3-dicyclohexylcyclopentane-1,3-dicarboxamide (precursor compound (a-8)) represented by the following formula (a-8) (yield: 76%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH:17][CH:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][N:17]([CH:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2cccc(CCNC3CCOC3)c2)cc1
Reactant: CN(C)C(=O)CCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN(CCc1cccc(OCc2ccccc2)c1)C1CCOC1
Temperature: 120 °C
Yield: 59.4 %

Procedure:
A mixture of 0.8 g (2.69 mmol) of [2-(3-benzyloxy-phenyl)-ethyl]-(tetrahydrofuran-3-yl)amine, 0.56 ml (4.03 mmol) of triethylamine and 0.415 ml (4.03 mmol) of 2-chloro-N,N-dimethyl-acetamide in 5 ml of dry dimethylformamide was heated to 120° C. for 2 hours with microwaves. Solvent was removed under vacuum and the crude residue was purified by flash chromatography (dichloromethane/methanol: 100:3, v:v). 0.611 g (59% yield) of the title compound were isolated as a yellow oil.
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O>>[Cl:17][C:14]1[CH:13]=[C:12]2[C:11](=[CH:16][CH:15]=1)[NH:10][C:7](=[O:9])[C:6]([N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)=[C:18]2[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C(O)Cn1cccn1
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)c1-n1cccn1
Yield: 49 %

Procedure:
from 2-(1H-pyrazol-1-yl acetic acid and (2-amino-5-chloro-phenyl)-phenyl-methanone according to general procedure 2. Yield 49%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(N1CCOCC1)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.[CH:48]([C:51]1[CH:52]=[C:53]([CH:60]=[CH:61][CH:62]=1)[O:54][CH:55]([CH3:59])[C:56](O)=[O:57])([CH3:50])[CH3:49]>CN(C=O)C.O>[CH:48]([C:51]1[CH:52]=[C:53]([CH:60]=[CH:61][CH:62]=1)[O:54][CH:55]([CH3:59])[C:56]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1)=[O:57])([CH3:49])[CH3:50]
Reactant: CC(Oc1cccc(C(C)C)c1)C(=O)O
Reactant: CC#CC(CC(=O)OCC)c1ccc(N)cc1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC#CC(CC(=O)OCC)c1ccc(NC(=O)C(C)Oc2cccc(C(C)C)c2)cc1
Reaction time: 72 h

Procedure:
To a solution of 200 mg (0.75 mmol) of ethyl 3-(4-aminophenyl)hex-4-ynoate, 258 mg (2.24 mmol) of N-ethylmorpholine, 126 mg (0.82 mmol) of HOBt hydrate and 128 mg (0.82 mmol) of EDAC in 3 ml of DMF was added a solution of 202 mg (0.74 mmol) of 2-(3-isopropylphenoxy)propionic acid in 2.5 ml of DMF. After 72 h at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. This gave 156 mg of ethyl 3-{4-[2-(3-isopropylphenoxy)propionylamino]phenyl}hex-4-ynoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15](O)=[N:16]3)=[CH:11][CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(OC([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[C:34]([O:39][CH3:40])[CH:33]=2)[C:28]([F:42])([F:41])[CH2:27]1)=O)(C)(C)C>>[F:42][C:28]1([F:41])[CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:15]3[N:14]=[CH:13][C:12]4=[CH:11][CH:10]=[C:9]([C:8]5[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=5)[N:17]4[N:16]=3)=[C:34]([O:39][CH3:40])[CH:33]=2)[CH2:30][CH2:31][NH:26][CH2:27]1
Reactant: COc1ncccc1-c1ccc2cnc(O)nn12
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2(F)F)ccc1N
Product: COc1cc(C2CCNCC2(F)F)ccc1Nc1ncc2ccc(-c3cccnc3OC)n2n1

Procedure:
7-(2-Methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (prepared as described in U.S. Pat. No. 8,471,005/Appl. WO2010071885; 65 mg, 0.27 mmol) and (±)-4-(4-amino-3-methoxy-phenyl)-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.29 mmol) were converted to the title compound by a procedure similar to Example 4, to afford a yellow foam (86 mg, 69% yield). 1H NMR (CDCl3): 8.72 (s, 1H), 8.49 (d, J=7.4 Hz, 1H), 8.28 (d, J=8.2 Hz, 1H), 8.24 (m, 1H), 7.51 (s, 1H), 7.14 (d, J=4.0 Hz, 1H), 7.08 (m, 1H), 6.86 (m, 3H), 4.02 (s, 3H), 3.92 (s, 3H), 3.30 (m, 1H), 3.21 (m, 1H), 3.02 (m, 1H), 2.90 (dd, J=30.8 (F_H vic. coupling), 13.7 Hz, 1H), 2.75 (m, 1H), 2.10 (m, 1H), 1.95 (m, 2H); LC/MS (ESI+): 467.0 (M+H).
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=23)=[N:5]1)#[N:2].C(N(CC)CC)C.[SH2:33].O>N1C=CC=CC=1>[O:10]=[C:9]1[CH:8]=[CH:7][C:6]([C:11]2[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=23)=[N:5][N:4]1[CH2:3][C:1](=[S:33])[NH2:2]
Reactant: N#CCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Reactant: S
Solvent: c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=S)Cn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O

Procedure:
Into a mixture of 3-(2-cyanomethyl-3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (2.0 g) and triethylamine (1.02 ml) in pyridine (10 ml) was introduced hydrogen sulfide at 50° C. for 6 hours. The mixture was poured into water. The resulting solid was collected by filtration to give 3-(3-oxo-2-thiocarbamoylmethyl-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (2.18 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=3[CH3:26])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[OH:36].[C:37]([O:41][CH2:42][CH3:43])(=[O:40])[CH2:38]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=3[CH3:26])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:36][CH2:38][C:37]([O:41][CH2:42][CH3:43])=[O:40]
Reactant: Cc1c(N(Cc2ccc(Oc3ccc(Cl)c(O)c3)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)CO
Product: CCOC(=O)COc1cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)ccc1Cl

Procedure:
The product from Example 91F and ethyl glycolate were processed as described in Example 62A to provide the title compound. MS (ESI+) m/z 597 (M+H)+.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[CH3:9][C:10]1[C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=[CH:12][CH:11]=1>CN(C)C=O>[CH3:9][C:10]1[C:15]([C:16]([O:18][CH3:1])=[O:17])=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: Cc1ccncc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cnccc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.4 %

Procedure:
In a nitrogen atmosphere, 6.89 g of potassium carbonate and 4.6 mL of methyl iodide were added in that order to N,N-dimethylformamide (100 mL) solution of 6.86 g of 4-methylnicotinic acid, and stirred at room temperature for 3 hours. The solvent was evaporated off under reduced pressure, then aqueous sodium hydrogencarbonate solution was added to the residue and extracted with chloroform. The chloroform layer was washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was separated and purified through silica gel column chromatography (hexane/ethyl acetate=50/50) to obtain 2.52 g of the entitled compound as a yellow oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2F)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCOC(=O)C1(NC(=O)c2ccncc2F)Cc2ccccc2C1
Solvent: C1COCCO1
Product: CCOC(=O)C1(NC(=O)c2ccncc2N2CCCCC2)Cc2ccccc2C1
Reaction time: 0.01 h
Yield: 200.6 %

Procedure:
A 10 mL microwave reaction vessel is charged with 2-[(3-fluoro-pyridine-4-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (354, 500 mg, 1.52 mmol), 1,4-dioxane (1.5 mL) and piperidine (1.51 mL, 15.23 mmol). A stirring bar is added. The reaction vial is crimped sealed. The reaction vial is placed in a Smith Microwave reaction apparatus. The temperature is set for 150° C. with a fixed hold time of 10 min. Pre-stir time is set for 20 sec. The reaction vial is removed from the apparatus. The stirring bar is extracted. The contents of the flask are transferred to a round bottom flask and the solvent removed under reduced pressure. Pumping to a constant weight gives 1.2 g of yellow semi-solid. The residue is dissolved in DCM (10 mL) and applied to an ISCO Companion that is fitted with a 40 g column (silica). The column is eluted with EtOAc/heptanes (5%) for 4 column volumes followed by a linear gradient to 65% EtOAc/heptanes over 10 column volumes and then 90% EtOAc/heptanes for 2 column volumes. 14 mL fractions are collected. Fractions 42-50 are combined and evaporated by pumping to constant weight to give white solid (0.56 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:47][C:48]1[S:49][CH:50]=[CH:51][N:52]=1.C(N(CC)CC)C>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:10]([NH:47][C:48]2[S:49][CH:50]=[CH:51][N:52]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)[C@H](CC1CCCCO1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1nccs1)[C@H](CC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.9 %

Procedure:
A solution of 2(R)-(3,4-dichloro-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (80 mg, 0.26 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluoro-phosphate (177 mg, 0.40 mmol), and 2-aminothiazole (40 mg, 0.40 mmol) in methylene chloride (10 mL) at 25° C. was treated with triethylamine (0.11 mL, 0.79 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water (10 mL) and extracted with methylene chloride 3×10 mL). The combined organic layers were sequentially washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a saturated sodium chloride solution (1×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 hexanes/ethyl acetate to 70/30 hexanes/ethyl acetate) afforded the 2(R)-(3,4-dichloro-phenyl)-3-(tetrahydro-pyran-2-yl)-N-thiazol-2-yl-propionamide (57 mg, 57%) as a white foam: EI-HRMS m/e calcd for C17H18Cl2N2O2S (M+) 384.066. found 384.1467.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](I)[CH:21]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OC(C1CCN(C2C=CC(C(=O)NC3C=CC(C4C=CC=CC=4)=C(C)C=3)=CN=2)CC1)=O)C>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:21]=[C:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]([CH3:26])=[CH:24][CH:25]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1
Agent: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(-c4ccccc4)c(C)c3)cn2)CC1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(-c4ccccc4)c3)cn2)CC1

Procedure:
5′-(6-methyl-biphenyl-3-yl-carbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester was prepared from 5′-(3-iodo-4-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester and phenylboronic acid following a method similar to the one described in the synthesis of 5′-(2-methyl-biphenyl-4-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester above. The product was isolated after silica gel column purification with 20-50% EtOAc in hexanes gradient. HRMS m/z calcd for C27H29N3O3 [M+H]+: 444.2282. Found: 444.2282
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([S:15](Cl)(=[O:17])=[O:16])=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[CH3:21][C:22]([NH2:25])([CH3:24])[CH3:23]>C(Cl)Cl>[C:22]([NH:25][S:15]([C:9]1[CH:8]=[C:7]2[C:12]([CH2:13][CH2:14][N:5]([C:3](=[O:4])[C:2]([F:20])([F:19])[F:1])[CH2:6]2)=[CH:11][CH:10]=1)(=[O:17])=[O:16])([CH3:24])([CH3:23])[CH3:21]
Reactant: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride (3 g) in DCM (50 ml) was added 2-methylpropan-2-amine (1.73 g). The reaction was then allowed to stir at room temperature 18 h. The reaction was partitioned between H2O (100 ml) and DCM (100 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×200 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as colourless oil. Yield: 3.56 g
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH:15]([CH3:17])[CH3:16])([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.C(O)(=O)C>C(O)C>[ClH:1].[C:13]([C@@:10]1([CH:15]([CH3:17])[CH3:16])[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([NH:26][CH3:27])=[O:25])=[CH:28][CH:29]=3)[N:7]=2)[C:9]1=[O:18])#[N:14]
Reactant: CC(C)[C@]1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Reactant: CNC(=O)c1ccc(N)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: CNC(=O)c1ccc(Nc2nccc(N3CC[C@@](C#N)(C(C)C)C3=O)n2)cc1
Product: Cl
Yield: 75.4 %

Procedure:
A solution of (3S)-1-(2-chloropyrimidin-4-yl)-3-isopropyl-2-oxopyrrolidine-3-carbonitrile (55 mg) obtained in Step A, 4-amino-N-methylbenzamide (37 mg) and acetic acid (13 μL) in ethanol (2 mL) was stirred in a microwave reactor at 150° C. for 1 hr, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate). To a solution of the residue (87 mg) in ethanol (3 mL) was added 1M hydrochloric acid (230 μL), and the solvent was evaporated under reduced pressure. The residue was recrystallized (diisopropyl ether/ethanol) to give the title compound (65 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[NH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][NH2:17].[H][H]>C(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=Cc1ccccn1
Reactant: NCCCNCCCN
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: c1ccc(CNCCCNCCCNCc2ccccn2)nc1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Pyridine-2-carboxaldehyde (4.3 g, 0.04 mole) and 1,5,9-triazanonane (2.6 g, 0.02 mole) [bis(aminopropyl)- amine; available from Aldrich Chemical Company] were dissolved in ca. 60 ml of absolute ethanol and warmed (ca. 50° C.) with stirring for 10 minutes. The solution was hydrogenated at room temperature over 1.5 g of 5% Pd on charcoal in an atmosphere of hydrogen. After the calculated amount of hydrogen (0.04 mole; ca. 0.90 1 at 25° C. and 1 atm. pressure) had been consumed, the charcoal catalyst was removed by filtration, and dry HCl gas was bubbled into the solution until no further white precipitate formed. After removing the precipitate by filtration of the cooled solution, the product was washed with absolute ethanol, dried, and recrystallized from 95% ethanol.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[F:13][C:14]1[N:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][CH:15]=1.O>ClCCl>[F:13][C:14]1[N:19]=[CH:18][C:17]([C:20]([N:3]([O:4][CH3:5])[CH3:2])=[O:21])=[CH:16][CH:15]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(F)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 250-mL round-bottom flask containing N,O-dimethyl hydroxylamine hydrochloride (3.5 g, 35.9 mmol) and triethylamine (15.0 mL, 108 mmol) was added a solution of 6-fluoropyridine-3-carbonyl chloride (5.70 g, 35.7 mmol, Intermediate 21, step a) in dichloromethane (200 mL) dropwise. The resulting mixture was stirred for 12 hours at room temperature, and 20 mL of water was added. The organic layer was separated, and the aqueous layer was extracted with 2×100 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by chromatography (silica gel column, 100:1 CHCl3/MeOH) to give the title compound as a white solid.