Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17](O)=[O:18])=[N:4][O:5][C:6]=1[C:7]1[CH2:16][CH2:15][C:10]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:9][CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:44][C:45]1[C:46](=[O:58])[N:47]([CH:52]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)[N:48]([CH3:51])[C:49]=1[CH3:50].C(N(CC)CC)C>CN1C(=O)CCC1.CS(C)=O>[CH:52]1([N:47]2[C:46](=[O:58])[C:45]([NH:44][C:17]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]4[CH2:16][CH2:15][C:10]5([CH2:11][CH2:12][CH2:13][CH2:14]5)[CH2:9][CH:8]=4)[O:5][N:4]=3)=[O:18])=[C:49]([CH3:50])[N:48]2[CH3:51])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]1
Reactant: Cc1c(C(=O)O)noc1C1=CCC2(CCCC2)CC1
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C1=CCC2(CCCC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-methyl-5-(spiro[4.5]dec-7-en-8-yl)isoxazole-3-carboxylic acid (95 mg, 0.364 mmol) in dry NMP (3 ml), HATU (152 mg, 0.400 mmol) was added followed by 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate D) (84 mg, 0.400 mmol) and triethylamine (0.111 mL, 0.800 mmol) and this was stirred at room temperature for 16 hours. The reaction mixture was partitioned between EtOAc (30 mL) and 1M NaOH (aq) (30 mL) and the organic phase was washed with water (30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give an orange oil. The crude material was dissolved in DMSO and purified using UV-directed automated reverse phase chromatography over a 9.5 minute gradient of 50-98% MeCN in water (0.1% formic acid). The product fraction was added to EtOAc (50 mL) and washed with a saturated aqueous NaHCO3 solution (50 mL). The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[C:5](Br)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1B(O)O.C(Cl)Cl>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[C:5]([C:16]3[C:17]([CH3:22])=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=3[CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(Cl)c2cccc(Br)c2n1
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(-c2cccc3c(Cl)cc(C)nc23)c(C)c1
Temperature: 80 °C
Yield: 88.4 %

Procedure:
Part B: In a mixture of 270 ml dimethoxyethane and 45 ml water, after bubbling through nitrogen gas for 30 minutes, a quantity of 5.0 g ( 19.5 mmol) of 2-methyl-4-chloro-8-bromo-quinoline, 3.5 g (21 mmol) of 2,4,6-trimethyl phenylboronic acid, 13.2 g (42 mmol) Ba(OH)2.8H2O and 0.69 g (0.6 mmol) tetrakis(triphenylphosphine)palladium were subsequently dissolved. After heating to 80° C. for 16 hours and subsequent cooling, 250 ml of water and 500 ml of CH2Cl2 were added. After separation the organic layer was dried over sodium sulphate and concentrated in vacuo. The product was purified on a silicagel column using dichloromethane as eluent. A total of 5.1 g of 2-methyl-4-chloro-8-(2,4,6-trimethylphenyl)-quinoline was obtained (88% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C=CC=CC=1.[Cl:22][C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:23]([Cl:22])=[O:25])[CH:13]=[CH:14][CH:15]=1
Reactant: COc1cccc(Nc2ccccc2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(N(C(=O)Cl)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a cooled solution of 3-methoxy-N-phenylaniline (100.0 mg, 0.502 mmol) and pyridine (0.102 mL, 1.267 mmol) in DCM (500 mL) was added triphosgene (120.0 mg, 0.406 mmol). The solution was allowed to warm up to room temperature and stirred overnight. The organic solvent was evaporated. The residue was dissolved in ethyl acetate, washed with water, brine, dried over MgSO4 and concentrated to provide the title compound (105.0 mg). LCMS m/z=261.9 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.79 (s, 3H), 6.90-7.31 (m, 3H), 7.32-7.52 (m, 4H), 7.52-7.70 (m, 2H).
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[C:16]3[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](O)=[O:29])[CH:23]=[CH:24][C:25]=1[Cl:26].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[N:1]1([CH2:6][C:7]2([C:28](=[O:29])[CH2:27][C:22]3[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=3)[C:16]3[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc2c1CCNC2CN1CCCC1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cccc2c1CCNC2(CN1CCCC1)C(=O)Cc1ccc(Cl)c(Cl)c1

Procedure:
Prepared as Ex. No. 1, from 1.2 g (4.88 mmoles) of 1-(pyrrolidin-1-yl)methyl-5-methoxy-1,2,3,4-tetrahydroisoquinoline, 1.1 g (5.37 mmoles) of 3,4-dichlorophenylacetic acid and 2.2 g (10.68 mmoles) of dicyclohexylcarbodiimide in 50 ml of dry methylene chloride.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:46][C@@H:47]([C:49]2[CH:54]=[CH:53][C:52]([O:55][CH2:56][C:57]3C=CC=CC=3)=[C:51]([NH:63][CH:64]=[O:65])[CH:50]=2)[OH:48])[CH2:26][C@H:27]([OH:45])[C:28]2[CH:33]=[CH:32][C:31]([O:34]CC3C=CC=CC=3)=[C:30]([NH:42][CH:43]=[O:44])[CH:29]=2)=[CH:17][CH:16]=1)C1C=CC=CC=1.C[OH:68]>C(O)(=O)C.[OH-].[OH-].[Pd+2].ClCCl>[C:56]([OH:68])(=[O:55])[CH3:57].[C:56]([OH:68])(=[O:55])[CH3:57].[OH:34][C:31]1[CH:32]=[CH:33][C:28]([C@@H:27]([OH:45])[CH2:26][N:25]([CH2:46][C@H:47]([OH:48])[C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[C:51]([NH:63][CH:64]=[O:65])[CH:50]=2)[CH2:24][CH2:23][CH2:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH2:10])=[CH:20][CH:19]=2)=[CH:29][C:30]=1[NH:42][CH:43]=[O:44]
Reactant: O=CNc1cc([C@@H](O)CN(CCCCc2ccc(CCCCNC(=O)OCc3ccccc3)cc2)C[C@H](O)c2ccc(OCc3ccccc3)c(NC=O)c2)ccc1OCc1ccccc1
Reactant: CO
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: NCCCCc1ccc(CCCCN(C[C@H](O)c2ccc(O)c(NC=O)c2)C[C@H](O)c2ccc(O)c(NC=O)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A mixture of {4-[4-(4-{bis-[2-(4-benzyloxy-3-formylaminophenyl)-2-(R)-hydroxyethyl]-amino}butyl)phenyl]butyl}carbamic acid benzyl ester (10) (0.17 g, 0.19 mmol), palladium dihydroxide (50 mg, 10% Pd(OH)2 on carbon, 50% wet), eight drops of acetic acid, methanol (10 mL), and dichloromethane (5 mL) was stirred at rt for 18 h under atmospheric hydrogen pressure. The catalyst was filtered through a Celite pad and the filtrate was concentrated by rotary evaporation and further dried under high vacuum to give the desired amine diacetic acid salt 13 as a white solid (0.10 mg, 98%); m/z (ESI) 579 [C32H42N4O6+H]+.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]=[N+:22]=[N-:23])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[C:37]([C:39]1[CH:40]=[C:41]([OH:45])[CH:42]=[CH:43][CH:44]=1)#[CH:38].CCN(C(C)C)C(C)C>C1COCC1.CCOCC.[Cu]I>[CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:38]=[C:37]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([OH:45])[CH:40]=5)[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C#Cc1cccc(O)c1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN=[N+]=[N-])nn23)CC1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(Cn4cc(-c5cccc(O)c5)nn4)nn23)CC1
Reaction time: 28 h
Yield: 60.7 %

Procedure:
To a stirred clear yellow solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(azidomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.070 g, 0.140 mmol), 3-ethynylphenol (0.083 g, 0.701 mmol) and DIEA (0.122 ml, 0.701 mmol) in THF (5 mL) was added CuI (0.053 g, 0.280 mmol) at rt. After 28 h, the reaction mixture was diluted with Et2O (50 mL), washed with water (2×10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated to give yellow oil which was purified by prep-HPLC to afford (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(3-hydroxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.0528 g, 0.085 mmol, 61.0% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.75-7.99 (m, 2H), 7.52 (t, J=1.8 Hz, 1H), 7.22-7.30 (m, 2H), 6.84-6.89 (m, 1H), 6.51 (s, 1H), 5.97-6.07 (m, 1H), 5.86 (br. s., 1H), 5.78 (s, 2H), 5.44 (d, J=16.7 Hz, 1H), 5.19 (dd, J=1.6, 10.4 Hz, 1H), 4.14-4.29 (m, 2H), 4.00 (d, J=4.7 Hz, 2H), 2.62 (s, 3H), 1.82-2.03 (m, 3H), 1.65-1.73 (m, 1H), 1.31 (s, 3H), 1.24 (t, J=7.1 Hz, 3H), 1.23 (s, 9H). LCMS (M+H)=618.6.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:9][CH:8]=1>C(Cl)(Cl)Cl>[CH3:5][O:4][C:2]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:19][CH:20]=1)=[O:3]
Reactant: COC(=O)Cl
Reactant: Nc1ccc(OCCn2ccnc2)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1ccc(OCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
Methyl chloroformate (0.5 g) was added to a stirred solution of 1-[2-(4-aminophenoxy)ethyl]imidazole (1.0 g) in chloroform (50 ml) and the mixture was stirred at room temperature for 2 hours and then evaporated. The residue was dissolved in water and made basic by the addition of sodium bicarbonate. The resulting precipitate was filtered off, washed with water and crystallised from methanol/water to give 1-[2-(4-methoxycarbonylaminophenoxy)ethyl]imidazole (1.13 g), m.p. 152°-153° C., Found: C, 59.77; H, 5.81; N, 15.92. C13H15N3O3 requires: C, 59.76; H, 5.79; N, 16.08%.
Reaction SMILES: C(CC1C=CC(C[CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=CC=1)(O)=O.[NH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH2:11]([N:12]([CH2:27][C:28]1[CH:29]=[CH:30][C:21]([CH2:14][CH2:13][N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:22][CH:23]=1)[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[C@@H:21]1[CH2:22][CH2:23][C:28]2[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:29]=2[CH2:30]1)[CH3:10]
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Reactant: C1CCNCC1
Product: CCN(Cc1ccc(CCN2CCCCC2)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 21.2 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and piperidine (20 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (1.9 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:24][Mg]Br.[NH4+].[Cl-].CC[O:31][C:32]([CH3:34])=[O:33]>O1CCCC1>[C:32]([OH:33])(=[O:31])/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18].[F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:32]([CH3:34])([OH:33])[CH3:24])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: CCOC(C)=O
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)CCN1CCC(c2noc3cc(F)ccc23)CC1
Product: O=C(O)/C=C/C(=O)O
Reaction time: 16 h

Procedure:
To a solution of ethyl 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propionate (3.21 g, 10 mmol) in tetrahydrofuran (THF, 100 ml), was added methylmagnesium bromide (10 ml, 30 mmol, 3M solution in ether) dropwise over 15 minutes at room temperature under N2. The resulting mixture was stirred for 16 hours. The mixture was slowly hydrolyzed with aqueous NH4Cl solution. The THF solution was diluted with EtOAc (300 ml), then was washed with water and brine. The organic solution was separated and dried over MgSO4. After removal of solvent, the crude product was purified by flash chromatography (25 g, SiO2 ; eluted with 1 CH3OH:99 DCM). The material thus purified weighed 2.36 g (77%) as white crystals. This was converted to the fumarate salt by treatment with fumaric acid (895 mg) in ethanol. Recrystallization from ethanol yielded white crystals, 2.47 g, m.p.=156°-158° C. ANALYSIS: Calculated for C17H23FN2O2.C4H4O4 : 59.70%C 6.44%H 6.63%N Found: 59.40%C 6.27%H 6.28%N
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([O:15][C:16]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=1[F:26])(=[O:14])=[O:13])=[CH:7]2.[CH3:27][O:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:30]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:27][O:28][C:29]1[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[CH:31][C:30]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([O:15][C:16]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=1[F:26])(=[O:13])=[O:14])=[CH:7]2
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Br)cccc2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1cc(C(F)(F)F)ccc1-c1cccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Temperature: 90 °C
Yield: 65.9 %

Procedure:
A vial was charged with perfluorophenyl 5-bromonaphthalene-2-sulfonate (285.84 mg, 0.631 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (277 mg, 1.261 mmol), potassium phosphate (402 mg, 1.892 mmol), and Pd(AmPhos)2Cl2 (22.33 mg, 0.032 mmol). The vial was flushed with Ar (g), then dioxane (1577 μl) and water (526 μl) was added. The vial was sealed and heated in a microwave for 20 min at 90° C. The mixture was diluted with water and extracted with EtOAc (three times). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The product was purified by chromatography on silica gel (0 to 20% EtOAc/Heptane) to give perfluorophenyl 5-(2-methoxy-4-(trifluoromethyl)phenyl)naphthalene-2-sulfonate (228.1 mg, 0.416 mmol) as a white foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.62 (d, J=1.9 Hz, 1H), 8.07 (d, J=8.2 Hz, 1H), 7.85 (dd, J=2.0, 9.0 Hz, 1H), 7.79-7.71 (m, 2H), 7.64 (dd, J=1.3, 7.1 Hz, 1H), 7.47-7.38 (m, 2H), 7.29 (s, 1H), 3.77 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH:20]([C:22]2[CH:34]=[CH:33][CH:32]=[CH:31][C:23]=2[O:24][CH2:25][CH2:26][CH2:27][C:28](O)=[O:29])[CH3:21])[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1C=CC2N(O)N=[N:41][C:39]=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC.CN.Cl>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH:20]([C:22]2[CH:34]=[CH:33][CH:32]=[CH:31][C:23]=2[O:24][CH2:25][CH2:26][CH2:27][C:28]([NH:41][CH3:39])=[O:29])[CH3:21])[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(c1ccccc1OCCCC(=O)O)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)CCCOc1ccccc1C(C)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 97.4 %

Procedure:
A mixture of acid 4-[2-(1-([(4-chlorophenyl)sulfonyl]-2,5-difluoroanilino}ethyl)phenoxy]butanoic acid (107 mg, 0.21 mmol), HOBT (31 mg, 0.23 mmol), EDCI (44 mg, 0.23 mmol), Et3N (88 μL, 0.63 mmol) and CH3NH2.HCl (16 mg, 0.23 mmol) in CH2Cl2 (1.0 mL) was stirred at 25° C. for 13 h. The mixture was diluted with ethyl acetate. The organic solution was washed with H2O and sat. NaCl solution then dried over MgSO4. Concentration and chromatography afforded the amide (107 mg, 97%) as colorless gum: Rf 0.32 (10:20, hexane-ethyl acetate); 1H NMR (CDCl3, 300 MHz) δ 7.64 (d, 2H, J=6.9 Hz), 7.42 (d, 2H, J=7.8 Hz), 7.18 (t, 1H, J=8.7 Hz), 6.36-6.91 (m, 7H), 6.26 (q, 1H, 1=6.9 Hz), 4.13 (m, 1H), 4.05 (m, 1H), 2.78 (m, 4H), 2.57 (m, 1H), 2.23 (m, 2H), 1.55 (br s, 3H); LCMS m/z 524 (M+H+, C25H25ClF2N2O4S requires 522.99).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([NH:27][NH2:28])=O)[N:20]=4)=[O:17])[CH:11]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:29]N(C)C=O.CN(C)C(=O)C.[CH3:40][O:41][CH2:42][C@@H:43]([NH2:45])[CH3:44].C(O)(=O)C>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[N:9]=[CH:8][C:7]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5[N:45]([C@@H:43]([CH3:44])[CH2:42][O:41][CH3:40])[CH:29]=[N:28][N:27]=5)[N:20]=4)=[O:17])[CH:11]=3)=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: COC[C@H](C)N
Reactant: NNC(=O)c1cccc(NC(=O)c2cc(-c3ccc(C4CC4)nc3)ccn2)n1
Reactant: CN(C)C=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: COC[C@H](C)n1cnnc1-c1cccc(NC(=O)c2cc(-c3ccc(C4CC4)nc3)ccn2)n1
Temperature: 150 °C
Yield: 63 %

Procedure:
To a suspension of 6-cyclopropyl-N-(6-(hydrazinecarbonyl)pyridin-2-yl)-3,4′-bipyridine-2′-carboxamide, a compound of formula (3) (75 mg, 0.20 mmol) in toluene (0.20 M) was added N,N-dimethylformamide/N,N-dimethylacetamide (67 μL, 0.50 mmol), (S)-2-methoxy-1-methyl-ethylamine (72 mg μL, 0.80 mmol), and acetic acid (11 μL, 0.20 mmol). The reaction was heated to 150° C. for 30 minutes in a microwave reactor. The reaction mixture was concentrated under reduced pressure, and the residue suspended in acetonitrile/diethyl ether (15 mL, 1:1 ratio), filtered and washed with acetonitrile/diethyl ether (2×10 mL). The solid thus obtained was dried under reduced pressure to afford 57 mg (63% yield) of (S)-6-cyclopropyl-N-(6-(4-(1-methoxypropan-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3,4′-bipyridine-2′-carboxamide as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3].[N:11]1([S:17](Cl)(=[O:19])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>N1C=CC=CC=1.CCOC(C)=O>[CH2:1]([C:4]1[N:9]=[C:8]([NH:10][S:17]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:19])=[O:18])[CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: O=S(=O)(Cl)N1CCCCC1
Reactant: CCCc1cccc(N)n1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCc1cccc(NS(=O)(=O)N2CCCCC2)n1
Yield: 32 %

Procedure:
A solution of 6-propyl-pyridin-2-ylamine (0.2 g) and piperidine-1-sulfonyl chloride (0.296 g, Bull. Soc. Chim. Fr.; 1936, 2143) in pyridine (7 mL) was heated to reflux for 15 h. After concentration of the reaction mixture in vacuo the residue was taken up in EtOAc, which was then washed with 1N aqueous HCl, saturated brine, dried over sodium sulphate and concentrated in vacuo. The residue was applied to a silica gel column with EtOAc/toluene (9:1 to 1:1) as eluent. Combination of the purified fractions and concentration in vacuo gave the desired piperidine-1-sulfonic acid (6-propyl-pyridin-2-yl)-amide (0.133 g) as a colorless amorphous solid. MS (ESI−): 282.0 ([M−H]−).
Reaction SMILES: [OH-].[K+].[C:3]1([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)[CH2:16][C:17]([C:19]([OH:21])=[O:20])=[O:18].Cl>O>[C:3]1([CH2:9][C:10]([OH:14])([C:11]([OH:13])=[O:12])[CH2:16][C:17](=[O:18])[C:19]([OH:21])=[O:20])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)CC(=O)C(=O)O
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(=O)CC(O)(Cc1ccccc1)C(=O)O
Yield: 37 %

Procedure:
To a solution of 13.8 g of potassium hydroxide (85% purity) dissolved in 25 ml of water were added 5.0 g (30.5 mmol) of phenylpyruvic acid and 12.1 g (91.4 mmol) of oxalacetic acid, and the mixture was allowed to react at room temperature for 72 hours. The reaction mixture was adjusted at pH 2.2 with conc. hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried on anhydrous magnesium sulfate, and condensed to yield a residue. This was recrystallized from ethyl acetate and toluene to yield 2.8 g (11.3 mmol) of 4-phenylmethyl-4-hydroxy-2-ketoglutaric acid as crystals.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.[CH3:8][S:9]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1)(=[O:11])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.C(OCC)(=O)C>[CH3:8][S:9]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16][S:1][C:2]2[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=2)=[CH:14][CH:13]=1)(=[O:10])=[O:11]
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: Cn1ccnc1S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccnc1SCc1ccc(S(C)(=O)=O)cc1
Reaction time: 18 h

Procedure:
To a solution of 2-mercapto-N-methylimidazole (570 mg, 4.9 mmol) and 4-methanesulfonylbenzyl chloride (1 g, 4,9 mmol) in DMF (10 mL) at 21° C. was added cesium carbonate (0.8 g, 2.5 mmol). After 18 h, the reaction mixture was diluted with water and ethyl acetate. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated to provide the 2-(4-methanesulfonyl-benzylsulfanyl)-1-methyl-1H-imidazole compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:17]1(N2CC2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:26][N:27]([CH:29]=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:27]3[CH2:29][C@H:26]3[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:16])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: c1ccc(N2CC2)cc1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)cc1
Product: O=C(c1ccc(-c2ccc(Cl)cc2)cc1)N1C[C@H]1c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 0.232 g of 4'-chlorobiphenyl-4-carboxylic acid in 3 ml of dry DMF, 0.18 g of N,N'-carbonyl-diimidazole are added with stirring at room temperature under argon atmosphere. After one hour a solution of 0.12 g of phenyl-aziridine in 0.5 ml of dry DMF is added dropwise. The reaction mixture is stirred for 21 hours and thereafter worked up as described in example 1. The compound is obtained as a pale yellow oil and used without purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C@H:12]([CH2:16][CH3:17])[C:13]([OH:15])=[O:14])[CH2:7][CH2:6]2.[C:18]([O-])(O)=O.[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C@H:12]([CH2:16][CH3:17])[C:13]([O:15][CH3:18])=[O:14])[CH2:7][CH2:6]2
Reactant: CC[C@H](C(=O)O)[C@@H]1CCc2cc(OC)ccc21
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H](C(=O)OC)[C@@H]1CCc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
A suspension of the acid prepared in Example 21 (220.0 g, 0.94 mol), NaHCO3 (237.0 g, 2.82 mol), CH3l (200 g, 1.41 mol) in DMF (2.0 L) was stirred under argon at rt for 18 h. Adding additional CH3l (100 g, 0.71 mol) and stirring for an additional 24 h at rt caused completion of the reaction. The reaction mixture was poured into 4.0 L water, and extracted with EtOAc (2×2 L). The combined organic layers were sequentially washed with water (2×1 L), NaOH (1 L, 1 N aqueous solution), water (2×1 L), and brine (0.5 L). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (233 g, 99%) as a light yellow. 1H NMR (300 MHz, DMSO-d6) δ 6.90 (d, 1H), 6.78 (d, 1H), 6.66 (dd, 1H), 3.70 (s, 3H), 3.60 (s, 3H), 3.20 (m, 1H), 2.80 (m, 2H), 2.40 (m, 1H), 2.08 (m, 1H), 1.80 (m, 1H), 1.58 (m, 1H), 1.40 (m, 1H), 0.80 (t, 3H).