Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[CH2:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[C:41]([CH3:43])[N:40]=[C:39]([CH3:44])[CH:38]=2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[CH2:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[C:39]([CH3:44])[N:40]=[C:41]([CH3:43])[CH:42]=2)[CH:32]=1)=[O:30])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Product: C=Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-5-vinyl-phenyl)-carbamic acid tert-butyl ester (Example J34) (227 mg, 0.75 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow solid (199 mg, 48%).
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([Cl:14])=[C:10](OC)[CH:11]=1.[OH2:15]>C(Cl)Cl>[Cl:14][C:9]1[CH:10]=[CH:11][C:6]([Br:5])=[C:7]([OH:15])[CH:8]=1
Reactant: COc1cc(Br)ccc1Cl
Reactant: O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(Cl)ccc1Br
Reaction time: 0.17 h

Procedure:
9 ml of boron tribromide is added dropwise to a solution containing 20 g of 5-bromo 2-chloro anisole in 200 ml of methylene chloride. Agitation is carried out for 10 minutes at 0° C., then for 24 hours at 20° C. and the reaction medium is poured into a water and ice mixture. The resultant suspension is agitated for 30 minutes, extraction is carried out with methylene chloride, followed by saturation with sodium chloride and extraction twice with methylene chloride. The organic phases are collected, dried over magnesium sulphate, evaporated under reduced pressure and 18.5 g of 5-chloro 2-bromophenol is obtained. M.p.=56° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([CH3:20])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]2[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[CH:9]=1)[CH3:6])[CH3:2].[CH:22]([C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31](N2C=CN=C2)=[O:32])=[CH:27][CH:26]=1)([CH3:24])[CH3:23].Cl>C1(C)C=CC=CC=1.O>[CH:22]([C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]([N:16]2[CH2:17][CH2:18][CH2:19][CH:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([O:7][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:21])([CH3:20])[CH3:6])[CH:9]=3)[CH2:15]2)=[O:32])=[CH:27][CH:26]=1)([CH3:24])[CH3:23]
Reactant: CC(C)c1ccc(COC(=O)n2ccnc2)cc1
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C2CCCNC2)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1cccc(C2CCCN(C(=O)OCc3ccc(C(C)C)cc3)C2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.4 %

Procedure:
To a solution of 2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid ethyl ester (Preparation 2; Method D; 7.60 g, 17.21 mmol) in 20 mL toluene was added imidazole-1-carboxylic acid-(4-isopropyl)benzyl ester (4.20 g, 17.21 mmol) and stirred for 18 h at ambient temperature. The reaction was diluted with water (300 mL), acidified with 1 N HCl and extracted with diethyl ether (2×200 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 10% ethyl acetate/hexanes to yield 6.23 g (77%) of 3-[3-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-isopropyl-benzyl ester as a clear oil.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[N:27]=[CH:26][C:9]2[C:10]3[N:14]([CH2:15][CH2:16][O:17][C:8]=2[CH:7]=1)[CH:13]=[C:12]([C:18]1[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=1)[N:11]=3.[NH3:29]>CO>[CH:23]([N:19]1[C:18]([C:12]2[N:11]=[C:10]3[C:9]4[CH:26]=[N:27][C:6]([O:5][CH2:4][C:3]([NH2:29])=[O:2])=[CH:7][C:8]=4[O:17][CH2:16][CH2:15][N:14]3[CH:13]=2)=[N:22][CH:21]=[N:20]1)([CH3:25])[CH3:24]
Reactant: COC(=O)COc1cc2c(cn1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Reactant: N
Solvent: CO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(OCC(N)=O)cc1OCC2
Temperature: 50 °C
Yield: 50 %

Procedure:
[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-acetic acid methyl ester (88 mg, 0.23 mmol) was dissolved in a solution of ammonia in methanol (7N, 5 mL) and the reaction mixture heated at 50° C. for 2 h, during which a white precipitate formed. The reaction mixture was concentrated in vacuo and the residue subjected to reverse phase preparative HPLC (C-18, 10-90% MeCN in water, 0.1% formic acid, 25 min gradient) to yield 427 as a white solid (42 mg, 50%). LCMS: RT=2.85 min, [M+H]+=370; 1H NMR (400 MHz, d6-DMSO) 9.07 (1H, s), 7.88 (1H, s), 7.86 (1H, s), 7.41 (1H, s), 7.18 (1H, s), 6.45 (1H, s), 5.87 (1H, sept, J=6.7 Hz), 4.66 (2H, s), 4.60-4.44 (4H, m), 1.44 (6H, d, J=6.7 Hz).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@@:22]([C:26]4[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=4)[C:29]([O:31]C)=[O:30])([CH3:25])[CH2:23][OH:24])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[OH-].[Na+].Cl>C1COCC1>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@@:22]([C:26]4[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=4)[C:29]([OH:31])=[O:30])([CH3:25])[CH2:23][OH:24])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc([C@](C)(CO)NC(=O)c2c(C)nc3c(OCC4CCCCC4)cccn23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@@](C)(CO)c1cccc(C(=O)O)c1
Temperature: 40 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
To a mixture of 86 mg of methyl 3-[(2R)-2-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-1-hydroxypropan-2-yl]benzoate, 1.9 ml of methanol, and 1.9 ml of THF was added 0.36 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at 40° C. for 16 hours. The reaction mixture was left to be cooled to room temperature and 1 M hydrochloric acid was then added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 52 mg of 3-[(2R)-2-({ [8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-1-hydroxypropan-2-yl]benzoic acid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=2)[NH:16][N:15]=[C:14]3[CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:38][N:39]1[CH:43]=[C:42]([S:44](Cl)(=[O:46])=[O:45])[N:41]=[C:40]1[CH3:48]>CN(C1C=CN=CC=1)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=2)[NH:16][N:15]=[C:14]3[CH:23]2[CH2:28][CH2:27][N:26]([S:44]([C:42]3[N:41]=[C:40]([CH3:48])[N:39]([CH3:38])[CH:43]=3)(=[O:46])=[O:45])[CH2:25][CH2:24]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2cc(C(N)=O)c3[nH]nc(C4CCNCC4)c3c2)cc1
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(-c2cc(C(N)=O)c3[nH]nc(C4CCN(S(=O)(=O)c5cn(C)c(C)n5)CC4)c3c2)cc1
Yield: 13.3 %

Procedure:
Following the general procedure of Example 11, 5-[4-(acetylamino)phenyl]-3-(4-piperidinyl)-1H-indazole-7-carboxamide (Example 71) (0.07 mmol), diisopropylethylamine (100 uL, 0.56 mmol), DMAP (25 mg, 0.014 mmol) and 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (33 mg, 0.17 mmol) were reacted to give the title compound (5 mg, 13% for 3 steps).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([NH2:36])[CH:33]([CH3:35])[CH3:34]>>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:20][CH:21]=3)[CH2:13][CH:12]([C:27]3[O:28][N:36]=[C:32]([CH:33]([CH3:35])[CH3:34])[N:31]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)C(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: CC(C)c1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
200 mg (0.480 mmol) of the compound from Example 63A and 98 mg (0.961 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 2. Yield: 62 mg (27% of theory)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CN
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In one aspect, substrates A and B were prepared as follows. To a solution of (S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanoic acid (1w) in THF was added methyl 2-aminoacetate hydrochloride (2w), Et3N and HATU. The mixture was stirred at room temperature for 16 h. The reaction was filtered through Celite. The reaction filtrate was diluted with 100 mL of water and stirred for 15 min. The suspension was filtered off, rinsed with water and dried to afford (S)-methyl 2-(2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)acetate (3w).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH:22](Cl)[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:30](=O)([O-])[O-:31].[K+].[K+]>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH:22]([O:31][CH3:30])[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(Cl)c2ccncc2)cc1
Agent: [K+]
Solvent: CO
Product: COC(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 60 °C

Procedure:
A suspension of 4-tert-butyl-N-[4-chloro-2-(chloro-pyridin-4-yl-methyl)-phenyl]-benzenesulfonamide (113 mg, 0.25 mmol) and potassium carbonate (69 mg, 0.5 mmol) in anhydrous methanol was heated at 60° C. overnight, the solid residue was then removed by filtration and product was purified by preparative HPLC. MS: (M+H)=445.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]#[N:13].[H-].[Na+].Cl[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1>C1(C)C=CC=CC=1.C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)[C:12]#[N:13]
Reactant: Clc1ccc2ccccc2n1
Reactant: N#CCc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#CC(c1ccc2ccccc2n1)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.7 %

Procedure:
To a solution of 2-quinolylacetonitrile (14.5 g, 86.2 mmol) in toluene (200 mL) was added slowly NaH (6.9 g of 60% oil dispersion, 172 mmol). The reaction mixture was stirred at ambient temperature for 15 min at which point H2 evolution was no longer evident. A solution of 2-chloroquinoline (14.1 g, 86.2 mmol) in toluene (150 mL) was added to the reaction flask, and the reaction mixture was then heated at reflux for 18 h. The reaction mixture was cooled to ambient temperature, diluted with THF, and quenched with H2O. The organic solution was washed with 1N HCl (200 mL), saturated aqueous solution of NaHCO3, and brine. An orange solid precipitated from the organic layer and was isolated via vacuum filtration. The mother liquor was dried over MgSO4 and the volatile components were removed with a rotary evaporator. The resulting solid was combined with the orange powder isolated via filtration. The solid was washed with a mixture of ether and heptane to afford 14.7 g (57.6%) of product. Results of 1H NMR spectroscopy and electrospray mass spectroscopy are consistent with the product.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH:3]([CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH2:11]1)[CH2:4]/[C:5](=[N:7]/[OH:8])/[NH2:6].CCN(C(C)C)C(C)C.[F:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1>C(Cl)Cl>[F:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([NH:6]/[C:5](=[N:7]\[OH:8])/[CH2:4][CH:3]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=3)[CH2:11]2)[C:2]([F:1])([F:26])[F:27])=[O:43])=[CH:40][CH:39]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: N/C(CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F)=N\O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N/C(CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F)=N\O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
In a 10 mL round-bottomed flask, (Z)-4,4,4-trifluoro-N′-hydroxy-3-((3-(3-(trifluoromethyl)phenyl)-piperidin-1-yl)methyl)butanimidamide (120 mg, 302 μmol) and DIEA (117 mg, 158 μl, 906 μmol) were combined with CH2Cl2 (2.00 ml) to give a colorless solution. 4-Fluorobenzoyl chloride (47.9 mg, 302 μmol) in CH2Cl2 (1 ml) was added drop-wise and the resulting mixture was stirred at room temperature overnight. The crude reaction mixture was concentrated in vacuo to afford 120 mg (38%) of (Z)-4-fluoro-N-(4,4,4-trifluoro-1-(hydroxyimino)-3-((3-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)butyl)benzamide and used as is. MH+=520.
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5]C1)#[N:2].C(C1(C2C=CC(OC)=C(C=2)[CH:27]=[O:28])CC1)#N>>[C:1]([C:3]1([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[C:13]([CH:14]=2)[CH:27]=[O:28])[CH2:8][CH2:7][CH2:6][CH2:5]1)#[N:2]
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Reactant: COc1ccc(C2(C#N)CCCCC2)cc1
Product: COc1ccc(C2(C#N)CCCC2)cc1C=O

Procedure:
This compound was prepared from 4-(1-Cyanocyclohexyl)anisole in the same manner of Compound 2.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:33])[CH2:23][C:24]([C:26]1[S:27][CH:28]=[CH:29][C:30]=1[C:31]#[N:32])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[NH:7][C:24]([C:26]4[S:27][CH:28]=[CH:29][C:30]=4[C:31]#[N:32])=[CH:23][C:22](=[O:33])[NH:21][C:9]=3[CH:10]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1sccc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccsc1C1=CC(=O)Nc2cc(-c3ccc(F)cc3)ccc2N1

Procedure:
Prepared from {3-[3-(3-cyano-thiophen-2-yl)-3-oxo-propionylamino]-4′-fluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K54) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as an orange solid (209 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])([O-])=O.O.O.Cl[Sn]Cl.N.O>C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10]
Reactant: C=CCOC(=O)C=Cc1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOC(=O)C=Cc1cccc(N)c1
Yield: 99.5 %

Procedure:
Crude allyl 3-nitrocinnamate (3 g, 12.9 mM) was dissolved in ethyl acetate (10 ml) and added slowly to a stirred suspension of SnCl2.2H2O(14.52 g, 64 mM) in ethyl acetate (20 ml). The mixture was refluxed under argon for 3 hours, cooled, and poured into a mixture of ammonia (sg 880, 15 ml) and water (5 ml). Ethyl acetate (50 ml) was added, and the organic layer separated by decantation. Two further extractions with ethyl acetate (each 50 ml) were made similarly. The combined extracts were washed with water and brine, dried (MgSO4) and evaporated to give title compound (2.6 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[C:26][CH2:27][NH:28][C:29](=[O:31])[O-:30])=[N:4][CH:5]=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:11]([Cl:24])[CH:10]=1>CN(C)C=O.[Cu]I>[C:17]([O:31][C:29](=[O:30])[NH:28][CH2:27][C:26]1[NH:1][C:2]2[C:7]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)=[C:11]([Cl:24])[CH:10]=3)=[N:6][CH:5]=[N:4][C:3]=2[CH:25]=1)([CH3:22])([CH3:18])[CH3:16]
Reactant: Nc1c(C#CCNC(=O)[O-])ncnc1Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2[nH]1
Temperature: 80 °C
Reaction time: 12 h
Yield: 148.5 %

Procedure:
A mixture of tert-butyl (3-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrimidin-4-yl]prop-2-ynylcarbamate (720 mg) and copper(I) iodide (55.2 mg) in N,N-dimethylformamide (7.0 mL) was stirred at 80° C. for 12 hrs. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, eluent, ethyl acetate→methanol:ethyl acetate=1:9) to give the title compound (604 mg) as pale-yellow powder crystals.
Reaction SMILES: C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:37][C:38]1[CH:63]=[CH:62][C:41]([O:42][C:43]2[CH:48]=[CH:47][C:46]([S:49]([NH:52][C:53]3([C:59]([OH:61])=O)[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)(=[O:51])=[O:50])=[CH:45][CH:44]=2)=[CH:40][CH:39]=1.Cl.[CH2:65]([O:72][NH2:73])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>CN(C)C=O>[CH2:65]([O:72][NH:73][C:59]([C:53]1([NH:52][S:49]([C:46]2[CH:45]=[CH:44][C:43]([O:42][C:41]3[CH:62]=[CH:63][C:38]([F:37])=[CH:39][CH:40]=3)=[CH:48][CH:47]=2)(=[O:50])=[O:51])[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)=[O:61])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCOCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NOCc1ccccc1)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Diisopropyl ethylamine (3.89 grams, 0.030 mole) and (benzotriazol-1-yloxy)tris-(dimethylamino)-phosphonium hexafluorophosphate (13.27 grams, 0.030 mole) were added sequentially to a solution of 4-[4-(4-fluorophenoxy)-benzenesulfonylamino] tetrahydropyran-4-carboxylic acid (11.22 grams, 0.028 mole) in anhydrous N,N-dimethylformamide (140 mL). The resulting solution was stirred at room temperature for 16 hours. Additional diisopropyl ethylamine (4.0 mL, 0.051 mole) and O-benzyl hydroxylamine hydrochloride (5.46 grams, 0.034 mole) were then added and the resulting mixture was stirred at 60° C. for 18 hours. After concentration under vacuum, the residue was treated with 0.5N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium bicarbonate solution, water, and brine. The solution was dried over magnesium sulfate, filtered and concentrated to one fourth original volume. Addition of an equal volume of hexane precipitated 4-[4-(4-fluorophenoxy)benzenesulfonylamino]-tetrahydropyran-4-carboxylic acid N-benzyloxyamide (11.595 g, 81.6%) as a white crystalline solid (mp 175-176° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:14])=[CH:4][C:5]([Cl:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[N:15]([O-])=O.[Na+].[Sn](Cl)Cl>Cl.O>[ClH:13].[Cl:13][C:5]1[CH:4]=[C:3]([F:14])[C:2]([NH:1][NH2:15])=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(N)c(F)cc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(NN)c(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 116 %

Procedure:
Then, 19 g (87.4 mmol) of ethyl 5-amino-2-chloro-4-fluorobenzoate was dissolved in 120 ml of hydrochloric acid, followed by cooling to 0° C., to which a solution of 6.3 g (91.7 mmol) of sodium nitrite dissolved in 10 ml of water was added dropwise at 10° C. or lower. The mixture was stirred at 0° C. for 30 minutes and then cooled to −30° C., into which a solution of 58 g (0.31 mol) of anhydrous tin (II) chloride dissolved in 40 ml of hydrochloric acid was poured, followed by further stirring at 0° C. for 3 hours. The precipitated crystals were collected by filtration and then dried, which afforded 13.6 g (50.7 mmol) of crude ethyl 2-chloro-4-fluoro-5-hydrazinobenzoate hydrochloride.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:28]([O:32][C:33]([N:35]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C:36]1[C:45]2[C:40](=[CH:41][C:42]([NH:46][CH:47]([C:51]3[CH:56]=[CH:55][C:54]([C@@H:57]([CH3:79])[CH2:58][O:59][C:60](=[O:78])[NH:61][C:62]4[CH:67]=[C:66]([CH2:68][NH:69][CH3:70])[C:65]([O:71][C@@H:72]([CH3:76])[CH2:73][O:74][CH3:75])=[C:64]([F:77])[CH:63]=4)=[C:53]([CH3:80])[CH:52]=3)[C:48](O)=[O:49])=[CH:43][CH:44]=2)[CH:39]=[CH:38][N:37]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C=O)C>[C:28]([O:32][C:33]([N:35]([C:36]1[C:45]2[C:40](=[CH:41][C:42]([NH:46][CH:47]3[C:48](=[O:49])[N:69]([CH3:70])[CH2:68][C:66]4[CH:67]=[C:62]([CH:63]=[C:64]([F:77])[C:65]=4[O:71][C@@H:72]([CH3:76])[CH2:73][O:74][CH3:75])[NH:61][C:60](=[O:78])[O:59][CH2:58][C@H:57]([CH3:79])[C:54]4[C:53]([CH3:80])=[CH:52][C:51]3=[CH:56][CH:55]=4)=[CH:43][CH:44]=2)[CH:39]=[CH:38][N:37]=1)[C:81](=[O:82])[O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CNCc1cc(NC(=O)OC[C@H](C)c2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2C)cc(F)c1O[C@@H](C)COC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC[C@H](C)Oc1c(F)cc2cc1CN(C)C(=O)C(Nc1ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c1)c1ccc(c(C)c1)[C@@H](C)COC(=O)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
To a solution of BOP (196 mg, 0.444 mmol), 4-dimethylaminopyridine (136 mg, 1.109 mmol) in CH2Cl2 (40 mL), was added a solution of 37E (185 mg, 0.222 mmol) in DMF (10 mL) via a syringe pump over 6 h. The reaction mixture was stirred at rt for 16 h, then concentrated and purified by prep HPLC to give 37F (150 mg, 0.184 mmol, 83% yield) as a yellow solid. MS (ESI) m/z: 816.2 (M+H)+.
Reaction SMILES: Br[C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:25][NH:26][CH3:27]>CN(C=O)C>[CH3:25][N:26]([CH3:27])[C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: CNC
Reactant: O=Cc1ccc(-c2nc3nc(Br)nn3cc2-c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CN(C)c1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To 200 mg 4-(2-bromo-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (prepared as described above) in 6 mL DMF were added 0.24 mL of a dimethylamine solution (60% in water). The mixture was heated under microwave irradiation to 100° C. for 2.5 hours. The solvent was removed and the solid residue is was treated with ethyl acetate/petrolether (1:1) and stirred for 2 hours. The desired product was filtered, dried and was used without further purification.