Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[C:8]([O:15][CH3:16])=[N:9][CH:10]=[C:11]([Cl:14])[C:12]=1[CH3:13].ClC1C(C)=C([Mg]Cl)C(OC)=NC=1.[Cu]C#N.[Cl-].[Li+].ClC1C(C)=C([Cu])C(OC)=NC=1.[CH3:45][O:46][C:47]1[C:55]([O:56][CH3:57])=[C:54]([O:58][CH3:59])[CH:53]=[C:52]([CH3:60])[C:48]=1[C:49](O)=[O:50].N1C=CC=CC=1[Cu].O.N>O1CCCC1.S(Cl)(Cl)=O.O>[CH3:45][O:46][C:47]1[C:55]([O:56][CH3:57])=[C:54]([O:58][CH3:59])[CH:53]=[C:52]([CH3:60])[C:48]=1[C:49]([C:7]1[C:8]([O:15][CH3:16])=[N:9][CH:10]=[C:11]([Cl:14])[C:12]=1[CH3:13])=[O:50]
Reactant: COc1cc(C)c(C(=O)O)c(OC)c1OC
Reactant: COc1ncc(Cl)c(C)c1Br
Agent: COc1ncc(Cl)c(C)c1[Cu]
Agent: N#C[Cu]
Agent: [Cu]c1ccccn1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc(C)c(C(=O)c2c(OC)ncc(Cl)c2C)c(OC)c1OC
Temperature: -78 °C
Reaction time: 3 h
Yield: 107.7 %

Procedure:
(b-1) 6.8 ml (13.6 mmol) of isopropylmagnesium chloride (2M tetrahydrofuran solution) was cooled to 0° C., and a solution having 1.6 g (6.6 mmol) of 3-bromo-5-chloro-2-methoxy-4-methylpyridine dissolved in 5 ml of tetrahydrofuran was dropwise added, followed by stirring at the same temperature for 3 hours to prepare 5-chloro-2-methoxy-4-methyl-3-pyridylmagnesium chloride. The reaction solution was cooled to −78° C., and a solution having 1.2 g (13.3 mmol) of copper(I) cyanide and 1.15 g (27.1 mmol) of lithium chloride dissolved in 15 ml of tetrahydrofuran was dropwise added to prepare a 5-chloro-2-methoxy-4-methyl-3-pyridylcopper reagent. Separately, 3.2 g (14.3 mmol) of 2,3,4-trimethoxy-6-methylbenzoic acid prepared in Step (a) was subjected to reflux with heating in 7 ml of thionyl chloride for 3 hours, and the surplus thionyl chloride was distilled off under reduced pressure to prepare 2,3,4-trimethoxy-6-methylbenzoyl chloride, which was dissolved in 7 ml of tetrahydrofuran. The solution thus prepared was dropwise added at −78° C. to the above prepared pyridylcopper reagent, followed by stirring for 1 hour, and the temperature was increased to room temperature, followed by stirring further for 2 hours. Water and ammonia water were added to the reaction solution to terminate the reaction, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 2.6 g (yield: 57%) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-5-chloro-2-methoxy-4-methylpyridine (melting point 85 to 88° C.), and the compound was identified by 1HNMR.
Reaction SMILES: Cl.N[C@H](C)CSC1N(C)C=NN=1.SC1N(C)C=NN=1.C(O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1N1C=NC2C1=NC(Cl)=NC=2Cl)(=O)C.C([O:52][C@@H:53]1[C@H:57]([O:58]C(=O)C)[C@@H:56]([CH2:62][O:63]C(=O)C)[O:55][C@H:54]1[N:67]1[C:86]2[N:85]=[C:84]([Cl:87])[N:83]=[C:71]([NH:72][C@H:73]([CH3:82])[CH2:74][S:75][C:76]3[N:80]([CH3:81])[CH:79]=[N:78][N:77]=3)[C:70]=2[N:69]=[CH:68]1)(=O)C.C[O-].[Na+]>CO>[Cl:87][C:84]1[N:83]=[C:71]([NH:72][C@H:73]([CH3:82])[CH2:74][S:75][C:76]2[N:80]([CH3:81])[CH:79]=[N:78][N:77]=2)[C:70]2[N:69]=[CH:68][N:67]([C:86]=2[N:85]=1)[C@@H:54]1[O:55][C@H:56]([CH2:62][OH:63])[C@@H:57]([OH:58])[C@H:53]1[OH:52]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@H](C)CSc4nncn4C)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[C@@H](N)CSc1nncn1C
Agent: C[O-]
Solvent: CO
Product: C[C@H](CSc1nncn1C)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 17 %

Procedure:
The title compound was prepared according to method A as described in Example 1 by reacting 3-[(R)-2-amino-1-propylthio]-4-methyl-1,2,4-triazole hydrochloride [prepared by a Mitsunobu reaction as described in Example 1 using 2-[(R)-N-tert-butyloxycarbonyl]amino-1-propanol (3.5 g, 20 mmol) and 3-mercapto-4-methyl-1,2,4-triazole (2.3 g, 20 mmol) followed by acidic hydrolysis] (0.56 g, 2.2 mmol) with 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.0 g, 2.2 mmol), followed by deacylation of the purified 2',3',5'-tri-O-acetyl-2-chloro-N-[(R)- 1-(4-methyl-1,2,4-triazol-3-yl)thio-2-propyl]adenosine using sodium methoxide in methanol to provide the title 2-chloro-N[(R)-1-(4-methyl-1,2,4-triazol-3-yl)thio-2-propyl]adenosine (0.17 g, 17%) as a foam after column chromatography. 1H NMR (DMSO-d6) δ1.24 (3H, d, --CHCH3), 3.56, 3.67 (2H, ABX, 5'a and H-5'b), 3.95 (1H, q, H-4), 4.14 (1H, br q, H-3'), 4.15-4.42 (2H, m, --CH2S--), 4.52 (1H, br q, H-2'), 4.80 (1H, m, --CHCH3), 5.07 (1H, br, 5'-OH), 5.22, 5.50 (2H, 2 br, 2'- and 3'-OH), 5.82 (1H, d, H-1'), 8.33 (1H, d, --NH), 8.39, 8.41 (2H, 2s, H-2 and Ar--H). HPLC retention time 7.79 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([CH2:8]O)[O:6][CH:7]=1.O=S(Cl)[Cl:13]>ClCCl>[Cl:13][CH2:8][C:5]1[O:6][CH:7]=[C:2]([OH:1])[C:3](=[O:10])[CH:4]=1
Reactant: O=c1cc(CO)occ1O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=c1cc(CCl)occ1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.96 %

Procedure:
To a stirred solution of 5-hydroxy-2-hydroxymethyl-pyran-4-one (1) (100.0 g, 703.68 mmol) in dichloromethane (750 mL) was added SOCl2 (102.0 mL) very slowly and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the solvent was evaporated to remove volatile compounds under reduced pressure to get a crude compound. It was then purified by hexane wash to get 2-chloromethyl-5-hydroxy-pyran-4-one (2) (70.0 g, 61.96%) as an off white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[O:21])=[CH:16][CH:15]=1)[C:12]#[N:13].[CH3:27]I.C[O-].[Na+]>C(Cl)Cl.O.CO.COCCOC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[O:21])=[CH:16][CH:15]=1)([CH3:27])[C:12]#[N:13]
Reactant: N#CC(Sc1nc2ccccc2s1)c1ccc(C(=O)c2cccs2)cc1
Reactant: CI
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CO
Product: CC(C#N)(Sc1nc2ccccc2s1)c1ccc(C(=O)c2cccs2)cc1
Reaction time: 3.5 h

Procedure:
Methanol (5 ml) and 1 ml of DME were added to 788 mg of alpha-(2-benzothiazolylthio)[p-(2-thienylcarbonyl)phenyl]acetonitrile, and the mixture was stirred in an argon atmosphere under ice cooling. Methyl iodide (0.20 ml) and 0.81 ml of a 2.7 M methanol solution of sodium methoxide were added. The mixture was stirred under ice cooling for 1 hour, and then at room temperature for 3.5 hours. Water (20 ml) and 30 ml of methylene chloride were added, and the insoluble matter was removed by filtration. The filtrate was shaken, and the organic layer was separated. The aqueous layer was extracted with 20 ml of methylene chloride twice. The organic layers were combined, washed with 20 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (silica gel; methylene chloride) to afford 73 mg of alpha-(2-benzothiazolylthio)alpha-[p-(2-thienylcarbonyl)phenyl]propionitrile as colorless crystals.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:9]1[CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:35]=[N+:36]=[N-:37].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]4[NH:37][N:36]=[N:35][N:24]=4)=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:9]1[CH3:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(Cc2ccccc2)c2cc(-c3ccc(OCC#N)cc3)ccc2n1Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(Cc2ccccc2)c2cc(-c3ccc(OCc4nnn[nH]4)cc3)ccc2n1Cc1ccccc1

Procedure:
The desired product was prepared using a procedure similar to step 6 of example 3. Thus, [4-(1,3-dibenzyl-2-methyl-1H-indol-5-yl)-phenoxy]-acetonitrile (0.160 g, 0.362 mmol) was reacted with NaN3 (0.118 g, 1.808 mmol) and NH4Cl (0.097 g, 1.808 mmol) in DMF (5 ml) to give the product (0.136 g, 0.280 mmol, 77%) as a white solid, mp 190-192° C. 1H NMR (DMSO-d6) δ 2.35 (s, 3H), 4.10 (s, 2H), 5.43 (s, 2H), 5.49 (s, 2H), 6.99 (d, J=7.0 Hz, 2H), 7.09-7.13 (m, 3H), 7.20-7.30 (m, 8H), 7.40 (d, J=8.4 Hz, 1H), 7.54 (d, J=8.9 Hz, 2H), 7.60 (d, J=1.7 Hz, 1H); IR (solid) 3030, 2905, 2850, 1605, 1520, 1480, 1440, 1360, 1270, and 1250 cm−1; [ESI(−)], m/z 484 (M−H)−; Anal. Calcd. for C31H27N5O: C, 76.88; H, 5.60; N, 14.42; Found: C, 76.71; H, 5.57; N, 14.37.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.N1CCC[C@H]1C(O)=O.[CH3:18][C:19]([CH3:21])=[O:20].BrC1C=CC=CC=1C=O>CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:18][C:19](=[O:20])[CH3:21])=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(Br)cc1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=Cc1ccccc1Br
Solvent: CCOCC
Product: CC(=O)C=Cc1ccc(Br)cc1
Yield: 80 %

Procedure:
The p-bromobenzaldehyde (1 mmol) and the L-proline (30 mol %) are dissolved in N,N′-dimethylimidazolium methyl H-phosphonate (1 ml). The acetone (1 ml) is added. The mixture is stirred at room temperature until disappearance of the bromobenzaldehyde (followed by Thin Layer Chromatography). 4-(4-bromophenyl)but-3-en-2-one is isolated by extraction with ether (3×5 ml). The product is purified by column chromatography (0.96 g; yield=80%).
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].Cl.[CH3:22][NH:23][CH3:24].C(N(CC)CC)C>O1CCOCC1>[CH3:22][N:23]([CH3:24])[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]
Reactant: CNC
Reactant: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
A mixture of 2-trifluoroacetyl-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride (400 mg, 1.22 mmol, J. Med. Chem. 1980, 23, 837), dimethylamine hydrochloride (150 mg, 1.83 mmol), and triethylamine (0.50 mL, 3.66 mmol) in dioxane (10 mL) was refluxed with stirring for 30 min, cooled to room temperature, concentrated, and purified by flash column chromatography (10→50% ethyl acetate/hexanes) to give 337 mg (82%) of the title compound of Example 247, Step A as a yellow oil. 1H NMR (CDCl3, 300 MHz, 9:5 mixture of rotamers) δ 7.67-7.52 (c, 2H), 7.36 (t, 1H), 4.87 (s, 1.3H), 4.81 (s, 0.7H), 3.96-3.86 (c, 2H), 3.08-3.02 (c, 2H), 2.72 (s, 6H); MS (TS) 337 (MH+).
Reaction SMILES: BrC1C2N(N=C(Cl)N=2)C=CC=1.COC1(B(O)O)C=CC(C(F)(F)F)=CN1.[Cl:27][C:28]1[N:48]=[C:31]2[C:32]([C:36]3[C:37]([O:46][CH3:47])=[N:38][CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=3)=[CH:33][CH:34]=[CH:35][N:30]2[N:29]=1.[C:49]([O:53][C:54]([N:56]1[CH2:61][CH2:60][CH:59]([C:62]2[CH:67]=[CH:66][C:65]([NH2:68])=[CH:64][CH:63]=2)[CH2:58][CH2:57]1)=[O:55])([CH3:52])([CH3:51])[CH3:50].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[Cl:27][C:28]1[N:48]=[C:31]2[C:32]([C:36]3[C:37]([O:46][CH3:47])=[N:38][CH:39]=[C:40]([C:42]([F:44])([F:45])[F:43])[CH:41]=3)=[CH:33][CH:34]=[CH:35][N:30]2[N:29]=1.[C:49]([O:53][C:54]([N:56]1[CH2:61][CH2:60][CH:59]([C:62]2[CH:67]=[CH:66][C:65]([NH:68][C:28]3[N:48]=[C:31]4[C:32]([C:36]5[C:37]([O:46][CH3:47])=[N:38][CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=5)=[CH:33][CH:34]=[CH:35][N:30]4[N:29]=3)=[CH:64][CH:63]=2)[CH2:58][CH2:57]1)=[O:55])([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Agent: COC1(B(O)O)C=CC(C(F)(F)F)=CN1
Agent: COc1ncc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12
Agent: Clc1nc2c(Br)cccn2n1
Product: COc1ncc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc12

Procedure:
2-Chloro-8-(2-methoxy-5-trifluoromethyl-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 2-methoxy-5-trifluoromethylpyridineboronic acid in a manner analogous to Example 2c (0.46 g, 65%). MP=183-185° C. MS=329 (MH)+. 277b) [4-{4-[8-(2-Methoxy-5-trifluoromethyl-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-methoxy-5-trifluoromethyl-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester, with 2,2′-bis-dicyclohexylphosphanyl-biphenyl as the ligand in a manner analogous to Example 2d (0.233 g, 41%). MP=142-144° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.75 (s, 1H), 8.80 (d, 1H), 8.65 (s, 1H), 8.55 (s, 1H), 7.85 (d, 1H), 7.55 (d, 2H), 7.02 (m, 3H), 4.05 (m, 2H), 3.90 (s, 3H), 2.6-2.8 (m, 3H), 1.65 (m, 2H), 1.40 (m, 11H). MS=569 (MH)+.
Reaction SMILES: [Na].[CH2:2]([O:9][C:10]1[CH:18]=[CH:17][C:13]([CH:14]=[N:15][OH:16])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.CO.C(OCC)(=O)C.O>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][N:15]([C:19](=[O:21])[CH3:20])[OH:16])=[CH:17][CH:18]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: ON=Cc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N(O)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
Sodium cyanoborohydrodide (21.3 g) was added in portions to a solution of 4-benzyloxybenzaldehyde oxime (51 g) in acetic acid (250 ml) at ca 50° (cooling). After the reduction was complete, acetic anhydride (22.5 ml) was added in one portion, and the mixture was stirred for 1 hour. The mixture was then poured into water, and the neutral product was isolated with ethyl acetate. The residue was treated with potassium carbonate (2 g) in methanol (400 ml) to hydrolyse the O-acetyl material, then the solvent was evaporated. Addition of 20% citric acid solution (400 ml) and isolation with ethyl acetate furnished N-(4-Benzyloxybenzyl)acetohydroxamic acid (32 g), m.pt. 119°-120° [from ethyl acetate-light petroleum (b.p.t. 60°-80°)].
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[C:10](OC(=O)C)(=[O:12])C.C(O)=O>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl>[F:9][C:4]1[CH:3]=[C:2]([I:1])[CH:8]=[CH:7][C:5]=1[NH:6][CH:10]=[O:12]
Reactant: Nc1ccc(I)cc1F
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O=CO
Solvent: CCOC(C)=O
Product: O=CNc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a cooled solution (0° C.) of 4-iodo-2 fluoroaniline (3.05 g, 12.9 mmol) in tetrahydrofuran (15 mL) and toluene (15 mL), was slowly added a mixture of acetic anhydride (1.39 mL, 14.7 mmol) and formic acid (0.83 mL, 22.0 mmol). The reaction mixture was stirred at rt overnight, then diluted with ethyl acetate (100 mL) and 1N aqueous HCl (100 mL). The layers were separated, and the organic layer was washed with water and saturated sodium carbonate solution, and dried over sodium sulfate. The solvent was removed under reduced pressure to afford 2-fluoro-4-iodophenylformamide as an off-white solid (3.32 g, 97%). GC-MS ret. time 2.27 min, m/z 265 (M+); 1H NMR (300 MHz, CDCl3) δ: 7.37-7.51 (m, 3H), 8.13 (t, 1H), 8.46 (s, 1H).
Reaction SMILES: [Cl:1][C:2](=[CH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:17]([Cl:18])=[C:16]([O:19][CH:20]([F:22])[F:21])[N:15]([CH3:23])[N:14]=2)[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])[C:3](Cl)=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:33][O:34][NH2:35]>C1(C)C=CC=CC=1.O>[CH3:33][O:34][NH:35][C:3](=[O:4])[C:2]([Cl:1])=[CH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:17]([Cl:18])=[C:16]([O:19][CH:20]([F:21])[F:22])[N:15]([CH3:23])[N:14]=2)[C:10]([F:24])=[CH:9][C:8]=1[Cl:25]
Reactant: CON
Reactant: Cn1nc(-c2cc(C=C(Cl)C(=O)Cl)c(Cl)cc2F)c(Cl)c1OC(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CONC(=O)C(Cl)=Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc1Cl
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 4.5 g (10 mmol) of 2-chloro-3-(2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorophenyl)acryloyl chloride in 25 ml of toluene was treated with 25 ml of water, 14.4 g (0.1 mol) of potassium carbonate and 1.7 g (20 mmol) of methoxyamine hydrochloride. After the mixture had been stirred for 16 hours at approximately 20° C., it was heated for a further 2 hours at 40° C. The reaction mixture was subsequently diluted with 200 ml of toluene and 200 ml of water. The solids were then filtered off. The organic phase was dried over magnesium sulfate and finally concentrated. Yield: 3.1 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([NH2:14])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:21](Cl)(=[O:25])[CH2:22][CH2:23][CH3:24].O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]([CH3:11])([CH3:13])[CH3:12])[C:5]([NH:14][C:21](=[O:25])[CH2:22][CH2:23][CH3:24])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C#Cc1nc(Cl)ccc1N
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCCC(=O)Nc1ccc(Cl)nc1C#CC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
To a solution of 6-chloro-2-(3,3-dimethyl-but-1-ynyl)-pyridin-3-ylamine (11.5 g, 55.2 mmol) and pyridine (13.1 g, 166 mmol) in CH2Cl2 (150 mL) was added butyryl chloride (6.5 g, 61 mmol) dropwise at 0° C. The mixture was allowed to warm to room temperature and was stirred at this temperature overnight. Water (50 mL) was added dropwise at −0° C. The resulting mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude N-[6-chloro-2-(3,3-dimethyl-but-1-ynyl)-pyridin-3-yl]-butyramide (16 g), which was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz) δ 8.72 (d, J=9.0 Hz, 1H), 7.88 (brs, 1H), 7.23 (d, J=8.4 Hz, 1H), 2.40 (d, J=7.2 Hz, 2H), 1.83-1.75 (m, 2H), 1.40 (s, 9H), 1.04 (d, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:3](=[N:17][NH2:18])[N:4]=[C:5]([CH3:16])[NH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[CH:19]1([CH2:24][C@H:25]([CH2:29][N:30]([CH:39]=[O:40])[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH:19]1([CH2:24][C@@H:25]([C:26]([NH:18][NH:17][C:3]2[C:2]([F:1])=[C:7]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[N:6]=[C:5]([CH3:16])[N:4]=2)=[O:27])[CH2:29][N:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:39]=[O:40])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1nc(=NN)c(F)c(NCc2ccccn2)[nH]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: Cc1nc(NCc2ccccn2)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)n1
Reaction time: 8 h
Yield: 48.5 %

Procedure:
5-Fluoro-2-methyl-6-[(2-pyridinylmethyl)amino]-4(1H)-pyrimidinone hydrazone (0.0954 g, 0.3846 mmol) and (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.141 g, 0.4622 mmol) were dissolved in DMF (3 mL). NMM (0.13 mL, 1.1824 mmol) was added, followed by HOAt (0.063 g, 0.4632 mmol) and EDC (0.088 g, 0.459 mmol). After stirring overnight the reaction mixture was purified by RP-HPLC to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-2-methyl-6-[(2-pyridinylmethyl)amino]-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide as a white solid (0.0999 g, 48%). LCMS: (M+H)+=536.3.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:24][CH:25]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]1)[C:11]1[CH:12]=[C:13]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]O)[CH:14]=[CH:15][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:51]1(=[O:61])[NH:55][C:54](=[O:56])[C:53]2=[CH:57][CH:58]=[CH:59][CH:60]=[C:52]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:24][CH:25]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]1)[C:11]1[CH:12]=[C:13]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:55]2[C:51](=[O:61])[C:52]3[C:53](=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:54]2=[O:56])[CH:14]=[CH:15][CH:16]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN1CCC(OC(c2cccc(SCCCCCO)c2)c2nc3ccccc3[nH]2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(OC(c2cccc(SCCCCCN3C(=O)c4ccccc4C3=O)c2)c2nc3ccccc3[nH]2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentan-1-ol (35 mg) in tetrahydrofuran are added triphenylphosphine (31 mg) and phthalimide (18 mg). The reaction mixture is cooled to 0° C. and diethyl azodicarboxylate (31 μL) is added. The reaction mixture is stirred at 0° C. for 30 minute. The mixture is evaporated to dryness and the residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 98/2/0.2 to 95/5/0.5) to give 2-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentyl)isoindole-1,3-dione (example 305B).
Reaction SMILES: [NH2:1][CH:2]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)[C:3]([N:5]([CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][N:13]=[CH:12]2)=[O:4].[CH2:36]([NH:43][C:44](=[O:52])[NH:45][C@H:46]([CH3:51])[CH2:47][C:48](O)=[O:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH2:36]([NH:43][C:44](=[O:52])[NH:45][CH:46]([CH3:51])[CH2:47][C:48]([NH:1][CH:2]([C:3](=[O:4])[N:5]([CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][N:13]=[CH:12]2)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[CH:27][CH:26]=1)=[O:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(CN(Cc1cccc2cn[nH]c12)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Reactant: C[C@H](CC(=O)O)NC(=O)NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CN(Cc1cccc2cn[nH]c12)C(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)CC(C)NC(=O)NCc1ccccc1)OCC
Reaction time: 0.67 h

Procedure:
To a solution of 2-Amino-3-(4-tert-butoxy-phenyl)-N-(2,2-diethoxy-ethyl)-N-(1H-indazol-7-ylmethyl)-propionamide in CH2Cl2 (50 mL) was added a solution of (3R)-3-(3-Benzyl-ureido)-butyric acid (1.44 g, 6.1 mmol), EDCI (1.17 g, 1.2 eq), HOBt (0.93 g, 1.2 eq), DIEA (2.13 mL, 12.2 mmol) in CH2Cl2 (100 mL) stirred for 40 min. The reaction mixture was stirred at room temperature for 14 h, and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The crude compound was used next step without further purification. MS ESI 701 (M+H), 723 (M+Na).