Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C@H:2]([C:7]([NH:9][C@H:10]([C:16]([NH:18][C@H:19]([C:31]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:47]([NH:49][NH:50]C(OCC(Cl)(Cl)Cl)=O)=[O:48])[CH2:43][CH2:44][S:45][CH3:46])=[O:40])[C@H:35]([CH2:37][CH3:38])[CH3:36])=[O:32])[CH2:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[NH2:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]>CN(C=O)C.C(O)(=O)C.[Zn]>[NH:1]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C@H:2]([C:7]([NH:9][C@H:10]([C:16]([NH:18][C@H:19]([C:31]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:47]([NH:49][NH2:50])=[O:48])[CH2:43][CH2:44][S:45][CH3:46])=[O:40])[C@H:35]([CH2:37][CH3:38])[CH3:36])=[O:32])[CH2:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[NH2:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCSC)C(=O)NNC(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCSC)C(=O)NN
Reaction time: 0.67 h

Procedure:
17.9 g (17.5 mM) of Boc-Leu-Gln-Asp(OBzl)-Ile-Met-NH-NH-Troc are dissolved in a mixture of 200 ml of DMF and 50 ml of acetic acid and strongly stirred with mechanical stirring means. 11.5 g of powdered zinc (300 mesh=47 μm) are added in one operation and stirring is continued for 1 hour and 40 mins. at ambient temperature. The solid is drained, washed in DMF and the filtrate is introduced in 740 g of ice. The mixture is left to stand for one night, and then drained. The precipitate is washed with large quantities of water and dried in the open, then in a desiccator +P205.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[C:17]([CH3:18])=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15]([CH3:24])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]>C(O)=O>[CH:1]([NH:8][C:9]1[C:17]([CH3:18])=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15]([CH3:24])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=[O:3]
Reactant: CCOC(=O)c1c(C)cc(C(=O)O)c(N)c1C
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CCOC(=O)c1c(C)cc(C(=O)O)c(NC=O)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To 14.5 ml of 90% formic acid was added 30 ml of acetic anhydride. The mixture was warmed, and then heated to 50°-60° C. for two hours. To the mixture cooled to room temperature was added portionwise with stirring 15.0 g of 2-amino-4-ethoxycarbonyl-3,5-dimethylbenzoic acid. The mixture was further stirred at room temperature for 3 hours and poured into ice water. The resulting precipitate was filtered and recrystallized from ethyl acetate/n-hexane to yield 11.8 g (70.5% of theory) of 2-formylamino-4-ethoxycarbonyl-3,5-dimethylbenzoic acid melting at 144.5°-146° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30]([NH:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: COC(=O)c1ccc(CSc2ccc(F)cc2N)cc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(CSc2ccc(F)cc2NS(=O)(=O)c2cc3ccccc3o2)cc1
Yield: 65.9 %

Procedure:
Following General Procedure B, the title compound (929 mg, 66%) was prepared from methyl 4-(((2-amino-4-fluorophenyl)thio)methyl)benzoate (873 g, 2.99 mmol) and benzofuran-2-sulfonyl chloride (646 mg, 2.99 mmol) in pyridine (5 ml).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[N:22]1([C:28]2[CH:37]=[C:36]([C:38](O)=[O:39])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:38]([C:36]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=[C:28]([N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)[CH:37]=4)=[O:39])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(O)c1cc(N2CCCCC2)nc2ccccc12
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)c2cc(N3CCCCC3)nc3ccccc23)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-piperidin-1-ylquinoline-4- carboxamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1, 1′-biphenyl-4-carboxamide and 2-(piperidin-1-yl)quinoline-4-carboxylic acid using method B. NMR; δH CDCl3 7.90,(1H, d), 7.83-7.78,(4H, m), 7.67,(1H, b), 7.52,(1H, t), 7.42,(2H, d), 7.33,(1H, d), 7.26, (1H, m), 7.21,(1H, t), 7.01,(1H, s), 6.30,(1H, t), 3.63,(4H, s), 3.31,(2H, m), 2.27,(3H, s), 1.62,(6H, m), 1.07,(1H, m), 0.57,(2H, m), 0.28,(2H, m). LCMS: retention time 3.32 min, MH+519.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]([OH:22])[N:6]([C:13]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[C:7]2=[O:12].CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.[I:42]I>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([I:42])=[C:8]2[C:4]=1[CH:5]([OH:22])[N:6]([C:13]([CH3:14])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:21])[C:7]2=[O:12]
Reactant: II
Reactant: COc1cccc2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(I)c2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 77 %

Procedure:
In a similar manner to Step 3 of Example 16, 4-methoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (3.55 g, 11.9 mmol) was dissolved in THF (140 mL), and the solution was treated with TMEDA (4.00 mL, 26.2 mmol), sec-butyllithium-hexane solution (0.99 mol/L, 26.4 mL, 26.2 mmol) and iodine (3.62 g, 14.3 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=9/1, 7/3) to obtain 4-methoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (3.88 g, yield 77%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[NH:15][C:16](=[O:19])[CH2:17][CH3:18])=[CH:12][CH:11]=[C:10]([Cl:20])[CH:9]=2)=[O:5].N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl>[C:32]([NH:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[NH:15][C:16](=[O:19])[CH2:17][CH3:18])=[CH:12][CH:11]=[C:10]([Cl:20])[CH:9]=2)=[O:5])(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CCC(=O)Nc1c(C(=O)c2cc(Cl)ccc2N)[nH]c2cc(Cl)ccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)Nc1c(C(=O)c2cc(Cl)ccc2NC(C)=O)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a solution of 2-(2-amino-5-chlorobenzoyl)-6-chloro-3-(propionylamino)indole (Example 389, 217 mg, 0.576 mmol) and pyridine (0.12 ml, 1.50 mmol) in dichloromethane (10 ml) was added acetyl chloride (53 μl, 0.749 mmol) at 0° C. After stirring at room temperature for 1 h, the mixture was concentrated and the residue was diluted with ethyl acetate (100 ml). The solution was washed with 2N aqueous HCl (30 ml×2), saturated aqueous sodium bicarbonate (30 ml), and dried (MgSO4). Removal of solvent gave a crystalline residue. Recrystallization from ethyl acetate gave 163 mg (68%) of the title compound. m.p.: 264-266° C. IR (KBr) ν: 3260, 1676, 1655, 1578, 1547, 1508, 1313, 1234, 1205, 1006, 918, 841 cm−1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][NH:15][C:16](=[O:27])[C@@H:17]([NH:21][S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[CH:18]([CH3:20])[CH3:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[CH:12].I[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][NH:15][C:16](=[O:27])[C@@H:17]([NH:21][S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[CH:18]([CH3:20])[CH3:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[C:12][C:29]1[S:30][CH:31]=[CH:32][CH:33]=1
Reactant: Ic1cccs1
Reactant: C#CCOc1ccc(CCNC(=O)[C@@H](NS(=O)(=O)CC)C(C)C)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(OCC#Cc2cccs2)c(OC)c1)C(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2 g of (S)-2-(ethylsulfonyl-amino)-3-methyl-butyric acid N-[2-(3-methoxy-4-propargyloxy-phenyl)-ethyl]-amide, 2.1 g of 2-iodothiophene and 2 ml of triethylamine are heated to 40° C. in 50 ml of chloroform. 70 mg of bis(triphenylphosphine)palladium(II) chloride and 32 mg of copper(I) iodide are added thereto. The reaction mixture is stirred for one hour at 60° C.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:25]([C:28]1[CH:29]=[C:30]([CH2:37][C:38](Cl)=[O:39])[CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1)([O-:27])=[O:26]>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:38](=[O:39])[CH2:37][C:30]4[CH:29]=[C:28]([N+:25]([O-:27])=[O:26])[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[CH:31]=4)[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: O=C(Cl)Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN1CCC(OC(=O)Cc2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)N(c2nnc(C3CC3)s2)C1=O

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. α-(3,5-Dinitrophenyl)-acetyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-[α-(3,5-dinitrophenyl)acetyloxy]-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH2:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[C:20](OC)(OC)[CH:21]([CH3:23])[CH3:22]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:20]([CH:21]([CH3:23])[CH3:22])=[N:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reactant: COC(OC)(OC)C(C)C
Product: CC(C)c1nnc(C2CCN(C(=O)OC(C)(C)C)CC2)o1

Procedure:
25 g 4-hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester was refluxed with 125 mL 1,1,1-trimethoxy-2-methyl-propane overnight. The excess of reagent was removed under vacuum and the residue was purified by chromatography on silica gel to give 16 g of the desired product. 1H NMR (400 MHz, MeOD): δ 4.08-4.04 (m, 2H, CH2), 3.20-3.13 (m, 2H, 2CH), 3.01 (br, 2H, CH2), 2.07-2.03 (m, 2H, CH2), 1.75-1.68 (m, 2H, CH2), 1.46 (s, 9H, 3CH3), 1.36 (d, J=6.8 Hz, 6H, 2CH3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[C:14]([O:18][C:19]([N:21]1[CH:25]=[C:24]([CH2:26]Br)[N:23]=[CH:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH:25]=[C:24]([CH2:26][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=2)[C:3]([O:2][CH3:1])=[O:13])[N:23]=[CH:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)n1cnc(CBr)c1
Product: COC(=O)C(Cc1cn(C(=O)OC(C)(C)C)cn1)c1ccc(Cl)c(Cl)c1

Procedure:
4-[2-(3,4-Dichlorophenyl)-2-methoxycarbonyl-ethyl]-imidazole-1-carboxylic acid tert-butyl ester was prepared by the procedures described in Example 78, Step 1, substituting 3-tert-butoxycarbonylamino-propionic acid tert-butyl ester with (3,4-Dichlorophenyl)-acetic acid methyl ester and substituting 4-Bromo-1-bromomethyl-2-fluoro-benzene with 4-Bromomethyl-imidazole-1-carboxylic acid tert-butyl ester (prepared from 4(5)-hydroxymethylimidazole hydrochloride according to the literature: J. Med. Chem. 1997, 40, 2208). 1H NMR (CDCl3, 400 MHz) δ 7.96 (s, 1H), 7.42 (s, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.02 (s, 1H), 4.08 (t, J=7.6 Hz, 1H), 3.66 (s, 3H), 3.32 (dd, J=14.4 Hz, J=8.4 Hz, 1H), 2.92 (dd, J=14.4 Hz, J=6.8 Hz, 1H). LCMS (APCI+) m/z 299, 301, 303 [M-Boc+H]+; Rt=3.72 min.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][CH:11]=3)[N:6]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:5]=12.[H-].[Na+].[CH3:22][O:23][CH2:24][CH2:25][N:26]1[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[N:28]=[C:27]1S(C)(=O)=O.O>CN(C=O)C>[CH3:22][O:23][CH2:24][CH2:25][N:26]1[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[N:28]=[C:27]1[O:19][C:16]1[CH:17]=[CH:18][C:13]([N:6]2[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[N:4]3[CH:3]=[CH:2][N:1]=[C:5]23)=[CH:14][CH:15]=1
Reactant: Oc1ccc(-n2c3ncccc3n3ccnc23)cc1
Reactant: COCCn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1c(Oc2ccc(-n3c4ncccc4n4ccnc34)cc2)nc2cccnc21
Reaction time: 0.17 h

Procedure:
To a solution of 4-(9H-imidazo[1′,2′:1,2]imidazo[4,5-b]pyridin-9-yl)phenol (175 mg) obtained in Example 9, step C) in DMF (2 ml) was added sodium hydride (60% in oil, 30 mg) at room temperature by small portions. After stirring for 10 min, a solution of 3-(2-methoxyethyl)-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine[191 mg) in DMF (2 ml) was added, and the obtained mixture was stirred under microwave irradiation at 180° C. for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/THF) and recrystallized from ethanol to give the title compound (198 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]CCCC)=[O:24])=[CH:18][C:17]=3[C:30]#[N:31])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[H][H]>N.CO.[Ni]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][C:5]([CH3:34])([CH3:6])[CH3:4])=[O:24])=[CH:18][C:17]=3[CH2:30][NH2:31])=[CH:13][CH:12]=2)=[O:10])=[CH:34][CH:35]=1
Reactant: CCCCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C#N)c1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(CN)c1
Yield: 29.1 %

Procedure:
To tent-Butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)acetate (1.09 g, 2.22 mmol) in 6 ml of 7 N ammonia in methanol at ambient temperature was added Raney-Ni (0.019 g) and the reaction was stirred under a balloon of hydrogen gas at ambient temperature. The reaction was filtered and concentrated to give tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-(aminomethyl)phenyl)acetate (0.160 g, 15%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[C:16]([OH:18])=O)[CH:7]=[CH:8][CH:9]=1.Cl.[CH3:25][O:26][C:27]([C:29]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28].C(Cl)CCl>CN(C=O)C.C1C=CC2N(O)N=NC=2C=1>[CH3:25][O:26][C:27]([C:29]1([NH:36][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:13]([O:12][CH2:11][CH2:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][CH2:2][OH:1])[CH:5]=3)[CH:14]=2)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)=[O:28]
Reactant: COc1ccc(C(=O)O)cc1OCCc1cccc(CCO)c1
Reactant: COC(=O)C1(N)CCCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(CCO)c3)c2)CCCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.9 %

Procedure:
The compound of step 1 (280 mg, 0.885 mmol) was dissolved in DMF (1.3 ml) and HOBT (24 mg), 1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride (221 mg, 1.06 mmol) and EDIA (578 mg, 4.43 mmol) were added. The mixture was cooled in an ice bath and EDC (254 mg, 1.33 mmol) was added. The mixture was stirred at room temperature for 3 days and partitioned between EA and water. The aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by RP HPLC (water/ACN gradient) to yield the title compound (120 mg).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1.C1C[O:24][CH2:23][CH2:22]1>>[F:13][C:14]1[C:19]([C:23](=[O:24])[CH3:22])=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1
Reactant: Fc1cccc(F)n1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: CC(=O)c1ccc(F)nc1F
Temperature: 25 °C

Procedure:
A solution of freshly distilled diisopropylamine (14.7 mL, 104.3 mmol) in 10 mL of anhydrous THF was cooled to −78° and treated with 1.6 M solution of n-BuLi in hexanes (64.0 mL, 102.5 mmol). The resulting solution naturally warmed to −20° and was maintained at −20° for 1.5 hours. The solution was cooled to −78° and 2,6 difluoro pyridine (37-1) was added dropwise. The reaction was continued with stirring for 2 hours at −78° C. before a solution of 9.7 mL (86.9 mmol) of the Weinryb amide was added in 20 mL of THF. The resulting solution was warmed to ambient temperature overnight before quenching with a brine solution. The mixture was extracted with EtOAc (3×), and the combined organic layers were washed with H2O (1×), brine (2×), dried over MgSO4, and concentrated in vacuo. The crude product was purified via flash silica gel chromatography (0-40% EtOAc/Hexane) to yield the desired product 37-2. 1H NMR (CDCl3): 2.68 (s, 3H), 6.95 (d, 1H), 8.50 (q, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([S-:6])=[S:5])[CH3:2].[K+].Cl[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>CC(C)=O>[C:4](=[S:6])([O:3][CH2:1][CH3:2])[S:5][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CCOC(=S)[S-]
Reactant: CC(C)(C)OC(=O)CCl
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=S)SCC(=O)OC(C)(C)C
Yield: 102 %

Procedure:
Potassium ethylxanthate (58.0 g, 364 mmol) was suspended in 200 mL of dry acetone at room temperature. tert-Butyl chloroacetate (50 g, 332 mmol) was added dropwise with stirring. After 18 hrs potassium chloride was removed by fitration, and the solvent was evaporated. The residue was taken up into ether, washed with 5% NaHCO3, water, and brine, dried over MgSO4, filtered, and evaporated to leave 80 g of O-ethyl S-(tert-butoxycarbonyl)methyl dithiocarbonate as a thick oil. This oil was stirred with ethanolamine (323 mmol) for 2 hrs at room temperature. The reaction mixture was taken up into ethyl acetate, washed with 1.2N HCl, water, and brine, dried over MgSO4, filtered, and evaporated. The residue was vacuum dis-tilled to give 30 g of mercapto-acetic acid tert-butyl ester as a clear oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][CH:17]4[CH2:22][CH2:21][CH2:20][N:19]([C:23]5[N:28]=[CH:27][C:26]([C:29]6[CH:33]=[CH:32][N:31]([CH2:34][CH2:35][O:36]C7CCCCO7)[N:30]=6)=[CH:25][N:24]=5)[CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.O1CCOCC1.[ClH:49]>C(Cl)Cl>[ClH:49].[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][CH:17]4[CH2:22][CH2:21][CH2:20][N:19]([C:23]5[N:24]=[CH:25][C:26]([C:29]6[CH:33]=[CH:32][N:31]([CH2:34][CH2:35][OH:36])[N:30]=6)=[CH:27][N:28]=5)[CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(-c6ccn(CCOC7CCCCO7)n6)cn5)C4)c3n2)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(-c6ccn(CCO)n6)cn5)C4)c3n2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
6-(1-methyl-1H-pyrazol-4-yl)-1-((1-(5-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-3-yl)pyrimidin-2-yl)piperidin-3-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (28 mg, 0.049 mmol) was dissolved in CH2Cl2 (5 ml), and then 4 N HCl dioxane (1 ml) was added, followed by stirring at room temperature for 1 hour. After the reaction was completed, the reaction mixture was purified with ether to give 2-(3-(2-(3-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanolhydrochloride (21.5 mg, 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3=[N:19][N:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=[C:11]3[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:37][C:38]1[CH:46]=[C:45]([Cl:47])[CH:44]=[CH:43][C:39]=1[C:40](Cl)=[O:41]>C(Cl)Cl>[Cl:37][C:38]1[CH:46]=[C:45]([Cl:47])[CH:44]=[CH:43][C:39]=1[C:40]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3=[N:19][N:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=[C:11]3[CH2:10][CH2:9]2)=[O:7])=[CH:28][CH:29]=1)=[O:41]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)Cn1cc2c(n1)-c1ccccc1N(C(=O)c1ccc(N)cc1)CC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cn1cc2c(n1)-c1ccccc1N(C(=O)c1ccc(NC(=O)c3ccc(Cl)cc3Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 0.940 g of ethyl 6-(4-aminobenzoyl)-5,6-dihydropyrazolo[4,3-d] [1]benzazepine-2(4H)-acetate in 25 ml of methylene chloride is added 369 μl of triethylamine followed by the dropwise addition of 373 μl of 2,4-dichlorobenzoyl chloride in 3.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours, washed with water, saturated NaHCO3, brine and the organic layer treated with activated carbon, and filtered through MgSO4. The filtrate is concentrated in vacuo to a residue which is purified by flash chromatography on silica gel using 25% ethyl acetate in methylene chloride to give 380 mg of the desired product as white crystals, m.p. 164°-167° C. The mother liquors are combined, evaporated in vacuo to a residue which is dissolved in 25% ethyl acetate in chloroform to give 535 mg of off-white solid, m.p. 160°-163.5° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][C@H:9]([CH3:11])[CH2:8][CH2:7][C@H:6]1[C:12]([OH:14])=O)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[C:1]([O:4][CH:5]1[CH2:10][CH:9]([CH3:11])[CH2:8][CH2:7][CH:6]1[C:12]([Cl:18])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@H](C)CC[C@H]1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)OC1CC(C)CCC1C(=O)Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (1R, 2S, 4R)-2-Acetoxy-4-methyl-cyclohexanecarboxylic acid (109 mg, 0.54 mmol) in dichloromethane (2.7 ml) was added oxalyl chloride (545 ul, 1.09 mmol) followed by 1 drop of dimethylformamide. The reaction mixture was stirred for 4 h at room temperature. The solvents were then removed to obtain 119 mg (99%) of (1R*, 2S*, 4R*)-2-Acetoxy-4-methyl-cyclohexanecarboxylic acid chloride. NMR 1H (CDCl3, 400 MHz): 5.45 ppm (s, 1H); 2.46-2.42 ppm (m, 1H); 2.02 ppm (s, 3H); 2.02-1.96 ppm (m, 1H); 1.91-1.76 ppm (m, 3H); 1.70-1.61 ppm (m, 1H); 1.16-1.08 ppm (m, 1H); 0.99-0.88 ppm (m, 1H); 0.87 ppm (d, 3H).