Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:6])[C:3]([OH:5])=[O:4].ClC(OCC(C)C)=O.C(N(CC)CC)C.[NH2:22][CH:23]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1)[C:24]([N:26]1[CH2:31][CH2:30][N:29]2[CH2:32][C@H:33]([O:35][C:36]3[CH:41]=[N:40][C:39]([CH:42]4[CH2:44][CH2:43]4)=[CH:38][N:37]=3)[CH2:34][C@H:28]2[CH2:27]1)=[O:25]>ClCCl>[CH:42]1([C:39]2[N:40]=[CH:41][C:36]([O:35][C@H:33]3[CH2:32][N:29]4[CH2:30][CH2:31][N:26]([C:24](=[O:25])[CH:23]([NH:22][C:3](=[O:4])[CH:2]([F:6])[F:1])[C:45]5[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=5)[CH2:27][C@@H:28]4[CH2:34]3)=[N:37][CH:38]=2)[CH2:43][CH2:44]1.[F:1][C:2]([F:52])([F:6])[C:3]([OH:5])=[O:4]
Reactant: O=C(O)C(F)F
Reactant: NC(C(=O)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1)c1cccc(C(F)(F)F)c1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC(C(=O)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1)c1cccc(C(F)(F)F)c1)C(F)F
Product: O=C(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 458.4 %

Procedure:
A solution of 2,2-difluoroacetic acid (0.0083 mL, 0.131 mmol) in anhydrous dichloromethane (1 mL) at 0° C. under N2 was treated with isobutyl chloroformate (0.014 mL, 0.105 mmol) and triethylamine (0.025 mL). The resulting mixture was stirred at 0° C. for 40 minutes, and the product from Example 200 (50 mg, 0.088 mmol) was added, followed by triethylamine (0.060 mL). The resulting mixture was stirred at room temperature for 90 minutes and partitioned between water and dichloromethane (3×). The combined organic layers were concentrated in vacuo, and the crude product was purified by column chromatography on C18 silica gel using a solvent gradient of 0-100% acetonitrile in water (0.1% trifluoroacetic acid). The title compound was obtained as a trifluoroacetic acid salt (23 mg). 1H NMR (300 MHz, CDCl3) δ ppm 0.89-1.06 (m, 4 H) 1.92-4.89 (m, 14 H) 5.38-5.56 (m, 1 H) 5.70-5.89 (m, 1 H) 7.46-7.76 (m, 4 H) 7.86-8.10 (m, 2 H); MS (ESI) m/z 540 (M+H)+.
Reaction SMILES: C1N2CN3CN(C2)C[N:2]1C3.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:14].C(Cl)[Cl:25]>>[ClH:25].[NH2:2][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:14]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: ClCCl
Reactant: C1N2CN3CN1CN(C2)C3
Product: Cl
Product: NCC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 72 %

Procedure:
Hexamethylenetetramine (20.1 g) was added to a solution of 2-bromo-1-(4-nitrophenyl)ethanone (step A product, 25 g) in DCM (250 ml) and the mixture was stirred for 1 hour. It was then filtered and the residue was dissolved in ethanolic HCl (40 mL HCl in 162 ml EtOH). The ethanolic solution was stirred for 3 hours and was left undisturbed for 2 days. The solution was filtered and the residue was washed with water and dried to yield 11.8 g (72%) of the title compound. 1HNMR (DMSO-d6, 300 MHz): δ 8.3 (bs, 3H), 8.38 (d, 2H), 8.27 (d, 2H), 4.68 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:22]=[C:21]([NH:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH:20]=[CH:19][N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: CC(C)(CO)Nc1ccnc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(Nc2nccc(NC(C)(C)CO)n2)ccc1-n1cnc(C)c1
Yield: 62 %

Procedure:
Prepared in analogy to example 81b) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2-(2-chloro-pyrimidin-4-ylamino)-2-methyl-propan-1-ol, using potassium carbonate as a base. The title compound was isolated as a slightly orange solid in a yield of 62%. MS ISP (m/e): 369.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=7.91 (d, 1H), 7.62 (d, 1H), 7.43 (d, 1H), 7.20-7.10 (m, 2H), 6.87 (s, 1H), 6.79 (s, 1H), 5.88 (d, 1H), 4.74 (s, 1H), 3.84 (s, 3H), 3.69 (s, 2H), 2.29 (s, 3H), 1.42 (s, 6H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][CH:3]=1.N1([C:20]2[CH:21]=[C:22]([NH:26][C:27]([C:29]3[CH:30]=[C:31](C4C=CC(C5N=C(C)ON=5)=CC=4C)[C:32]([CH3:35])=[CH:33][CH:34]=3)=[O:28])[CH:23]=[CH:24][CH:25]=2)CCOCC1.C[CH:50]([OH:52])C>>[CH3:50][O:52][C:20]1[CH:21]=[C:22]([NH:26][C:27]([C:29]2[CH:34]=[C:33]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)=[CH:4][CH:3]=3)[C:32]([CH3:35])=[CH:31][CH:30]=2)=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)O
Reactant: Cc1nc(-c2ccc(-c3cc(C(=O)Nc4cccc(N5CCOCC5)c4)ccc3C)c(C)c2)no1
Reactant: Cc1nnc(-c2ccc(I)cc2)o1
Product: COc1cccc(NC(=O)c2ccc(C)c(-c3ccc(-c4nnc(C)o4)cc3)c2)c1

Procedure:
Example 37 was prepared using 2-(4iodophenyl)-5-methyl-[1,3,4]oxadiazole (Intermediate 15) and N-3-methoxy-phenyl)-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 6) with propan-2-ol as the solvent.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][N:7]=[C:6](SC)[C:5]=2[N:4]=[CH:3]1.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17]>>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:6]1[C:5]2[N:4]=[CH:3][N:2]([CH3:1])[C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: CSc1nccc2c1ncn2C
Reactant: NCc1ccccc1Cl
Product: Cn1cnc2c(NCc3ccccc3Cl)nccc21

Procedure:
A mixture of 17.9 of 1-methyl-4-methylthio-1H-imidazo(4,5-c)pyridine (m.p. 170°-175°) and 28 g of o-chlorobenzylamine is heated to 170°-180° for 20 hours. After cooling and customary working up, 4-o-chlorobenzylamino-1-methyl-1H-imidazo(4,5-c)pyridine of m.p. 173°-176° is obtained.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[C:21]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=4)=[N:20]3)[CH2:15][CH2:14]2)=[O:12])[CH:6]=1)(=O)C.[OH-].[Na+].Cl>C1COCC1.CC(C)=O.CO>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([C:21]2[C:22]([CH3:26])([CH3:25])[C:23](=[O:24])[N:19]([CH:16]3[CH2:17][CH2:18][N:13]([C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([OH:4])[CH:6]=4)=[O:12])[CH2:14][CH2:15]3)[N:20]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH3:34]
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc(OC(C)=O)c4)CC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc(O)c4)CC3)C(=O)C2(C)C)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 g 3-({4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}carbonyl)phenyl acetate (compound described in example 12) are dissolved in a mixture of 200 ml THF, 100 ml acetone and 200 ml of methanol. To this mixture 200 ml of 2 M methanolic sodium hydroxide solution are added, and the reaction mixture is stirred at RT for 1 h until the reaction is completed according to TLC analysis. The reaction mixture is acidified with concentrated aqueous hydrochloric acid, and the solvents are largely removed under reduced pressure, while the crude product is precipitating. The solids are collected and washed with water to yield the title compound.
Reaction SMILES: [F:1][CH:2]([F:32])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([O:12][C:13]1[CH:17]=[C:16]([N:18]2[C:26]3[CH:25]=[C:24]([CH2:27][OH:28])[N:23]=[CH:22][C:21]=3[N:20]=[CH:19]2)[S:15][C:14]=1[C:29]([NH2:31])=[O:30])[CH3:11].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>ClCCl>[CH3:33][S:34]([O:28][CH2:27][C:24]1[N:23]=[CH:22][C:21]2[N:20]=[CH:19][N:18]([C:16]3[S:15][C:14]([C:29](=[O:30])[NH2:31])=[C:13]([O:12][CH:10]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[O:3][CH:2]([F:1])[F:32])[CH3:11])[CH:17]=3)[C:26]=2[CH:25]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: CC(Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1OC(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1OC(F)F

Procedure:
In a similar manner as described for example 49 (step 1), 115 mg of 3-{(1-[2-(difluoromethoxy)phenyl]ethoxy}-5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxamide, 57 mg of methanesulfonyl chloride, and 51 mg of triethylamine in 3 ml dichloromethane give [1-(5-carbamoyl-4-{1-[2-(difluoromethoxy)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate as crude material that is used for step 2 without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)=[O:7].[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[O:7]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)[CH2:5][CH2:4][CH2:3][CH2:2][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1
Reactant: O=C(CCCCCl)c1ccc(C(F)(F)F)cc1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-[4-(trifluoromethyl)phenyl]-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 461.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][C:4]=1[O:18][CH3:19].O.[C-:21]#[N:22].[Na+]>CN(C)C=O>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:21]#[N:22])=[C:4]([O:18][CH3:19])[CH:5]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-c2nc3ccccc3o2)ccc1CC#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (318 mg, 1 mmol), dimethylformamide (7.5 mL) and deionzed water (2.5 mL) was stirred at rt. Sodium cyanide (150 mg, 3.0 mmol) was added to reaction. After 3 h, dimethylformamide (10 mL) was added to help dissolve solids in reaction mixture. Let reaction mixture stir overnight at rt. Workup was done by washing reaction with brine (3×30 mL), extraction with EtOAc, combined organic extracts, dried (Na2SO4), filtered and removed solvent in vacuo. Flash chromatography of resulting orange solid on silica gel using a gradient elution of 1:9 EtOAc:hexanes to 1:3 EtOAc:hexanes afforded the desired intermediate, [4-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]acetonitrile as a yellow solid. 1H NMR(CDCl3, 300 MHz) δ 7.86–7.36 (m, 7H), 3.99 (s, 3H), 3.74 (s, 2H), 2.59–1.91 (m, 8H). MS (ESI) 265 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([O:18]C)[N:8]2[CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:4]([NH2:20])[N:3]=1.[NH2:21][CH:22]([CH2:24][CH2:25][CH3:26])[CH3:23]>C(O)CO.CCOC(C)=O.C(Cl)Cl>[NH2:20][C:4]1[N:3]=[C:2]([NH:21][CH:22]([CH3:23])[CH2:24][CH2:25][CH3:26])[N:10]=[C:9]2[C:5]=1[NH:6][C:7](=[O:18])[N:8]2[CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COc1nc2c(N)nc(Cl)nc2n1CC1CCOCC1
Reactant: CCCC(C)N
Solvent: ClCCl
Solvent: OCCO
Solvent: CCOC(C)=O
Product: CCCC(C)Nc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 170 °C

Procedure:
To a solution of 2-chloro-8-methoxy-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (40 mg) in ethylene glycol (1.5 mL) was added 2-aminopentane (0.16 mL) and the mixture was heated in a microwave at 170° C. for 2×30 mins. A further portion of 2-aminopentane (0.08 mL) was added and the reaction was heated in a microwave at 180° C. for 30 mins. The mixture was taken up in EtOAc (15 mL) and was washed with water (3×15 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to give a brown residue. This was taken up in DCM and concentrated in a vacuum oven to give the title compound as a brown solid (18 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:19]=[C:20]=S.[NH2:22][C:23]1[C:38]([NH2:39])=[CH:37][C:26]([C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=2)=[O:28])=[C:25]([O:40][CH3:41])[CH:24]=1.CC(C)N=C=NC(C)C>CN(C=O)C>[Br:36][C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:27]([C:26]2[C:25]([O:40][CH3:41])=[CH:24][C:23]3[NH:22][C:20]([NH:19][C:3]4[CH:4]=[C:5]([CH2:6][NH:7][C:8]([C:10]5([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]5)=[O:9])[CH:17]=[CH:18][C:2]=4[Cl:1])=[N:39][C:38]=3[CH:37]=2)=[O:28])=[CH:35][CH:34]=1
Reactant: COc1cc(N)c(N)cc1C(=O)Nc1ccc(Br)cc1
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COc1cc2[nH]c(Nc3cc(CNC(=O)C4(C(F)(F)F)CC4)ccc3Cl)nc2cc1C(=O)Nc1ccc(Br)cc1

Procedure:
The title compound was prepared in accordance with the procedure in Example 72, step (a) using N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide ((200 mg; 0.60 mmol) see Example 59, step (c)), 4,5-diamino-N-(4-bromophenyl)-2-methoxybenzamide (202 mg; 0.60 mmol), DIC (76 mg; 0.60 mmol) and DMF (4 mL). Yield: 63 mg (16%). 400 MHz 1H-NMR (DMSO-d6, ppm) 11.12 (0.36H, s, minor tautomer) 11.00 (0.57H, s, major tautomer) 10.22-10.14 (1H, m) 8.94 (0.57H, s, major tautomer) 8.76 (0.36H, s, minor tautomer) 8.61-8.52 (1H, m) 8.48-8.41 (1H, m) 7.86-7.69 (3H, m) 7.53-7.45 (2H, m) 7.42-7.35 (1H, m) 7.21 (0.38H, s, minor tautomer) 7.10 (0.59H, s, major tautomer) 6.87-6.79 (1H, m) 4.29 (2H, d, J=5.8 Hz) 3.93 (3H, s) 1.49-1.39 (2H, m) 1.28-1.23 (2H, m). MS m/z: 636, 638, 640 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:6][C:7](=[O:24])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][CH:20]=[N:19][CH:18]=2)=[C:13]([O:22][CH3:23])[CH:12]=1)=[O:9])([CH3:5])[CH3:4].[CH3:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.ClCCl>[CH3:23][O:22][C:13]1[CH:12]=[C:11]([NH:10][C:8](=[O:9])[C:7]([NH:6][C:3]([CH3:5])([CH3:4])[CH2:2][NH:1][CH2:25][C:26]2[CH:33]=[CH:32][C:29]([CH3:30])=[CH:28][CH:27]=2)=[O:24])[CH:16]=[CH:15][C:14]=1[C:17]1[O:21][CH:20]=[N:19][CH:18]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: COc1cc(NC(=O)C(=O)NC(C)(C)CN)ccc1-c1cnco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(NC(=O)C(=O)NC(C)(C)CNCc2ccc(C)cc2)ccc1-c1cnco1

Procedure:
30 mg (0.09 mmol) of N-(2-amino-1,1-dimethyl-ethyl)-N′-(3-methoxy-4-oxazol-5-yl-phenyl)-oxalamide, 11.3 mg (0.095 mmol) of 4-methylbenzaldehyde and 30 mg (0.14 mmol) of sodium triacetoxyborohydride were dissolved in 2 ml of a 5% acetic acid dichloromethane mixture for 16 hours. The reaction mixture was then diluted with 8 ml of dichloromethane and washed with water, saturated sodium hydrogen carbonate and brine. The resulting organic solution was then dried with magnesium sulphate, filtered and evaporated to give N-[3-methoxy-4-(5-oxazolyl)phenyl-N′-[2-(4-methylbenzylamino)-1,1-dimethylethyl]oxalamide as a yellow solid MS: m/e 437.3 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:23]=1)[C:11](ON1C(=O)CCC1=O)=[O:12].Cl.[NH2:32][CH2:33][C@@H:34]([C:57]([O:59][CH3:60])=[O:58])[NH:35][C:36](=[O:56])[C:37]1[C:42]([Cl:43])=[CH:41][C:40]([C:44]([NH:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([OH:54])[CH:49]=2)=[O:45])=[CH:39][C:38]=1[Cl:55].C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:23]=1)[C:11]([NH:32][CH2:33][C@@H:34]([C:57]([O:59][CH3:60])=[O:58])[NH:35][C:36](=[O:56])[C:37]1[C:42]([Cl:43])=[CH:41][C:40]([C:44]([NH:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([OH:54])[CH:49]=2)=[O:45])=[CH:39][C:38]=1[Cl:55])=[O:12]
Reactant: O=C(ON1C(=O)CCC1=O)c1cc(OC2CCCCO2)cc(OC2CCCCO2)c1
Reactant: COC(=O)[C@H](CN)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CNC(=O)c1cc(OC2CCCCO2)cc(OC2CCCCO2)c1)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Yield: 51.5 %

Procedure:
A solution of 1-[[3,5-bis[(tetrahydro-2H-pyran-2-yl)oxy]benzoyl]oxy]-2,5-pyrrolidinedione (2.10 g, 5.0 mmol), 3-amino-N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine, methyl ester hydrochloride (Example 75; 2.00 g, 4.2 mmol), and triethylamine (500 mg, 4.9 mmol) in N,N-dimethylformamide (20 Ml) was stirred at room temperature overnight. The solvent was evaporated and ethyl acetate (125 mmol) was added. The solution was washed with 0.2 M HCl (125 Ml) and the aqueous wash was back-extracted with ethyl acetate (100 Ml). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate and brine (30 Ml each), evaporated, and chromatographed (50–100% ethyl acetate/hexanes) to give 3-[[3,5-bis[(tetrahydro-2H-pyran-2-yl)oxy]benzoyl]amino]-N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]-carbonyl]benzoyl]-L-alanine, methyl ester (1.61 g, 52%) as a white foam.
Reaction SMILES: [ClH:1].[CH2:2]([C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1)[CH2:3][CH2:4][C:5]#[CH:6].[N:13]([CH2:16][CH2:17][C:18]1[CH:22]=[CH:21][S:20][CH:19]=1)=[N+:14]=[N-:15]>>[ClH:1].[S:20]1[CH:21]=[CH:22][C:18]([CH2:17][CH2:16][N:13]2[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:7]3[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=3)[N:15]=[N:14]2)=[CH:19]1
Reactant: C#CCCCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCCc1ccsc1
Agent: Cl
Product: Nc1nc(CCCc2cn(CCc3ccsc3)nn2)c[nH]1
Yield: 40.8 %

Procedure:
4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.090 g, 0.485 mmol) was reacted with 3-(2-Azido-ethyl)-thiophene (0.089 g, 0.581 mmol) following the general procedure for click reactions outlined above to produce 4-{3-[1-(2-Thiophen-3-yl-ethyl)-1H-[1,2,3]triazol-4-yl]-propyl}-1H-imidazol-2-ylamine hydrochloride (0.067 g, 41%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.42 (s, 1H), δ 7.12 (d, 1H), δ 6.83 (s, 1H), δ 6.70 (d, 1H), δ 6.29 (s, 1H), δ 4.41 (t, 2H), δ 3.04 (t, 2H), δ 2.50 (t, 2H), δ 2.29 (t, 2H), δ 1.72 (m, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 146.8, 146.8, 137.7, 127.8, 127.6, 125.7, 122.6, 121.9, 109.0, 50.7, 30.7, 27.9, 23.7 ppm; HRMS (ESI) calcd for C14H18N6S (M+) 302.1313. Found 302.1317.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=O)[CH:3]=[N:2]1.[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][NH2:17])[CH3:13].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][NH:17][CH2:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][N:2]=[CH:3]2)[CH3:13]
Reactant: CCOC(CN)OCC
Reactant: O=Cc1cccc2cn[nH]c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(CNCc1cccc2cn[nH]c12)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1H-Indazole-7-carbaldehyde (1.75 g, 12 mmol) in MeOH (50 mL) was added aminoacetaldehyde diethyl acetal (1.74 mL, 12 mmol) and acetic acid (1.03 mL, 18 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was added to a stirred solution of sodium cyanoborohydride (816 mg, 13 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. Then H2O and ethyl acetate were added to the reaction mixture. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was used next step without further purification.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:13]([C:14](Cl)=[O:15])=[CH:12][C:11]([CH3:17])=[N:10]1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)C>[C:18]([O:22][C:23]([N:25]1[CH2:26][CH2:27][CH:28]([N:31]([C:14]([C:13]2[N:9]([CH3:8])[N:10]=[C:11]([CH3:17])[CH:12]=2)=[O:15])[CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:30]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1cc(C(=O)N(CC(C)C)C2CCN(C(=O)OC(C)(C)C)CC2)n(C)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.9 %

Procedure:
Triethylamine (1.8 ml, 12.8 mmol) and 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (0.5 g, 3.2 mmol) is added to a stirred solution of 4-isobutylamino-piperidine-1-carboxylic acid tert-butyl ester (0.82 g, 3.2 mmol), and diethyl ether (30 ml). The reaction is stirred for 5 minutes at room temperature. The reaction is poured into 5% citric acid and extracted with ethyl acetate. The ethyl acetate is washed with sodium bicarbonate and brine and dried over sodium sulfate. The sodium sulfate is filtered off and the crude product is concentrated on a rotary evaporator to yield (1.15 g, 96% crude) of 4-{[(1,3-dimethyl-1H-pyrazol-5-yl)-carbonyl]-isobutyl-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=379 (M++1); 1H NMR (CD3OD) (broad peaks due to rotamers) δ=6.29-6.17 (1H, br m), 4.23-4.10 (2H, br m), 3.98-3.90 (1H, br m), 3.78 (3H, br s), 3.25 (2H, d), 2.89-2.57 (2H, br m), 2.25 (3H, s), 2.20-2.04 (1H, br m), 1.86-1.70 (3H, br m), 1.46 (9H, s), 1.00-0.74 (6H, br m).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C@H:19]([C@@H:22]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C@H:23]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:24]([OH:34])[CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:20][OH:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[CH2:11]([O:18][C@H:19]([C@@H:22]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C@H:23]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:24](=[O:34])[CH2:25][O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH:20]=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)C(=O)COCc1ccccc1
Temperature: -5 °C
Reaction time: 0.67 h
Yield: 90 %

Procedure:
To a stirred solution of oxalyl chloride (12.8 mL, 147.7 mmol) in DCM (150 mL) was added drop wise a solution of DMSO (13.1 mL) in DCM (90 mL) over 10 min at −78° C. and then the reaction mixture was stirred at same temperature for 40 min. Then a solution of (2S,3R,4R,5R)-2,3,4,6-tetrakis(benzyloxy)hexane-1,5-diol 2 in DCM (75 mL) was added drop wise to the reaction mixture over a period of 15 min keeping the reaction mixture below −70° C. After stifling the reaction mixture for 2 h at below −70° C., Et3N (62.15 mL, 443 mmol) was added drop wise over a period of 10 min and then the reaction mixture was allowed to warm to −5° C. over a period of 2 h. The reaction mixture was concentrated under reduced keeping the temperature below 25° C. to afford crude (2R,3R,4S)-2,3,4,6-tetrakis(benzyloxy)-5-oxohexanal 3 (18 g, 90%) as sticky yellowish oil which was used for the next step without any purification.