Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[C:10](O)(=O)/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>O>[CH3:9][C:3]1[C:2]2[N:1]=[C:10](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc(N)c1N
Reactant: O=C(O)/C=C/c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc2[nH]c(/C=C/c3ccccc3)nc12
Temperature: 180 °C
Yield: 13 %

Procedure:
A mixture of 2,3-diaminotoluene (2.44 g, 20 mmol), (E)-cinnamic acid (2.96 g, 20 mmol) and polyphosphoric acid (10 g) was heated to 180° C. for 90 min. The hot mixture was poured into water (100 ml), basified with 50% aqueous solution of sodium hydroxide and extracted with dichloromethane (3×100 ml). The combined extracts were washed with water (100 ml) and brine (100 ml), dried (magnesium sulfate) and concentrated to dryness. Purification by column chromatography (silica gel, 300 g; n-hexane/ethyl acetate (7/3)) yielded 0.61 g (13%) of the titled compound as red solids. 1H-NMR (CDCl3) δ: 9.53 (1H, br.s), 8.72-8.67 (1H, m), 7.95 (1H ddd, J=7.7, 7.7, 1.8 Hz), 7.60-7.49 (3H, m), 7.43-7.31 (3H, m), 7.23-7.14 (3H, m), 7.09-7.04 (1H, m), 2.63 (3H, br.s)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[S:13](C#N)[C:14]#[N:15].[Na].[Br-].[Na+].BrBr>CO>[C:1]([C:5]1[C:6]([S:13][C:14]#[N:15])=[CH:7][C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CSC#N
Reactant: Cc1ccc(C(C)(C)C)cc1O
Agent: BrBr
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(SC#N)c(C(C)(C)C)cc1O
Temperature: 40 °C
Reaction time: 17 h

Procedure:
In a 5 L flask were placed 350 g (2.13 mol) of 5-tert-butyl-2-methyl-phenol, sodium thiocyanide (555 g, 6.85 mol) and MeOH (1400 mL), and the resulting mixture cooled to 7° C. A solution of sodium bromide (214 g, 2.08 mol), bromine (126 mL, 2.38 mol), and MeOH (1800 mL) was added slowly and the temperature raised to 40° C. over a period of 30 minutes. The precipitants were filtered and the filtrate concentrated by half. Saturated sodium carbonate (3.5 L) and H2O (4.5 L) were added. The mixture was extracted with EtOAc (3 L), and the organic layers were combined and concentrated. To this residue were added t-butylmethyl ether (500 mL) and hexanes (500 mL), and the mixture was allowed to stand for 17 hours at -5° C. The precipitants were filtered to give the title compound, m.p. 99-102° C. 1H NMR (CDCl3) δ 1.46 (s, 9 H), 2.22 (s, 3 H), 5.01 (s, 1 H), 6.89 (s, 1 H), 7.49 (s, 1 H).
Reaction SMILES: C[O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[N:17]3[N:18]=[C:19]([NH2:21])[N:20]=[C:16]3[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=2)=[CH:5][CH:4]=1.COC1C=C(C=C(OC)C=1)CC1N2N=C(N)N=C2C2C=CC=CC=2N=1>>[NH2:21][C:19]1[N:20]=[C:16]2[N:17]([C:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:23][CH:22]=3)=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)[N:18]=1
Reactant: COc1ccc(Cc2nc3ccccc3c3nc(N)nn23)cc1
Agent: COc1cc(Cc2nc3ccccc3c3nc(N)nn23)cc(OC)c1
Product: Nc1nc2c3ccccc3nc(Cc3ccc(O)cc3)n2n1
Yield: 71 %

Procedure:
Operating as in Example 39, but employing 5-(4-methoxy-benzyl)-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine, prepared as described in Example 3, instead of 5-(3,5-dimethoxy-benzyl)-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine, the title compound was obtained in 71% yield.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[C:16]([Cl:18])[N:15]=[C:14]2[C:10]=1[NH:11][CH:12]=[N:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:25](Br)([CH3:27])[CH3:26]>CS(C)=O>[CH2:1]([NH:8][C:9]1[N:17]=[C:16]([Cl:18])[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:25]([CH3:27])[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(NCc2ccccc2)c2[nH]cnc2n1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)n1cnc2c(NCc3ccccc3)nc(Cl)nc21
Reaction time: 8 h
Yield: 85.1 %

Procedure:
A mixture of 6-benzylamino-2-chloropurine (1) 1.32 g, 5.08 mmol), potassium carbonate (4.3 g, 31 mmol) and isopropylbromide (5.5 ml, 58 mmol) in 35 ml of dry dimethyl sulfoxide was vigorously shaken overnight. The reaction mixture was evaporated in vacuum and then partitioned between water and ethylacetate. The organic layer was dried (sodium sulfate) and evaporated. Crystallization from methanol afforded 1.305 g (85%) of product 2, m.p. 181-182° C. For C15H16N5Cl(301.78) calculated: 59.70% C, 5.34% H, 23.21% N, 11.75% Cl; found: 59.52% C, 5.36% H, 23.01% N. FTIR spectrum (cm−1): 1713, 1626, 1572, 1537, 1497, 1471, 1456, 1425, 1398, 1355, 1314, 1292, 1255, 1228, 1202. ′H NMR (400 MHz, (CH3)2SO): 1.48D (6H, J=6.8, (CH3)2CH); 4.57 m (1H, CH(CH3)2); 4.66bd (2H, J=6.1, CH2); 7.19 ft, (1 H, J=7.2, J=1.7, H-p); 7.27dd (2H, J=7.2, H-m); 7.34dd (2H, J=7.2, J=1.7, H-o); 7.69s (1 H, H-C8).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:55])[C:19]([C:30]3[N:31]=[C:32]([NH:35]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:33][CH:34]=3)=[N:20][O:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:23])[C:15](=[O:56])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C(NCC)C>C(O)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:55])[C:19]([C:30]3[N:31]=[C:32]([NH2:35])[S:33][CH:34]=3)=[N:20][O:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:23])[C:15](=[O:56])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC(=O)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: O=CO
Solvent: CCNCC
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC(=O)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Temperature: 45 °C
Reaction time: 0.17 h

Procedure:
A mixture of 0.27 g of the product of Step A and 2 ml of 50% aqueous formic acid was stirred at 45° C. for 10 minutes and was thn evaporated to dryness. The residue was triturated with ether and 1.55 g of raw product were recovered which was dissolved in 0.5 ml of methanol. 5 ml of ether were added thereto to recover 0.14 g of the syn isomer of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl-2-(phenylcarbonyloxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([NH:12][C:13](=[O:15])C)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[OH-:19].[NH4+]>>[C:7]([O:15][C:13](=[O:19])[NH:12][C:5]1[CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]([Cl:1])=[CH:3][C:4]=1[N+:16]([O-:18])=[O:17])([CH3:8])([CH3:2])[CH3:6]
Reactant: [OH-]
Reactant: CC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1[N+](=O)[O-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1[N+](=O)[O-]

Procedure:
Reaction of N-(4-chloro-2-nitro-5-trifluoromethyl-phenyl)-acetamide [CAS 157554-77-3] (4.02 g, 14.2 mmol) with Boc-anhydride (3.26 g, 14.9 mmol) according to the general procedure A (method c) and subsequent reaction with ammonium hydroxide (25%; 4.38 ml, 28.4 mmol) gave after aqueous work up and purification by column chromatography on silica gel (hexane/ethyl acetate 4:1) (4-chloro-2-nitro-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (3.39 g, 70%) as an orange oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([Mg]Br)#[CH:15]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:14]#[CH:15])([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Solvent: C1CCOC1
Product: C#CC1(O)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure A. In a solution of 3-Oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3.0 g, 16.2 mmol) in tetrahydrofuran (40 mL) was dropped in ethynyl magnesium bromide (70 mL, 35 mmol) at −78° C. Then the solution was stirred overnight at room temperature. Then the reaction mixture was quenched with saturated NH4Cl and extracted with dichloromethane, dried with anhydrous sodium sulfate to afford 3-Ethynyl-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g, 44%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:6]=1[NH:19][C:20]([C:22]1[C:31](=[O:32])[C:30]([CH2:36][CH2:37][CH3:38])([CH2:33][CH2:34][CH3:35])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]=1[OH:39])=O)(=[O:4])=[O:3].N12CCCN=C1CCCCC2>N1C=CC=CC=1>[CH2:12]([O:11][C:9]1[CH:8]=[CH:7][C:6]2[NH:19][C:20]([C:22]3[C:31](=[O:32])[C:30]([CH2:33][CH2:34][CH3:35])([CH2:36][CH2:37][CH3:38])[C:29]4[C:24]([C:23]=3[OH:39])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[N:1][S:2](=[O:4])(=[O:3])[C:5]=2[CH:10]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCC1(CCC)C(=O)C(C(=O)Nc2ccc(OCc3ccccc3)cc2S(N)(=O)=O)=C(O)c2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)=C(O)c2ccccc21
Temperature: 140 °C
Reaction time: 18 h
Yield: 37.9 %

Procedure:
A solution of the compound of Example 2E (300 mg, 0.547 mmol) in anhydrous pyridine (5.2 mL) was treated with 1,8 diazabicyclo[5.4.0]undec-7-ene (82 μL, 0.55 mmol) and stirred at 140° C. for 18 hours, cooled to 25° C. and the pyridine removed by short path distillation under high vacuum (50° C./0.3 mm Hg). A solution of the residue in ethyl acetate was washed with water (2×) and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with ethyl acetate in hexane to give the title compound (110 mg, 38%). 1H NMR (300 MHz, DMSO-d6): δ 8.11 (d, J=7.72 Hz, 1 H), 7.64 (m, 1 H), 7.41 (m, 8 H), 5.21 (s, 2 H), 2.14 (m, 2 H), 1.83 (m, 2 H), 0.87 (m, 2 H), 0.64 (m, 8 H).
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[NH:26][C:27]1[S:28][C:29]2[CH:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:30]=2[N:31]=1>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[NH:26][C:27]1[S:28][C:29]2[CH:35]=[C:34]([NH:36][C:1](=[O:10])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[O:8][CH3:9])[CH:33]=[CH:32][C:30]=2[N:31]=1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Reactant: COc1ccccc1C(=O)Cl
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)c5ccccc5OC)cc4s3)c2cc1OC

Procedure:
N-[2-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl]-2-methoxybenzamide was prepared from o-anisoyl chloride (17 μL, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 2 (yellowish solid, 42 mg, 86 μmol, 76%). LC/ESI-MS: m/z=488 [M+H]+; m/z=486 [M−H]−; Rt=3.27 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:24]O)=[N:21][C:22]=3[CH3:23])[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:51]1[CH2:54][CH:53]([C:55]([O:57][CH3:58])=[O:56])[CH2:52]1.C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:24][N:51]4[CH2:54][CH:53]([C:55]([O:57][CH3:58])=[O:56])[CH2:52]4)=[N:21][C:22]=3[CH3:23])[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: COC(=O)C1CNC1
Reactant: Cc1nc(CO)ccc1-c1noc(-c2ccc(CC(C)C)c(Cl)c2)n1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2ccc(-c3noc(-c4ccc(CC(C)C)c(Cl)c4)n3)c(C)n2)C1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 23 (23g) using {5-[5-(3-chloro-4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-6-methylpyridin-2-yl}methanol (0.15 g, 0.42 mmol) that was obtained in Example 24 (24i), carbon tetrabromide (0.22 g, 0.67 mmol), triphenylphosphine (0.18 g, 0.67 mmol), methyl 3-azetidinecarboxylate hydrochloride (96 mg, 0.63 mmol), and N,N-diisopropylethylamine (0.22 ml, 1.3 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1 to 2:1 or 3:1) as the eluent to afford the title compound (0.11 g) in a yield of 58% as a pale yellowish oily product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6](Cl)=[O:7])=[CH:2]1.[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10]>C(Cl)Cl>[CH2:9]([N:11]([CH2:12][CH3:13])[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:7])[CH3:10]
Reactant: O=C(Cl)c1ccsc1
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
Thiophene-3-carbonyl chloride was dissolved in methylene chloride (100 mL) and added to a mixture of diethylamine (43.8 g, 0.6 mol) and methylene chloride (100 mL) placed in an ice bath. Following the addition, the ice bath was removed and the resulting reaction mixture stirred at room temperature over a period of 4 h. The reaction mixture was washed several times with water and the organic layer dried over anhydrous magnesium sulfate and concentrated. Vacuum distillation of the crude residue afforded the title compound as a light yellow oil (yield: 91%): GC-Ms: 183; 1H NMR (300 MHz, CDCl3, ppm) δ: 7.36(d, 1H), 7.22-7.19(m, 1H), 7.08-7.06(m, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.O1CCCC1.Cl[CH2:16][C:17]1[CH:36]=[CH:35][C:20]([O:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:19][CH:18]=1>O>[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:35][CH:36]=2)[N:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: Cc1cc(C)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)n(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
Sodium hydride (60%, oily, 880 mg) was added to a mixture of 3,5-dimethylpyrazole (2.11 g) and tetrahydrofuran (50 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. After 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (6.28 g) was added to the reaction mixture, the mixture was refluxed for 24 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and 3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazole (5.49 g, yield: 74%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 86–87° C.
Reaction SMILES: Br[CH2:2][C:3](=[C:5]([C:8]#[N:9])[C:6]#[N:7])[CH3:4].[CH3:10][C:11]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:12]=1[NH2:13]>C(O)(C)C>[NH2:7][C:6]1[N:13]([C:12]2[C:14]([CH3:19])=[CH:15][C:16]([CH3:18])=[CH:17][C:11]=2[CH3:10])[CH:2]=[C:3]([CH3:4])[C:5]=1[C:8]#[N:9]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CC(CBr)=C(C#N)C#N
Solvent: CC(C)O
Product: Cc1cc(C)c(-n2cc(C)c(C#N)c2N)c(C)c1

Procedure:
A mixture 2-(2-bromo-1-methyl-ethyl idene)-malononitrile and 2,4,6-trimethylaniline (17.330 g, 91.24 mmol) in 40 mL of isopropanol was stirred at room temperature for 15 hours. The reaction mixture was concentrated to dryness and diluted with chloroform and water. The chloroform layer was neutralized with dilute sodium hydroxide and washed with brine, separated, dried and concentrated to give 33.000 g of brown oily solid. The solid was purified through silica gel column chromatography to give 9.35 g (47.5%) of the title compound as an orange-yellow solid. 1H NMR (CDCl3) δ 2.0(s, 6H), 2.15(s, 3H), 2.35(s, 3H), 3.75(brs, 2H), 5.8(s, 1H), 6.95(s, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[N:23]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[N:22]=[N:21][CH:20]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([C@@H:32]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1C(=O)N([Br:51])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]4[N:23]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[N:22]=[N:21][CH:20]=4)=[CH:15][CH:16]=3)=[C:9]([Br:51])[N:8]([C@@H:32]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2cc(-c3ccc(OCc4cnnn4COC(=O)C(C)(C)C)cc3)c3c(N)ncnc32)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2c(Br)c(-c3ccc(OCc4cnnn4COC(=O)C(C)(C)C)cc3)c3c(N)ncnc32)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a cooled solution of (R)-tert-butyl 3-(4-amino-5-(4-((1-(pivaloyloxymethyl)-1H-1,2,3-triazol-5-yl)methoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (81) (506 mg, 0.856 mmol) in DCM (20 mL) was added NBS (167 mg, 0.942 mmol). The resulting mixture was stirred at 0° C. for 2 hr. The reaction was quenched with water and extracted with DCM (20 mL×2). The combined organic layer was dried over Na2SO4. The solvent was removed under vacuum and the residue was purified by flash chromatography (silica gel, 0 to 15% MeOH in DCM, with 0.5% TEA) to provide (R)-tert-butyl 3-(4-amino-6-bromo-5-(4-((1-(pivaloyloxymethyl)-1H-1,2,3-triazol-5-yl)methoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (82) (344 mg, 60%). LC-MS (ESI): m/z (M/M+2) 668.8/670.8
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:14]2[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[O:9][CH2:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[CH:20]1([CH2:26][C@H:27]([NH:40][C:41](=O)[O:42]C2C=CC([N+]([O-])=O)=CC=2)[CH2:28][N:29]([CH3:39])[C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:9][CH2:10][C:11](=[O:13])[CH3:12])[C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:41]([NH:40][C@@H:27]([CH2:26][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[CH2:28][N:29]([CH3:39])[C:30](=[O:31])[O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:38])[CH3:36])=[O:42])[CH2:15]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCNC1
Reactant: CN(C[C@H](CC1CCCCC1)NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)OCC[Si](C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.4 %

Procedure:
A mixture of 1-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)propan-2-one, obtained as described above, (S)-4-nitrophenyl 1-cyclohexyl-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)propan-2-ylcarbamate (0.390 g, 0.81 mmol), and DIPEA (2.5 mL) in CH2Cl2 was stirred at rt for 16 h. After the reaction mixture was evaporated under reduced pressure, the crude product was purified by reversed-phase HPLC to afford 0.0487 g (11.4% in three steps) of 2-(trimethylsilyl)ethyl (S)-2-((R)-3-((R)-(3-chlorophenyl)(2-oxopropoxy)methyl)piperidine-1-carboxamido)-3-cyclohexylpropyl(methyl)carbamate. MS ESI +ve m/z 624 (M+H).
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13]/[C:14](/[C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)=[C:15](/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)\[CH:16]=[O:17])=[O:11])([O-:3])=[O:2].CC(=CC)C.P(=O)(O)(O)[OH:40].[O-]Cl=O.[Na+]>CC(O)(C)C.C1COCC1>[CH3:33][S:30]([C:27]1[CH:28]=[CH:29][C:24](/[C:14](/[CH2:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][N+:1]([O-:3])=[O:2])=[C:15](\[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)/[C:16]([OH:40])=[O:17])=[CH:25][CH:26]=1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)c1ccc(/C(COC(=O)CCCCCO[N+](=O)[O-])=C(/C=O)c2ccccc2)cc1
Reactant: O=P(O)(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(/C(COC(=O)CCCCCO[N+](=O)[O-])=C(/C(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4.3 g of (2Z)-2-[4-(methylsulfonyl)phenyl]-4-oxo-3-phenylbut-2-enyl 6-(nitrooxy)hexanoate in a solvent mixture of 50 mL of THF with 50 mL of t-BuOH, 5 mL of 2-methyl-2-butene was added followed by the addition of 20 mL of 2 M phosphoric acid and 20 mL of 1 M of NaClO2. The resulting mixture was stirred at rt for 15 min. The organic phases were separated and the aqueous phase was extracted with EtOAc. The organic phases were combined, dried over Na2SO4, filtered, and then evaporated. The crude was purified by flash chromatography over silica gel (5–100% EtOAc/hexane) to afford 3.8 g of the titled compound as white solid. 1H NMR (acetone-d6, 500 M Hz): δ 7.79 (d, 2H), 7.45 (d, 2 H), 7.22–7.15 (m, 3 H), 7.15–7.10 (m, 2 H), 5.31 (s, 2 H), 4.51 (t, 2 H), 3.07 (s, 3 H), 2.23 (t, 2 H), 1.72–1.65 (m, 2 H), 1.52–1.45 (m, 2 H), 1.37–1.29 (m, 2 H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][C:10]([O:12]CC)=[O:11])=[CH:7][N:6]([CH2:15][C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:28]=3[CH3:29])=[CH:20][CH:21]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][N:6]([CH2:15][C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:28]=3[CH3:29])=[CH:20][CH:21]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)cc1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
After a mixture of ethyl 3-ethoxy-1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-ylacetate (605 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-ethoxy-1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-ylacetic acid (518 mg, yield: 91%). This was recrystallized from ethanol-hexane. Melting point: 126–127° C.
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([F:21])([F:20])([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[N:35]1[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:37]=[N:36]1>>[OH:28][C@@H:25]1[CH2:26][CH2:27][N:23]([C:3]2[C:2]([C:37]3[NH:36][N:35]=[CH:39][CH:38]=3)=[CH:22][C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([S:16]([F:20])([F:19])([F:21])([F:17])[F:18])=[CH:14][CH:15]=3)=[O:8])=[CH:5][N:4]=2)[CH2:24]1
Reactant: O=C(Nc1ccc(S(F)(F)(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Product: O=C(Nc1ccc(S(F)(F)(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 8 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(pentafluorosulfanyl)phenyl)nicotinamide (Stage 17.1) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford a beige solid. HPLC (Condition 4) tR=4.68 min, UPLC-MS (Condition 3) tR=0.92 min, m/z=476.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.91 (m, 2H) 2.93 (d, J=11.73 Hz, 1H) 3.19-3.34 (m, 2H) 3.36-3.49 (m, 1H) 4.12-4.24 (m, 1H) 4.81 (d, J=3.13 Hz, 1H) 6.38 (s, 1H) 7.73-7.89 (m, 3H) 7.92-8.09 (m, 3H) 8.73 (d, J=1.96 Hz, 1H) 10.37 (s, 1H) 12.82-13.17 (m, 1H).