Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH:18]=[O:19].[N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>ClCCl>[OH:21][N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([C:14]1[N:13]([CH3:12])[CH:17]=[CH:16][N:15]=1)=[O:19]
Reactant: O=Nc1ccccc1
Reactant: Cn1ccnc1C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cn1ccnc1C(=O)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (3.8 mg, 0.025 mmol) was added under argon to a solution of 1-methyl-1H-imidazole-2-carbaldehyde (110 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (1.82 mg, 0.005 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][S-:12]>C(Cl)Cl>[F:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([S:12][CH3:11])[CH:9]=1
Reactant: N#Cc1ccc(F)cc1F
Reactant: C[S-]
Solvent: ClCCl
Product: CSc1cc(F)ccc1C#N
Reaction time: 48 h

Procedure:
2,4-difluorobenzonitrile (2.0 g, 14.38 mmol) and thiomethoxide (1.02 g, 14.38 mmol) were placed in an oven dried 100 mL round bottom flask fitted with a reflux condenser. Toluene (40 mL) was added and the reaction solution was put under an atmosphere of Argon. The reaction was heated to 90 deg C. over 48 hours. The crude reaction was cooled and concentrated in vacuo. The residue was taken up in methylene chloride and extracted with water. The organic phase was dried (MgSO4), filtered and concentrated to afford a white solid. The solid was dissolved in a minimal amount of methylene chloride and purified on an ISCO column (110 g silica) with a gradient of 100% hexanes to 80% hexanes/20% ethylacetate over 15 min, then 20% EtOAc/80% Hexanes for 5 min. The collected fractions were evaporated in vacuo to afford the desired material in a 7.5:1 ratio 4-fluoro-2-(methylthio)benzonitrile: 2-fluoro-4-(methylthio)benzonitrile. The white solid was carried on to the next step without further purification.
Reaction SMILES: [OH:1][CH:2]([CH3:6])[C:3](O)=[O:4].[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[O:33][CH2:34][CH2:35][NH:36][CH3:37])[N:26]=[CH:25][N:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[O:33][CH2:34][CH2:35][N:36]([CH3:37])[C:3](=[O:4])[CH:2]([OH:1])[CH3:6])[N:26]=[CH:25][N:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CC(O)C(=O)O
Product: CC(O)C(=O)N(C)CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 56 %

Procedure:
The procedure described in Example 1 was repeated using 2-hydroxypropanoic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 1, preparation of starting materials) to give the title compound in 56% yield; NMR spectrum (DMSO-d6) 1.08 (d, 3H), 3.11 (s, 3H), 3.82-4.12 (m, 2H), 4.36-4.47 (m, 3H), 4.52-4.72 (m, 1H), 5.31 (s, 2H), 7.18 (d, 1H), 7.25 (d, 1H), 7.34 (d, 1H), 7.35-7.40 (m, 1H), 7.52-7.62 (m, 2H), 7.70-7.76 (m, 1H), 7.86-7.91 (m, 1H), 7.94-7.97 (m, 1H), 8.44 (s, 1H), 8.61 (d, 1H), 9.75 (s, 1H); Mass spectrum MH+ 508.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15](=[O:16])[NH:14][C:13](=[O:17])[C:12](C(O)=O)=[N:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]>C1(OC2C=CC=CC=2)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15](=[O:16])[NH:14][C:13](=[O:17])[CH:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1nn(-c2cccc([N+](=O)[O-])c2)c(=O)[nH]c1=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1cnn(-c2cccc([N+](=O)[O-])c2)c(=O)[nH]1
Temperature: 25 °C
Yield: 39.6 %

Procedure:
A solution of 2-(3-nitrophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid (3 g) in diphenylether (30 mL) was refluxed for 1 hour and cooled to room temperature. The mixture was quenched with 1M NaOH solution. The basic aqueous layer was then acidified and extracted with ethyl acetate (×3). The organic layers were successively washed with brine, dried over MgSO4, filtered and concentrated. 1 g (40% yield) of 2-(3-nitrophenyl)-1,2,4-triazine-3,5(2H,4H)-dione 9(C) was recovered and used in next step without any further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:16][CH:15]=3)=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9].[Br:26]NC(=O)CCC(N)=O>C(O)(=O)C>[Br:26][C:12]1[S:11][C:4]2[NH:5][C:6](=[O:10])[C:7]([C:8]#[N:9])=[C:2]([OH:1])[C:3]=2[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:16][CH:15]=1
Reactant: N#Cc1c(O)c2c(-c3ccc(C#CCCCO)cc3)csc2[nH]c1=O
Reactant: NC(=O)CCC(=O)NBr
Solvent: CC(=O)O
Product: N#Cc1c(O)c2c(-c3ccc(C#CCCCO)cc3)c(Br)sc2[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-hydroxy-3-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (35 mg, 0.1 mmol) in acetic acid (1 mL) was added N-bromosuccinamide (18 mg, 0.1 mmol) in a single portion at room temperature, and stirred at rt overnight. The reaction mixture was concentrated and purified by reverse phase HPLC to afford the titled compound. MS (ESI) m/e 428 (M−H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.68–1.75 (m, 2H), 3.51–3.57 (m, 2H), 4.54 (t, J=5.26 Hz, 2H), 7.19 (d, J=8.48 Hz, 2H), 7.31 (d, J=8.48 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:14][CH2:15][S:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10](B(O)O)=[C:6]2[C:5](=[O:36])[N:4]([CH3:37])[C:3]1=[O:38].Br[C:40]1[S:41][CH:42]=[C:43]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[N:44]=1.C(=O)([O-])O.[Na+]>C(OCCCC)(=O)C.O.C(Cl)Cl>[CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:14][CH2:15][S:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]([C:40]3[S:41][CH:42]=[C:43]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[N:44]=3)=[C:6]2[C:5](=[O:36])[N:4]([CH3:37])[C:3]1=[O:38]
Reactant: CCOC(=O)c1csc(Br)n1
Reactant: Cn1c(=O)c2c(B(O)O)n(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCCCOC(C)=O
Product: CCOC(=O)c1csc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
(1,3-dimethyl-2,4-dioxo-6-(2-(tritylthio)ethyl)-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)boronic acid (Intermediate F) (1001 mg, 1.906 mmol), ethyl 2-bromothiazole-4-carboxylate (409 mg, 1.732 mmol), sodium hydrogen carbonate (291 mg, 3.46 mmol) and Pd-118 (113 mg, 0.173 mmol) were suspended in n-butyl acetate (12.3 ml) and heated to 80° C. Water (3.08 ml) was then added and the mixture heated at 80° C. for 21 hours. The mixture was then cooled to room temperature and diluted with water (100 ml) and DCM (100 ml). The mixture was extracted with DCM (3×100 ml) and the combined organic extracts were washed with water (50 ml) and brine (50 ml). Silica-TMT (30 g) was added and the mixture stirred at room temperature for 5 mins, then filtered. The residue was rinsed with DCM (20 ml) and the filtrates evaporated under vacuum. The resultant residue was rinsed with diethyl ether and filtered to afford the title compound.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].[CH3:11][O:12][C:13](Cl)=[O:14].[OH-].[Na+]>O>[CH3:11][O:12][C:13]([NH:10][C:8](=[NH:9])[O:7][CH3:6])=[O:14]
Reactant: COC(=O)Cl
Reactant: COC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=N)NC(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
246 g of O-methylisourea sulfate are dissolved in 300 ml of water and 163 ml of chloroformic acid methyl ester are added dropwise at 10° C., followed by 170 g of NaOH, dissolved in 510 ml of water. The mixture is stirred at room temperature for a further 3 hours. The reaction solution is then extracted with ethyl acetate and this extract is dried with anhydrous sodium sulfate. Evaporation under reduced pressure at a maximum bath temperature of 40° C. gives the N-methoxycarbonyl-O-methylisourea as an oil, which gradually solidifies to form crystals with a melting point of 40° C. Yield 150 g.
Reaction SMILES: [CH2:1]([NH:9][C:10]1[N:18]=[C:17]([C:19]#[N:20])[N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][NH:14]2)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:21]([O:29][C@H:30]1[C@@H:34]([O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:33](OC(=O)C)[O:32][C@@H:31]1[CH2:48][O:49][CH3:50])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[C@H]1[C@@H](OC(=O)C2C=CC=CC=2)[C@@H](OC(=O)C)O[C@@H]1COC)(=O)C1C=CC=CC=1.S([O-])([O-])(=O)=O.[NH4+].[NH4+].C[Si](C)(C)N[Si](C)(C)C.Br[Si](C)(C)C>[Bi](Br)(Br)Br.ClCCl.C(#N)C>[C:21]([O:29][C@H:30]1[C@@H:34]([O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:33]([N:14]2[CH:13]=[N:12][C:11]3[C:15]2=[N:16][C:17]([C:19]#[N:20])=[N:18][C:10]=3[NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:32][C@@H:31]1[CH2:48][O:49][CH3:50])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: N#Cc1nc(NCCc2ccccc2)c2nc[nH]c2n1
Agent: Br[Bi](Br)Br
Agent: COC[C@H]1O[C@H](OC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CC#N
Product: COC[C@H]1O[C@@H](n2cnc3c(NCCc4ccccc4)nc(C#N)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1

Procedure:
The title compound was prepared by a similar method to preparation 11 using 6-(phenethylamino)-9H-purine-2-carbonitrile (3.8 g, 11.2 mmol) (preparation 45), (2R,3R,4R,5S)-5-(acetyloxy)-4-(benzoyloxy)-2-(methoxymethyl)tetrahydro-3-furanyl benzoate and (2R,3R,4R,5R)-5-(acetyloxy)-4-(benzoyloxy)-2-(methoxymethyl)tetrahydro-3-furanyl benzoate (preparation 4) (6 g, 14.5 mmol), ammonium sulfate (200 mg, 1.2 mmol), 1,1,1,3,3,3-hexamethyidisilazane (150 ml), bromotrimethylsilane (8 ml, 177 mmol), acetonitrile (80 ml), dichloromethane (80 ml) and bismuth tribromide (0.35 g, 0.24 mmol). The product was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol (99.5:0.5). This gave the title compound (7.9 g) as a white foam. MS: 619 (MH+).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[C:30]([O:34][C:35](=[O:44])[NH:36][CH:37]1[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35](=[O:44])[NH:36][CH:37]1[CH2:38][CH2:39][CH:40]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:9]2)[CH2:41][CH2:42]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NC1CCC(N2CC(NC(=O)CNc3noc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of (N-Azetidin-3-yl-2-(5-trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and (4-oxo-cyclohexyl)-carbamic acid tert-butyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH2:7]S[C:5]2=[N:8][N:9]=[C:10]([CH:11]([O:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[N:4]2[N:3]=1.C(OC(=O)C)(=O)C.Cl.[PH2](O)=O>>[CH3:1][C:2]1[CH:7]=[C:5]2[NH:8][N:9]=[C:10]([CH:11]([O:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[N:4]2[N:3]=1
Reactant: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)c1nnc2n1N=C(C)CS2
Agent: Cl
Agent: O=[PH2]O
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)c1n[nH]c2cc(C)nn12

Procedure:
Process of claim 2 wherein 6-methyl-3-(1-[4-nitrophenoxy]tridecyl)-7H-1,2,4-triazolo[3,4-b]-[1,3,4]thiadiazine] is reacted with acetic anhydride, and the acylated intermediate thereby produced is reacted with HCl in the presence of hypophosphorous acid to produce 6-methyl-3-[1-(4-nitrophenoxy)tridecyl]-1H-pyrazolo-[5,1-c]-1,2,4-triazole.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH3:22][NH:23][CH3:24]>>[CH3:22][N:23]([CH3:24])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: CNC
Product: CN(C)c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
A mixture of 100 mg (0.314 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide and 0.185 ml (0.925 mmol) of dimethylamine (33% in ethanol) in a closed vial is heated in a microwave reactor at 150° C. for 15 minutes. After cooling, the reaction mixture is concentrated to dryness and the residue crystallized from tetrahydrofuran/water yielding 90 mg of the title compound as an orange powder, m.p. 245-260° C. (decomp.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[C:12]([C:21](O)=[O:22])[CH:11]=1)#[N:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[OH:48][CH:49]1[CH2:52][NH:51][CH2:50]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[C:12]([C:21]([N:51]2[CH2:52][CH:49]([OH:48])[CH2:50]2)=[O:22])[CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:15]=1)#[N:2]
Reactant: CCOC(=O)c1cc(C(=O)O)cc(-c2ccc(C)cc2C#N)c1
Reactant: OC1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1cc(C(=O)N2CC(O)C2)cc(-c2ccc(C)cc2C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2′-cyano-5-(ethoxycarbonyl)-4′-methylbiphenyl-3-carboxylic acid (90 mg, 0.29 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (120 mg, 0.61 mmol), 1-hydroxybenzotriazole hydrate (93 mg, 0.61 mmol), and methylene chloride (5 mL) were added 3-hydroxyazetidine hydrochloride (67 mg, 0.61 mmol) and N,N-diisopropylethylamine (0.21 mL, 1.2 mmol). The mixture was stirred at room temperature overnight, and then concentrated under reduced pressure. The residue was purified via flash chromatography to afford the desired product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.[CH:14]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:36])[C:28]1=[O:37])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:29]2([OH:36])[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:27]([CH:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:28]2=[O:37])=[C:4]([OH:8])[CH:3]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1cccc(Br)c1
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc(Br)cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
To a stirred solution of 3-bromophenol (11.9 g, 69.2 mmol) in dichloromethane (160.0 mL) at 0° C. was added isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 38.0 mL, 76.1 mmol). The solution was stirred at 0° C. for 30 min, then 1-benzhydrylindoline-2,3-dione (10.0 g, 34.6 mmol) was added. The reaction was stirred at ambient temperature for 16 h, then concentrated in vacuo to dryness. The residue obtained was dissolved in ethyl acetate (400.0 mL) and washed with saturated ammonium chloride solution (3×100.0 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to dryness. Purification by flash chromatography with 30% ethyl acetate in hexanes afforded 3-(4-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (11.7 g, 70%) as a beige solid: 1H NMR (300 MHz, CDCl3) δ9.09 (br s, 1H), 7.47-7.16 (m, 11H), 7.12-7.00 (m, 3H), 6.92-6.84 (m, 2H), 6.72-6.66 (m, 1H), 6.51-6.45 (m, 1H), 4.57 (br s, 1H); MS (ES+) m/z 484.2 (M+1), 486.2 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]12[O:12][CH2:11][C:8]([CH3:13])([CH2:9][O:10]1)[CH2:7][O:6]2.[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+].[Na+].[I-:39]>C(#N)C>[I-:39].[CH3:13][C:8]12[CH2:11][O:12][C:5]([CH2:4][CH2:3][CH2:2][P+:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([O:10][CH2:9]1)[O:6][CH2:7]2
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC12COC(CCCCl)(OC1)OC2
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC12COC(CCC[P+](c3ccccc3)(c3ccccc3)c3ccccc3)(OC1)OC2
Yield: 59.7 %

Procedure:
A mixture of Intermediate 22 (5 g), triphenylphosphine (33.6 g), NaHCO3 (7 g) and NaI (19.3 g) in acetonitrile (175 ml) was heated under reflux for 17 h. After cooling the inorganic solids were filtered off and washed with dichloromethane. The combined filtrates were evaporated and the residue was triturated firstly with ER (discarded) and then with CH2Cl2. The CH2Cl2 extracts were evaporated in vacuo and the residue, which solidified on trituration with ER, was crystallised from EA-acetonitrile to give the title compound (8.1 g) m.p. 189°-191°.
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.[Cl:22][C:23]1[C:24]([N:32]2[CH2:37][CH2:36][CH:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:34][CH2:33]2)=[CH:25][C:26]([NH:30][CH3:31])=[C:27]([CH:29]=1)[NH2:28].CC(C)N=C=NC(C)C>CN(C=O)C.O>[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[NH:19][C:20]1[N:30]([CH3:31])[C:26]2[CH:25]=[C:24]([N:32]3[CH2:37][CH2:36][CH:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:34][CH2:33]3)[C:23]([Cl:22])=[CH:29][C:27]=2[N:28]=1
Reactant: CNc1cc(N2CCC(c3ccccc3)CC2)c(Cl)cc1N
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: O
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2Cl)nc2cc(Cl)c(N3CCC(c4ccccc4)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (200 mg; 0.60 mmol) and 5-chloro-2-methylamino-4-(4-phenyl-piperidin-1-yl)aniline (190 mg; 0.60 mmol) in DMF (4 mL) was stirred overnight at rt. DIC (76 mg; 0.60 mmol) was added and the mixture was heated at 90° C. for 1.5 h. The mixture was poured in water, extracted with EtOAc and the combined organic layer was dried over Na2SO4, filtered and concentrated and the residue was purified by column chromatography.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.CCCCCC.[B:33](OC(C)C)([O:38]C(C)C)[O:34]C(C)C.Cl>C(OCC)C>[CH:1]([C:4]1[CH:5]=[C:6]([B:33]([OH:38])[OH:34])[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)c1cc(B(O)O)cc(C(C)C)c1
Temperature: -60 °C
Reaction time: 1.5 h

Procedure:
To the solution of 3,5-diisopropylbromobenzene (5.76 g, 23.9 mmol) and tetramethylethylenediamine (3.6 mL, 23.9 mmol) in diethyl ether (30 mL), solution of n-butyllithium in n-hexane (14.5 mL, 23.9 mmol) was dropped at −60° C. Reaction solution was stirred for 1.5 hours at −60° C., and further was stirred for 30 minutes at 0° C., then, solution of triisopropyl borate (6.6 mL) in diethyl ether (5 mL) was dropped at −60° C. Reaction solution was stirred for 30 minutes at −60° C., and further, was stirred overnight at room temperature, then, diluted hydrochloric acid (50 mL) was added. Resulting solid part was filtered to obtain the crude product of 3,5-diisopropylphenylboronic acid (5.9 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH2:14][CH2:15][C:16]([O:18]CC)=[O:17].[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>ClC1C=CC=CC=1Cl>[CH3:8][C:6]1[CH:7]=[C:2]2[C:3](=[CH:4][CH:5]=1)[N:9]1[C:10]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N:11][CH:12]=[C:13]1[C:21](=[O:22])[NH:1]2
Reactant: CCOC(=O)CCc1nccn1-c1ccc(C)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Clc1ccccc1Cl
Product: Cc1ccc2c(c1)[nH]c(=O)c1cnc(CCC(=O)O)n12

Procedure:
Ethyl 3-[1-(2-amino-4-methylphenyl)-1H-imidazol-2-yl]-propanoate as synthesized in above Example 181, 160 mg, 1,1′-carbonyldiimidazole 143 mg and 1,2-dichlorobenzene 6 mL were mixed and heated under reflux for 1.5 hours. The reaction liquid was allowed to cool off, and the precipitate was recovered by filtration and washed with ethyl acetate. After being dried under reduced pressure, the product was mixed with 3 mL of ethanol and 3.0 mL of 1N aqueous sodium hydroxide solution and heated under reflux for 20 minutes. Cooling the reaction liquid off, 3.0 mL of 1N hydrochloric acid was added. The precipitated crystals were recovered by filtration, washed with water and dried in flowing air under heating to provide 82 mg of the title compound.
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:72]2[N:73]=[C:74]([NH:77]C(OC(C)(C)C)=O)[S:75][CH:76]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][NH:42][C:43]([N:52](C(OC(C)(C)C)=O)[CH2:53][CH:54]3[CH2:57][N:56](C(OC(C)(C)C)=O)[CH2:55]3)=[N:44]C(OC(C)(C)C)=O)[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:77][C:74]1[S:75][CH:76]=[C:72](/[C:22](=[N:21]/[O:20][C:17]2([C:15]([OH:16])=[O:14])[CH2:18][CH2:19]2)/[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:32])=[O:33])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][NH:42][C:43]([NH:52][CH2:53][CH:54]3[CH2:55][NH:56][CH2:57]3)=[NH:44])[CH:38]=[N:37]2)=[O:24])[N:73]=1
Reactant: CC(C)(C)OC(=O)N=C(NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1)N(CC1CN(C(=O)OC(C)(C)C)C1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1)NCC1CNC1
Yield: 12 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-((2,3-bis(tert-butoxycarbonyl)-3-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)guanidino)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (300 mg, 0.248 mmol), DCM (3 mL) and TFA (1.90 mL, 24.85 mmol). The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; AcN-water with 0.1% formic acid modifier, 24 mL/min) affording the title compound (19 mg, 12%). LCMS: Rt=0.32 min, m/z=641.3 (M+1), Method 2m_acidic; 1H NMR (400 MHz, DMSO-d6) δ 10.26 (br s, 1H), 8.79 (br s, 3H), 7.78-7.54 (m, 3H), 7.14 (s, 2H), 6.84 (s, 1H), 5.06 (br s, 1H), 4.88 (dd, J=14.1, 3.94 Hz, 1H), 4.70-4.59 (m, 1H), 4.54-4.46 (m, 1H), 4.35 (d, J=3.8 Hz, 2H), 4.00-3.89 (m, 2H), 3.76-3.65 (m, 2H), 3.08-2.94 (m, 1H), 1.30-1.09 (m, 4H).