Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[C:4]([N+:13]([O-])=O)[CH:3]=1.[Sn](Cl)(Cl)(Cl)Cl>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[C:4]([NH2:13])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1-n1ccnc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Product: Nc1cc(Br)ccc1-n1ccnc1
Yield: 92.3 %

Procedure:
To a solution of 1-(4-bromo-2-nitro-phenyl)-1H-imidazole (1.80 g; 6.72 mmol; 1 eq) in ethanol (90 mL) is added dehydrated tin chloride (7.58 g; 33.58 mmol; 5 eq). The reaction mixture is allowed to stir under reflux for 20 hours until completion of the reaction. The crude reaction mixture is then concentrated under vacuum. The resulting mixture is dissolved in water/ethyl acetate 1:2 (40 mL). The aqueous phase is basified until pH 9 is reached with solid hydrogen carbonate. The milky white aqueous phase is then extracted twice with ethyl acetate (2×100 mL). The combined organic phases are washed with brine (100 mL), dried over sodium sulfate and concentrated under vacuum to provide a beige powder. Purification by chromatography on silica gel (dichloromethane/methanol 97:3), afforded the title compound (1.47 g; 6.2 mmol; 92%) as a yellow powder.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>C(O)C>[Cl:8][C:7]1[C:2]([NH:11][NH2:12])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: NN
Reactant: Clc1cnc(Cl)c(Cl)c1
Solvent: O
Solvent: CCO
Product: NNc1ncc(Cl)cc1Cl
Yield: 70.9 %

Procedure:
A reaction flask was loaded with 2,3,5-trichloropyridine (9.1 g) and ethanol (25 ml), followed by dropwise addition of hydrazine monohydrate (3 g) to the flask in 5 minutes with stirring. The resultant mixture was heated and stirred at 50 to 60° C. for 5 hours. Thereafter, the heating was stopped, and the reaction mixture was left to cool. The precipitated white crystals were filtrated for collection and dried to give 3,5-dichloro-2-hydrazinopyridine (6.3 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH2:33])[N:18]=[C:17]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[S:45](Cl)(=[O:47])=[O:46]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH:33][S:45]([C:41]3[S:40][CH:44]=[CH:43][CH:42]=3)(=[O:47])=[O:46])[N:18]=[C:17]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ccncc2)nc1OCCN
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ccncc2)nc1OCCNS(=O)(=O)c1cccs1

Procedure:
According to the procedure described in Example 4a) 20 mg 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-benzene-sulfonamide was reacted with thiophene-2-sulfonylchloride to give 20 mg 4-tert.-butyl-N-[6-(2-(thiophene-2-sulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-benzene-sulfonamide. LC-MS: tR=5.17 min, [M+1]+=696.57.
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[C:6]([I:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([N:11]([CH3:10])[C:2]2[C:7]([CH3:8])=[C:6]([I:9])[CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CNC1CCCCC1
Reactant: Cc1c(I)ccnc1F
Product: Cc1c(I)ccnc1N(C)C1CCCCC1

Procedure:
2-Fluoro-4-iodo-3-methylpyridine (700 mg) in N-methylcyclohexanamine (2.2 ml) was heated at 180(C in a Biotage Initiator microwave reactor for 18 hours. The reaction mixture was loaded onto a silica gel cartridge, and was eluted with 0-100% dichloromethane in hexanes to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:10][C:11](=[O:12])[C:5]2=[CH:4][N:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:10][C:11](=[O:12])[C:5]2=[CH:4][N:3]=1)(=[O:25])[CH3:24]
Reactant: CCCOc1ccccc1-c1nc2nc(N)ncc2c(=O)[nH]1
Reactant: CC(=O)OC(C)=O
Product: CCCOc1ccccc1-c1nc2nc(NC(C)=O)ncc2c(=O)[nH]1

Procedure:
A stirred mixture of 7-amino-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.59 g) and acetic anhydride (5 ml) was heated under reflux for 1.5 hours. Excess acetic anhydride was removed under reduced pressure. The solid residue was washed with water and triturated with hot methanol to yield the title compound, 0.57 g, m.p. 273-4° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH2:34][C:35](O)=[O:36].CCN=C=NCCCN(C)C>>[Cl:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH2:34][C:35]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:36]
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: O=C(O)Cc1ccc(F)cc1Cl
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)Cc4ccc(F)cc4Cl)c3)c2c1
Yield: 16 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 2-chloro-4-fluorophenylacetic acid (0.13 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 38 mg (14% yield) of the title compound. 1H NMR (DMSO-d6) δ 10.4 (s, 1H), 8.6 (s, 1H), 8.1 (br s, 1H), 7.9 (dd, 1H), 7.75 (m, 2H), 7.65 (d, 1H), 7.52–7.4 (m, 3H), 7.35 (s, 1H), 7.2 (m, 1H), 3.9 (s, 2H); ES-MS (m/z) 423 [M]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:27])[CH2:4][CH3:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].C([NH:41][CH2:42][CH2:43]Br)(OC(C)(C)C)=O>C(#N)C>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:43][CH2:42][NH2:41])=[C:19]([CH2:25][CH3:26])[CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:27])[CH2:4][CH3:5])[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc(C)c1O
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc(C)c1OCCN
Temperature: 80 °C
Reaction time: 12 h
Yield: 65.8 %

Procedure:
To a mixture of 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (700 mg, 1.82 mmol) and K2CO3 (760 mg, 5.45 mmol) in acetonitrile (14 mL), 2-(Boc-amino)-ethylbromide (839 mg, 3.63 mmol) is added. The mixture is stirred at 80° C. for 12 h. The mixture is filtered and the filtrate is concentrated. The residue is dissolved in DCM (10 mL) and treated with TFA (1.4 mL). The mixture is stirred at rt for 19 h before another portion of TFA (0.7 mL) is added. Stirring is continued at rt for another 21 h. The mixture is diluted with DCM and washed with 1 M aq. NaOH. The washing is extracted back with DCM. The combined organic extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC. The product containing fractions are combined, concentrated, dissolved in methanol:water 9:1 and filtered over Amberlyst A-21. The filtrate is evaporated and dried to give the title compound (513 mg) as a pale yellow resin; LC-MS: tR=0.44 min; [M+1]+=429.20; 1H NMR (D6-DMSO): δ1.03 (t, J=7.0 Hz, 6H), 1.23 (t, J=7.5 Hz, 3H), 2.22 (s, 3H), 2.35 (s, 3H), 2.58 (q, J=7.3 Hz, 4H), 2.73 (q, J=7.5 Hz, 2H), 3.05 (t, J=5.5 Hz, 2H), 3.73 (s, 3H), 3.86 (t, J=5.5 Hz, 2H), 7.75 (s, 2H), 7.80 (s, 1H).
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[CH3:11][O:12][C:13]1[CH:30]=[CH:29][CH:28]=[CH:27][C:14]=1[CH2:15][NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25].FC(F)(F)[C:33](O)=[O:34]>>[CH:33]([C:28]1[CH:29]=[CH:30][C:13]([O:12][CH3:11])=[C:14]([CH:27]=1)[CH2:15][NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:34]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccccc1CNC(=O)c1ccc(Cl)cc1Cl
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1ccc(C=O)cc1CNC(=O)c1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 23 h

Procedure:
9.04 g of hexamethylene tetramine was added to a solution of 10.0 g N1-(2-methoxybenzyl)-2,4-dichlorobenzamide in trifluoroacetic acid (200 mL), followed by stirring at 50° C. for 23 hours. The reaction solution was left and cooled to room temperature and then concentrated. The residue was diluted with ice-water and adjusted to pH 11 to 12 with 1N aqueous sodium hydroxide solution. The solution was extracted with ethyl acetate. The organic layer was washed with 1 N aqueous sodium hydroxide solution (×3), 1 N hydrochloric acid (×2) and brine, dried over anhydrous sodium sulfate and filtered thorough 100 g silica gel. After concentrating the filtrate, the residue was suspended in ethyl acetate. The solid was collected by filtration and washed with ethyl acetate, to give 7.15 g of N1-(5-formyl-2-methoxybenzyl)-2,4-dichlorobenzamide as a colorless solid.
Reaction SMILES: C([Li])CCC.[CH3:6][S:7]([CH3:9])=[O:8].[CH:10]([S:13]([N:16]1[C:20]2[CH:21]=[C:22]([C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[NH2:33])(=[O:15])=[O:14])([CH3:12])[CH3:11]>O1CCCC1>[CH:10]([S:13]([N:16]1[C:20]2[CH:21]=[C:22]([C:25]([OH:32])([CH2:6][S:7]([CH3:9])=[O:8])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[NH2:33])(=[O:14])=[O:15])([CH3:12])[CH3:11]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(=O)c3ccccc3)cc21
Reactant: CS(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(O)(CS(C)=O)c3ccccc3)cc21
Temperature: 25 °C

Procedure:
Lithium methyl sulfinyl carbanion was prepared by reacting 37 ml. of a 1.6 M solution of n-butyl lithium in tetrahydrofuran with 5 ml. of dimethyl sulfoxide dissolved in 70 ml. of tetrahydrofuran. After stirring the reaction mixture under nitrogen for thirty minutes at 0°-5° C., a mixture of 4.0 g. of 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole in 60 ml. of tetrahydrofuran was added in one portion. The reaction mixture was stirred for one hour at 0° C., and then was warmed to room temperature and stirred for an additional twelve hours at 24° C., followed by thirty-six hours of stirring at 50° C. The reaction mixture next was diluted with 100 ml. of water, and the organic solvent was removed by evaporation under reduced pressure. The aqueous mixture was acidified to pH 2 with 1 N hydrochloric acid, and then filtered. The filtrate was neutralized with sodium carbonate, and the product was extracted therefrom into ethyl acetate. The extracts were combined and the solvent was removed by evaporation under reduced pressure to provide 1-isopropylsulfonyl-2-amino-6-(α-hydroxy-α-methylsulfinylmethylbenzyl)benzimidazole.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:16])=[CH:10][C:11]=2[N+:13]([O-:15])=[O:14])[CH2:6][CH2:5]1)(=O)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Br:16][C:9]1[CH:8]=[C:7]2[C:12](=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=1)[NH:4][CH2:5][CH2:6]2
Reactant: CC(=O)N1CCc2cc(Br)cc([N+](=O)[O-])c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cc(Br)cc2c1NCC2
Yield: 96 %

Procedure:
1-Acetyl-5-bromo-7-nitroindoline (5.05 g, 17.7 mmol) was added to a mixture comprising 6 ml of ethanol and 40 ml of 6N hydrochloric acid. The obtained mixture was heated under reflux for 3 hours, neutralized with sodium carbonate and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 4.13 g of 5-bromo-7-nitroindoline. This compound (301 mg, 1.24 mmol) was added to 10 ml of toluene, followed by the addition of 580 mg (2.55 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. The obtained mixture was refluxed by heating under stirring for 3.5 hours and filtered to remove insolubles. The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography to give 252 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]([CH3:16])[CH2:7]P(OCC)(OCC)=O)[CH3:2].[Li]CCCC.[CH:23]([C:26]1[C:27]([O:41][CH2:42][CH2:43][CH3:44])=[C:28]([C:35]([CH2:39][CH3:40])=[CH:36][CH:37]=O)[CH:29]=[C:30]([CH:32]([CH3:34])[CH3:33])[CH:31]=1)([CH3:25])[CH3:24]>CN1CCCN(C)C1=O.C1COCC1>[CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]([CH3:16])[CH:7]=[CH:37][CH:36]=[C:35]([C:28]1[CH:29]=[C:30]([CH:32]([CH3:33])[CH3:34])[CH:31]=[C:26]([CH:23]([CH3:25])[CH3:24])[C:27]=1[O:41][CH2:42][CH2:43][CH3:44])[CH2:39][CH3:40])[CH3:2]
Reactant: CCCOc1c(C(=CC=O)CC)cc(C(C)C)cc1C(C)C
Reactant: CCOC(=O)C=C(C)CP(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCCOc1c(C(=CC=CC(C)=CC(=O)OCC)CC)cc(C(C)C)cc1C(C)C
Reaction time: 0.17 h
Yield: 95.3 %

Procedure:
To a solution of 4-(diethoxy-phosphoryl)-3-methyl-but-2-enoic acid ethyl ester (10.6 mL, 43.6 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 20 mL) and THF (80 mL) at −78° C. was added n-BuLi dropwise (1.6 M in hexanes, 27.2 mL, 43.6 mmol). After 10 min, 3-(3,5-diisopropyl-2-propoxy-phenyl)-pent-2-enal (Intermediate 6, 8.77 g, 29.0 mmol) in THF (15 mL and 5 mL rinse) was added slowly to the reaction. The mixture was stirred at −78° C. for 2h, was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was separated, washed successively with H2O, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (2.5% EtOAc-hexanes) to yield the title compound as a yellow syrup (11.4 g, 95%).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][CH2:25][C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].C([BH3-])#N.[Na+].C(O)(=O)C.[CH2:41]([C:43]1[CH:44]=[CH:45][C:46]([CH:49]=O)=[N:47][CH:48]=1)[CH3:42]>CO>[CH2:41]([C:43]1[CH:44]=[CH:45][C:46]([CH2:49][N:24]([CH2:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[CH:14][CH:13]=3)=[O:32])=[CH:18][CH:19]=2)[CH2:25][C:26]2[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=2)=[N:47][CH:48]=1)[CH3:42]
Reactant: CCc1ccc(C=O)nc1
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CNCc3nccn3C)cc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ccc(CC)cn3)Cc3nccn3C)cc2)cc1
Yield: 91.2 %

Procedure:
The compound (191 mg) obtained in Example 15-5 was dissolved in anhydrous methanol (4.0 ml) and added with sodium cyanoborohydride (41.5 mg), acetic acid (0.50 ml), and the compound (71.4 mg) obtained in Example 16-1 and the whole was stirred at room temperature for 2 days under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in chloroform and added with a 1 mol/l sodium hydroxide aqueous solution, followed by stirring for a while. Then, the solution was subjected to extraction with chloroform and washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (222 mg) of the subject compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(O)(C)(C)C>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([C:26]#[N:27])([CH3:29])[CH3:28])=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CC(C)(C#N)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(C(C)(C)C#N)cc1
Yield: 86.9 %

Procedure:
Ethyl 4,6-dichloro-1,5-naphthyridine-3-carboxylate (6.4 g, 23.6 mmol) and 2-(4-aminophenyl)-2-methylpropionitrile (5.6 g, 35 mmol) were dissolved in tert-butanol (200 mL), to the system added potassium carbonate (16.4 g, 119 mmol), and the reaction mixture was stirred under reflux for 2 h. After confirming a disappearance of the raw materials by a thin layer chromatography plate (ethyl acetate:petroleum ether=1:3), the reaction mixture was suction filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether to give 8.1 g of a pale yellow solid.
Reaction SMILES: C[CH2:2][N:3](C(C)C)[CH:4](C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1C2C(COC([N:54]3[CH2:62][C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[CH:55]3[C:63]([OH:65])=O)=O)C3C(=CC=CC=3)C=2C=CC=1.CNC>C(Cl)Cl.CCO>[CH3:2][N:3]([CH3:4])[C:63]([CH:55]1[C:56]2[C:61](=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH2:62][NH:54]1)=[O:65]
Reactant: O=C(O)C1c2ccccc2CN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: CN(C)C(=O)C1NCc2ccccc21
Reaction time: 0.25 h
Yield: 204.6 %

Procedure:
1.66 g of DIPEA and then 5.73 g of BOP are added to a solution of 5 g of 2-(9-fluorenylmethoxycarbonyl)isoindoline-1-carboxylic acid (commercial) in 100 ml of DCM and the mixture is left stirring for 15 minutes at AT. 4.6 ml of a 5.6M solution of dimethylamine in EtOH are subsequently added and the mixture is left stirring for 30 minutes at AT. The reaction mixture is concentrated under vacuum, the residue is taken up in water and extracted with DCM, the organic phase is washed with a 5% KHSO4 solution and dried over Na2SO4, and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, elution being carried out with a DCM/AcOEt (70/30, v/v) mixture. 5 g of the expected product are obtained.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([O:18]CC)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[OH-].[Li+]>C1COCC1.CO>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([OH:18])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
107 g of ethyl 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 2A; 300 mmol, 1 equivalent) were dissolved in 2.8 l of THF/methanol (1:1), 1.5 of 1 N aqueous lithium hydroxide solution (1.5 mol, 5 equivalents) were added and the mixture was stirred at RT for 16 h. The organic solvents were removed under reduced pressure and the resulting aqueous solution was adjusted in an ice bath to pH 3-4 using 1 N aqueous hydrochloric acid. The resulting solid was filtered off, washed with water and isopropanol and dried under reduced pressure. This gave 92 g (95% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1.P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:13]=2)[C:34](=[O:35])[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([OH:26])=[CH:28][CH:29]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: Clc1ccc(NCCc2cccc(OCc3ccccc3)c2)cc1Cl
Solvent: Clc1ccccc1
Solvent: ClP(Cl)Cl
Product: O=C(Cc1ccc(O)cc1)N(CCc1cccc(OCc2ccccc2)c1)c1ccc(Cl)c(Cl)c1
Temperature: 135 °C
Yield: 98.7 %

Procedure:
To a solution of (3,4-dichlorophenyl) {2-[3-(phenylmethoxy)phenyl]ethyl}amine (4.32 g, 0.011 mol) in chlorobenzene (40 ml) was added 4-hydroxy phenyl acetic acid (2.43 g, 0.014 mol), followed by phosphorus trichloride (5 ml, 0.005 mol). The reaction was allowed to reflux at 135° C. overnight. Solvent was removed and the reaction was basified with 10% sodium hydroxide solution. The reaction was diluted with ethyl acetate and water. The organic was washed with brine, dried with MgSO4, filtered, and concentrated to provide the title compound (5.5 g, 99% yield): ES-MS (m/z) 506 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:55])[C:7]([O:10]/[N:11]=[C:12](/[C:42]1[N:43]=[C:44]([NH:47]C(OC(C)(C)C)=O)[S:45][CH:46]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][NH:33]C(OC(C)(C)C)=O)[C:27]1=[O:41])=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:33][CH2:32][CH2:31][N:28]1[CH2:29][CH2:30][N:26]([CH2:25][C@@H:17]2[C@H:16]([NH:15][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:55])=[O:5])/[C:42]3[N:43]=[C:44]([NH2:47])[S:45][CH:46]=3)[C:19](=[O:20])[N:18]2[S:21]([OH:24])(=[O:22])=[O:23])[C:27]1=[O:41]
Reactant: CC(C)(C)OC(=O)NCCN1CCN(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1CCN(CCN)C1=O)c1csc(N)n1)C(=O)O
Yield: 4.2 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((3-(2-((tert-butoxycarbonyl)amino)ethyl)-2-oxoimidazolidin-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (42 mg, 0.051 mmol), TFA (237 μl, 3.08 mmol) in DCM (500 μL). The crude residue was purified by reverse phase prep HPLC (Xselect CSH, 30×100 mm, 5 μM, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min) to afford the title compound (1.2 mg, 4%). LC/MS: Rt=0.35 min, m/z=563.2 (M+1) Method 2m_acidic; 1H NMR (400 MHz, D2O): δ 1H NMR 6.99 (s, 1H), 5.32 (d, J=5.9 Hz, 1H), 4.56-4.50 (m, 1H), 3.70 (dd, J=15.1, 9.6 Hz, 1H), 3.59-3.49 (m, 1H), 3.46 3.30 (m, 4H), 3.29-3.20 (m, 2H), 3.08-3.02 (m, 2H), 1.40 (s, 3H), 1.38 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[CH:5][NH:4][N:3]=1.[F:8][C:9]([F:26])([F:25])[C:10](=O)[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=O>C(O)(=O)C.O>[Br:7][C:6]1[CH:5]=[N:4][N:3]2[C:10]([C:9]([F:8])([F:26])[F:25])=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=3)=[N:1][C:2]=12
Reactant: Nc1n[nH]cc1Br
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(Br)c3n2)cc1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
A stirred mixture of commercially available 3-amino-4-bromo-pyrazole (14.00 g, 86.4 mmol) and 4,4,4-trifluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (Example C.1 step 1) (24.56 g, 86.4 mmol) in acetic acid (170 mL) was heated under reflux conditions for 2.5 h. The reaction mixture was cooled to room temperature, diluted with water (340 mL), the precipitate was filtered off, washed with water and dried in air at 60° C. to give the 3-bromo-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (31.77 g, 90%) as a yellow solid. MS (EI) 410.0 [(M)+], 412.0 [(M+2)+]; mp 136° C.