Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8](I)=[CH:9][CH:10]=3)[C@@:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:4]=2[CH:3]=1.[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:26]4[CH:27]=[N:22][CH:23]=[N:24][CH:25]=4)=[CH:9][CH:10]=3)[C@@:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:4]=2[CH:3]=1
Reactant: OB(O)c1cncnc1
Reactant: NC1=N[C@]2(CO1)c1cc(Br)ccc1Oc1ccc(I)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: NC1=N[C@]2(CO1)c1cc(Br)ccc1Oc1ccc(-c3cncnc3)cc12
Temperature: 65 °C

Procedure:
100 ml RBF was charged with (R)-2′-bromo-7′-iodo-5H-spiro[oxazole-4,9′-xanthen]-2-amine (1.5 g, 3.28 mmol), pyrimidin-5-ylboronic acid (0.488 g, 3.94 mmol), tetrakis(triphenylphosphine)palladium(0) (0.284 g, 0.246 mmol). DME (23.44 mL) followed by sodium carbonate (4.92 mL, 9.85 mmol) (2M solution) were added and the mixture was heated at 65° C. for 24 h. The mixture was diluted with water and EtOAc, filtered and organic layer was separated and concentrated. The crude material was purified by flash chromatography on 40 g RediSep column using 5-70% gradient of DCM/MeOH/NH4OH in DCM to give (S)-2′-bromo-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].Cl>C(Cl)Cl.O>[CH3:22][S:23]([NH:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:25])=[O:24]
Reactant: Nc1cc(O)ccc1Oc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(O)ccc1Oc1ccccc1
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
20.1 g of 3-amino-4-phenoxyphenol and 23.7 g of pyridine were dissolved in 200 ml of methylene chloride. To the resulting solution being ice-cooled was dropwise added a solution of 12.6 g of methanesulfonyl chloride in 60 ml of methylene chloride, at the same temperature in 30 minutes. The mixture was subjected to reaction at the same temperature for 2 hours. 200 ml of water was added thereto and then 4N hydrochloric acid was added to adjust the pH to 3. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and then dried with anhydrous magnesium sulfate. Thereafter, the organic layer was subjected to distillation under reduced pressure to remove the solvent. The resulting crystal was recrystallized from benzene to obtain 23.7 g (yield: 84.9%) of 3-methylsulfonylamino-4-phenoxyphenol having a melting point of 138°-140° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[NH2:5].[F:15][C:16]1[CH:27]=[CH:26][C:19]([C:20]([CH2:22][C:23]([CH3:25])=O)=[O:21])=[CH:18][CH:17]=1>CO>[CH3:1][O:2][C:3](=[O:14])[CH:4]([NH:5][C:23]([CH3:25])=[CH:22][C:20](=[O:21])[C:19]1[CH:26]=[CH:27][C:16]([F:15])=[CH:17][CH:18]=1)[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CC(=O)CC(=O)c1ccc(F)cc1
Solvent: CO
Product: COC(=O)C(Cc1ccc(O)cc1)NC(C)=CC(=O)c1ccc(F)cc1
Yield: 95.9 %

Procedure:
To a solution of L-tyrosine methyl ester (4.00 g, 20.51 mmol) in methanol (150 ml) is added 1-(4-fluorobenzoyl)acetone (4.06 g, 22.56 mmol), then the mixture is heated to reflux for 24 h. The solvent is evaporated under a vacuum. To the residue is added ethanol (50 ml), then the ethanol is distilled off under atmospheric pressure. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give the title compound (7.03 g, 96%).
Reaction SMILES: N[S:2]([C:5]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([CH:20]([CH2:22][CH3:23])[CH3:21])[C:6]=1[C:7]([N:9](CC)CC)=[O:8])(=[O:4])=[O:3]>C(O)(=O)C>[CH:20]([C:14]1[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=[C:5]2[C:6]=1[C:7](=[O:8])[NH:9][S:2]2(=[O:4])=[O:3])([CH2:22][CH3:23])[CH3:21]
Reactant: CCC(C)c1cc(OC)cc(S(N)(=O)=O)c1C(=O)N(CC)CC
Solvent: CC(=O)O
Product: CCC(C)c1cc(OC)cc2c1C(=O)NS2(=O)=O

Procedure:
A mixture of acetic acid (200 mL) and 2-aminosulfonyl-6-sec-butyl-4-methoxy-N,N-diethylbenzamide. (51.7 g) was refluxed overnight. The acetic acid was removed by distillation, the residue was poured into ice/2M NaOH (80 mL). The aqueous solution was washed with CH2Cl2, acidified with concentrated HCl and the precipitate which formed was collected by filtration to afford 4-sec-butyl-6-methoxysaccharin.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([NH2:12])=[O:11].Cl[CH2:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[C:18]=2[N:19]=1>>[CH2:24]([C:20]1[C:18]2[N:19]=[C:15]([CH2:14][O:8][C:7]3[C:2]([F:1])=[C:3]([C:10]([NH2:12])=[O:11])[C:4]([F:9])=[CH:5][CH:6]=3)[S:16][C:17]=2[CH:23]=[CH:22][CH:21]=1)[CH3:25]
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: CCc1cccc2sc(CCl)nc12
Product: CCc1cccc2sc(COc3ccc(F)c(C(N)=O)c3F)nc12
Yield: 17 %

Procedure:
Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide and 2-(chloromethyl)-4-ethyl-1,3-benzothiazole according to Method B, scheme 2. Yield 17%, mp 184-186° C., HPLC-MS (method 1): m/z 349 [M+H]+, Rt=4.16 min.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1N)([CH3:3])[CH3:2].N([O-])=O.[Na+].[I-:18].[K+]>O.Cl>[CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[I:18])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1I
Yield: 44.2 %

Procedure:
To a solution of 7.09 g (40 mmol) of 2, 6-diisopropylaniline in 54 ml of water and 18 ml of conc. hydrochloric acid was dropwise added a solution of 2.76 g (40 mmol) of sodium nitrite in 16 ml of water with sufficient stirring and ice cooling, and the resultant mixture was stirred for further 10 minutes. A solution of 6.64 g (40 mmol) of potassium iodide in 6 ml of water was added to the mixture, and the mixture was stirred for 4 hours at room temperature and refluxed with heating for 1 hour. After cooling, the reaction mixture was extracted with hexane, and the extract was washed with aqueous sodium nitrite and saturated saline in this order, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was chromatographed on a silica gel column, eluting with hexane to give 5.09 g of 2, 6-diisopropylphenyl iodide as an oil.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH2:7]([C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14])[CH2:8][CH2:9][CH3:10]>C1C=CC=CC=1>[CH2:7]([C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH:14][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])[CH2:8][CH2:9][CH3:10]
Reactant: C=C1CC(=O)O1
Reactant: CCCCc1cccc(N)c1
Solvent: c1ccccc1
Product: CCCCc1cccc(NC(=O)CC(C)=O)c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
3.9 g of diketene were added to a mixture of 6.9 g of m-(n-butyl)-aniline and 70 ml of benzene and the mixture was stirred for 2 hours at 30° C. The benzene was evaporated under reduced pressure and the residue was chromatographed over silica gel. Elution with an 8-2 mixture of methylene chloride and ethyl acetate yielded 8.5 g of m-(n-butyl)-acetylacetanilide in the form of an oil with a refractive index of nD 20 = 1.5355.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[CH:9][C:10]3[C:16](=[O:17])[C:15]([C:18]([OH:20])=[O:19])=[CH:14][N:13]([CH2:21][CH3:22])[C:11]=3[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:30]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)([O-:32])=[O:31]>CN(C)C=O>[N+:30]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[N:8]=[CH:9][C:10]4[C:16](=[O:17])[C:15]([C:18]([OH:20])=[O:19])=[CH:14][N:13]([CH2:21][CH3:22])[C:11]=4[N:12]=3)[CH2:6][CH2:5]2)=[CH:35][CH:34]=1)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(Cc4ccc([N+](=O)[O-])cc4)CC3)nc21
Temperature: 90 °C
Yield: 69.9 %

Procedure:
A mixture of 2.0 g of 2-(1-piperazinyl)-8-ethyl-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid, 1.34 g of triethylamine, 2.14 g of p-nitrobenzyl bromide, and 50 ml of dimethylformamide was heated at 90° C. for 14 hours with stirring and concentrated to dryness under reduced pressure. Addition of 50 ml of water to the residue resulted in the separation of a solid, which was collected and recrystallized from dimethylformamide to give the product (2.02 g), m.p. 259°-261° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:18]=[C:17]2[C:12]([C:13]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:14][C:15]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:16]2)=[N:11][C:10]=1[Cl:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](=[O:34])([O-])[OH:32].[Na+]>O1CCCC1>[CH2:1]([NH:8][C:9]1[N:18]=[C:17]2[C:12]([C:13]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:14][C:15]([N:19]3[CH2:20][CH2:21][N:22]([C:31]([O:32][C:2]([CH3:7])([CH3:3])[CH3:1])=[O:34])[CH2:23][CH2:24]3)=[N:16]2)=[N:11][C:10]=1[Cl:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc2c(N3CCCC3)nc(N3CCNCC3)nc2nc1NCc1ccccc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N3CCCC3)c3nc(Cl)c(NCc4ccccc4)nc3n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.02 g (2.40 mmol) 7-benzylamino-6-chloro-2-piperazino-4-pyrrolidino-pteridine are placed in 10 ml of tetrahydrofuran, 1.05 g (4.80 mmol) BOC-anhydride and 5 ml saturated sodium hydrogen carbonate solution are added. The mixture is stirred for 1.5 hours at ambient temperature, then evaporated down in vacuo. The aqueous residue is diluted with water, the precipitate is suction filtered, washed and dried.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@@H:9]([OH:12])[C@H:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:38]1[C:43](O)=[CH:42][CH:41]=[C:40]([CH3:45])[CH:39]=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:43]2[CH:42]=[CH:41][C:40]([CH3:45])=[CH:39][CH:38]=2)[C@H:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1ccc(O)cc1
Reactant: CCOC(=O)N1CC[C@@H](O)[C@H](c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)N1CC[C@H](Oc2ccc(C)cc2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 6.23 g of trans-1-ethoxycarbonyl-3-phenyl-4-piperidinol, 7.21 g of triphenylphosphine, 2.97 g of p-cresol and 250 ml of benzene is added dropwise, at 50° C. under nitrogen, a solution of 4.79 g of diethyl azodicarboxylate in 250 ml of benzene. After the addition is complete, the mixture is stirred overnight at room temperature. The reaction mixture is processed according to the procedure of Example 75 to give the product as a gum.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][OH:13])[C:8]([O:14][CH3:15])=[CH:7][C:6]=1[OH:16])=O.C([O-])(=O)C.[Na+].O.C(OCC)(=O)C>CO>[CH3:15][O:14][C:8]1[C:9]([CH2:11][CH2:12][OH:13])=[CH:10][C:5]2[CH:3]=[CH:2][O:16][C:6]=2[CH:7]=1
Reactant: COc1cc(O)c(C(=O)CBr)cc1CCO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2occc2cc1CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
16.4 g of the above 2-bromo-1-(2-hydroxy-5-(2-hydroxyethyl)-4-methoxyphenyl)-1-ethanone was dissolved in 70 ml of methanol. Thereafter, 17.3 g of sodium acetate was added to the obtained solution, and the obtained mixture was then heated to reflux for 5 minutes. After cooling, water and ethyl acetate were added to the reaction mixture, and an organic layer was separated. The organic layer was successively washed with water and a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent was then distilled away under a reduced pressure. The residue was dissolved in 150 ml of methanol. Thereafter, 6.30 g of sodium borohydride was dividedly added to the obtained solution, and the obtained mixture was stirred at a room temperature for 1 hour. Subsequently, 6 mol/l hydrochloric acid was added to the reaction solution, so that the pH thereof was adjusted to pH 1. The obtained solution was further stirred at a room temperature for 1 hour. This reaction mixture was concentrated under a reduced pressure. Thereafter, water and ethyl acetate were added thereto, and an organic layer was separated. The organic layer was successively washed with water and a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent was then distilled away under a reduced pressure. The residue was purified by column chromatography (eluent: hexane:ethyl acetate=4:1), so as to obtain 1.48 g of a light yellow crystal, 2-(6-methoxy-1-benzofuran-5-yl)-1-ethanol.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([C:16](=[O:26])[CH2:17][CH2:18][CH2:19][C:20]#[C:21][Si](C)(C)C)[N:6]=1)([CH3:4])[CH3:3].O.O.[F-].[K+]>CN(C)C=O>[CH3:4][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[N:8]=[C:7]([C:16](=[O:26])[CH2:17][CH2:18][CH2:19][C:20]#[CH:21])[N:6]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1nc(C(=O)CCCC#C[Si](C)(C)C)nc(C(C)(C)C)c1O
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCCCC(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Temperature: 50 °C
Reaction time: 47 h

Procedure:
A mixture of 1-[4,6-bis(1,1-dimethylethyl)-5-hydroxypyrimidin-2-yl]-6-trimethylsilyl-5-hexyn-1-one (0.87 g, 2.3 mmol), Example 8, and potassium fluoride dihydrate (0.91 g, 9.7 mmol) in N,N-dimethylformamide (12 mL) is warmed to 50° C. After stirring for 47 hours at 50° C., the solvent is removed under vacuum and the organic residue is diluted with water. This mixture is extracted with ethyl acetate and the combined extracts are washed with saturated aqueous ammonium chloride solution and brine. The organic is concentrated under vacuum and the organic residue purified by flash chromatorgraphy (SiO2, 20% ethyl acetate (hexane) followed by recrystallization from methanol and water to give 0.48 g (68%) of the title compound), mp 64°-66° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=1[OH:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH2:30]([O:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Cl)=[CH:40][CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=1[O:27][CH2:42][C:41]1[CH:44]=[CH:45][C:38]([O:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:39][CH:40]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1O
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1OCc1ccc(OCc2ccccc2)cc1
Yield: 50.5 %

Procedure:
(2S)-[2-(4-Benzyloxy-benzyloxy)-5-bromo-benzoylamino]-3-biphenyl-4-yl-propionic acid methyl ester (302 mg, 50%) was prepared from (2S)-3-Biphenyl-4-yl-2-(5-bromo-2-hydroxy-benzoylamino)-propionic acid methyl ester (400 mg, 0.92 mmol) and 4-benzyloxybenzyl chloride (256 mg, 0.39) as described in general procedure H and purified over silica gel (8:2, DCM-hexanes).
Reaction SMILES: C1(OC)C=CC=CC=1.C(OC([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][O:23][CH2:24][C@H:25]([NH:32][C:33]([C:35]2[CH:43]=[C:42]3[C:38]([C:39]([CH3:44])=[CH:40][NH:41]3)=[CH:37][CH:36]=2)=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18][CH2:17]1)=O)(C)(C)C>>[CH3:44][C:39]1[C:38]2[C:42](=[CH:43][C:35]([C:33]([NH:32][C@H:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:24][O:23][CH2:22][CH:19]3[CH2:18][CH2:17][NH:16][CH2:21][CH2:20]3)=[O:34])=[CH:36][CH:37]=2)[NH:41][CH:40]=1
Reactant: Cc1c[nH]c2cc(C(=O)N[C@@H](COCC3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc3)ccc12
Solvent: COc1ccccc1
Product: Cc1c[nH]c2cc(C(=O)N[C@@H](COCC3CCNCC3)c3ccccc3)ccc12

Procedure:
Using deprotection method B, but without addition of anisole, 4-{(R)-2-[(3-methyl-1H-indole-6-carbonyl)amino]-2phenylethoxymethyl}piperidine-1-carboxylic acid tert-butyl ester (1.5 g crude, 3.0 mmol) afforded the title compound as a crude residue, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3=[CH:14][CH2:15][CH2:16][CH2:17][C:12]3([CH2:18][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[NH:11][C:10]2=[O:27])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C=O)C>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][C:13]12[CH2:14][CH2:15][CH2:16][CH2:17][C:12]1([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=1)[NH:11][C:10](=[O:27])[N:9]2[C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:36]
Reactant: N#Cc1ccc(CC23CCCC=C2N(c2cc(Cl)cc(Cl)c2)C(=O)N3)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC12CCCCC1(Cc1ccc(C#N)cc1)NC(=O)N2c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[1-(3,5-Dichlorophenyl)-2-oxo-1,2,3,4,5,6-hexahydro-benzimidazol-3a-ylmethyl]benzonitrile (150 mg) (0.38 mmol) in DMF (5 ml) was carefully dropped on a suspension of NaH 60% (18.2 mg) (1.2 eq) in DMF (5 ml) at RT. The reaction mixture was stirred for 1 h at RT, then ethyl bromoacetate (0.052 ml) (1.2 eq) was added. After one night, the reaction mixture was poured on water and extracted with tBuOMe. The organic layer was washed with water, dried over Na2SO4 and concentrated. The residue was purified on SiO2 chromatography (eluent EtOAc/cyclohexane—2/8) to give [7a-(4-Cyano-benzyl)-3-(3,5-Dichlorophenyl)-2-oxo-2,3,5,6,7,7a-hexahydro-benzimidazol-3a-yl]-acetic acid ethyl ester (46.5 mg) as a white solid. 1H NMR (CDCl3): 7.55 (2H, d), 7.25 (2H, d), 7.1 (1H, m), 6.8 (2H, m), 5.0 (1H, m), 4.45 (1H, d), 4.2 (2H, q), 3.75 (1H, d), 3.05 (1H, d), 2.90 (1H, d), 2.5-2.1 (2H, m), 2.1-1.8 (4H, m), 1.25 (3H, t).
Reaction SMILES: [Cl:1][C:2]([F:14])([F:13])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([OH:12])=O)=[CH:5][CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:28][O:29][C:30](=[O:33])[CH2:31][NH2:32]>O1CCCC1>[Cl:1][C:2]([F:14])([F:13])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([NH:32][CH2:31][C:30]([O:29][CH3:28])=[O:33])=[O:12])=[CH:5][CH:4]=1
Reactant: COC(=O)CN
Reactant: O=C(O)c1ccc(C(F)(F)Cl)[nH]c1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)CNC(=O)c1ccc(C(F)(F)Cl)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
300 mg (1.34 mmol) of 6-[chloro(difluoro)methyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid were dissolved in 5 ml of tetrahydrofuran, 435 mg (2.68 mmol) of N,N-carbonyldiimidazole were added and the mixture was stirred initially at room temperature for 30 min and then under reflux for 30 min. A mixture of 168 mg (1.34 mmol) of glycine methyl ester hydrochloride in 3 ml of tetrahydrofuran was then added, and the mixture was heated under reflux for a further 2 h. The solution was evaporated to dryness, the residue was taken up in ethyl acetate and the solution was washed with 1N hydrochloric acid and water, dried and concentrated. This gave 92 mg (23% of theory) of a light-brown powder.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][C:3]=1C.[CH:14](Cl)(Cl)Cl.IC>C(=O)([O-])[O-].[Ag+2].C(N(CC)CC)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:14])=[N:4][CH:3]=1
Reactant: Cc1[nH]c(=O)c2ccccc2c1Br
Reactant: ClC(Cl)Cl
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CI
Solvent: CCN(CC)CC
Product: COc1ncc(Br)c2ccccc12
Reaction time: 72 h
Yield: 60 %

Procedure:
To a stirred suspension of 4-bromo-3-methyl-2H-isoquinolin-1-one (1.86 g, 7.81 mmol), silver carbonate (2.92 g, 10.6 mmol) and chloroform (150 mL) is added dropwise over 10 min iodomethane (7.3 mL, 117 mmol) and the mixture is stirred in the dark for 3 d. Triethylamine is added and the solids are removed by filtration through a pad of Celite. The filtrate is concentrated and the residue is purified by chromatography eluting with dichloromethane. Product containing fractions are combined and concentrated to afford 4-bromo-1-methoxyisoquinoline (1.19 g, 60% yield) as an oil that solidified on standing. LC/MS: MS m/e=252/254 (M+H); RT 4.68; 1H NMR (CDCl3, δ ppm) 8.19 (1H, d), 8.09 (1H, d), 7.71 (1H, t), 7.50 (1H, t), 4.10 (3H, s); 2.71 (3H, s).
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([NH2:8])[CH:3]=1.CCN(C(C)C)C(C)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>ClCCCl>[Br:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([NH:8][S:18]([CH3:21])(=[O:20])=[O:19])[CH:3]=1
Reactant: Cn1nc(N)cc1Br
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cn1nc(NS(C)(=O)=O)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.8 %

Procedure:
5-Bromo-1-methyl-1H-pyrazol-3-amine (500 mg, 2.84 mmol) and DIPEA (2.47 mL, 14.2 mmol) were stirred in anhydrous 1,2-dichloroethane (8 mL) at room temperature, then mesyl chloride (550 μL, 7.1 mmol) in 1,2-dichloroethane (1.5 mL) was added dropwise. The mixture was stirred at room temperature for 3 h, then partitioned between DCM and water. The organic phases were separated and washed with brine, then dried over sodium sulfate and concentrated. To the resulting orange/brown solid was added 1M tetrabutylammonium fluoride in THF (10.5 mL) and the mixture was heated at reflux for 4 h. The reaction mixture was concentrated and diluted with DCM (40 mL), then washed with water (4×25 mL), followed by brine (25 mL). The organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with 35-50% EtOAc in heptane followed by 5-10% MeOH in DCM, to afford the title compound (388 mg, 54%) as a white solid. δH (250 MHz, CDCl3) 6.33 (s, 1H), 3.85 (s, 3H), 3.02 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][C:24]1[C:32]2[CH:31]3[CH2:33][CH:28]([CH2:29][CH2:30]3)[C:27]=2[N:26]([CH3:34])[N:25]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][C:24]1[C:32]2[CH:31]3[CH2:33][CH:28]([CH2:29][CH2:30]3)[C:27]=2[N:26]([CH3:34])[N:25]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: Cn1nc(CON)c2c1C1CCC2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cn1nc(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)c2c1C1CCC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (10.0 mL) were added 3-[(aminooxy)methyl]-1-methyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazole 149 (0.172 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 150 (0.34 g, 83%) as a white foam.