Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:28])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:27])[C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=O)[CH2:12][CH2:11]1.[NH2:35][C:36]1[S:40][C:39]([C:41]([N:43]([CH3:55])[CH2:44][CH2:45][N:46]([CH3:54])[C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:42])=[C:38]([CH3:56])[CH:37]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH4-].[Na+]>C(Cl)Cl.C(O)(=O)C>[C:1]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:28])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:35][C:36]2[S:40][C:39]([C:41](=[O:42])[N:43]([CH2:44][CH2:45][N:46]([C:47]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:53])[CH3:54])[CH3:55])=[C:38]([CH3:56])[CH:37]=2)[CH3:27])[CH2:12][CH2:11]1
Reactant: Cc1cc(N)sc1C(=O)N(C)CCN(C)C(=O)OC(C)(C)C
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)sc1C(=O)N(C)CCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.1 %

Procedure:
The compound (210 mg, 0.450 mmol) obtained in Example 4g and the compound (134 mg, 0.409 mmol) obtained in Example 89c were dissolved in methylene chloride (4 mL), acetic acid (79 μL) and sodium triacetoxyborohydride (130 mg, 0.614 mmol) were added, and the mixture was stirred at room temperature for 12 hours. Sodium borohydride (16 mg, 0.409 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1→ethyl acetate:methanol=50:1, v/v) to give the title compound (153 mg; yield, 49%) as a light yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1.[N-:30]=[N+:31]=[N-:32].[Na+].O>CN(C=O)C>[N:30]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1)=[N+:31]=[N-:32]
Reactant: BrCc1cccc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cccc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.9 %

Procedure:
A solution of 2-bromomethyl-6-(triphenylmethoxymethyl)pyridine (3.04 g, 6.84 mmol) in DMF (25 mL) was treated with sodium azide (650 mg, 10 mmol) and stirred at room temperature for 20 h. The reaction was poured into water (100 mL), extracted with EtOAc (2×50 mL) and the combined organic phase was washed with brine (25 mL), dried (MgSO4) and concentrated in vacuo to give the product (2.75 g, 99%) as a yellow oil; IR νmax (Film)/cm−1 3060, 2103, 1679, 1594, 1448, 1096 and 706; NMR δH (400 MHz, CDCl3) 4.36 (2H, s), 4.39 (2H, s), 7.20-7.33 (10H, m), 7.49-7.52 (6H, m) and 7.72-7.80 (2H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Br-:12].[Br-:13].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.O>[Br:12][C:6]1([Br:13])[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: O
Product: O=C1Nc2cc(Cl)ccc2C1(Br)Br
Reaction time: 3.5 h
Yield: 101.2 %

Procedure:
At room temperature, to a solution of 6-chlorooxindole (10.0 g, 59.7 mmol ) in t-BuOH (500 mL) and water (2.6 mL) was added pyridinium tribromide (57.25 g, 79 mmol, 3 eq) and the reaction was stirred for 3.5 hr. The reaction was diluted with water (500 mL) and extracted with EtOAc (3×). The combined organic extracts were washed with sat. aq. NaHCO3 (3×), dried over MgSO4, filtered and concentrated to give the title compound as a tan solid (19.66 g, 100% yield). NMR (400 MHz, DMSO-d6): consistent. MS: (API-ES+) m/z 325 [M+H].
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[CH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:32])=[O:31])=[CH:26][CH:25]=1)[C:18]([CH3:33])=[C:17]2[CH2:34][C:35]([OH:37])=[O:36]>CC(C)=O>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[CH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:32])(=[O:9])=[O:31])=[CH:26][CH:25]=1)[C:18]([CH3:33])=[C:17]2[CH2:34][C:35]([OH:37])=[O:36]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2c(c1)C(CC(=O)O)=C(C)C2=Cc1ccc(S(C)=O)cc1
Solvent: CC(C)=O
Product: COc1ccc2c(c1)C(CC(=O)O)=C(C)C2=Cc1ccc(S(C)(=O)=O)cc1

Procedure:
5-methoxy-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acid is prepared by the addition of 1.0 mol of m-chloroperbenzoic acid per mol of 5-methoxy-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetic acid in an acetone solution.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].Cl[CH:9]([C:15](=O)[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].Cl>C(O)C.CCOCC>[CH2:13]([O:12][C:10]([C:9]1[N:1]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]2=[N:7][C:15]=1[CH3:16])=[O:11])[CH3:14]
Reactant: Nc1cnccn1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1c(C)nc2cnccn12
Yield: 57.9 %

Procedure:
A solution of pyrazin-2-amine (3.6 g, 37.9 mmol) and ethyl 2-chloro-3-oxobutanoate (5.24 ml, 37.9 mmol) in ethanol (30 ml) was heated at reflux for 9 hours. A 1N solution of HCl in ether was added and the mixture was concentrated under reduced pressure. The residue was triturated with 3×50 ml acetonitrile and filtered to yield crude 2-Methyl-imidazo[1,2-a]pyrazine-3-carboxylic acid ethyl ester (4.5 g, 58%) as an amorphous solid which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([O:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18]Br)[CH:14]=2)[N:9]=[CH:8]1)=[O:4].[CH2:22]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][CH:27]=1)[C:23]#[CH:24].C(=O)([O-])[O-].[Ca+2]>CC(N(C)C)=O>[CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([O:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][N:25]([C:26]3[CH:27]=[CH:28][C:29]([C:32](=[O:34])[CH3:33])=[CH:30][CH:31]=3)[CH2:22][C:23]#[CH:24])[CH:14]=2)[N:9]=[CH:8]1)=[O:4]
Reactant: C#CCNc1ccc(C(C)=O)cc1
Reactant: CC(C)(C)C(=O)OCn1cnc2ccc(CBr)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)N(C)C
Product: C#CCN(Cc1ccc2ncn(COC(=O)C(C)(C)C)c(=O)c2c1)c1ccc(C(C)=O)cc1
Temperature: 80 °C
Yield: 186.8 %

Procedure:
A suspension of 5.79 g (12.5 mmol) of 75% pure 2,2-dimethylpropanoic acid, [6-(bromomethyl)-4-oxo-3(4H)-quinazolinyl]methyl ester (European patent application 204,529), 2.89 g (16.7 mmol) of 1-[4-(2-propynylamino)phenyl]ethanone (see Example A), and 3.34 g (33.4 mmol) of dry calcium carbonate in 100 ml of dimethylacetamide (DMA) is stirred at 80° C. for eighteen hours. The suspension is poured into a water-ice mixture and stirred. The suspension is extracted with ethyl acetate. The ethyl acetate solution is dried (magnesium sulfate) and concentrated to give 10.4 g of a yellow oil. This is dissolved in a minimum amount of dichloromethane and applied to a column of 1 kg of flash silica gel packed in dichloromethane/methanol (100:1). Elution with the same solvent gives 2.83 g (50.8%) of impure product as a yellow gum followed by 2.34 g (42.0% assuming 75% pure bromomethyl compound) of the product as a cream colored foam. This is used as is without characterization in the next reaction.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:18])[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])=[N:4][CH:3]=1.Br[CH2:20][C:21]1[N:22]=[CH:23][S:24][CH:25]=1>>[Br:1][C:2]1[S:6]/[C:5](=[N:7]\[C:8](=[O:18])[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])/[N:4]([CH2:20][C:21]2[N:22]=[CH:23][S:24][CH:25]=2)[CH:3]=1
Reactant: BrCc1cscn1
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(Br)s1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(Br)cn1Cc1cscn1
Yield: 52 %

Procedure:
A mixture of Example 84A (1001 mg, 3.33 mmol) and commercially available 4-(bromomethyl)thiazole were processed using the method described for Example 83B to afford the title compound (660 mg, 52% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.78 (s, 3H), 5.54 (s, 2H), 7.12 (d, J=9.2 Hz, 1H), 7.49 (dd, J=8.8, 2.7 Hz, 1H), 7.69 (dd, J=15.9, 2.4 Hz, 2H), 7.93 (s, 1H), 9.10 (d, J=2.0 Hz, 1H) MS (DCI) m/z 445 (M+H)+; Anal. Calculated for C15H11BrClN3O2S2: C, 40.51; H, 2.49; N, 9.45. Found: C, 40.85; H, 2.90; N, 9.62.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:27])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[C:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:12]=1)[CH2:5]O.B(Br)(Br)[Br:29]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:27])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:12]=1)[CH2:5][Br:29]
Reactant: COc1ccc(Oc2c(Cl)cc(CO)cc2Cl)cc1Cc1ccc(F)cc1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Oc2c(Cl)cc(CBr)cc2Cl)cc1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
To a stirred solution of 3,5-dichloro-4-[3′-(4-fluorobenzyl)-4′-methoxyphenoxy]benzyl alcohol (0.53 g, 1.29 mmol) in CH2Cl2 (20 mL) at −78° C. was added BBr3 (0.82 g, 3.2 mmol). The reaction mixture was stirred at room temperature for 16 h, poured into ice water (100 mL) and extracted with CH2Cl2 (200 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (1:4) to afford 3,5-dichloro-4-[3′-(4-fluorobenzyl)-4′-hydroxyphenoxy]benzyl bromide as a colorless oil (0.4 g, 67%): 1H NMR (300 MHz, CDCl3): δ 7.39 (s, 2 H), 7.14 (dd, J=5.4, 8.7 Hz, 2 H), 6.95 (t, J=8.7 Hz, 2 H), 6.66 (d, J=9.0 Hz, 1 H), 6.62 (d, J=2.7 Hz, 1 H), 6.53 (dd, J=3.0, 8.7 Hz, 1 H), 4.04 (s, 2 H), 3.90 (s, 2 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:4); Rf=0.8.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][O:4][CH:3]([C:7](OC)=[O:8])[CH2:2]1.[BH4-].[Li+].O>O1CCCC1>[OH:8][CH2:7][CH:3]1[O:4][CH2:5][CH2:6][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2]1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(CO)C1
Reaction time: 1 h

Procedure:
The crude product from step (i) (62.6 mmol) was dissolved in dry tetrahydrofuran (THF) (100 ml) and added dropwise at 0° C. to a suspension of lithium borohydride (2.50 g, 115 mmol) in dry THF (100 ml). The mixture was allowed to attain room temperature over night. Water (10 ml) was added and after stirring for 1 h the mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic phase was washed with 0.5 M hydrochloric acid, saturated sodium hydrogen carbonate and water. Drying over magnesium sulfate and concentration gave the title compound as a crude product (13.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=2)([OH:14])[CH2:9][NH:10][CH2:11][CH2:12]O)=[CH:4][CH:3]=1.OS(O)(=O)=O>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=3)[O:14][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OCCNCC(O)(c1ccc(Cl)cc1)c1ccc(I)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Clc1ccc(C2(c3ccc(I)cc3)CNCCO2)cc1
Reaction time: 20 h
Yield: 43.2 %

Procedure:
A solution of 1-(4-chloro-phenyl)-2-(2-hydroxy-ethylamino)-1-(4-iodo-phenyl)-ethanol (701 mg, 1.68 mmol) in DCM (10 mL) was treated with concentrated H2SO4 (0.1 mL, 1.9 mmol). After 20 hours, another portion of H2SO4 (1.0 mL, 19 mmol) was added and the mixture stirred for a further 2 hours. The mixture was diluted with ethyl acetate and washed with saturated potassium carbonate and brine then dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (SiO2), eluting with 0.5% triethylamine in ethyl acetate to afford the title compound (290 mg, 43%); LCMS (PS-A2) Rt 2.40 min [M+H]+400.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:5](=[CH:10][C:11]([N:24]([CH2:31][CH:32]=[CH2:33])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:12]([N:14]([CH2:21][CH:22]=[CH2:23])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1)[C:6](OC)=[O:7].[NH3:35]>CO>[CH2:21]([N:14]([C:12]1[CH:13]=[C:4]2[C:3](=[O:2])[NH:35][C:6](=[O:7])[C:5]2=[CH:10][C:11]=1[N:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:31][CH:32]=[CH2:33])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH:22]=[CH2:23]
Reactant: C=CCN(c1ccccc1)c1cc(C(=O)OC)c(C(=O)OC)cc1N(CC=C)c1ccccc1
Reactant: N
Solvent: CO
Product: C=CCN(c1ccccc1)c1cc2c(cc1N(CC=C)c1ccccc1)C(=O)NC2=O
Temperature: 120 °C

Procedure:
In an autoclave, 457 mg (1 mmol) of 4,5-bis(N-allylanilino)phthalic acid dimethyl ester are dissolved in 5 ml of methanol, and 15 ml of ammonia are Used for the purpose of amide formation. The autoclave is closed and then heated at 120° C. for 24 hours, then cooled and opened, and the ammonia is driven off with nitrogen. The residue is rinsed out with ethyl acetate and filtered, and the filtrate is chromatographed on silica gel with hexane/ethyl acetate 3:1. The product fractions are concentrated by evaporation and crystallized from hexane/ethyl acetate, yielding the title compound in the form of yellow crystals, FAB-MS: 410 [M+ +H], m.p. 122°-127° C. As byproduct of the reaction, 4,5-Bis-(N-allyl-N-phenylamino)phthalic acid monoamide was isolated and recrystallized from hexane/ethyl acetate to yield yellow crystals, FAB-MS: 428 [M+ +H], m.p. 114°-116° C.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:28])[CH:11]=[C:12]([CH3:27])[N:13]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH:14]=1)C1C=CC=CC=1>Cl>[C:17]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=[C:15]([N:13]2[CH:14]=[C:9]([OH:8])[C:10](=[O:28])[CH:11]=[C:12]2[CH3:27])[CH:16]=1
Reactant: Cc1cc(=O)c(OCc2ccccc2)cn1-c1cccc(-c2ccccc2)c1
Agent: Cl
Product: Cc1cc(=O)c(O)cn1-c1cccc(-c2ccccc2)c1
Temperature: 140 °C

Procedure:
6.0 g (16.3 mmol) 5-(benzyloxy)-1-biphenyl-3-yl-2-methylpyridin-4(1H)-one was suspended in 150 ml 4 N aq HCl. The reaction mixture was heated at 140° C. for 18 h, then cooled to rt, concentrated in vacuo, suspended in CH2Cl2, and collected by filtration to give 1-biphenyl-3-yl-5-hydroxy-2-methylpyridin-4(1H)-one. LCMS (M+H)+=278.2.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[C:14]([CH2:17][N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]([NH:28][C:29]([C:31]2[NH:32][C:33]3[C:38]([CH:39]=2)=[CH:37][C:36]([Cl:40])=[CH:35][CH:34]=3)=[O:30])[C:19]1=[O:41])(O)=[O:15].[Li+].[BH4-]>C1COCC1>[Cl:40][C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:29]([NH:28][CH:20]1[CH2:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:18]([CH2:17][CH2:14][OH:15])[C:19]1=[O:41])=[O:30])=[CH:39]2
Reactant: O=C(O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1Cc2ccccc2N(CCO)C1=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1 h
Yield: 77 %

Procedure:
Triethylamine (0.168 mL, 1.21 mmol) then ethyl chloroformate (0.115 mL, 1.21 mmol) were added to N-[1-(carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-5-chloroindole-2-carboxamide (Example 2, 437 mg, 1.10 mmol) in anhydrous THF (10 mL) at 0° C. followed by stirring for 1 h. LiBH4 (2.0 M in THF, 0.69 mL, 1.37 mmol) was added slowly and the mixture stirred for a further 30 min. The reaction was carefully quenched with 1M HCl (50 mL) and EtOAc (100 mL) and the organic layer was further washed with sat. aqueous NaHCO3 (30 mL), brine (30 mL), dried (MgSO4), filtered and evaporated. The residue was triturated with refluxing Et2O (10 mL) and after cooling the solid was filtered and dried to afford the title compound (325 mg, 77%) a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)=[O:20].O>CC(C)=O>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([C:19](=[O:20])[CH2:18][O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[O:9][CH3:10])=[CH:22][CH:23]=1
Reactant: COc1cc(F)ccc1O
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(F)ccc1OCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-fluoro-2-methoxy-phenol (3.0 g, 21.1 mmol) in acetone (250 mL) is treated with cesium carbonate (8.3 g, 25.3 mmol) followed by 2-bromo-1-(4-bromo-phenyl)-ethanone (5.9 g, 21.1 mmol). The resulting mixture is stirred at room temperature for 2 h. Water (600 mL) is added slowly to the vigorously stirring solution. After stirring for 30 minutes, the precipitate is filtered off and washed with copious water to give 1-(4-bromo-phenyl)-2-(4-fluoro-2-methoxy-phenoxy)-ethanone (G-1).
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23]>ClCCl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:12][C:22](=[O:24])[CH3:23])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(Oc2ccccc2)cc1
Reaction time: 1 h
Yield: 89.4 %

Procedure:
Commercial available 4-phenoxy-aniline (4.16 g, 20.8 mmol) was dissolved in dichloromethane (100 mL), and triethylamine (3.05 g, 31.1 mmol) and acetic anhydride (2.22 g, 20.8 mmol) were added in drops. The mixture was stirred for 1 h at 0° C. to room temperature. After completion of the reaction, the mixture was filtered using dichloromethane and crystallized to give the title compound (4.50 g, 18.6 mmol)
Reaction SMILES: O[CH2:2][C:3]1([C:6]2[C:11]([O:12][CH2:13][O:14][CH3:15])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:16][OH:17])[CH2:5][CH2:4]1.[Li]CCCC.CCCCCC.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>O1CCCC1>[CH3:15][O:14][CH2:13][O:12][C:11]1[C:6]2[C:3]3([CH2:2][O:17][CH2:16][C:7]=2[CH:8]=[CH:9][CH:10]=1)[CH2:4][CH2:5]3
Reactant: COCOc1cccc(CO)c1C1(CO)CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOc1cccc2c1C1(CC1)COC2
Reaction time: 0.25 h
Yield: 92.6 %

Procedure:
To a solution of (2-[1-(hydroxymethyl)cyclopropyl]-3-{[(methyloxy)methyl]oxy}phenyl)methanol (Intermediate 134, 450 mg) in dry tetrahydrofuran (10 ml) at 0° C., a solution of BuLi in hexane (1.6M, 1.180 mL, 1.889 mmol) was slowly added and the reaction mixture was stirred for 15 minutes at the same temperature. A solution of tosyl chloride (360 mg, 1.889 mmol) in dry tetrahydrofuran (5 ml) was slowly added and the reaction mixture was stirred for 15 minutes at 0° C. A second equivalent of a solution of BuLi in hexane (1.6M, 1.180 mL, 1.889 mmol) was added and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with an aqueous saturated solution of NaHCO3 (10 ml) diluted with water (10 ml) and extracted with ethyl acetate (2×30 ml). The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 25 g SNAP column and cyclohexane/ethyl acetate as eluents from 100:0 to 8:2. This afforded the title compound 5-{[(methyloxy)methyl]oxy}-1H-spiro[2-benzopyran-4,1′-cyclopropane] as a colourless oil (385 mg).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]([CH2:27][CH:28]([CH3:55])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:41]([S:42]([NH:45][C:46]3[C:51]([O:52][CH3:53])=[N:50][C:49]([CH3:54])=[CH:48][N:47]=3)(=[O:44])=[O:43])=[CH:40][CH:39]=[CH:38][N:37]=2)=[CH:32][CH:31]=1)[Si](C(C)(C)C)(C)C>C1COCC1.O>[OH:19][CH2:27][CH:28]([CH3:55])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:41]([S:42]([NH:45][C:46]3[C:51]([O:52][CH3:53])=[N:50][C:49]([CH3:54])=[CH:48][N:47]=3)(=[O:44])=[O:43])=[CH:40][CH:39]=[CH:38][N:37]=2)=[CH:32][CH:31]=1
Reactant: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(CC(C)CO[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(CC(C)CO)cc1
Reaction time: 0.75 h
Yield: 80.5 %

Procedure:
Tetrabutylammonium fluoride (0.4 ml of a 1.0 M solution in THF) was added to a solution of 2-[4-(2-((tert-butyldimethylsiloxy)methyl)propyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (118 mg) in THF (5 ml) at ambient temperature. More tetrabutylammonium fluoride solution was added after 0.25 hour (0.4 ml), after 0.75 hour (1.0 ml) and finally after 1.5 hours (0.2 ml). The reaction mixture was stirred for a further 0.5 hour, diluted with water (10 ml) and the reaction mixture was extracted with dichloromethane (4×10 ml). The combined organic extracts were dried over MgSO4 and evaporated to give an amber oil. This was purified by gradient elution with 0-50% methanol/dichloromethane through a silica gel Mega Bond Elut column to give 2-[4-(3-hydroxy-2-methylpropyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (75 mg) as a white crystalline solid, m.p. 118-119° C.; 1H NMR (DMSO-d6): 0.95 (d, 3H), 1.35 (m, 1H), 2.0 (m, 1H), 2.3 (s, 3H), 2.5 (m, 1H), 2.9 (m, 1H), 3.5 (m, 2H), 3.8 (s, 3H), 6.65 (s, 1H), 7.2 (m, 4H), 7.35 (s, 1H), 7.5 (m, 1H), 8.7 (d, 1H), 8.8 (dd, 1H); mass spectrum (+ve ESP): 429 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1N2C(CCOC2(C)C)[CH2:3]1.[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[N:18]1[CH:21]([CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH2:20][C:19]1=[O:31]>>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[N:18]1[C@@H:21]([CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C@H:20]([CH:2]([OH:1])[CH3:3])[C:19]1=[O:31]
Reactant: O=C1CC(CCOC2CCCCO2)N1C1CCCCO1
Reactant: CC1(C)OCCC2CC(=O)N21
Product: CC(O)[C@@H]1C(=O)N(C2CCCCO2)[C@H]1CCOC1CCCCO1

Procedure:
Following the procedure described for the preparation of 8-oxo-2,2-dimethyl-7α and β-(1-hydroxyethyl)-3-oxa-1-azabicyclo[4.2.0]octane from 8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane and using 1-(2-tetrahydropyranyl)-4-[2-(2-tetrahydropyranyl)oxyethyl]-2-azetidinone one obtains a diastereomeric mixture of both cis and trans-1-(2-tetrahydropyranyl)-3-(1-hydroxyethyl)-4-[2-(2-tetrahydropyranyl)-oxyethyl]-2-azetidinone.