Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:18][C:19](=[O:24])[CH2:20][CH2:21][CH2:22]Br)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:22][CH2:21][CH2:20][C:19]([OH:24])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1OCc1ccccc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)CCCOc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a 250 mL flask, equipped with a reflux condenser, magnetic stirrer, and under inert atmosphere, was added 2-benzyloxy-phenol (8.0 g, 40 mmol), 4-bromobutanoic acid ethyl ester (5.7 mL, 40 mmol), potassium carbonate (7.2 g, 52 mmol), and ethanol (100 mL). The reaction mixture was heated to reflux with stirring for 8 hours. The reaction was cooled to room temperature and the insoluble byproduct was removed by suction filtration. 2N aqueous sodium hydroxide (30 mL) was added to the filtrate. This solution was heated to 50° C. for 2 hours. The solution was cooled to room temperature, the ethanol removed under reduced pressure, and the resulting solution was adjusted to pH 9. The aqueous solution was washed with ethyl acetate (2×30 mL) and residual ethyl acetate was removed under reduced pressure. The solution was cooled to 0° C. with an external ice bath and then acidified to pH 2 with 6N aqueous hydrochloric acid. The precipitated product was collected by suction filtration and dried under vacuum. The product (7.2 g, 63%) was isolated as a white powder. 1H-NMR (400 MHz, DMSO-d6): δ 12.0, s, 1H(COOH); δ 7.4, multiplet, 5H (Benzylic aryl H's); δ 7.0, multiplet, 2H (Aryl H's); δ 6.9, multiplet, 2H (Aryl H's); δ 5.0, s, 2H (Benzylic CH2); δ 4.0, t, 2H (CH2 α to phenoxy); δ 2.4, t, 2H(CH2 α to COOH); δ 1.9, multiplet, 2H (remaining CH2 group).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([Cl:20])=[O:16])=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid (4.2 g, 14.89 mmol) was dissolved in CH2Cl2 (42 mL) under N2 atmosphere. Oxalyl chloride (2.6 mL, 29.78 mmol) and DMF (5 drops) were added and the reaction stirred for 2.5 hours at room temperature. Then, additional oxalyl chloride (5 mL, 57.3 mmol) was added. After 30 minutes, the reaction mixture was concentrated and placed under high vacuum. The crude material was used directly in the next step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>O1CCOCC1>[CH2:30]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22])[CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCCCCN1C(=O)[C@@]2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 25 °C
Yield: 71.6 %

Procedure:
A suspension of (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (1.0 g, 3.4 mmol), cesium carbonate (3.3 g, 10.2 mmol) and 1-bromopentane (1.02 g, 6.77 mmol) in anhydrous 1,4-dioxane (25 mL) was heated at reflux under nitrogen for 2 h. The reaction mixture was allowed to cool to ambient temperature, filtered and concentrated in vacuo. Purification of the residue by column chromatography and eluted with a 15% to 50% gradient of ethyl acetate in hexanes, followed by recrystallization from methanol afforded (S)-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one as an off-white solid (0.89 g, 72%): mp 111-113° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ7.23-7.30 (m, 1H), 7.13 (dd, J=7.4, 0.9 Hz, 1H), 7.00-7.03 (m, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.46 (s, 1H), 6.19 (s, 1H), 4.73 (ABq, 2H), 4.19-4.05 (m, 4H), 3.86-3.59 (m, 2H), 1.82-1.62 (m, 2H), 1.43-1.28 (m, 4H), 0.89 (t, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ177.2, 155.2, 144.5, 142.4, 138.2, 132.5, 128.7, 123.9, 123.0, 121.1, 111.4, 108.5, 99.3, 80.1, 64.5, 63.9, 58.0, 40.3, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 366.0 (M+1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[C:30]([F:31])=[CH:29][CH:28]=[C:27]([F:32])[C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][NH:13][C:12]2[N:16]=[CH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22](Cl)[CH:21]=3)=[CH:19][C:11]1=2>>[Cl:6][C:7]1[C:30]([F:31])=[CH:29][CH:28]=[C:27]([F:32])[C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][NH:13][C:12]2[N:16]=[CH:17][C:18]([C:20]3[CH:21]=[CH:22][N:23]=[C:24]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:25]=3)=[CH:19][C:11]1=2
Reactant: C1CCNC1
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccnc(Cl)c4)cc32)c1Cl
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccnc(N5CCCC5)c4)cc32)c1Cl
Temperature: 87 °C
Reaction time: 72 h
Yield: 35 %

Procedure:
Pyrrolidine (1 mL) was added to 1-(2-chloro-3,6-difluorobenzyl)-7-(2-chloropyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (32 mg). The reaction mixture was stirred at 87° C. for 72 hours and then concentrated. The residue was purified by normal phase column chromatography eluting with 5% methanol in CH2Cl2 to give the title compound as a yellow solid (35% yield). LCMS: m/z=442.21 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.03 (4H, m), 3.33 (2H, m), 3.53 (6H, m), 4.53 (2H, d, J=1.3 Hz), 5.06 (1H, bs), 6.43 (1H, d, J=0.8 Hz), 6.68 (1H, dd, J=5.4, 1.4 Hz), 7.02 (1H, m), 7.12 (2H, m), 7.79 (1H, d, J=1.8 Hz), 8.15 (1H, d, J=5.6 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:10]1([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=Cc1ccc(O)cc1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Oc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 4-hydroxylbenzaldehyde (10 g, 81.9 mmol) in anhydrous CH2Cl2 (500 mL) at RT, under N2, pyrrolidine (10.2 mL, 122.9 mmol) was added, followed by NaBH(OAc)3 (34.6 g, 163.9 mmol) and AcOH (19.7 g, 327.8 mmol). After the mixture was stirred at RT for 24 h, a saturated solution of NaHCO3(aq) (150 mL) was added. The mixture was vigorously stirred for an additional 1 h and then extracted with CH2Cl2 (3×200 mL). The combined organic layer was washed with brine (300 mL), dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound as amber oil. This was used crude in the next step. MS m/z: 178 (M+1). Calc'd for C11H15NO-177.2.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[N:28]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=1>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])(=[O:17])=[O:16])[CH2:12][N:11]2[CH2:34][C:31]2[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=2)=[O:9])[CH2:5][CH2:6]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2)CC1
Reactant: O=Cc1ccncc1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2Cc2ccncc2)CC1

Procedure:
(2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K5 was reductively aminated with pyridine-4-carbaldehyde in analogy to experiment L3 to give (2S,4R)-1-pyridin-4-ylmethyl-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 479.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.[N:21]1C=CC(B(O)O)=CC=1>>[N:21]1[CH:5]=[CH:6][C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)=[CH:2][CH:3]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3ccncc3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 4-pyridylboronic acid (153 mg, 1.24 mmol) were coupled to yield 2-pyridin-4-yl-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 45 mg (15%) as a beige solid: m.p. 250° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 3.13 (m, 2H), 3.41 (m, 2H), 7.29 (app t, J=7.8 Hz, 1H), 7.63 (m, 3H), 7.72 (dd, J=7.2, 0.9 Hz, 1H), 8.14 (br t, 1H), 8.69 (d, J=6.0 Hz, 2H), 11.82 (br s, 1H). MS (FAB, MH+) 364. Anal. (C16H13N3O) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH3:23][N:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:30]=2)[C:25]1=[O:43]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:29]3[CH:30]=[C:31]4[C:26](=[CH:27][CH:28]=3)[C:25](=[O:43])[N:24]([CH3:23])[CH2:33][CH2:32]4)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Reactant: CN1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4ccc5c(c4)CCN(C)C5=O)n[nH]c3n2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 8, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one. LCMS (M+H)+=484.1/486.0.
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6](=[O:13])[C:7](=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>COCCOC.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>[CH3:11][C:10]1[C:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:3][CH:4]=[C:5]2[C:9]=1[NH:8][C:7](=[O:12])[C:6]2=[O:13]
Reactant: Cc1c(Br)ccc2c1NC(=O)C2=O
Reactant: OB(O)c1ccccc1
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: O
Solvent: COCCOC
Product: Cc1c(-c2ccccc2)ccc2c1NC(=O)C2=O
Yield: 55.5 %

Procedure:
6-Bromo-7-methyl-1H-indole-2,3-dione (100 mg, 0.38 mmol) and phenylboronic acid (53 mg, 1.1 eq) were dissolved in 10 mL DME. Pd(PPh3)4 (22 mg, 0.05 eq) were added followed by NaHCO3 (65 mg, 2.0 eq) dissolved in 10 mL water. The mixture was refluxed for 2.5 hr and the organic solvent was removed by evaporation. The mixture was extracted with ethyl acetate and the combined organic layers were dried over Na2SO4 and purified by SiO2 chromatography to give the title compound (50 mg, 51%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[N:6]2[CH2:12][CH2:13][OH:14].[CH2:22]1[NH:27][CH2:26][CH2:25][N:24]2[C:28](=[O:31])[CH2:29][CH2:30][CH:23]12.C(N(CC)CC)C>C(O)C>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:5]1[N:6]([CH2:12][CH2:13][OH:14])[C:7]2[C:3]([N:4]=1)=[C:2]([N:27]1[CH2:26][CH2:25][N:24]3[C:28](=[O:31])[CH2:29][CH2:30][CH:23]3[CH2:22]1)[N:10]=[C:9]([CH3:11])[N:8]=2
Reactant: O=C1CCC2CNCCN12
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3Cl)n(CCO)c2n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(N2CCN3C(=O)CCC3C2)c2nc(-c3ccccc3Cl)n(CCO)c2n1
Temperature: 82.5 °C
Yield: 75618.7 %

Procedure:
Charge a 500 mL three necked round bottomed flask with 2-[6-chloro-8-(2-chlorophenyl)-2-methyl-purin-9-yl]ethanol (13.3 g, 0.0412 mmol) and ethanol (200 mL), followed by 2,3,4,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-6-one (6.365 g, 0.0453 mol) and triethylamine (14.8 mL, 3.5 eq). Heat the mixture to 80-85° C. for 24 h. Cool the reaction to room temperature and concentrate under vacuum to give a yellow solid as the crude product. Purify the crude material by column chromatography, using 400 g of silica gel and eluting with dichloromethane/methanol (50:1), to give the product as a yellow solid (13.3 g). 1H NMR (dmso-d6): δ 7.55-7.41 (m, 4H); 5.72 (bs, 2H); 4.16-3.92 (m, 3H); 3.71 (s, 2H); 3.71-3.68 (m, 1H); 3.02-2.93 (m, 2H); 2.74 (m, 1H); 2.70 (s, 3H); 2.44 (m, 2H); 2.32-2.29 (m, 1H); 1.76-1.69 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:30][C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2cccc(F)c2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 13w from {3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A of Example 13a, and 3-fluorobenzenesulfonyl chloride with the following exception. The sulfonyl chloride was dissolved in CH2Cl2 (1 mL) and 0.28 mL was added to the reaction mixture. MS 552 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:26]2[CH2:27][CH2:28][CH:23]([C:20]3[CH:21]=[CH:22][C:17]([C:16]([F:15])([F:29])[F:30])=[CH:18][CH:19]=3)[CH2:24][CH2:25]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: FC(F)(F)c1ccc(C2CCNCC2)cc1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@](O)(CN1CCC(c2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 70 °C
Reaction time: 3 h
Yield: 53.5 %

Procedure:
(R)-2-Chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (0.329 g, 1.51 mmol) and 4-(4-trifluoromethylphenyl)piperidine (0.40 g, 1.66 mmol) were dissolved in DMF (5 ml) followed by stirring at 70° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate twice. The organic phases were combined, washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to afford (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethylphenyl)piperidin-1-yl]propan-2-ol (0.361 g, yield 54%) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:5]([CH:6]=[O:7])[C:4]=1[OH:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([O:11][C:4]1[C:3]([O:2][CH3:1])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: COc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc(C=O)c1OCc1ccccc1
Yield: 98.8 %

Procedure:
50 g (0.3 mole) of 3-methoxysalicylaldehyde are heated to reflux for 3 hours with 51.3 g (0.3 mole) of benzyl bromide and 48.4 g of potassium carbonate in 300 ml of acetone. After filtration, the filtrate is concentrated. 71.8 g of the title compound are obtained as a yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:28])[CH2:25][O:26][CH3:27])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12].[N:29]1([C:33]([C:35]2[CH:36]=[CH:37][C:38](Cl)=[N:39][CH:40]=2)=[O:34])[CH2:32][CH2:31][CH2:30]1>C(#N)C>[N:29]1([C:33]([C:35]2[CH:36]=[CH:37][C:38]([O:7][C:8]3[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:28])[CH2:25][O:26][CH3:27])[CH:22]=3)[C:11]([NH:13][C:14]3[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=3)=[O:12])=[N:39][CH:40]=2)=[O:34])[CH2:32][CH2:31][CH2:30]1
Reactant: O=C(c1ccc(Cl)nc1)N1CCC1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Yield: 65.7 %

Procedure:
Potassium carbonate (0.181 g, 1.31 mmol) was added to a mixture of 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (0.2 g, 0.66 mmol) and 5-(azetidin-1-ylcarbonyl)-2-chloropyridine (129 mg, 0.66 mmol) in acetonitrile (5.0 mL) and the stirred mixture heated at 160° C. in a ‘Biotage initiator Microwave’ for 6 hours. The mixture was allowed to reach RT and pressure and was partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl acetate layer was separated, washed with water (5×50 mL) brine (50 mL), dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 0-5% methanol in ethyl acetate, to give the desired compound (202 mg). 1H NMR δ (CDCl3): 1.33 (d, 3H), 2.38 (quin, 2H), 3.40 (s, 3H), 3.61-3.47 (m, 2H), 3.74 (s, 3H), 4.42-4.18 (m, 4H), 4.58 (sextet, 1H), 6.80 (d, 1H), 6.91 (t, 1H), 6.97 (d, 1H), 7.21 (t, 1H), 7.26 (d, 1H), 7.33 (t, 1H), 8.09-8.05 (m, 1H), 8.42 (d, 1H), 8.92 (s, 1H); m/z 466 (M+H)+
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:14])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].[Br:15]Br>C(O)(=O)C>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:14])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Reaction time: 0.5 h

Procedure:
A solution of 5-acetyl-2-chlorobenzenesulphonamide (4.7 g) in glacial acetic acid (100 ml) was treated with bromine (3.2 g) in glacial acetic acid (20 ml), added dropwise with vigorous stirring at 50°. After an initial induction period of 5 minutes the colour of bromine was discharged. The addition took 30 minutes. The resulting solution was stirred for 15 minutes before removing the acetic acid under reduced pressure. The resulting white solid was dissolved in acetone (30 ml), diluted with benzene (250 ml) and the solution concentrated until the volume of solution was 150 ml. On cooling white crystals were deposited, 4.1 g, m.p. 168-172°.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][CH2:18][C:17]3[C:16]([OH:20])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[CH:25]1>>[OH:20][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH2:18][CH2:19][CH:10]([N:9]([CH2:21][CH2:22][CH3:23])[CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][N:4]([C:33]([C:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[NH:24][CH:25]=3)=[O:34])[CH2:3][CH2:2]1)[CH2:11]2
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: CCCN(CCN1CCNCC1)C1CCc2c(O)cccc2C1
Product: CCCN(CCN1CCN(C(=O)c2c[nH]c3ccccc23)CC1)C1CCc2c(O)cccc2C1
Yield: 51.6 %

Procedure:
Compound 10f was prepared following Procedure G using 39b (50 mg, 0.16 mmol) and indole-3-carboxylic acid (35 mg, 0.21 mmol) to give 40f (38 mg, 53%) after column chromatography. 1H NMR (400 MHz, CD3OD) δ 1.03-1.07 (t, 3H, J=7.2 Hz), 1.83-1.96 (m, 3H), 2.32 (s, 1H), 2.53-2.67 (m, 5H), 2.81-2.83 (m, 2H), 3.09-3.18 (m, 4H), 3.41-3.47 (m, 2H), 3.56-3.59 (m, 1H), 3.79 (bs, 4H), 6.61-6.63 (d, 1H, J=8.4 Hz), 6.64-6.66 (d, 1H, J=8.4 Hz), 6.96-6.99 (t, 1H, J=7.2 Hz), 7.13-7.21 (m, 1H), 7.41-7.51 (m, 1H), 7.62-7.64 (m, 1H), 7.71-7.73 (d, 1H, J=7.2 Hz), 7.83-7.84 (1H, J=7.2 Hz). The free base of 40f was converted into its HCl salt. m.p. 147-151° C. Anal. [C28H36N4O2.3HCl] C, H, N.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]3[N:27]=[CH:26][N:25]([CH2:28][CH2:29][OH:30])[N:24]=3)[C@H:17]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[S:39](Cl)([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40].C(N(CC)CC)C>ClCCl>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[O:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]3[N:27]=[CH:26][N:25]([CH2:28][CH2:29][O:30][S:39]([C:42]4[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=4)(=[O:41])=[O:40])[N:24]=3)[C@H:17]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:37])[F:38])[CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H](O[C@H]1OCCN(Cc2ncn(CCO)n2)[C@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCn2cnc(CN3CCO[C@H](O[C@H](C)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The alcohol from step (a), above, (1.81 g, 3.22 mM) was dissolved in dichloromethane (20 ml), tosyl chloride (1.84 g, 9.66 mM) and triethylamine (1.34 ml, 9.66 mM) were added and the reaction stirred at room temperature for 18 hrs. The solvent was removed and the residue redissolved in ethyl acetate and washed with water and brine, dried (MgSO4) and evaporated. The product was purified on silica eluting with methanol-clichloromethane mixtures (1.87 g).
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:10]([OH:12])=[O:11])[CH3:9])=[O:6])[CH:2]=[CH2:3].Cl.[C:14](=O)(O)[O-].[Na+]>CO>[CH3:14][O:11][C:10](=[O:12])[C@H:8]([CH3:9])[NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6]
Reactant: O=C([O-])O
Reactant: C=CCOC(=O)N[C@@H](C)C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N[C@@H](C)C(=O)OC

Procedure:
A solution of 0.06 mol of N-(allyloxycarbonyl)alanine, prepared as described by H. Kunz and C. Unverzagt in Angew. Chem. Int. Ed. Engl., 1984, 23, 436-437, and 0.066 mol of HCl in 100 mL of CH3OH is stirred at reflux for 8 hours. The solution is then cooled and treated with 0.066 mol of sodium bicarbonate. The solvent is removed by rotary evaporator, and the residue is dissolved in diethyl ether, filtered, dried over MgSO4, and filtered. The solvent is removed by rotary evaporator to give N-(allyloxycarbonyl)alanine methyl ester.