Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10]>O=[Mn]=O.C1C=CC=CC=1>[CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10]
Reactant: Cn1c(CO)cnc1[N+](=O)[O-]
Agent: O=[Mn]=O
Solvent: c1ccccc1
Product: Cn1c(C=O)cnc1[N+](=O)[O-]
Yield: 40.5 %

Procedure:
To a solution of 0.15 g. of 1-methyl-2-nitro-5-hydroxymethylimidazole in 20 ml. of benzene, 0.33 g. of MnO2 is added and the reaction mixture is heated on the steambath for 2 hours. After filtration and evaporation to dryness under vacuum, the crude product is crystallized from ethyl acetate and 0.060 g. (40.5%) of 1-methyl-2-nitro-5-imidazolaldehyde is obtained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[CH3:38][N:37]([CH3:39])[CH2:36][CH2:35][N:33]([CH3:34])[C:31]([C:16]1[CH:17]=[C:18]2[C:23](=[C:14]([CH:12]([N:6]([C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[CH3:7])[CH3:13])[CH:15]=1)[O:22][C:21]([N:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)=[CH:20][C:19]2=[O:30])=[O:32]
Reactant: CNc1ccc(F)cc1
Reactant: CC(Br)c1cc(C(=O)N(C)CCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: CC(c1cc(C(=O)N(C)CCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1ccc(F)cc1
Yield: 47.7 %

Procedure:
4-fluoro-N-methylaniline (82 mg, 0.66 mmol) was reacted with 8-(1-bromoethyl)-N-(2-(dimethylamino)ethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (90 mg, 0.16 mmol) using a procedure similar to the one described in example 3.00 to give N-(2-(dimethylamino)ethyl)-8-(1-((4-fluorophenyl)(methyl)amino)ethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (39.0 mg, 46.4%) as a white solid. Mass Spectrum: M+H+ 511. NMR Spectrum: (DMSOd6) at 323° K: 1.55 (d, 3H), 2.04 (bs, 6H), 2.40 (bs, 2H), 2.68 (s, 3H), 2.93 (s, 3H), 3.22-3.36 (m, 4H), 3.37 (bs, 2H), 3.44-3.58 (m, 4H), 5.45 (q, 1H), 5.50 (s, 1H), 6.82 (dd, 2H), 7.01 (dd, 2H), 7.56 (d, 1H), 7.83 (d, 1H).
Reaction SMILES: O.[C:2]1(C)C=CC(S(O)(=O)=O)=C[CH:3]=1.C[O:14][CH:15](OC)[C:16]1[C:40]([O:41][CH2:42]OC)=[C:39]([C:45]([F:48])([F:47])[F:46])[CH:38]=[CH:37][C:17]=1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(Br)C=C>CC(C)=O.CN(C)C=O.O>[CH2:42]([O:41][C:40]1[C:16]([CH:15]=[O:14])=[C:17]([CH:37]=[CH:38][C:39]=1[C:45]([F:46])([F:47])[F:48])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:30][CH:31]=2)=[CH:24][CH:25]=1)[CH:2]=[CH2:3]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COCOc1c(C(F)(F)F)ccc(COc2ccc(-c3ccc(CC(=O)OC)cc3)cc2)c1C(OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C=CCBr
Solvent: CN(C)C=O
Product: C=CCOc1c(C(F)(F)F)ccc(COc2ccc(-c3ccc(CC(=O)OC)cc3)cc2)c1C=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 84 %

Procedure:
After p-toluenesulfonic acid monohydrate (1.01 g, 5.31 mmol) was added to a solution of methyl (4′-{[2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzyl]oxy}-1,1′-biphenyl-4-yl)acetate (2.38 g, 4.45 mmol) obtained in Example (6-7) in acetone (14 ml), the mixture was stirred at room temperature for 14 hours. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a residue. Potassium carbonate (738 mg, 5.34 mmol) and allyl bromide (0.462 ml, 5.34 mmol) were successively added to a solution of the obtained residue in N,N-dimethylformamide (4 ml) and the mixture was stirred at 50° C. for 2 hours. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=50/1-2/1) to give methyl (4′-{[3-(allyloxy)-2-formyl-4-(trifluoromethyl)benzyl]oxy}-1,1′-biphenyl-4-yl)acetate (1.81 g, yield: 84%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]1[CH:13]=CC=C[CH:9]=1.C=CC>CC(C)=O>[CH:8]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:13])[CH3:9].[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Solvent: Oc1ccccc1
Solvent: C=CC
Solvent: CC(C)=O
Product: CC(C)c1ccccc1

Procedure:
In industry, phenol is normally prepared by means of benzene alkylation with propylene to give isopropyl benzene, oxidation to the corresponding tert-hydroperoxide and subsequent cleavage to phenol and acetone in the presence of an acid catalyst.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].Cl.[CH2:33]([NH2:35])[CH3:34].C(N(CC)CC)C.O>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]/[NH:35][CH2:33][CH3:34])/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[C@H:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: CCN
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCN/C=C1\C(=O)O[C@H](COC)[C@@]2(C)C1=C(O)C(=O)C1=C2[C@H](OC(C)=O)C[C@]2(C)[C@@H](O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.3 %

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added 100 mg of ethylamine hydrochloride and 100 μL triethylamine. The reaction mixture is stirred at room temperature for 24 h. Water is added and the CH2Cl2 is removed, filtered through K2CO3 and concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexanes to give a yellow powder (32 mg, 29%). MS (ESI) m/z 476.22813 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:14][C:15]#[C:16][Si](C)(C)C)[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:14][C:15]#[CH:16])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)CC#C[Si](C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC[C@H](C)NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-4-Methyl-N-(5-(trimethylsilyl)pent-4-yn-2-yl)benzenesulfonamide (2.0 g, 6.5 mmol) was dissolved in 15 mL MeOH and treated with K2CO3 (1.3 g, 9.7 mmol). The resulting mixture was stirred for 2 h at RT. The reaction mixture was quenched with sat. NH4Cl and the solvent removed. The residue was partitioned between EtOAc/H2O. The organic layer was washed with sat. NaHCO3, H2O, brine, dried over MgSO4 and concentrated. The residue was purified using SiO2 (80% hexanes: 20% acetone) to afford the title compound. MS (m/z): 238.3 (M+H) (Calc'd for C12H15NO2S: 237.32).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:18])([F:17])[CH:14]([F:16])[F:15])=[CH:7][N:6]=1)=[O:4].[OH-].[Li+]>>[F:18][C:13]([F:17])([CH:14]([F:16])[F:15])[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCC(F)(F)C(F)F)cn1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCC(F)(F)C(F)F)cn1
Yield: 94 %

Procedure:
In a manner analogous to that described in example 17b), the hydrolysis of the 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid methyl ester with lithium hydroxide yielded the title compound as a light yellow solid (yield 94% of theory). MS (ISP): m/z=253 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[CH:36][C:4]=1[CH2:5][N:6]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:7](=[O:28])[CH2:8][CH2:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([O:20]C)=[O:19])=[CH:12][CH:11]=1.[Li+].[OH-].CCOC(C)=O>C1COCC1.O>[CH3:1][O:2][C:3]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[CH:36][C:4]=1[CH2:5][N:6]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:7](=[O:28])[CH2:8][CH2:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1
Reactant: CCCCCCCN(Cc1cccc(OC)c1OC)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCN(Cc1cccc(OC)c1OC)C(=O)CCc1ccc(OCc2ccccc2C(=O)O)cc1
Yield: 79.4 %

Procedure:
Methyl 2-[(4-{3-[(2,3-dimethoxybenzyl)(heptyl)amino]-3-oxopropyl}phenoxy)methyl]-benzoate (39 mg, 0.069 mmol) was dissolved in THF/water (2/1, 2 ml) and LiOH (3.3 mg, 0.14 mmol) was added. The reaction was performed I a single node microwave oven (150° C., 7 min). Workup was done by adding EtOAc (10 ml) and washing the organic phase with two potions of HCl (2×5 ml, 1 M). The organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 30 mg of 2-[(4-{3-[(2,3-dimethoxybenzyl)(heptyl)-amino]-3-oxopropyl}phenoxy)methyl]benzoic acid (yield 78.9).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:3])=[O:2].[C:20]1(=[O:26])[NH:24][C:23](=[O:25])[CH:22]=[CH:21]1>C1(C)C=CC=CC=1.ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH:11]=[CH:12][CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:22]2[CH:21]1[C:20](=[O:26])[NH:24][C:23]2=[O:25])([O-:3])=[O:2]
Reactant: O=C1C=CC(=O)N1
Reactant: O=[N+]([O-])c1ccccc1/C=C/C=C/c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C2C(c3ccccc3[N+](=O)[O-])C=CC(c3ccccc3)C12
Temperature: 130 °C

Procedure:
7.5 g (29.8 mmole) (E,E)-1-(2-nitrophenyl)-4-phenyl-1,3-butadiene and 2.9 g (29.9 mmole) maleic acid imide are heated in 10 ml toluene to 130° C. for 12 hours. After addition of 1.5 g (15.5 mmole) maleic acid imide it is heated at 130° C. for a further 24 hours. After cooling, it is diluted with 40 ml dichloromethane, the product filtered off, and crystallized from ethanol. One obtains 1,3,3a,4,7,7a-hexahydro-4-(2-nitrophenyl)-1,3-dioxo-7-phenyl-2H-isoindole in the form of pale yellow crystals, which decompose from 200°-208° C.
Reaction SMILES: BrC=C([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([NH:10][CH3:11])=[O:9])C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[CH3:31][N:32]1[CH2:45][CH2:44][C:35]2[NH:36][C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][C:42]=3[C:34]=2[CH2:33]1>CN(C=O)C.[Cu]I>[CH3:31][N:32]1[CH2:45][CH2:44][C:35]2[N:36]([C:7]3([CH:6]=[CH:5][CH:14]=[CH:13][CH2:12]3)[C:8]([NH:10][CH3:11])=[O:9])[C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][C:42]=3[C:34]=2[CH2:33]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CNC(=O)c1cccc(C(C)=CBr)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CNC(=O)C1(n2c3c(c4cc(C)ccc42)CN(C)CC3)C=CC=CC1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
3-(1-Bromoprop-1-en-2-yl)-N-methylbenzamide (202 mg, 0.8 mmol) was dissolved in DMF (5 mL) and potassium phosphate (424 mg, 2 mmol) was added followed by copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol). 2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was added and the mixture purged with nitrogen for 2 min. The reaction mixture was stirred at 85° C. overnight. Water was added and the solid mass was filtered under vacuum. The crude product was purified on silica (100-200 mesh) using 0-7% MeOH:DCM as eluent. Yield: 101 mg. 1H NMR (CD3OD, oxalate salt) δ (ppm): 8.1 (s, 1H), 7.8 (m, 2H), 7.6 (t, 1H), 7.3 (s, 1H), 7.15 (d, 1H), 7.1 (d, 1H), 7.05 (s, 1H), 4.6 (bs, 2H), 3.7 (bs, 2H), 3.1 (bs, 5H), 3.0 (s, 3H), 2.4 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:32]=[C:31]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)[CH:30]=[CH:29][C:12]=1[CH2:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:10][C:11]1[CH:32]=[C:31]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)[CH:30]=[CH:29][C:12]=1[CH2:13][N:14]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)=[CH:17][CH:16]=1)[C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: O=C(Cl)C1CCCCC1
Reactant: Clc1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CCCCC1)N(Cc1ccc(OC2CCCCO2)cc1Cl)c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.1 %

Procedure:
To a solution of cyclohexanecarbonyl chloride (990 mg, 6.75 mmol) in methylene chloride (30 mL) was added a mixture of (2-chloro-4-(tetrahydro-pyran-2-yloxy)-benzyl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (1.94 g, 4.5 mmol) and triethylamine (1.3 mL, 9.0 mmol) in methylene chloride (15 mL) dropwise. The reaction mixture was stirred at room temperature for 24 hr. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and the aqueous solution was washed with methylene chloride. The organic solution was dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was purified by Biotage® chromatography using 5% methanol/methylene chloride to afford the title compound of Step A as an oil (2.12 g). MS 541.3 (M+1)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[N:14]3[N:21]=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([OH:32])=O)=[N:28][CH:29]=4)[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:66]1([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:18])([F:19])[F:20])[N:14]3[N:21]=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([N:69]5[CH2:68][CH2:67][N:66]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[CH2:71][CH2:70]5)=[O:32])=[N:28][CH:29]=4)[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4ccc(C(=O)O)nc4)cc3N2)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4ccc(C(=O)N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cc3N2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
To a solution of 5-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)picolinic acid (458 mg, 1.02 mmol) in DMF (4.0 mL) was added N,N-diisopropylethylamine (535 μl, 3.06 mmol) and HATU (427 mg, 1.12 mmol). After stirring 1 h at rt, tert-butyl piperazine-1-carboxylate (209 mg, 1.12 mmol) was added and the reaction was stirred overnight at room temperature. Water was added and the resulting light brown precipitate was collected by filtration (0.5385 g). Purification by column chromatography (15% to 100% ethyl acetate/heptane afforded tert-butyl 4-(5-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)picolinoyl)piperazine-1-carboxylate (332 mg, 54%) as a light yellow solid.
Reaction SMILES: [C:1](=[O:13])([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[O:2][CH:3](Cl)[CH3:4].CCCCCCC.CC(OC)(C)C.[C:27]([O:31][C:32]([NH:34][C@H:35]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[C:51]([Cl:53])[CH:50]=[CH:49][C:48]=2[F:54])=[CH:43][CH:42]=1)[CH2:36][C:37]([OH:39])=[O:38])=[O:33])([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:27]([O:31][C:32]([NH:34][C@H:35]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[C:51]([Cl:53])[CH:50]=[CH:49][C:48]=2[F:54])=[CH:43][CH:42]=1)[CH2:36][C:37]([O:39][CH:3]([O:2][C:1]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:13])[CH3:4])=[O:38])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: CC(OC(=O)C[C@@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)OC(C)(C)C)OC(=O)OC1CCCCC1
Reaction time: 0.08 h
Yield: 97 %

Procedure:
1-chloroethyl cyclohexyl carbonate was resolved by HPLC on a preparative Chiralpak ID column using Heptane/TBME 98:2 and a polarimetric detector. From this resolution, Peak 2 was determined to have 98% ee on a Chiralpak ID column and was used in the subsequent step. To a solution of 1-chloroethyl cyclohexyl carbonate (second-eluting isomer from a Chiralpak ID column Heptane/TBME 98:2) (1.75 g, 8.47 mmol) and (R)-3-((tert-butoxycarbonyl)amino)-4-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)butanoic acid (1.5 g, 3.68 mmol) in 35 mL anhydrous DMF at 0° C. was added cesium carbonate (1.2 g, 3.68 mmol). After the reaction mixture was stirred for 5 min, the ice-bath was removed and the reaction mixture was stirred at 23° C. for 4.5 hours. LCMS showed that the reaction was approximately 40% complete. The reaction mixture was stirred approximately 18 hours, at which point LCMS showed the reaction was approximately 95% complete. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride (pH of aqueous layer approximately 6-7). After separation, the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed once with water, once with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography on an Isco RediSep 120 g silica cartridge (0-20% ethyl acetate-heptane) to afford (3R)-1-(((cyclohexyloxy)carbonyl)oxy)ethyl 3-((tert-butoxycarbonyl)amino)-4-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)butanoate (2.07 g, 97% yield, 95.8% ee as determined on analytical supercritical fluid HPLC using a Chiralpak AD-H 5-55% MeOH with 20 mM NH4OH in CO2. LCMS (ES+) C30H37ClFNO7: Calc.: 577.2; Found: 578.3[M+H]+.
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].N1C2[C:26](=[CH:27][CH:28]=CC=2)[C@@:25]2([C:43]3C(=CC4OCCOC=4[CH:42]=3)OC2)C1=O.BrCCCCCC.BrCCCCC>>[CH2:42]([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])[CH2:43][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Solvent: CCCCCCBr
Solvent: CCCCCBr
Product: CCCCCCN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 7.3 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 1-bromohexane to replace 1-bromopentane, 1′-hexyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (83%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.25-7.29 (dt, J=7.74, 7.71, 1.05 Hz, 1H), 7.13 (d, J=7.4 Hz, 1H), 6.98-7.04 (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), 1.80-1.63 (m, 2H), 1.44-1.22 (m, 6H), 0.87 (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, 121.2, 111.4, 108.5, 99.3, 80.1, 64.5, 63.9, 58.0, 40.3, 31.4, 27.4, 26.5, 22.5, 14.0; MS (ES+) m/z 379.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9]1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>C1(C)C=CC=CC=1.O1CCOCC1>[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:43]
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)C1(CCNC(=O)OC(C)(C)C)CCCC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=S)C1(CCNC(=O)OC(C)(C)C)CCCC1
Reaction time: 24 h
Yield: 74.4 %

Procedure:
To a solution of N-[[1-[2-[[(1,1-dimethylethoxy)carbonyl]amino]ethyl]cyclopentyl]carbonyl]-4-nitro-L-phenylalanine methyl ester (1.00 g, 2.16 mmol) in toluene/dioxane (1:1, 10 mL) was added Lawesson's reagent (0.524 g, 1.29 mmol). The resultant mixture was warmed to 50° C. and was stirred for 24 h. The reaction mixture was filtered through a sintered glass funnel and the filtrate was concentrated in vacuo. Purification of the crude product by silica gel flash column chromatography (hexane-ethyl acetate, 6:1 then 4:1), afforded N-[[1-[2-[[(1,1-dimethylethoxy)carbonyl]amino]ethyl]cyclopentyl]thioxomethyl]-4-nitro-L-phenylalanine methyl ester (460 mg, 44%; 65% based on recovered starting material) as a light yellow oil. HR MS: Obs. mass, 478.2014. Calcd. mass, 478.2012 (M−H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][N:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: CN1CC=C(c2c[nH]c3ncccc23)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccc(F)cc3)c3ncccc23)CC1

Procedure:
(21.1 mg, 48%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-7-azaindole (24.9 mg, 0.12 mmol) and 4-fluorobenzenesulfonyl chloride (47 mg, 0.24 mmol); HRMS-FAB+ for C19H18N3O2SF: calculated MH+:372.11819; found:372.11690.