Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[CH:3]([F:5])[F:4].C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]([F:14])([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][Br:22])[CH:3]([F:4])[F:5]
Reactant: Cc1ccccc1OC(F)(F)C(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)C(F)(F)Oc1ccccc1CBr

Procedure:
To a stirred solution of 2-(1,1,2,2-tetrafluoroethoxy)toluene (2.5 g, 12.2 mmol) in CCl4 (75 mL) was added NBS (2.1 g, 13 mmol) and AIBN (0.65 g, 3 mmol). The mixture was refluxed for 6 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (75 mL) and water (50 mL). The organic phase was separated, dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using hexanes as eluant to give 2-(1,1,2,2-tetrafluoroethoxy)benzyl bromide as a colorless liquid (TLC Rf =0.7 (hexanes)).
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][CH:4]1[O:6][CH2:5]1.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>>[CH2:14]([NH:15][CH2:5][CH:4]([OH:6])[CH2:3][CH:2]([CH3:7])[CH3:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][CH2:5][CH:4]([OH:6])[CH2:3][CH:2]([CH3:7])[CH3:1]
Reactant: NCCCCCCN
Reactant: CC(C)CC1CO1
Product: CC(C)CC(O)CNCCCCCCNCC(O)CC(C)C

Procedure:
Condensation of 4-methyl-1-pentene oxide and hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[2-hydroxy-4-methylpentylamine] (I: R = (CH3)2CHCH2, R' = H, X = (CH2)6, Z = H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([NH2:11])[CH:7]=[C:8]([Br:10])[CH:9]=1)=O.[CH:12]([NH2:14])=O>C(OCC)(=O)C>[Br:10][C:8]1[CH:9]=[C:5]2[N:6]([CH:7]=1)[N:11]=[CH:12][NH:14][C:3]2=[O:2]
Reactant: COC(=O)c1cc(Br)cn1N
Reactant: NC=O
Solvent: CCOC(C)=O
Product: O=c1[nH]cnn2cc(Br)cc12
Yield: 50 %

Procedure:
A solution of 1-amino-4-bromo-1H-pyrrole-2-carboxylic acid methyl ester (2.9 g, 13.2 mmol) in formamide (12 mL) was heated at 180° C. for 5 hrs. The mixture was diluted with ethyl acetate (300 mL), and then washed with water (100 mL*2), brine (100 mL*3). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was washed with PE/EA (4:1, 50 mL) to give 6-bromo-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (1.4 g, yield 50%) as yellow solid. MS (ES+) requires: 213, 215. found 214, 216 [M+H]+; purity: 92%.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10]2[CH2:13][CH:12]([C:14]3[N:18]([CH3:19])[C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[N:15]=3)[CH2:11]2)[CH:4]=1)[NH2:2].[CH3:24][C:25]([OH:27])=O>CC(N(C)C)=O.CC(N(C)C)=O>[CH3:4][C:5]1[N:6]=[C:7]([C@@H:25]([OH:27])[CH3:24])[N:1]([C:3]2[CH:4]=[C:5]([N:10]3[CH2:11][CH:12]([C:14]4[N:18]([CH3:19])[C:17]5[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=5[N:15]=4)[CH2:13]3)[N:6]=[C:7]([CH3:9])[N:8]=2)[N:2]=1
Reactant: Cc1nc(NN)cc(N2CC(c3nc4ccccc4n3C)C2)n1
Reactant: CC(=O)O
Solvent: CC(=O)N(C)C
Product: Cc1nc(N2CC(c3nc4ccccc4n3C)C2)cc(-n2nc(C)nc2[C@H](C)O)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of Intermediate 2 (11.0 g, 35.6 mmol) in AcOH (100 mL) was added to crude Intermediate 13 (24.2 g, 89 mmol, prepared by heating the corresponding primary amide in neat DMA-DMA at 50° C. overnight followed by removal of excess DMA-DMA by rotary evaporation). The reaction mixture was allowed to stir for 10 min at room temperature and then heated at 80° C. for 1 h. Sampling of the reaction by LCMS suggested cyclization to the silyl-protected hydroxy triazole had occurred. The reaction was allowed to stir at 80° C. for an additional 16 h at which point complete de-silylation of the hydroxy group had occurred. The reaction was cooled to room temperature, poured carefully over saturated aqueous sodium bicarbonate solution (200 mL), and the aqueous layer was made basic to pH˜8 by the addition of solid sodium bicarbonate. The solution was extracted with ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-10% 2-propanol/DCM) to give Example 1 as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.76-7.74 (m, 1H), 7.35-7.28 (m, 3H), 6.96 (m, 1H), 6.62 (s, 1H), 5.12-5.07 (m, 1H), 4.71-4.58 (br s, 4H), 4.34-4.24 (m, 1H), 3.75 (s, 3H), 2.54 (s, 3H), 2.43 (s, 3H) 1.71 (d, J=6.6 Hz, 3H); MS: m/z=405.5 (M+H).
Reaction SMILES: [OH-:1].[Na+].C[O:4][C:5]([C:7]1[CH:31]=[CH:30][C:10]([CH2:11][C:12]23[CH2:19][CH2:18][CH2:17][N:16]2[C:15](=[O:20])[N:14]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)[C:13]3=[O:29])=[CH:9][CH:8]=1)=[O:6]>CO.O.O>[Cl:28][C:23]1[CH:22]=[C:21]([NH:14][C:15]([N:16]2[CH2:17][CH2:18][CH2:19][C@@:12]2([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([C:5]([OH:4])=[O:6])=[CH:31][CH:30]=2)[C:13]([OH:1])=[O:29])=[O:20])[CH:26]=[C:25]([Cl:27])[CH:24]=1
Reactant: [OH-]
Reactant: COC(=O)c1ccc(CC23CCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C[C@@]2(C(=O)O)CCCN2C(=O)Nc2cc(Cl)cc(Cl)c2)cc1
Temperature: 45 °C
Yield: 87.2 %

Procedure:
NaOH (0.406 g) was added to a solution of 5-(4-methoxycarbonylbenzyl)-3-(3,5-dichlorophenyl)-1,3-diazabicyclo[3.3.0]octane-2,4-dione (0.601 g) in MeOH/H2O (20 mL/4 mL) and the mixture was heated at 45° C. for 18 hours. The reaction mixture was cooled, acidified, diluted with water and extracted with EtOAc. The extract was washed with water, brine, dried (MgSO4), filtered, and concentrated. The residue was recrystallized from EtOAc/hexane (1:1) to give N-[N-(3,5-dichlorophenyl)carbamoyl]-2-(4-carboxybenzyl)proline (0.529 g). mp. 144.6° C.; MS (m/z) 459 (M++Na). (2) A mixture of the compound obtained above (0.074 g) and SOCl2 (1.0 mL) was heated at 100° C. for 1 hour. The solution was evaporated. The residue was dissolved in toluene, evaporated and dried under vacuum. The residue was dissolved in THF (4 mL) and the solution was added to an ice cold solution of dimethylamine (1 mL, 2M in THF) in THF (1 mL). The reaction mixture was stirred for 3 hour at room temperature and diluted with EtOAc and water. The organic layer was separated and washed with 0.5 N HCl (10 mL), water and brine. It was dried (MgSO4), filtered, and concentrated. Purification by chromatography (Silica gel: EtOAc, Chromatotron) afforded the titled compound (47 mg). MS (m/z) 468 (M++Na).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:25]3[CH2:28][C@H:27]([CH2:29]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:41][NH:42][CH3:43]>C1COCC1>[CH3:41][N:42]([CH2:29][C@@H:27]1[CH2:26][C@H:25]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:12]=3)[N:9]=2)[CH2:28]1)[CH3:43]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](c3nc(-c4cccc(OCc5ccccc5)c4)c4c(N)nccn43)C2)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C[C@H]1C[C@@H](c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn32)C1
Temperature: 50 °C

Procedure:
A sealed tube containing a solution of cis-toluene-4-sulfonic acid 3-[8-amino-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]cyclobutylmethyl ester (100 mg, 0.18 mmol) in THF (3 mL) was charged with dimethylamine solution (1.8 mL, 3.6 mmol, 2.0 M in THF), sealed, and heated at 50° C. overnight. The mixture was concentrated and the residue was diluted with ethyl acetate (40 mL), washed with sat. aq. NaHCO3 (2×15 mL) and brine (2×15 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was recrystallized to afford a white solid; LC-MS (ES, Pos.): m/z 428 [MH+]; 1H NMR (CDCl3, 400 MHz) δ 2.23 (s, 6H), 2.24-2.32 (m, 2H), 2.42 (d, J=6.1 Hz, 2H), 2.61-2.69 (m, 3H), 3.64 (m, 1H), 4.98 (br s, 2H, NH2), 5.15 (s, 2H), 7.00-7.04 (m, 2H), 7.12 (d, J=5.0 Hz, 1H), 7.23-7.27 (m, 2H), 7.31-7.46 (m, 6H).
Reaction SMILES: C=[C:2]([CH2:22][CH3:23])[CH2:3][C:4]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.I([O-])(=O)(=O)=[O:25].[Na+]>CC(C)=O.O.O[Os](O)(O)(O)(=O)=O.[K]>[O:25]=[C:2]([CH2:22][CH3:23])[CH2:3][C:4]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:6][CH2:5]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C(CC)CC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[Os](=O)(O)(O)(O)O
Agent: [K]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C1(CC(=O)CC)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h

Procedure:
Potassium tetrahydroxydioxidoosmium (0.041 g, 0.111 mmol) was added to a solution of 1-tert-butyl 4-ethyl 4-(2-methylenebutyl)piperidine-1,4-dicarboxylate (1.0 g, 3.07 mmol) in acetone (20 mL) and water (20 mL) and stirred for 10 min. Solid sodium periodate (2.62 g, 12.26 mmol) was added in four portions during 1 hour and the reaction temperature was maintained below 40° C. using an ice-bath. The resulting mixture was stirred for 1 hour at room temperature. At this point LCMS showed incomplete reaction. Another 0.036 eq. of potassium tetrahydroxydioxidoosmium (0.041 g, 0.111 mmol) was added and the mixture was then stirred at rt for 2 hours. LCMS after 2 hours showed completion of the reaction. The suspension was filtered and filtrate was concentrated to remove acetone, and the aqueous layer was extracted with DCM (15 mL×3). The combined organic layers were washed with 10% Na2S2O3 solution (20 ml×2), dried over anhydrous Na2SO4, filtered, then concentrated to get the crude product which was purified by silica gel column chromatography (80 g RediSep Gold column) using (0-35) % EtOAc/Hexanes as mobile phase and the title compound was isolated.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([Cl:19])[CH:17]=3)[CH2:12][CH2:11][C:10]=12)=[O:5])[CH3:2].O(C(C)(C)C)[Li].[C:26]([O:30][C:31]([N:33]1[CH2:36][C:35]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])([CH2:37]OS(C)(=O)=O)[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:37][C:35]2([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:34][N:33]([C:31]([O:30][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:32])[CH2:36]2)[N:8]=[C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([Cl:19])[CH:17]=3)[CH2:12][CH2:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(COS(C)(=O)=O)CN(C(=O)OC(C)(C)C)C1
Reactant: CCOC(=O)c1[nH]nc2c1CCc1cnc(Cl)cc1-2
Agent: [Li]OC(C)(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2c(nn1CC1(NC(=O)OC(C)(C)C)CN(C(=O)OC(C)(C)C)C1)-c1cc(Cl)ncc1CC2
Temperature: 90 °C

Procedure:
8-Chloro-4,5-dihydro-2H-1,2,7-triaza-cyclopenta[a]naphthalene-3-carboxylic acid ethyl ester (320 mg; 1.15 mmol) in DMF (4 ml) is treated at 5° C. with LiOtBu (1N in THF; 1.16 ml; 1.16 m mol) for 5 minutes. 3-tert-butoxycarbonylamino-3-methanesulfonyloxymethyl-azetidine-1-carboxylic acid tert-butyl ester (0.32 mg; 1.15 mmol) is added and the mixture heated to 90° C. for 30 minutes. The reaction mixture is poured on brine and extracted with TBME three times. The combined organic phases are dried over Na2SO4, evaporated to dryness and yield the title compound as colorless crystals. 1H-NMR (400 MHz; DMSO-d6: 8.38 (s, 1H); 7.65 (s, 1H); 7.42 (bs, 1H); 5.00 (bs, 2H); 4.34 (q, 2H); 4.03 (bd, 2H); 3.79 (m, 2H); 3.00 (m, 2H); 2.95 (m, 2H); 1.40 (s, 18H); 1.36 (t, 3H). MS (m/z) ES+: 562 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][O:12][CH3:13])[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2.[Cl:19]N1C(=O)CCC1=O.CN(C)C=O>O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]2[C:10]=1[N:9]([CH2:11][O:12][CH3:13])[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2
Reactant: CCOC(=O)c1cc2cccc(N)c2n1COC
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2c(Cl)ccc(N)c2n1COC
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
A mixture of ethyl 7-amino-1-(methoxymethyl)-1H-indole-2-carboxylate (3.18 g), N-chlorosuccinimide (1.74 g) and N,N-dimethylformamide (20 ml) was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (0.91 g, yield 25%) as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:30]([O:32]C)=[O:31])[C:26]([O:28]C)=[O:27])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>O.CO>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:26]([OH:28])=[O:27])[C:30]([OH:32])=[O:31])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C(CCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(CCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 103.1 %

Procedure:
A mixture of dimethyl 2-[7-(4,5-diphenyl-2-oxazolyl)heptyl]propanedioate (6.00 g, 13 mmol), 5N sodium hydroxide solution (13.4 mL), water (120 mL) and methanol (20 mL) was stirred at room temperature. After 10 minutes, the mixture was heated to reflux for 1 hour before adding water (80 mL,) and 5N NAOH solution (13 mL). After a further 3 hours at reflux, the mixture was cooled, acidified with 2N HCl solution and extracted with diethyl ether. The combined extracts were dried over sodium sulphate and the solvent evaporated to leave a white solid, 2-[7-(4,5-diphenyl-2-oxazolyl)heptyl]propanedioic acid (5.65 g, 100%). An analytical sample was prepared by recrystallizing 1.15 g from a mixture of CH2Cl2, diethyl ether and hexane to give pure product (1.05 g), m.p. 115°-117° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O.Cl.C(=O)=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: Cl
Agent: O=C=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(Br)ccc1Cl
Reaction time: 8 h
Yield: 100 %

Procedure:
8.00 kg 2-chloro-5-bromobenzoic acid was suspended in 80.00 L methylene chloride (KF of methylene chloride<0.1% H2O) and 0.02 L of DMF added at 20° C. 5.18 Kg oxalyl chloride were slowly added and the internal temperature maintained below 25° C. The addition was slightly exothermic; gas evolution of HCl and CO2 occurred. The reaction was run at 20-25° C. overnight; a clear solution was obtained. The mixture was concentrated in vacuum to an oily residue and degased at 40° C. in vacuum. Yield of 2-chloro-5-bromobenzoic acid chloride: 8.63 kg (33.98 mol, yield 100.0%)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.CN(C=O)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[O:53]1[CH2:57][CH2:56][CH2:55][C@@H:54]1[C:58](O)=[O:59]>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:58]([C@H:54]2[CH2:55][CH2:56][CH2:57][O:53]2)=[O:59])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: O=C(O)[C@H]1CCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1)[C@H]1CCCO1
Reaction time: 1 h
Yield: 28.3 %

Procedure:
To a solution of 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.070 g, 0.189 mmol) in dry THF: DMF (4:1 mL) was added TBTU (0.182 g, 0.567 mmol) and TEA (3 mL) and stirred for 1 h under nitrogen atmosphere. To the reaction mixture (R)-(+)tetrahydro-2-furoic acid (0.032 g, 0.283 mmol) was added and stirred for 18 h at room temperature. The reaction mass was quenched in water, extracted with ethyl acetate and concentrated to afford crude product which was purified by column chromatography eluting with MeOH:DCM to afford 0.025 g of the desired title product. 1H NMR (400 MHz, DMSO d6): δ 1.23 (s, 2H), 1.74-1.92 (m, 3H), 2.09-2.24, (m, 1H), 3.75-3.80 (m, 1H), 3.89-3.94 (m, 1H), 4.26-4.37 (m, 3H), 7.43-7.45 (d, J=8.4 Hz, 1H), 7.61-7.63 (d, J=8.4 Hz, 2H), 7.85-7.87 (d, J=8.8 Hz, 2H), 8.19-8.21 (d, J=8.8 Hz, 2H), 8.50-8.53 (m, 1H), 12.71 (br s, 1H); MS (m/z): 465.55 (M−H−).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[C:4]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Si](OCC)(OCC)(OCC)OCC.[CH:31]([C:34]1[CH:40]=[CH:39][CH:38]=[C:37]([CH:41]([CH3:43])[CH3:42])[C:35]=1[NH2:36])([CH3:33])[CH3:32].OS(O)(=O)=O>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](/[C:9](=[N:36]/[C:35]2[C:37]([CH:41]([CH3:42])[CH3:43])=[CH:38][CH:39]=[CH:40][C:34]=2[CH:31]([CH3:33])[CH3:32])/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[OH:17]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: Cc1cc(Br)c(O)c(C(=O)c2ccccc2)c1
Agent: CCO[Si](OCC)(OCC)OCC
Agent: O=S(=O)(O)O
Product: Cc1cc(Br)c(O)c(/C(=N/c2c(C(C)C)cccc2C(C)C)c2ccccc2)c1
Temperature: 170 °C
Reaction time: 35 h
Yield: 69.1 %

Procedure:
In a 50 mL Claisens flask under an argon atmosphere, a mixture of 13.5 g (46.3 mmol) of 33, 20.2 g (97.2 mmol) of Si(OEt)4, and 9.03 g (50.9 mmol) of 2,6-diisopropylaniline was heated to 170° C., and then 0.37 mL of 96% H2SO4 was added. This mixture was stirred at this temperature for 35 hr, and the formed ethanol was slowly distilled off Later, 300 mL of cold water was added, and the product was extracted with 2×100 mL of diethyl ether. The combined extract was dried over K2CO3 and then evaporated to dryness. The product was isolated by flash-chromatography on silica gel 60 (40-63 um, eluent: from hexanes to hexanes-diethyl ether, 100:1, vol.). This procedure gave 14.4 g (69%) of 34.
Reaction SMILES: [CH3:1][N:2]([CH3:21])/[CH:3]=[N:4]/[S:5]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6].C1C(=O)N([Br:29])C(=O)C1.ClC1C=CC=CC=1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>[CH3:1][N:2]([CH3:21])/[CH:3]=[N:4]/[S:5]([C:8]1[C:9]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][Br:29])=[CH:18][CH:19]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:6])=[O:7]
Reactant: Cc1ccc(-c2ccccc2S(=O)(=O)/N=C/N(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: Clc1ccccc1
Product: CN(C)/C=N/S(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Temperature: 100 °C
Yield: 41 %

Procedure:
4′-Methylbiphenyl-2-sulfonic acid 1-dimethylaminometh-(E)-ylideneamide (540.0 mg, 1786 μmol), NBS (318 mg, 1.8 mmol), and benzoyl peroxide (4.3 mg, 17.8 μmol) were dissolved in chlorobenzene (7.0 mL, 69 mmol) and the resulting solution was heated at 100° C. for 90 minutes. The mixture was cooled to room temperature and water was added. The mixture was extracted with DCM, washed with saturated NaHCO3 and saturated aqueous NaCl, extracted again with DCM, dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography (40 g, 0-100% EtOAc in hexanes), then taken up in EtOAc (4.5 mL) and DCM (1.5 mL). Additional DCM (3.0 mL) was added and the mixture was heated at 60° C. The mixture was cooled in the freezer overnight, then concentrated. The material was taken up in DCM (2 mL), EtOAc (6 mL) was added, and the resulting solution placed in the freezer. A precipitate formed and was filtered to yield the title compound (279 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([O:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=[O:6])[CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(Cl)(Cl)Cl>[CH3:3][C:2]([CH3:15])([O:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:12][CH:13]=1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 102.8 %

Procedure:
To a 500 mL round bottomed flask with a stirring bar and an argon inlet was added 4-(1,1-dimethylethoxycarbonylamino)phenol (8.20 g, 39.19 mmol), Cs2CO3 (25.54 g, 78.38 mmol), DMF (75 mL), and ethyl bromoacetate (4.78 mL, 43.11 mmol). This heterogeneous mixture was stirred at ambient temperature for 3.5 h. The mixture was diluted with a little CHCl3 and filtered through a frit to remove the salts. The DMF was removed under high vacuum and the residue was suspended in 500 mL of EtOAc. This mixture was washed with H2O (3×), and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo, gave an oil. This material was chromatographed on 400 g of silica gel using 20% EtOAc-hexane as eluant. There was obtained 11.9 g (100%) of ethyl (4-(1,1-dimethylethoxycarbonylamino)phenoxy)acetate as an oil.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH:5]1[CH:10]=[C:9]2[CH:11]([OH:19])[C:12]3[C:17]([O:18][C:8]2=[CH:7][CH:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3>C(N(CC)CC)C>[CH3:1][NH:2][C:3]([O:19][CH:11]1[C:9]2[CH:10]=[CH:5][CH:6]=[CH:7][C:8]=2[O:18][C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:4]
Reactant: CN=C=O
Reactant: OC1c2ccccc2Oc2ccccc21
Solvent: CCN(CC)CC
Product: CNC(=O)OC1c2ccccc2Oc2ccccc21
Reaction time: 0.67 h

Procedure:
Methyl isocyanate (20 g.) was added slowly, with stirring, to a filtered solution of 30 g. of xanthydrol in 100 ml. of anhydrous triethylamine. After standing for 40 minutes to a 20° C. water bath, the mixture was filtered. The collected solid was washed with anhydrous diethyl ether and dried in vacuo to give 9-(N-methylcarbamoyloxy)xanthene.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>O.CS(C)=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Oc1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CC(=O)COc1ccc(Br)cc1
Reaction time: 0.42 h
Yield: 68 %

Procedure:
A solution of 50% (w/w) NaOH in water (188 mL) in DMSO (800 mL) was stirred at room temperature until a precipitate formed, treated dropwise with a solution of 4-bromophenol (101.2 g) in DMSO (200 mL) over 25 minutes, stirred for 25 minutes, treated with ethyl 4-chloro-3-oxobutanoate (102.2 g) over 40 minutes, adjusted to pH 3 with 6M HCl, treated with water (200 mL) over 12 minutes, stirred for 5 hours, treated with water (150 mL) over 20 minutes, and filtered. The solid was washed with sequentially with water and 40% ethanol/water and dried under vacuum (100 mm Hg) at 50° C. with a nitrogen bleed to provide 119.8 g of the desired product. 1H NMR (300 MHz, CDCl3) δ7.40 (m, 2H), 6.79 (m, 2H), 4.65 (s, 2H), 4.20 (q, 2H, J=7 Hz), 3.62 (s, 2H), 1.26 (t, 3H, J=7Hz).