Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13](Cl)(=[O:15])=[O:14])=[O:11])[N:3]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)(=[O:15])=[O:14])=[O:11])[N:3]=1
Reactant: C1CCNC1
Reactant: Cc1cc(C)nc(NC(=O)NS(=O)(=O)Cl)n1
Solvent: ClCCl
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)N2CCCC2)n1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a methylene chloride solution of [(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]sulfamoyl chloride, prepared as in Example 1, was added dropwise 2.9 g of pyrrolidine while maintaining the temperature at 20° C. The mixture was stirred for 16 hours and added to 50 ml of ice-water. Enough methylene chloride was added to dissolve the solids present and the methylene chloride solution was washed twice with equal volumes of water, dried over magnesium sulfate, filtered and evaporated in-vacuo. The residue, m.p. 180°-181° C., showed absorption peaks by infrared spectroscopy at 1690, 1605 and 1550 cm-1 and Nuclear Resonance Spectroscopy (60 MC) at 2.02 δ (mult.) and 3.64 δ (mult.) for the pyrrolidine hydrogens, 2.6 δ (singlet) for CH3 and 6.85 δpyrimidine H with integration ratios of 4:4:6:1, consistent for the desired structure.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]#[C:15][C:16]2[C:24]3[C:23]([Cl:25])=[N:22][C:21]([NH2:26])=[N:20][C:19]=3[N:18]([CH2:27][C:28]3[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[CH:30][N:29]=3)[CH:17]=2)(=O)=O)=CC=1.[F-].[Cs+].CO>CN(C=O)C.C(Cl)Cl>[C:15]([C:16]1[C:24]2[C:23]([Cl:25])=[N:22][C:21]([NH2:26])=[N:20][C:19]=2[N:18]([CH2:27][C:28]2[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[CH:30][N:29]=2)[CH:17]=1)#[C:14][CH:13]=[CH2:12]
Reactant: COc1c(C)cnc(Cn2cc(C#CCCOS(=O)(=O)c3ccc(C)cc3)c3c(Cl)nc(N)nc32)c1C
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CC#Cc1cn(Cc2ncc(C)c(OC)c2C)c2nc(N)nc(Cl)c12
Temperature: 70 °C
Yield: 79.7 %

Procedure:
A mixture of 4-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-ynyl 4-methylbenzenesulfonate (516 mg) and CsF (2.0 g) in DMF (7.0 mL) was heated to 70° C. for 1 h. Work-up and flash chromatogrpahy (1→3% MeOH in DCM) gave the title compound (280 mg), as a pale yellow oil. HPLC Rt=5.90 min.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH3:13].C([Li])CCC.[Cl:19][CH:20]1[C:29](=O)[C:28]2[C:23](=[CH:24][C:25]([N:31]([CH3:33])[CH3:32])=[CH:26][CH:27]=2)[O:22][CH2:21]1>C1COCC1>[Cl:19][C:20]1[CH2:21][O:22][C:23]2[C:28]([C:29]=1[C:7]1[CH:6]=[C:5]([O:8][CH3:9])[C:4]([O:10][CH3:11])=[C:3]([O:12][CH3:13])[CH:2]=1)=[CH:27][CH:26]=[C:25]([N:31]([CH3:33])[CH3:32])[CH:24]=2
Reactant: CN(C)c1ccc2c(c1)OCC(Cl)C2=O
Reactant: COc1ccc(I)c(OC)c1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C2=C(Cl)COc3cc(N(C)C)ccc32)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Iodotrimethoxybenzene (40 mg, 0.133 mmol) was dissolved into 1 mL of dry THF and cooled to −78° C. The butyl lithium solution 1.16 M (126 μL, 0.146 mmol, 1.1 eq.) was added dropwise and the mixture was stirred at −78° C. for 15 min. 3-Chloro-7-dimethylamino-chroman-4-one (30 mg, 0.133 mmol) in 1 mL of dry THF was added and the mixture was allowed to warn to room temperature. After 3 h, the mixture was quenched with a saturated aqueous solution of NH4Cl (10 mL) and extracted with EtOAc (2×10 mL). Combined organic extracts were dried with Na2SO4 and concentrated. The residue was diluted in a mixture of 2 mL of ethanol and 0.75 mL of concentrated hydrochloric acid, and stirred overnight at room temperature. A saturated solution of sodium bicarbonate was added until neutralization and the resulting solution was extracted with EtOAc (2×25 mL).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[Cl:29])[NH2:25].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH:25][C:24]1[CH:26]=[CH:27][C:28]([Cl:29])=[C:22]([Cl:21])[CH:23]=1)=[O:10]
Reactant: O=C(Cl)c1cccnc1Oc1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1cccnc1Oc1cccc(C(F)(F)F)c1

Procedure:
In the manner as in Example 1, 2.75 grams (0.009 mole) of 2(3-trifluoromethyphenoxy)nicotinoyl chloride, 1.5 grams (0.009 mole) 3,4-dichloroaniline, 0.9 grams (0.009 mole) triethylamine and 125 milliliters toluene were combined to yield 2.3 grams (59.8% of theoretical yield) of the desired product, a waxy solid. The structure was confirmed by mass spectrometry.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[S:11][C:7]=2[C:6]([C:16]([OH:18])=[O:17])=[CH:5][CH:4]=1.[CH:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21](O)[CH:20]=1.CN(C1C=CC=CN=1)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[N+:25]([C:24]1[CH:19]=[CH:20][C:21]([O:17][C:16]([C:6]2[C:7]3[S:11][C:10]([C:12]([F:13])([F:14])[F:15])=[N:9][C:8]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:18])=[CH:22][CH:23]=1)([O-:27])=[O:26]
Reactant: COc1ccc(C(=O)O)c2sc(C(F)(F)F)nc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2sc(C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.6 %

Procedure:
A suspension of 4-methoxy-2-trifluoromethylbenzothiazole-7-carboxylic acid (140 mg) in dichloromethane (10ml) was treated with p-nitrophenol (72 mg), dimethylaminopyridine (catalytic) and 1-(3-dimethylaminopropyl)-3-ethyl carbodimide hydrochloride (150 mg). The mixture was stirred at room temperature for 12 hours and the reaction washed with water (10 ml). The organic layer was separated, dried over magnesium sulphate (5 g) and evaporated in vacuo. Purification by flash chromatography (eluent 50% ethyl acetate/hexane) yielded the title compound as an off-white solid (150 mg). TLC Rf 0.13 (50% ethyl acetate in heptane).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)[C:3]=1[C:23](O)=[O:24].BrC1C=CC(N2C(C)=C(C(O)=O)C(C3C=NC=NC=3)=N2)=CC=1C(F)(F)F.Cl.Cl.[NH:54]1[CH2:59][CH2:58][CH:57]([N:60]2[CH2:64][CH2:63][CH2:62][C@H:61]2[CH2:65][OH:66])[CH2:56][CH2:55]1>>[OH:66][CH2:65][C@@H:61]1[CH2:62][CH2:63][CH2:64][N:60]1[CH:57]1[CH2:58][CH2:59][N:54]([C:23]([C:3]2[C:4]([C:17]3[CH:22]=[N:21][CH:20]=[N:19][CH:18]=3)=[N:5][N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=3)[C:2]=2[CH3:1])=[O:24])[CH2:55][CH2:56]1
Reactant: Cc1c(C(=O)O)c(-c2cncnc2)nn1-c1cccc(C(F)(F)F)c1
Reactant: OC[C@@H]1CCCN1C1CCNCC1
Agent: Cc1c(C(=O)O)c(-c2cncnc2)nn1-c1ccc(Br)c(C(F)(F)F)c1
Agent: Cl
Product: Cc1c(C(=O)N2CCC(N3CCC[C@H]3CO)CC2)c(-c2cncnc2)nn1-c1cccc(C(F)(F)F)c1

Procedure:
In analogy to the procedure described in Example 160E], a mixture of 5-methyl-3-pyrimidin-5-yl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid and 1-(4-bromo-3-trifluoromethyl-phenyl)-5-methyl-3-pyrimidin-5-yl-1H-pyrazole-4-carboxylic acid (example 173D]) and ((S)-1-piperidin-4-yl-pyrrolidin-2-yl)-methanoldihydrochloride (Example 161A]) gave a mixture of the title compound and example 176. Purification by reversed phase HPLC (MeCN:H2O) afforded [1-(4-bromo-3-trifluoromethyl-phenyl)-5-methyl-3-pyrimidin-5-yl-1H-pyrazol-4-yl]-[4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-methanone (Example 176) and [4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-[5-methyl-3-pyrimidin-5-yl-1-(3-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-methanone as a white solid (32%). MS: 515.5 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1ccc2ccccc2n1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc3ccccc3n2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 16, 50 mg, 0.15 mmol) in methylene chloride (1 mL) was treated with N,N-dimethylformamide (1 drop) and then cooled to 0° C. The reaction mixture was then treated dropwise with a 2M solution of oxalyl chloride in methylene chloride (0.11 mL, 0.23 mmol) and stirred at 0° C. for 30 min. The reaction mixture was then treated with a solution of 2-aminoquinoline (33 mg, 0.23 mmol) and pyridine (0.06 mL, 0.755 mmol) in N,N-dimethylformamide (2.5 mL). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred for 16 h. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 80/20 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-quinolin-2-yl-propionamide (46 mg, 66%) as a light yellow oil: EI-HRMS m/e calcd for C24H25ClN2O3S (M+) 457.1346, found 457.1353.
Reaction SMILES: C([O:5][C:6](=[O:56])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH:28][C:29](=[O:53])[CH2:30][N:31](C(OC(C)(C)C)=O)[CH:32]2[CH2:37][CH2:36][CH:35]([NH:38]C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)[B:15]2[O:23]C3C(C)(C4CC(C3)C4(C)C)[O:16]2)[C:8]=1OC)(C)(C)C.B(Cl)(Cl)Cl>>[NH2:38][CH:35]1[CH2:36][CH2:37][CH:32]([NH:31][CH2:30][C:29]([NH:28][CH:14]2[CH2:13][C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([C:6]([OH:5])=[O:56])[C:8]=3[O:23][B:15]2[OH:16])=[O:53])[CH2:33][CH2:34]1
Reactant: COc1c(CC(NC(=O)CN(C(=O)OC(C)(C)C)C2CCC(NC(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: NC1CCC(NCC(=O)NC2Cc3cccc(C(=O)O)c3OB2O)CC1

Procedure:
Prepared from 3-[2-{2-[tert-Butoxycarbonyl-(4-tert-butoxycarbonylamino-cyclohexyl)-amino]-acetylamino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester and BCl3 following the procedure described in Step 2 of Example 1. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 362 (MH)+.
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([O:20][CH3:21])=[C:10]([O:18][CH3:19])[C:11]=2[CH:15]([CH3:17])[CH3:16])[S:4]1(=[O:6])=[O:5].[Na].[C:23]1([N:29]2[C:33]([SH:34])=[N:32][N:31]=[N:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)C.O>CN(C)C=O>[C:23]1([N:29]2[C:33]([S:34][CH2:2][N:3]3[C:13](=[O:14])[C:12]4[C:7](=[CH:8][C:9]([O:20][CH3:21])=[C:10]([O:18][CH3:19])[C:11]=4[CH:15]([CH3:17])[CH3:16])[S:4]3(=[O:6])=[O:5])=[N:32][N:31]=[N:30]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: COc1cc2c(c(C(C)C)c1OC)C(=O)N(CCl)S2(=O)=O
Agent: [Na]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(c(C(C)C)c1OC)C(=O)N(CSc1nnnn1-c1ccccc1)S2(=O)=O
Yield: 51 %

Procedure:
By the method of Example 44 condensation of 2-chloromethyl-4-isopropyl-5,6-dimethoxysaccharin (1.46 g) and 1-phenyltetrazol-5-thiol sodium salt (0.92 g) in dimethylformamide (5 mL) and recrystallization of the product from ethanol-water afforded 2-(1-phenyltetrazol-5-yl)thiomethyl-4-isopropyl-5,6-dimethoxy-saccharin, 1.05 g, 51% yield, mp 69°-71° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][S:22]([NH:25][CH3:26])(=[O:24])=[O:23])[CH:19]=2)[NH:14][C:13]=1[Si:27]([CH3:30])([CH3:29])[CH3:28])(C(C)(C)C)(C)C.F>N1C=CC=CC=1.C(OCC)(=O)C>[OH:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][S:22]([NH:25][CH3:26])(=[O:24])=[O:23])[CH:19]=2)[NH:14][C:13]=1[Si:27]([CH3:30])([CH3:28])[CH3:29]
Reactant: CNS(=O)(=O)Cc1ccc2[nH]c([Si](C)(C)C)c(CCCO[Si](C)(C)C(C)(C)C)c2c1
Agent: F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CNS(=O)(=O)Cc1ccc2[nH]c([Si](C)(C)C)c(CCCO)c2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a solution of 0.0738 g (0.157 mmol, 1.0 equiv.) of 3-(3-t-butyldimethysilyloxypropyl)-2-trimethylsilyl-N-methyl-1H-indole-5-methanesulfonamide in 2 mL of pyridine at 0° C. was added 1 mL of 48% aqueous hydrofluoric acid. The solution was stirred for 20 minutes at 0° C. The solution was diluted with 25 mL of ethyl acetate and washed with 10 mL of 10% aqueous sodium carbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield 0.0551 g (99%) of 3-(3-hydroxypropyl)-2-trimethylsilyl-N-methyl-1H-indole-5-methanesulfonamide, homogeneous by 1H NMR and TLC.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].Cl[C:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].N1C=CC=CC=1.NN.C(=O)([O-])[O-].C(OCC=C)(=O)NN.C1(O)C=CC=CC=1>C(Cl)Cl>[C:6](=[O:7])([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[O:4][CH2:1][CH:2]=[CH2:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C=CCO
Agent: C=CCOC(=O)NN
Agent: NN
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: Oc1ccccc1
Product: C=CCOC(=O)Oc1ccccc1
Reaction time: 2 h
Yield: 97 %

Procedure:
Allyl phenyl carbonate was prepared in 97% yield by reacting 17.6 grams (0.3 mole) of allyl alcohol with 48.4 grams (0.3 mole) of phenyl chloroformate in the presence of 26.4 grams (0.33 mole) of pyridine and 300 ml of methylene chloride. The allyl phenyl carbonate soluation was washed with 5% HCl, water, dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated on a rotating evaporator under reduced pressure. The residual allyl phenyl carbonate (52.7 grams--0.29 mole) was dissolved in 200 ml of methanol and treated with 16.0 grams (0.32 mole) of 64% aqueous hydrazine at room temperature. After two hours, gase chromatography indicated that the carbonate had been completely converted to allyl carbazate and phenol. The reaction mixture was stripped of volatiles on the rotating evaporator. The residue was taken up in 200 ml of methylene chloride and washed with 50 grams of 25% sodium hydroxide to remove the phenol. The methylene chloride layer was washed with saturated salt solution, dried over sodium sulfate, filtered and the methylene chloride stripped off on the rotating evaporator. The residue weighed 9.2 grams and assayed 98.0% by gas chromatography. An additional 3.9 grams was recovered by reextracting the aqueous wash.
Reaction SMILES: [CH2:1]([SH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH3:28][C:29]([N:31](C)C)=[O:30]>>[CH2:1]([S:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:28][C:29]([NH2:31])=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCS
Reactant: CC(=O)N(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCCCCCCCCCCCCCCCCCSCCCCCCCCCCC(N)=O
Temperature: 100 °C
Reaction time: 5 h

Procedure:
In a 300 ml flask equipped with a stirrer, a condenser and a calcium chloride dryer tube were charged 13.2 g of octadecanthiol, 14.3 g of 11-bromoundedanamide, 1.7 g of potassium iodide, 20.7 g of potassium carbonate and 100 ml of DMAc, and the mixture was stirred at 100° C. for 5 hours. After cooling the reaction mixture to room temperature, the reaction mixture was poured into ice-water and precipitated crystals were collected by filtration under reduced pressure, and washed with distilled water. The resulting crystals were recrystallized from IPA to obtain 16.4 g of the title compound. Melting point: 108° C.
Reaction SMILES: O[C@H:2]1[CH2:37][N:5]2[C:6]3[C:11]([N:12]([C:14](=[O:36])[C:15]4[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:35])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:17][CH:16]=4)[CH2:13][C@@H:4]2[CH2:3]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C)C=O>[C:29]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([NH:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([N:12]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]4[CH2:37][C@@H:2]([N:42]5[C:41](=[O:43])[C:40]6=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]6[C:38]5=[O:48])[CH2:3][C@H:4]4[CH2:13]3)=[O:36])=[CH:20][CH:19]=2)=[O:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(Nc1ccc(C(=O)N2C[C@@H]3C[C@@H](O)CN3c3ccccc32)cc1)c1ccccc1-c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(=O)N2C[C@@H]3C[C@H](N4C(=O)c5ccccc5C4=O)CN3c3ccccc32)cc1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
To a solution of (2R,3aS)-2-hydroxy-5-[4-[(2-phenylbenzoyl)amino]benzoyl]-1,2,3,3a,4,5-hexahydro-pyrrolo[1,2-a]quinoxaline (1.2 g) prepared in Example 3, phthalimide (0.54 g) and triphenyl phosphine (0.96 g) in anhydrous N,N-dimethylformamide (10 ml), there was gradually dropwise added, under ice-cooling, a solution of diisopropyl azodicarboxylate (0.74 g) in anhydrous N,N-dimethylformamide (4 ml). After stirring the reaction solution at room temperature for 2 hours, it was poured into ice water and then extracted with ethyl acetate. The resulting organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was subjected to silica gel column chromatography and then eluted with hexane/ethyl acetate (1/1) to give 1.1 g (yield 73.0%) of the title compound as amorphous powder.
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:16])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4].[NH2:17][CH2:18][C:19]([O-:21])=[O:20].[Na+]>COCCO>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:7][C:6](=[O:16])[C:5]=1[C:3]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:4]
Reactant: COC(=O)c1c(O)c2ccccc2sc1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Solvent: COCCO
Product: O=C(O)CNC(=O)c1c(O)c2ccccc2sc1=O
Yield: 65.1 %

Procedure:
A mixture of 4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (105 mg, 0.44 mmol) and sodium glycinate (215 mg, 2.22 mmol) in 2-methoxyethanol (13 mL) was refluxed for 5 h. The reaction mixture was concentrated, and the crude residue dissolved in water (50 mL) and acidified to pH 3-4 using 1 N HCl. The precipitate was collected, rinsed with water and dried in vacuo to provide [(4-hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid (80 mg). MS ESI(−) m/e: 278.10 (M−1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[N:14]([N:15]=1)[C:13]1[CH:16]=[C:17]([Br:20])[CH:18]=[CH:19][C:12]=1[O:11][CH2:10][CH2:9]2)=O)C.[NH3:21].CO>>[Br:20][C:17]1[CH:18]=[CH:19][C:12]2[O:11][CH2:10][CH2:9][C:8]3[N:14]([N:15]=[C:6]([C:4]([NH2:21])=[O:3])[CH:7]=3)[C:13]=2[CH:16]=1
Reactant: CCOC(=O)c1cc2n(n1)-c1cc(Br)ccc1OCC2
Reactant: N
Solvent: CO
Product: NC(=O)c1cc2n(n1)-c1cc(Br)ccc1OCC2
Yield: 80 %

Procedure:
9-Bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acid ethyl ester (1.51 g, 4.48 mmol) in 2M ammonia/methanol solution (70 mL) was heated in a pressure bomb at approximately 120° C. (external temperature) for 30 h, then allowed to cool. The mixture was filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 50 to 100% ethyl acetate in cyclohexane) to give 9-Bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acid amide as a pale yellow solid (1.11 g, 80%). LCMS: RT=4.00 min, M+H+=308/310, [M+Na]+=330/332.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[OH:13][C:14]1[CH:15]=[C:16]([C:20]2([O:28][CH3:29])[CH2:25][CH2:24][O:23][C:22]([CH3:27])([CH3:26])[CH2:21]2)[CH:17]=[CH:18][CH:19]=1>>[CH3:29][O:28][C:20]1([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=3)[CH:15]=2)[CH2:25][CH2:24][O:23][C:22]([CH3:27])([CH3:26])[CH2:21]1
Reactant: COC1(c2cccc(O)c2)CCOC(C)(C)C1
Reactant: BrCc1ccc2ccccc2c1
Product: COC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCOC(C)(C)C1
Yield: 95.4 %

Procedure:
Using the procedure described in Example 5, 2-bromomethylnaphthalene (0.245 g) was reacted with 4-(3-hydroxyphenyl)-4-methoxy-2,2-dimethyltetrahydropyran (0.25 g) to give 4-methoxy-2,2-dimethyl-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran (0.38 g, 95%), as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:13]([CH3:29])=[CH:14][C:15]([F:28])=[C:16]([NH:18][C:19]([NH:21][CH2:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[CH:17]=3)[C:9]([CH3:30])=[N:8][C:6]=2[N:7]=1.CN(C1C=CC=CN=1)C.[C:40](OC(=O)C)(=[O:42])[CH3:41].C([O-])([O-])=O.[Na+].[Na+]>N1C=CC=CC=1.O.CO>[CH3:27][C:24]([CH3:25])([CH3:26])[CH2:23][CH2:22][NH:21][C:19](=[O:20])[NH:18][C:16]1[C:15]([F:28])=[CH:14][C:13]([CH3:29])=[C:12]([C:10]2[C:9]([CH3:30])=[N:8][C:6]3[N:7]=[C:2]([NH:1][C:40](=[O:42])[CH3:41])[N:3]=[CH:4][C:5]=3[CH:11]=2)[CH:17]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(F)c(NC(=O)NCCC(C)(C)C)cc1-c1cc2cnc(N)nc2nc1C
Agent: CN(C)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)Nc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)C)c(F)cc3C)c(C)nc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
Treat a cooled solution (0° C.) of 1-(5-(2-amino-7-methylpyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)-3-(3,3-dimethylbutyl)urea (0.167 g, 0.407 mmol) and catalytic dimethylaminopyridine (0.005 g, 0.041 mmol) in pyridine (4 mL) with acetic anhydride (0.269 ml, 2.85 mmol) and stir at RT overnight. Add saturated. Na2CO3 and MeOH and heat at 45° C. overnight. Treat the mixture with water, extract with 4:1 EtOAc/THF (3×), wash the combined organics with saturated. Na2CO3, then brine, dry over MgSO4, concentrate to dryness and purify via silica gel chromatography (15-100% EtOAc/Hexanes). Dissolve the resulting material in acetonitrile/H2O, freeze and lyophilize to afford the title compound as an off-white solid (55 mg, 30% yield). MS (m/z): 453.2 (M+1).