Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:19]([CH:20]([CH3:23])[CH:21]=[CH2:22])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:24])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.[H][H]>C(O)C.[Pd]>[OH:1][C:2]1[C:19]([CH:20]([CH3:23])[CH2:21][CH3:22])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:24])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: C=CC(C)c1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCC(C)c1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 65.9 %

Procedure:
To a solution of the known 3-hydroxy-2-(1-methyl-2-propenyl)estra-1,3,5(10)-trien-17-one (ref. Patton, 1962; Chemical Abstracts Registry Number [98543-85-2], 30 mg, 0.093 mmol) dissolved in 10 mL of anhydrous ethanol was added 20 mg of 5% Pd/C. The reaction flask was shaken under 2.7 atm. of hydrogen for 3 h. The reaction mixture was then filtered and the catalyst was washed with ethanol. After solvent removal, the crude product was purified by chromatography (silica gel eluted with 12.5% ethyl acetate in hexanes) and then recrystallized from methylene chloride-hexanes to give 20 mg of pure product: m.p. 186-187° C.; 1H NMR(CDCl3) δ0.85-0.90 (m, 3H, CH3), 0.91 (s, 3 h CH3), 1.20-1.24 (m, 3H, CH3), 2.81-2.89 (m, 2H, CH2), 6.51 (s, 1H, Ar—H), 7.06 (s, 1H, Ar—H); 13C NMR(CDCl3) δ12.17, 13.75, 20.44, 21.46, 25.93, 28.91, 29.83, 31.49, 33.87, 35.81, 38.33, 44.05, 48.01, 50.24, 115.37, 123.99, 124.17, 130.86, 131.88, 134.78, 157.267, 221.79.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH3:13][CH:14](O)[CH3:15]>CCOCC>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH:14]([CH3:15])[CH3:13])=[O:6]
Reactant: O=C(O)CCCBr
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(C)OC(=O)CCCBr
Temperature: 25 °C

Procedure:
A solution of 4-bromobutyric acid (50 g) in 2-propanol (200 mL) containing 1 mL of H2SO4 was refluxed for 3 h, then cooled to ambient temperature, diluted with ether (500 mL), washed with saturated NaHCO3 (3×300 mL), and brine (300 mL). The organic extract was dried (MgSO4), filtered and concentrated in vacuo to give isopropyl 4-bromo-butyrate (52 g) as an oil. This ester was dissolved in MeCN (380 mL). Ph3P (100 g) was added and the solution was heated at reflux for 72 h, after which TLC analysis (20% water/MeCN, C-18 RP TLC plates) showed complete reaction. The mixture was cooled and concentrated and the residue was slurried with toluene (400 mL) for 1 h. The solid was collected by filtration and was washed with toluene (100 mL) and then dried in vacuo at 50° C. to provide (3-(isopropoxycarbonyl)propyl)triphenylphosphonium bromide (100.6 g). 1H NMR (CDCl3): δ1.19-1.22 (d, 6H), 1.85-1.97 (mn, 2H), 2.85 (t, 2H), 3.95-4.10 (m, 2H), 4.89-5.03 (m, 1H), 7.65-7.94 (m, 15H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[C:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:28])=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(Cl)(Cl)(Cl)Cl>[C:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][Br:1])=[CH:37][CH:36]=1)(=[O:28])=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 97 %

Procedure:
N-Bromosuccinimide (387 mg, 2.17 mmol), α,α'-azobis(isobutyronitrile) (catalytic), 2'-(N-t-butylsulfamol)-4-methylbiphenyl (from Step D) (550 mg, 1.81 mmol) and carbon tetrachloride (50 ml) were heated with stirring at reflux for 3 hours. After cooling to room temperature the mixture was filtered and the filtrate evaporated to dryness. Flash chromatography (silica gel, initially 10 and then 20% ethyl acetate-hexane) afforded the title compound [699 mg, 77% pure (the remainder of the material was the corresponding dibromo derivative), 97% yield] as a white solid; 1H NMR (300 MHz, CDCl3) δ8.17 (dd, J=7.5, 1.6 Hz, 1H), 7.68-7.45 (m, 6H), 7.31 (dd, J=7.5, 1.6 Hz, 1H), 4.55 (s, 2H), 3.52 (s, 1H), 1.00 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:30])[N:5]=[C:6]([S:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[C:15]([CH:18]=2)[C:16]#[N:17])[NH:7][CH:8]=1)[CH3:2].[CH3:31]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[CH2:1]([C:3]1[C:4](=[O:30])[N:5]=[C:6]([S:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=3)=[C:15]([CH:18]=2)[C:16]#[N:17])[N:7]([CH3:31])[CH:8]=1)[CH3:2]
Reactant: CCc1c[nH]c(SCc2ccc(Oc3cccc(C(F)(F)F)c3)c(C#N)c2)nc1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: ClCCl
Product: CCc1cn(C)c(SCc2ccc(Oc3cccc(C(F)(F)F)c3)c(C#N)c2)nc1=O
Yield: 38.8 %

Procedure:
The same procedure as E64 from 5-{[(5-ethyl-4-oxo-1,4-dihydro-2-pyrimidinyl)thio]methyl}-2-{[3-(trifluoromethyl)phenyl]oxy}benzonitrile (250 mg, 0.579 mmol), DIPEA (0.202 mL, 1.159 mmol) and MeI (0.054 mL, 0.869 mmol) in DCM (2 mL). to afford the title compound (100 mg, 38.7% yield). LCMS: rt=3.25 min, [M+H+]=446
Reaction SMILES: CO[C:3](=[O:17])[C:4]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)=[CH:5][CH:6]([CH3:8])[CH3:7].[CH3:18][NH:19][C:20]([NH2:22])=[O:21].C[O-].[Mg+2].C[O-].CO>>[Cl:16][C:11]1[CH:10]=[C:9]([C:4](=[CH:5][CH:6]([CH3:7])[CH3:8])[C:3]([NH:22][C:20]([NH:19][CH3:18])=[O:21])=[O:17])[CH:14]=[CH:13][C:12]=1[Cl:15]
Reactant: CNC(N)=O
Reactant: COC(=O)C(=CC(C)C)c1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(=CC(C)C)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 32.4 %

Procedure:
The isomeric mixture of 2-(3,4-dichloro-phenyl)-4-methyl-pent-2-enoic acid methyl ester [749.0 mg, 2.74 mmol, (E):(Z)=3.5:1] and methyl urea (812.6 mg, 10.97 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt %, 16 mL, 10.97 mmol). The resulting reaction mixture was heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C. and then filtered through celite. The celite was thoroughly washed with ethyl acetate. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 9/1 hexanes/ethyl acetate) afforded impure 1-[2-(3,4-dichloro-phenyl)-4-methyl-pent-2-enoyl]-3-methyl-urea (280.2 mg) as a white solid. A second flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/2 hexanes/diethyl ether) again afforded impure 1-[2-(3,4-dichloro-phenyl)-4-methyl-pent-2-enoyl]-3-methyl-urea (114.6 mg) as a white solid. Recrystallization from hexanes/ethyl acetate afford pure (E)-1-[2-(3,4-dichloro-phenyl)-4-methyl-pent-2-enoyl]-3-methyl-urea (24.7 mg, 3%) as a white solid: mp 177-178° C.; FAB-HRMS m/e calcd for C14H16Cl2N2O2 (M+H)+315.0667, found 315.0652.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C@@:16]([OH:37])([CH3:36])[C:17]([O:19]C1C(C(C2C=CC=CC=2)(C)C)CCC(C)C1)=[O:18].[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C@@:16]([OH:37])([CH3:36])[C:17]([OH:19])=[O:18]
Reactant: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)C(=O)OC2CC(C)CCC2C(C)(C)c2ccccc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)C(=O)O)c1C
Reaction time: 16 h
Yield: 53 %

Procedure:
A solution of 0.907 g (about 1.35 mmol) of (-)-8-phenylmenthyl (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-hydroxy-2-methylbutanoate in 10 ml of ethanol is treated with 1 ml of 28% sodium hydroxide solution and the mixture is left to stand at room temperature for 16 hours. The mixture is then diluted with 50 ml of water and extracted three times with 50 ml of ether each time. The aqueous phase is acidified (pH 2) with 10% phosphoric acid and extracted three times with 50 ml of ether each time. The combined organic phases are dried over sodium sulphate and the solvent is subsequently removed on a rotary evaporator. There are obtained 212 mg of (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-hydroxy-2-methylbutanoic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][N:34]([CH:36]3[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]3)[CH:35]=2)O1.Cl>CO>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:12]([O:11][N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:31]3[CH:32]=[N:33][N:34]([CH:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[CH:35]=3)[CH:3]=2)[CH:8]=[CH:9]1)[CH3:13]
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl
Solvent: CO
Product: CC(On1ccc2ncc(-c3cnn(C4CCNCC4)c3)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate according to the procedure described in example 4. The resulting compound (BOC protected compound) was dissolved in methanol and was treated with HCl (4.0M solution in dioxane,) at room temperature for 30 min. Solvents were evaporated and the residue was dissolved in DCM and treated with Na2CO3/NaHCO3 and drops of water. The solution was then purified to give the entitled compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.[Br:9][C:10]1[CH:11]=[C:12]([CH2:20][CH2:21][CH2:22]N2CCOCC2)[N:13]2[C:18]=1[C:17]([NH2:19])=[N:16][CH:15]=[N:14]2>>[Br:9][C:10]1[CH:11]=[C:12]([CH2:20][CH2:21][CH2:22][N:5]2[CH2:6][CH2:7][CH2:8][C@H:4]2[CH2:3][O:2][CH3:1])[N:13]2[C:18]=1[C:17]([NH2:19])=[N:16][CH:15]=[N:14]2
Reactant: COC[C@@H]1CCCN1
Reactant: Nc1ncnn2c(CCCN3CCOCC3)cc(Br)c12
Product: COC[C@@H]1CCCN1CCCc1cc(Br)c2c(N)ncnn12

Procedure:
Intermediate V step 4 (947 mg, 2.8 mmol) was allowed to react with (2S)-2-(methoxymethyl)pyrrolidine (980 mg, 8.5 mmol) using the procedure to make 5-bromo-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine. The reaction was partitioned between EtOAc (100 mL) and saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was extracted with EtOAc (10 mL). The combined organic layer was washed with brine (10 mL) then dried with sodium sulfate. The reaction was concentrated under vacuum to quantitatively yield crude product. 1H-NMR (DMSO-d6) 7.83 (s, 1H), 6.61 (s, 1H), 3.25 (m, 1H), 3.19 (s, 3H), 3.12 to 2.72 (m, 6H), 2.23 (m, 1H), 2.04 (m, 1H), 1.77 (m, 3H), 1.62 (m, 2H), 1.40 (m, 1H); MS [M+H]+=622.2; LCMS RT=2.68.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[CH2:14]([O:16][C:17](=[O:33])[C:18]1[CH:30]=[C:29]([CH2:31]O)[CH:28]=[C:20]([C:21]([N:23]([CH3:27])[CH2:24][CH2:25][CH3:26])=[O:22])[CH:19]=1)[CH3:15].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:14]([O:16][C:17](=[O:33])[C:18]1[CH:30]=[C:29]([CH2:31][F:11])[CH:28]=[C:20]([C:21]([N:23]([CH3:27])[CH2:24][CH2:25][CH3:26])=[O:22])[CH:19]=1)[CH3:15]
Reactant: CCCN(C)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(CF)cc(C(=O)OCC)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 28.8 %

Procedure:
Add bis(2-methoxyethyl)aminosulfur trifluoride (220 mg, 1.0 mmol) to a polypropylene tube (5 mL), seal, cool to −78° C., add a solution of 5-hydroxymethyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (250 mg, 0.9 mmol) in dichloromethane 1.0 (1 mL) in 0.2 mL increments. Stir at −78° C. for 3 h then at room temperature overnight. Pour the reaction into saturated aqueous sodium bicarbonate. Extract with dichloromethane, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes) to give the title compound (73 mg, 29%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH2:13][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][OH:16])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:27]([CH3:29])=[CH2:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[C:21]([O:20][C:18]([N:17]1[C@@H:14]([CH2:13][C:10]2([CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12]2)[CH2:15][O:16][C:27]1([CH3:29])[CH3:28])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1(COCc2ccccc2)CC1
Reactant: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](CC2(COCc3ccccc3)CC2)COC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 31.4 g of 1-benzyloxymethyl-1-[2(S)-tert-butoxycarbonylamino-3-hydroxy-propan-1-yl]cyclopropane, 80 ml of 2-methoxypropene and 0.5 g of p-toluenesulfonic acid hydrate in 170 ml of methylene chloride is stirred at room temperature for 16 h. The mixture is concentrated and the residue is purified by means of FC over 900 g of silica gel (mobile phase G): Rf (G)=0.23.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([OH:22])[CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]2)=[CH:5][CH:4]=1)#[N:2].CCN(C(C)C)C(C)C.FC(F)(F)S(O[Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])(=O)=O>C(Cl)Cl>[Si:38]([O:22][C@@H:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]1)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]
Reactant: CCOC(=O)[C@H]1CCCN(C[C@@H](O)c2ccc(C#N)cc2)C1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1CCCN(C[C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(C#N)cc2)C1
Reaction time: 2 h
Yield: 95 %

Procedure:
To a mixture of (S)-ethyl 1-((S)-2-(4-cyanophenyl)-2-hydroxyethyl)piperidine-3-carboxylate (17.0 g, 56.2 mmol) and DIPEA (17.68 ml, 101 mmol) in CH2Cl2 (187 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (16 ml, 69.6 mmol) slowly. The reaction was monitored with HPLC. The reaction completed in 2 hours. The reaction mixture (a light brown solution) was quenched with water, the aqueous layer was extracted with DCM. The organic phase was combined and dried with Na2SO4. After concentration, the crude material was further purified on a silica gel cartridge (330 g silica, 10-30% EtOAc/hexanes gradient) to afford a purified product (S)-ethyl 1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-cyanophenyl)ethyl)piperidine-3-carboxylate (22.25 g, 53.4 mmol, 95% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.61 (2H, d), 7.45 (2H, d), 4.79 (1H, m), 4.15 (2H, m), 2.88 (1H, m), 2.75 (1H, m), 2.60 (1H, dd), 2.48 (1H, m), 2.40 (1H, dd), 2.33 (1H, tt), 2.12 (1H, tt), 1.90 (1H, m), 1.68 (1H, dt), 1.52 (1H, m), 1.48 (1H, m), 1.27 (3H, t), 0.89 (9H, s), 0.08 (3H, s), −0.07 (3H, s).
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[O:38][C:34]4=[CH:35][CH:36]=[CH:37][C:33]4=[CH:32][CH:31]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+].C(O)C.Cl>O>[O:38]1[C:34]2=[CH:35][CH:36]=[CH:37][C:33]2=[CH:32][CH:31]=[C:30]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:20]1[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:39])=[O:3])=[CH:14][CH:13]=2)[N:19]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3-c3ccc4cccc-4o3)oc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccccc2-c2ccc3cccc-3o2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1

Procedure:
To a 20 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-benzofur-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (0.268 mmoles), lithium hydroxide (0.535 mmoles, 0.268 mL of a 2N solution), and ethanol (5 mL). This solution was heated to reflux for 2 h. Distilled water was added to the mixture and the pH was adjusted to 3 using a 1N HCl solution. The organic layer was extracted with ethyl acetate, washed with brine, and concentrated in-vacuo. This crude oil was re-solvated in pure ethyl acetate and filtered over a pad of Celite. The filtrate was concentrated in-vacuo, and the crude oil was crystallized using acetonitrile. The crystals were collected and dried in-vacuo affording 2-(4-{2-[2-(4-benzofur-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) 8.04 (2H, d), 7.92 (2H, d), 7.58 (2H,dd), 7.26 (2H, m), 6.91(2H, d), 6.79 (2H, d), 4.17 (2H, t), 3.00 (2H, t) 2.39 (3H, s), 1.53 (6H, s).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])=[CH:5][CH:4]=1.[NH:21]([C:23]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)=[S:24])[NH2:22].CN(C)C=O>Cl.O>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:22][NH:21][C:23]([NH:25][C:26]3[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)=[S:24])[CH3:16])[C:10]=2[OH:18])=[CH:5][CH:4]=1
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Yield: 89.3 %

Procedure:
1-[5-(4-trifluoromethylphenyl)-1-methyl-4-hydroxy-1H-pyrazol-3-yl]ethanone (0.1694 mmol, HPLC purity 80%, 60.2 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.1694 mmol, 35.8 mg) were stirred with dimethylformamide (3 mL) and three drops of concentrated hydrochloric acid at room temperature for 8.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. Chloroform/n-hexane was added to the resulting solid, and the precipitated solid was recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (72.2 mg, yield 89%).
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](S(C)(=O)=O)[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.[NH3:39]>O1CCOCC1>[NH2:39][C:31]1[N:30]=[C:29]([C:26]2[C:4]3[CH:5]=[C:6]4[C:19](=[C:2]([F:1])[C:3]=3[O:28][N:27]=2)[N:18]2[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]2[C:8]2([C:9](=[O:16])[NH:10][C:11](=[O:15])[NH:12][C:13]2=[O:14])[CH2:7]4)[CH:34]=[CH:33][N:32]=1
Reactant: C[C@@H]1CN2c3c(cc4c(-c5ccnc(S(C)(=O)=O)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Reactant: N
Solvent: C1COCCO1
Product: C[C@@H]1CN2c3c(cc4c(-c5ccnc(N)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1

Procedure:
Starting materials: (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(2-(methylsulfonyl)pyrimidin-4-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione (Example 169) and ammonia in dioxane (0.5M)
Reaction SMILES: [C:1]([C:7]1[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]2[O:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][C:11]=2[CH:18]=1)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].C=O.Cl.[CH3:24]NC.Cl>CN(C)C=O.C(O)(=O)C>[CH2:24]=[C:2]([CH:3]([CH3:5])[CH3:4])[C:1]([C:7]1[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]2[O:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][C:11]=2[CH:18]=1)=[O:6]
Reactant: Cc1c(C(=O)CC(C)C)cc2cc(C(=O)O)oc2c1C
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C=C(C(=O)c1cc2cc(C(=O)O)oc2c(C)c1C)C(C)C
Temperature: 95 °C

Procedure:
A mixture of 5-isovaleryl-6,7-dimethylbenzofuran-2-carboxylic acid (8.5 g.), paraformaldehyde (2.0 g.), dimethylamine hydrochloride (3.3 g.) and acetic acid (1 ml.) is heated at 95°C. for 2.5 hours, treated with dimethylformamide (75 ml.), heated an additional 3.5 hours, poured into ice water (300 ml.) containing hydrochloric acid (5 ml.). The product is extracted into ether, washed with water, dried over magnesium sulfate, the solvent evaporated at reduced pressure to afford 5-(2-methyleneisovaleryl)-6,7-dimethylbenzofuran-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[C:18](SC)[S:19][CH3:20])[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)[CH:6]=[CH:7][CH:8]=1.O.[NH2:24][NH2:25]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:24][NH:25][C:18]=2[S:19][CH3:20])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(C(=O)c2ccccc2)=C(SC)SC)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1cccc(-c2c(-c3ccccc3)n[nH]c2SC)c1

Procedure:
To a solution of 2-(3-methoxyphenyl)-3,3-bis(methylthio)-1-phenylprop-2-en-1-one in EtOH (100 mL) was added hydrazine hydrate (5.36 mL, 110 mmol). The reaction mixture was refluxed overnight, additional hydrazine hydrate (1.00 mL, 20.6 mmol) was added, and the mixture was refluxed until the reaction was complete. The mixture was concentrated under reduced pressure, washed with H2O and extracted with CH2Cl2. The combined organic layers were washed with H2O, brine, dried over MgSO4 and concentrated to give the title compound (6.67 g). LCMS m/z=397 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[CH3:9][S-:10].[Na+].C(OCC)(=O)C>CN(C)C=O>[CH3:9][S:10][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8]
Reactant: C[S-]
Reactant: O=Cc1sccc1Br
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccsc1C=O
Reaction time: 3 h
Yield: 91.4 %

Procedure:
4.44 g of 3-bromo-2-thiophenecarboxaldehyde and 1.63 g of sodium thiomethoxide were dissolved in 20 ml of N,N-dimethylformamide, and the mixture was stirred for 3 hours under ice-cooling. Ethyl acetate was added to the reaction solution. The mixture was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:9), to give 3.36 g of the title compound as a yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].Br[CH2:18][C:19]#[N:20].O>CN(C)C=O>[C:19]([CH2:18][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:20]
Reactant: N#CCBr
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccccc2n1CC#N
Reaction time: 0.5 h

Procedure:
Ethyl indole-2-carboxylate (6.0 g) was dissolved in dimethylformamide (60 ml) and sodium hydride (60% in oil, 1.4 g) was added under ice-cooling. After stirring for 30 minutes, bromoacetonitrile (2.3 ml) was added and the mixture was stirred. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate to give 6.6 g of ethyl 1-cyanomethylindole-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH2:18])=[CH:16][N:15]=[CH:14]1.[F:19][C:20]([F:24])([F:23])[S:21]Cl.O>C(Cl)Cl>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:17]([NH2:18])=[C:16]([S:21][C:20]([F:24])([F:23])[F:19])[N:15]=[CH:14]1
Reactant: FC(F)(F)SCl
Reactant: Nc1cncn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: O
Solvent: ClCCl
Product: Nc1c(SC(F)(F)F)ncn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
To a solution of 4.8 g (14.91 mmole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-aminoimidazole in 400 ml of methylene chloride was added 1.3 ml (14.91 mmole) of trifluoromethanesulfenyl chloride at 0° C. The mixture was stirred at 0° C. for 4 h and then at RT for 15 h. Water was added and the mixture was partitioned between water and methylene chloride. The organic layer was dried over anhydrous sodium sulfate and the solvent removed. The residue was recrystallized from methylene chloride to give 3.36 g (52.51% yield) of the desired product., mp 134° C.