Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S([N:10]2[C:27]3[C:13]4=[C:14]([CH:24]=[CH:25][CH:26]=3)[C@H:15]3[O:20][CH2:19][C:18](=O)[N:17]([CH3:22])[C@@H:16]3[CH2:23][C:12]4=[CH:11]2)(=O)=O)=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:22][N:17]1[C@@H:16]2[CH2:23][C:12]3[C:13]4[C:27]([NH:10][CH:11]=3)=[CH:26][CH:25]=[CH:24][C:14]=4[C@H:15]2[O:20][CH2:19][CH2:18]1
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(cccc42)[C@H]2OCC(=O)N(C)[C@@H]2C3)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCO[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Yield: 24.3 %

Procedure:
A suspension of trans-4-(p-tolylsulphonyl)-4,6,6a,8,9,10a-hexahydro-7-methyl-7H-indolo-[3,4 gh]-[1,4]-benzoxazin-8-one (3.0 gms; 0.008 m) and lithium aluminum hydride (3.0 gm; 0.08 m) in tetrahydrofuran (200 ml) is refluxed for 17 hours. The cooled solution is hydrolyzed with water (6 ml). The solid is filtered, and the organic solvent is dried over anhydrous sodium sulfate. After filtration, the solvent is removed under reduced pressure (20 mm). The gum is crystallized from methanol (2-5 ml) to yield 420 mg of trans-4,6,6a,8,9,10a-hexahydro-7-methyl-7H-indolo-[3,4 gh]-[1,4]-benzoxazine. This solid is purified by chromatography (silica, CHCl3 /NH4OH) to give 330 mg of trans-4,6,6a,8,9,10a-hexahydro-7-methyl-7-H-indolo-[3,4 gh]-[1,4]-benzoxazine; m.p. 175°-177° (softening at 100°).
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:18]Cl>C(O)(=O)C>[Cl:18][C:14]1[CH:15]=[CH:16][C:8]2[C:7](=[O:17])[NH:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10](=[O:12])[C:9]=2[CH:13]=1
Reactant: ClCl
Reactant: O=c1[nH]c2ccccc2c(=O)c2ccccc12
Solvent: CC(=O)O
Product: O=c1[nH]c2ccccc2c(=O)c2cc(Cl)ccc12
Temperature: 25 °C

Procedure:
A mixture of 11.15 g of 5H-dibenz[b,e]azepin-6,11-dione and 600 ml of glacial acetic acid is heated on a steam bath until the solid dissolves. To the solution (70° C.) is added chlorine gas. Chlorine is bubbled throughout the solution until a precipitate begins to form. The mixture is allowed to cool to room temperature and is filtered to give 7.3 g of product, m.p. 290° C. to 295° C.
Reaction SMILES: [CH3:1][C:2](=[O:5])[C:3]#[CH:4].[Cl:6][C:7]1[CH:8]=[N:9][C:10](=[S:13])[NH:11][CH:12]=1>C(Cl)(Cl)Cl>[O:5]=[C:2]([CH3:1])[CH:3]=[CH:4][S:13][C:10]1[N:11]=[CH:12][C:7]([Cl:6])=[CH:8][N:9]=1
Reactant: C#CC(C)=O
Reactant: S=c1ncc(Cl)c[nH]1
Solvent: ClC(Cl)Cl
Product: CC(=O)C=CSc1ncc(Cl)cn1
Reaction time: 0.17 h
Yield: 72 %

Procedure:
3-Butyn-2-one (5 mmol) in chloroform (25 ml) was added dropwise over 10 min at room temperature to a stirred suspension of 5-chloropyrimidine-2-thione (4.5 mmol) in chloroform (25 ml). The mixture was stirred for an additional 10 min before the solvent was evaporated. The residue was crystallized from methanol; yield 72%, m.p. 89° C. 1H NMR (CDCl3): δ2.20 (Me-(Z)), 2.23 (Me-(E)), 6.52 (Hα, d, J 18 Hz (E)), 6.58 (Hα, d, J 10 Hz (Z)), 8.43 (Hβ, d, J 10 Hz (Z)), 8.57 (Hβ, d, J 18 Hz (E)), 8.62 (H-4, H-6); (E)/(Z)=1:1. IR (KBr): 1660 cm-1 (CO).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5](P(OCC)(OCC)=O)[F:6])[CH3:2].[H-].[Na+].O=[C:19]1[CH:26]2[CH2:27][C:22]3([O:29][C:30](=[O:36])[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2>C1COCC1>[F:6][C:5](=[C:25]1[CH:26]2[CH2:27][C:22]3([O:29][C:30](=[O:36])[CH2:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:21][CH:20]([CH2:28][CH:24]1[CH2:23]3)[CH2:19]2)[C:4]([O:3][CH2:1][CH3:2])=[O:15]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CC(C)(C)CC(=O)OC12CC3CC(C1)C(=O)C(C3)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)=C1C2CC3CC1CC(OC(=O)CC(C)(C)C)(C3)C2

Procedure:
1.48 ml of (diethoxy-phosphoryl)-fluoro-acetic acid ethyl ester are added dropwise to a suspension of 317 mg of NaH (55% in mineral oil) in 30 ml of THF at 0°. The mixture obtained is stirred, 1.37 g of 3,3-dimethyl-butyric acid 4-oxo-adamantan-1-yl ester in 10 ml of THF are added slowly and the mixture obtained is stirred at RT overnight. The mixture obtained is diluted with EtAc and the diluted mixture obtained is washed with 1M aqueous NaH2PO4 and saturated aqueous NaHCO3 solution. The organic layer obtained is dried, solvent is evaporated and the evaporation residue obtained is subjected to chromatography on silica gel. 3,3-Dimethyl-butyric acid 4-(fluoro-ethoxycarbonyl-methylene)-adamantan-1-yl ester is obtained in the form of an oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:10]([O:11][CH3:12])=[CH:9][C:7]([NH2:8])=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1.Cl[CH2:17][C:18]1[CH:28]=[CH:27][C:21]2[N:22]=[C:23]([S:25][CH3:26])[S:24][C:20]=2[CH:19]=1>CN(C=O)C>[Br:3][C:4]1[C:10]([O:11][CH3:12])=[CH:9][C:7]([NH:8][CH2:17][C:18]2[CH:28]=[CH:27][C:21]3[N:22]=[C:23]([S:25][CH3:26])[S:24][C:20]=3[CH:19]=2)=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1
Reactant: COc1cc(N)c([N+](=O)[O-])cc1Br
Reactant: CSc1nc2ccc(CCl)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(NCc2ccc3nc(SC)sc3c2)c([N+](=O)[O-])cc1Br
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 24.7 %

Procedure:
To a stirred mixture of DMF (15 mL) and NaH (60% in mineral oil, 75 mg, 1.9 mmol) at −10° C. under argon was added 4-bromo-5-methoxy-2-nitroaniline (490 mg, 2.2 mmol) in one portion. The mixture was stirred for 5 min at −10° C. A solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole from Example 36 (500 mg, 2.2 mmol) in DMF (5 mL) was added dropwise. After stirring at −10° C. for 1 h, the mixture was allowed to warm slowly to rt. The mixture was stirred at rt for 58 h and then partitioned between EtOAc (150 mL) and 1 M aq Na2CO3 (50 mL). The EtOAc layer was separated and washed with water (50 mL) and brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% hexanes to 100% EtOAc to afford 4-bromo-5-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline (239 mg, 25%) as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 9.02 (t, J=5.8 Hz, 1H), 8.23 (s, 1H), 8.06 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 6.40 (s, 1H), 4.80 (d, J=5.8 Hz, 2H), 3.77 (s, 3H), 2.78 (s, 3H). LCMS (ESI) m/z 440 and 442 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([O:23][CH3:24])[CH3:22])[C:12]([C:25](=[O:36])[C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[C:11]([CH:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[O:44])[CH2:39][CH2:38]3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([O:23][CH3:24])[CH3:22])[C:12]([CH:25]([OH:36])[C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=3)=[C:11]([CH:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][CH2:46][C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)=[O:44])[CH2:39][CH2:38]3)[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(C)c1nc2c(c(C3CCN(C(=O)OCc4ccccc4)CC3)c1C(=O)c1ccc(C(F)(F)F)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(C)c1nc2c(c(C3CCN(C(=O)OCc4ccccc4)CC3)c1C(O)c1ccc(C(F)(F)F)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
959 mg (6) Benzyl 4-((5S)-5-(tert-butyldimethylsilyloxy)-2-(1-methoxyethyl)-7,7-dimethyl-3-(4-(trifluoromethyl)benzoyl)-5,6,7,8-tetrahydroquinolin-4-yl)piperidine-1-carboxylate (Example VI (69) are dissolved in 15 ml ethanol. To the mixture 441 mg of sodiumborohydride is added. The reaction is stirred for 2 hours at 70° C. Then 8 equivalents of sodiumborohydride are added and the reaction is stirred over night at 70° C. The solvent is evaporated under vacuum. Water, ethylacetate and 1M hydrochloric acid are added. The aqueous phase is extracted with ethylacetate and the combined organic phases are washed with brine. After drying with natrium sulphate the solvents are evaporated under vacuum and the residue is chromatographed on isolate.
Reaction SMILES: C[Al](C)C.CCCCCC.[C:11]123[CH2:24][S:21](=[O:23])(=[O:22])[NH:20][C@@H:12]1[CH2:13][CH:14]([C:17]2([CH3:19])[CH3:18])[CH2:15][CH2:16]3.[NH2:25][CH2:26][C:27]([O-])=[O:28].CO[2H]>C1(C)C=CC=CC=1>[NH2:25][CH2:26][C:27]([C:12]12[NH:20][S:21](=[O:23])(=[O:22])[CH2:24][C:11]31[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:13]2)[CH2:15][CH2:16]3)=[O:28]
Reactant: NCC(=O)[O-]
Reactant: CC1(C)C2CCC13CS(=O)(=O)N[C@@H]3C2
Agent: C[Al](C)C
Agent: [2H]OC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC1(C)C2CCC13CS(=O)(=O)NC3(C(=O)CN)C2
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 158.7 %

Procedure:
Over 20 minutes, 2 M trimethylaluminum in hexane (40 ml, 1.2 eq) was added to (2R)-bornane-10,2-sultam (15.7 g, 1.1 eq) in toluene (110 ml) at 0° C., then left for 30 minutes. Ethyl N-(diphenylmethylene)[1,2-13C2, 15N, 2,2-2H2]glycinate (18.1 g, 66.4 mmol) in toluene (10 ml) was added and the reaction stirred overnight. Heating to 50° C. for 3-4 hours drove the reaction to completion. Workup was effected by cooling the reaction in ice and carefully adding MeOD (20 ml). After 1 hour, D2O (30 ml) was carefully added. Filtering, extracting with ethyl acetate (2×250 ml), drying over MgSO4 and purifying by silica gel flash chromatography (Hexane: Ethyl Acetate 10:1 to 1:1) gave (2R)-N-(diphenylmethylene)[1,2-13C2, 15N, 2,2-2H2]glycylbornane-10,2-sultam (28.7 g, 99% yield) as an orange oil.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:5]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:10][C:6]=2[N:7]=[CH:8][N:9]=1.[CH2:27]([O:29][C:30](=[O:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[CH3:28].ClCCl>C1COCC1.CN(C=O)C.O>[CH2:27]([O:29][C:30](=[O:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:4]1[C:5]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:10][C:6]=2[N:7]=[CH:8][N:9]=1)[CH3:28]
Reactant: CCOC(=O)CCCCCO
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CCCCCOc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add 42.8 mg sodium hydride (60% dispersion in oil, approx. 1.07 mmol) in portions, at RT, to a mixture of 300 mg (0.89 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and 214 mg (1.34 mmol) 6-hydroxyhexanoic acid ethyl ester in 1.0 ml THF and 0.7 ml DMF. Stir the mixture for 1 h at RT, and then add dichloromethane and water. Wash the organic phase with saturated sodium chloride solution, dry over sodium sulphate and concentrate by vacuum evaporation. After preparative RP-HPLC, 120.9 mg (29.5% of theor.) of the target compound is isolated from the residue.
Reaction SMILES: Cl[CH:2]([O:4]C)Cl.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].CCOCC>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[F:6][C:7]1[CH:12]=[C:11]([CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[CH:2]=[O:4]
Reactant: COc1ccccc1F
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(C=O)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of titanium tetrachloride (182 g, 0.96 mol, 1.2 equiv.) and α,α, -dichloromethylmethyl ether (110 g, 0.96 mol) in an equal volume of methylene chloride is slowly added (30 minutes) to a solution of o-fluoroanisole (101 g, 0.80 mol) in dry methylene chloride (50 ml) at 10-20° C. The mixture is stirred at room temperature for one hour, is poured over crushed ice water and ether (1 l ) with stirring. This mixture is stirred under nitrogen until solution occurs. The organic layer is extracted with water, aqueous sodium bicarbonate, and is dried (MgSO4). The solvent is evaporated at 30° C. The residual oil is vacuum-distilled through a jacketed Vigreux column to give 3-fluoro-4-methoxybenzaldehyde, B.P. 120-121° C. (10 mm Hg) Rf 0.6 on a silica-gel G plate with methylene chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C@@H:15]([OH:17])[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CS([C:21]1[N:26]=[CH:25][C:24]2=[CH:27][CH:28]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])[N:23]2[N:22]=1)=O.C(N(CC)C(C)C)(C)C.COCC(O)C>>[OH:17][C@@H:15]([CH3:16])[CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:21]3[N:26]=[CH:25][C:24]4=[CH:27][CH:28]=[C:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])[N:23]4[N:22]=3)=[CH:7][CH:6]=2)[CH2:13][CH2:12]1
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Reactant: C[C@H](O)CN1CCN(c2ccc(N)cc2)CC1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccccc5N(C)S(C)(=O)=O)n4n3)cc2)CC1
Yield: 56.2 %

Procedure:
(S)-1-[4-(4-Amino-phenyl)-piperazin-1-yl]-propan-2-ol (129.1 mg, 0.5488 mmol), N-[2-(2-M ethanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (100.0 mg, 0.2744 mmol) and N,N-Diisopropylethylamine (0.1434 mL, 0.8232 mmol) were dissolved in 1-Methoxy-2-propanol (1.00 mL, 10.2 mmol). The reaction was irradiated at 300 watts, 200° C. for 20 minutes or until HPLC showed consumption of starting material. The mixture was then reduced under nitrogen and the product was isolated and purified by Gilson prep HPLC to afford 82.63 mg of N-[2-(2-{4-[4-((S)-2-Hydroxy-propyl)-piperazin-1-yl]-phenylamino}-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide as a lyophilized powder. (M+H)=536.1. 1H NMR (400 MHz, DMSO, d6) δ 9.51 (s, 1H), 9.24 (s, 1H), 8.95 (s, 1H), 8.01 (d, 1H, J=7.52 Hz), 7.65 (d, 1H, J=7.65 Hz), 7.50 (m, 4H), 6.97 (m, 2H), 6.85 (m, 2H), 4.12 (m, 1H), 3.66 (m, 4H), 3.17 (m, 3H), 3.08 (s, 3H), 2.95 (m, 3H), 2.89 (s, 3H), 1.13 (d, 3H, J=5.08 Hz).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[O:18][C:19]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:20]=4[C:21]=3[C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])[CH:13]=2)[CH:8]=1)C.[OH-].[K+]>C1COCC1.O>[Cl:32][C:29]1[CH:30]=[CH:31][C:19]2[O:18][C:17]([C:12]3[CH:13]=[C:14]4[C:9](=[CH:10][CH:11]=3)[CH:8]=[C:7]([O:6][CH2:5][C:4]([OH:33])=[O:3])[CH:16]=[CH:15]4)=[C:21]([C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])[C:20]=2[CH:28]=1
Reactant: CCCCC(=O)c1c(-c2ccc3cc(OCC(=O)OCC)ccc3c2)oc2ccc(Cl)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(=O)c1c(-c2ccc3cc(OCC(=O)O)ccc3c2)oc2ccc(Cl)cc12
Yield: 90 %

Procedure:
Following the procedure described in Step 4 of Example 6, [6-(5-chloro-3-pentanoyl-benzofuran-2-yl)-naphthalen-2-yloxy]-acetic acid ethyl ester (0.26 g, 0. mmol) was hydrolyzed with potassium hydroxide (0.300 g, 5.36 mmol) in THF (20 mL) and water (10 mL). Crystallization from ethyl acetate afforded the title compound as an off-white solid (0.22 g), mp 158-160° C. Mass spectrum (−APCl, [M−H]−) m/z 435, 437. 1HNMR (400 MHz, DMSO-d6): δ13.14 (br s, 1H), 8.37 (d, 1H, J=1.2 Hz), 8.03-8.01 (m, 2 H), 7.97 (d, 1H, J=8.5 Hz), 7.81 (dd, 1H, J=8.3, 1.7 Hz), 7.77 (d, 1H, J=8.8 Hz), 7.48 (dd, 1H, J=8.8, 2.2 Hz), 7.40 (d, 1H, J=2.7 Hz), 7.32 (dd, 1H, J=9.0, 2.5 Hz), 4.85 (s, 2H), 2.69 (t, 2H, J=7.3 Hz), 1.55-1.48 (m, 2H), 1.13-1.05 (m, 2H), and 0.69 ppm (t, 3H, J=7.4 Hz). Elemental Analysis for C25H21ClO5.0.4H2O: Calculated: C, 67.61; H, 4.95; N, 0.00. Found: C, 67.51; H, 4.66; N, 0.05.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].I[CH:12]([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+].Cl>O.CC(=O)CC>[CH:12]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])([CH3:14])[CH3:13]
Reactant: CC(C)I
Reactant: O=C(O)c1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CC(C)Oc1cccc(C(=O)O)c1

Procedure:
Combine 3-hydroxybenzoic acid (100 mmol), 2-iodopropane (500 mmol), K2CO3 (300 mmol), and 2-butanone (300 mL). Heat at reflux for 72 h. Concentrate in vacuo to obtain a residue. Add water (500 mL) and cool in an ice bath. Adjust to pH 1 by dropwise addition of concentrated HCl. Extract with dichloromethane (3×200 mL). Extract the combined organic layers with water (200 mL), dry over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Purify to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:25])=[C:18](/[F:24])\[C:19](OCC)=[O:20])[C:3]=1[O:26][CH3:27].[H-].C([Al+]CC(C)C)C(C)C>>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:25])=[C:18](/[F:24])\[CH2:19][OH:20])[C:3]=1[O:26][CH3:27]
Reactant: CCOC(=O)/C(F)=C(/C)c1cc2c(c(Br)c1OC)C(C)(C)CC=C2C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: COc1c(/C(C)=C(/F)CO)cc2c(c1Br)C(C)(C)CC=C2C(C)C

Procedure:
Following General Procedure G-1, ethyl (2E)-3-(4-bromo-8-isopropyl-3-methoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-but-2-enoate (Compound A-124, 313 mg, 0.71 mmol) and diisobutylaluminum hydride (1 M in methylene chloride, 1.7 mL, 1.7 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 10% ethyl acetate in hexanes).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:21])[CH2:7][NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH2:2]1.[OH:22][C:23]1([C:30]2[S:34][CH:33]=[N:32][CH:31]=2)[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1>CC1CCCO1.[Pt]>[OH:22][C:23]1([C:30]2[S:34][CH:33]=[N:32][CH:31]=2)[CH2:24][CH2:25][CH:26]([N:1]2[CH2:4][CH:3]([NH:5][C:6](=[O:21])[CH2:7][NH:8][C:9](=[O:20])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[CH:11]=3)[CH2:2]2)[CH2:27][CH2:28]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(O)(c2cncs2)CC1
Agent: [Pt]
Solvent: CC1CCCO1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3cncs3)CC2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-[2-(3-azetidinylamino)-2-oxoethyl]-3-(trifluoromethyl)benzamide (3.44 kg, 4.8 w/w % in 2-MeTHF, 0.548 mol) in 2-methyl tetrahydrofuran (2-MeTHF, 3.3 kg) was added to an inertisized reactor. 4-hydroxy-4-(1,3-thiazol-5-yl)cyclohexanone (108.1 g, 0.537 mol) was added. Pt/C 5% wet (213.8 g) was added. The reactor was rinsed three times with N2, then rinsed three times with H2 and stirred vigorous for 12 hours at 25° C. and 1 bar H2. The catalyst was filtered and the mother liquor cooled to 15° C. 1N HCl (866 ml) was added to the mother liquor. Water (510 ml) was added and the mixture stirred for 30 minutes at 25° C. The layers were allowed to separate during 30 minutes and the organic layer was removed. 607 ml of isopropyl acetate (iPrOAc) was added to the water layer and stirred for 10 minutes. The layers were allowed to separate and the organic layer was removed. iPrOAc (607 ml) was added to the water layer and stirred for 10 minutes; the layers were allowed to separate and the organic layer was removed. 790 ml of iPrOAc was added to the water layer. Then, NaOH 50% (75.10 g) was added. The mixture was heated to 55° C., stirred for 30 minutes at 55° C., cooled to 25° C. over 2 hours and stirred for 3 hours at 25° C. The precipitate was filtered, washed with 152 ml iPrOAc and then washed three times with 152 ml water. The precipitate was dried for 20 hours at 40° C. under vacuum and N2 atmosphere to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:8]([CH3:22])=[N:9][N:10]2[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][C:13]([CH3:21])=[N:12][C:11]=12.FC(F)(F)C(O)=O.[N+:30]([O-])([OH:32])=[O:31]>ClCCl>[N+:30]([C:5]1[S:4][C:3]([C:7]2[C:8]([CH3:22])=[N:9][N:10]3[C:15]([CH:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[CH:14][C:13]([CH3:21])=[N:12][C:11]=23)=[C:2]([CH3:1])[CH:6]=1)([O-:32])=[O:31]
Reactant: CCC(CC)c1cc(C)nc2c(-c3sccc3C)c(C)nn12
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nc2c(-c3sc([N+](=O)[O-])cc3C)c(C)nn12
Temperature: 0 °C
Yield: 76.1 %

Procedure:
Dissolve 3-(3-methyl-thiophene-2-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (0.419 g, 1.33 mmol) in dichloromethane (2.5 mL), stir under an inert atmosphere, chill in an ice bath to 0° C. and add trifluoroacetic acid (5 mL). Add concentrated (70%) nitric acid (0.132 g, 1.47 mmol) to the reaction dropwise. The solution changes color from yellow to dark green. Stir 1 h under an inert atmosphere while in an ice bath and confirm the reaction is complete using TLC. Dilute the reaction with dichloromethane (80 mL) and quench with saturated sodium bicarbonate. Separate and extract the aqueous basic phase with dichloromethane (50 mL). Combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue using flash chromatography, eluting with 100% hexane/0% (30% ethyl acetate/hexane) to 0% hexane/100% (30% ethyl acetate/hexane) in a step gradient of 10% increments to give a yellow solid (0.363 g, 76%). 1H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 6.51 (s, 1H), 3.62-3.58 (m, 1H), 2.56 (s, 3H), 2.48 (s, 3H), 2.18 (s, 3H), 1.88-1.70 (m, 4H), 0.88 (t, J=7.5 Hz, 6H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH:22]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][N:22]([C:11](=[O:13])[C:10]([CH3:15])([CH3:14])[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:34]
Reactant: CC(C)(COCc1ccccc1)C(=O)O
Reactant: CCOC(=O)CNc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C(=O)C(C)(C)COCc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-(benzyloxy)-2,2-dimethylpropanoic acid from Step B (415 mg, 1.99 mmol) in DCM (20 mL) was added one drop of DMF (cat.) followed by the drop wise addition of oxalyl chloride (329 mg, 2.59 mmol) over 10 minutes, while at ambient temperature. After the evolution of gas has ceased, the reaction was cooled to 0° C., prior to the introduction of ethyl anilinoacetate (429 mg, 2.39 mmol) and triethylamine (302 mg, 2.99 mmol). After 2 hours at 0° C., the reaction was allowed to warm to ambient temperature and then stir for an additional 1 hour. The reaction mixture was applied directly to a silica gel column for purification, eluting with a gradient of CH2Cl2:MeOH—99.5:0.5 to 98:2. Product containing fractions were pooled and concentrated in vacuo to give the title compound. MS: m/z=370 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N+:13]([O-:15])=[O:14])[C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1)([O-:3])=[O:2].[NH2:16][CH2:17][CH2:18][OH:19]>O>[OH:19][CH2:18][CH2:17][NH:16][C:7]1[C:6]([N+:13]([O-:15])=[O:14])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][C:8]=1[CH2:9][CH2:10][OH:11]
Reactant: NCCO
Reactant: O=[N+]([O-])c1cc2c(c([N+](=O)[O-])c1)OCC2
Solvent: O
Product: O=[N+]([O-])c1cc(CCO)c(NCCO)c([N+](=O)[O-])c1

Procedure:
0.29 Mole (60.9 g) of 2,3-dihydro-5,7-dinitrobenzofuran is added in small portions at room temperature to 122 ml of 2-aminoethanol. After the addition is complete, the reaction medium is brought for 15 minutes to 95° C. 500 ml of water are added; after the mixture is cooled, the expected product is drained, and this, after being made into a paste in water and recrystallized from 75 ml of 96° strength ethanol, melts at 115° C.