Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:16](=[O:31])[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[CH:13]=2)[CH:8]=[N:7]1.Cl>CC(C)=O>[O:2]=[CH:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:16](=[O:31])[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[CH:13]=2)[CH:8]=[N:7]1
Reactant: COC(CCn1ncc2ccc(NC(=O)Cc3ccc(Oc4ccccc4)cc3)cc21)OC
Agent: Cl
Solvent: CC(C)=O
Product: O=CCCn1ncc2ccc(NC(=O)Cc3ccc(Oc4ccccc4)cc3)cc21
Temperature: 25 °C

Procedure:
A mixture of N-[1-(3,3-dimethoxypropyl)-1H-indazol-6-yl]-2-(4-phenoxyphenyl)acetamide (500 mg, 1.12 mmol) and 2N aqueous HCl (2.5 mL) in acetone (5 mL) was heated to 50 C for 3 hours, cooled to room temperature and concentrated under reduced pressure to a volume of ˜2 mL. Diethyl ether (15 mL) was added with stirring and the mixture was filtered. The filtered solid was washed with additional diethyl ether (10 mL) and air-dried to provide the title compound. MS (ESI) 398 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[S:19][CH:20]=[C:21]([Br:23])[CH:22]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[SH:38]>CO>[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38][CH:17]([C:18]1[S:19][CH:20]=[C:21]([Br:23])[CH:22]=1)[C@@H:12]([C:13]([O:15][CH3:16])=[O:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: COC(=O)/C(=C/c1cc(Br)cs1)NC(=O)OCc1ccccc1
Reactant: Nc1ccccc1S
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Sc1ccccc1N)c1cc(Br)cs1
Yield: 45.8 %

Procedure:
The title compound was prepared according to the method of Example 94b, employing methyl (2Z)-2-{[(benzyloxy)carbonyl]amino}-3-(4-bromo-2-thienyl)acrylate (96a) (8.13 g, 20.5 mmol), triethylamine (1.43 g, 14.1 mmol), and 2-aminothiophenol (14.0 g, 112 mmol) in anhydrous methanol (80 mL). Purification by flash chromatography on silica gel eluting with 4:1 (v/v) hexane/ethyl acetate yielded a solid, which was recrystallized from 6:1 (v/v) hexane/ethyl acetate to afford the title compound (4.90 g, 46%) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ3.44 (s, 3H), 4.63 (t, 1H, J=8.1 Hz), 4.92 (d, 1H, J=7.4 Hz), 5.09 (m, 21H), 5.46 (bs, 2H), 6.38 (t, 1H, J=7.5 Hz), 6.66 (d, 1H, J=8.3 Hz), 6.80 (s, 1H), 6.99-7.03 (m, 2H), 7.32-7.39 (m, 5H), 7.52 (s, 1H), 8.28 (d, 1H, J=9.2 Hz). MS APCI, m/z=521, 523. LC/MS: 2.71 min.
Reaction SMILES: C(OC(=O)CC[N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=4[O:32][CH3:33])=[CH:20][CH:19]=3)[CH:14]=2)[CH:9]=[CH:8]1)C.FC1C(F)=CC(C2C=CC(OCC3C=CC=C4C=3C=CN4)=CC=2)=C(OC)C=1.[CH2:62]([O:64][C:65](=[O:68])[CH2:66]Br)[CH3:63]>>[CH2:62]([O:64][C:65](=[O:68])[CH2:66][N:7]1[C:15]2[C:14](=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=4[O:32][CH3:33])=[CH:20][CH:19]=3)[CH:12]=[CH:11][CH:10]=2)[CH:9]=[CH:8]1)[CH3:63]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)CCn1ccc2ccc(COc3ccc(-c4cc(F)c(F)cc4OC)cc3)cc21
Agent: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3[nH]ccc23)cc1
Product: CCOC(=O)Cn1ccc2c(COc3ccc(-c4cc(F)c(F)cc4OC)cc3)cccc21

Procedure:
[4-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-acetic acid ethyl ester was synthesized by a procedure similar to 3-[6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propionic acid ethyl ester from starting materials 4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indole and bromo-acetic acid ethyl ester to yield the product as a white solid/wax (30 mg, 66%). LC-MS (ES) calculated for C26H23F2NO4, 451.2; found m/z 452 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:21]([C:30]2[CH:35]=[CH:34][C:33](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:32]([N+:47]([O-:49])=[O:48])[CH:31]=2)([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])[CH:7]=[CH:8][C:9]=1OS(C1C=CC(C)=CC=1)(=O)=O)([O-:3])=[O:2].[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C(#N)C>[NH:50]([C:33]1[CH:34]=[CH:35][C:30]([C:21]([C:6]2[CH:7]=[CH:8][C:9]([NH:1][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)([C:26]([F:28])([F:29])[F:27])[C:22]([F:25])([F:23])[F:24])=[CH:31][C:32]=1[N+:47]([O-:49])=[O:48])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C(c3ccc(OS(=O)(=O)c4ccc(C)cc4)c([N+](=O)[O-])c3)(C(F)(F)F)C(F)(F)F)cc2[N+](=O)[O-])cc1
Reactant: Nc1ccccc1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(C(c2ccc(Nc3ccccc3)c([N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)ccc1Nc1ccccc1
Yield: 218.6 %

Procedure:
In an alternative procedure, 7.3 g (0.01 mol) of 2,2-bis-(3-nitro-4-tosyloxyphenyl)-hexafluoropropane, 11.6 g (0.125 mol) of aniline and 50 ml of acetonitrile are heated under reflux for 24 hours. After the red-orange suspension has been cooled, the solid is removed and washed with acetonitrile. The solvent is removed from the filtrate, and the product is recrystallized twice from ethanol to give 6.3 g of 2,2-bis-(4-anilino-3-nitrophenyl)-hexafluoropropane (65% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][C:24](O)=[O:25])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][O:35][C:36]([N:38]1[CH2:42][CH2:41][NH:40][S:39]1(=[O:44])=[O:43])=[O:37]>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][C:24]([N:40]5[S:39](=[O:44])(=[O:43])[N:38]([C:36]([O:35][CH3:34])=[O:37])[CH2:42][CH2:41]5)=[O:25])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:32])([F:31])[F:33])[CH:3]=1
Reactant: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Reactant: COC(=O)N1CCNS1(=O)=O
Product: COC(=O)N1CCN(C(=O)CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)S1(=O)=O

Procedure:
Methyl 5-{[(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}-methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetyl}-1,2,5-thiadiazolidine-2-carboxylate 1,1-dioxide was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}-methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid (from Example 4) and 1,1-dioxo-1λ6-[1,2,5]thiadiazolidine-2-carboxylic acid methyl ester (from Example 339) following General Procedure C.
Reaction SMILES: CO.[CH3:3][S:4][C:5]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH3:10])[C:6]([O:8]C)=[O:7].[OH-].[Na+]>O>[CH3:3][S:4][C:5]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(C)(SC)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSC(C)(C(=O)O)c1cccs1
Yield: 99 %

Procedure:
Methanol (6 ml) and 4 ml of water were added to 1.08 g of methyl α-methylthio-α-(2-thienyl)propionate, and 500 mg of sodium hydroxide was added. The mixture was heated under reflux for 1 hour. Water (20 ml) was added, and the mixture was extracted with 10 ml of diethyl ether. The aqueous layer was adjusted to pH 1 with conc. hydrochloric acid, and extracted three times with 20 ml of diethyl ether. The organic layer was washed with 10 ml of water, and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure afforded 1.00 g of α-methylthio-α-(2-thienyl)propionic acid as colorless crystals in a yield of 99%.
Reaction SMILES: [Na].[CH3:2][O-:3].[Na+].F[B-](F)(F)F.CO[N+:12]1[N:13]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:14]=[C:15]([CH3:17])[CH:16]=1>CO.O>[CH3:2][O:3][C:16]1[C:15]([CH3:17])=[N:14][N:13]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=2)[N:12]=1
Reactant: CO[n+]1cc(C)nn1-c1ccc(C(F)(F)F)cc1
Reactant: C[O-]
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: COc1nn(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 23 °C
Reaction time: 6 h

Procedure:
Sodium metal (0.25 g, 11.0 mmol) was stirred at 23° C. in methanol (10 mL) until a clear solution was obtained. This sodium methoxide solution was added to crude 1-methoxy-4-methyl-2-[4-(trifluoromethyl)phenyl]-2H-1,2,3-triazolium tetrafluoroborate (1:1) (i.e. the product of Step B, 1.1 g, 3.2 mmol). The reaction mixture was stirred at 23° C. for 6 h, during which time a white precipitate formed. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (40 mL, 10 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel eluting with 0 to 10% ethyl acetate in hexanes to afford the title compound (0.82 g) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4](Br)[CH:3]=1.C([Li])CCC.[CH2:16]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:17]1[O:19][CH2:18]1>O1CCCC1.[Cu]Br.CSC.B(F)(F)F.CCOCC>[CH2:21]([O:20][CH2:16][C@@H:17]([OH:19])[CH2:18][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(F)cc1Br
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Agent: [Cu]Br
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CSC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(F)cc1C[C@H](O)COCc1ccccc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
To a solution of 4-fluoro-2-bromanisole (12.6 ml, 0.1 mol) in anhydrous tetrahydrofuran at −78° C. was added n-butyllithium (39 ml, 2.5 M in hexane) and the resulting mixture was allowed to stir at −78° C. for 3 h. Copper(I) bromide-dimethylsulfide (10.0 g, 0.05 mol) was then added at −78° C. and the reaction mixture was allowed to warm to 40° C. over 2 h. Benzyl(S)-(+)-glycidyl ether (3.71 ml, 0.025 mol) was added at −60° C. followed by boron trifluoride diethyl etherate (0.15 ml, 1.2 mmol) and the reaction mixture was allowed to warm to room temperature over 12 h. The solvent was removed in vacuo and purification by flash column chromatography (silica, ethyl acetate:hexanes 3:7) afforded 5.0 g (70%) of (S)-1-benzyloxy-3-(5-fluoro-2-methoxy-phenyl)propan-2-ol as a colorless oil. HRMS ESI m/e 308.1666 [M+NH4]+, Calc'd m/e 308.1662 [M+NH4]+; [α]D25=+8.1 (c 0.89% in methanol).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]3[O:13][CH2:14][O:15][C:9]=3[CH:8]=2)=[C:5]([NH2:16])[NH:4][N:3]=1.[C:17]1([C:23](=O)[CH2:24][C:25](OCC)=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH2:14]1[O:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]3[C:2]([CH3:1])=[N:3][N:4]4[C:23]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:24][C:25](=[O:26])[NH:16][C:5]=34)=[CH:8][C:9]=2[O:15]1
Reactant: Cc1n[nH]c(N)c1-c1ccc2c(c1)OCO2
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: c1ccncc1
Product: Cc1nn2c(-c3ccccc3)cc(=O)[nH]c2c1-c1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
3-Methyl-4-(3,4-methylenedioxyphenyl)-1H-pyrazol-5-amine (300 mg) and ethyl 3-phenyl-3-oxopropanoate (318 mg) are stirred overnight in a pyridine (10 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure 330 mg of the target compound is yielded by column chromatography.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]#[N:19])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:22][S:23]([O-:25])=[O:24].[Na+].C1C=CC=CC=1.CNCCNC>CS(C)=O.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2]>[CH3:22][S:23]([C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]#[N:19])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)(=[O:25])=[O:24]
Reactant: CS(=O)[O-]
Reactant: N#CN1CCC([C@H]2C[C@H]2COCc2ccc(Br)cc2)CC1
Agent: [Cu+2]
Agent: CNCCNC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: c1ccccc1
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(COC[C@@H]2C[C@@H]2C2CCN(C#N)CC2)cc1
Temperature: 120 °C

Procedure:
The product of step C (310 mg, 0.89 mmol), sodium methanesulfinate (109 mg, 1.06 mmol), Cu(OTf)2.C6H6 (89 mg, 0.178 mmol), and MeNHCH2CH2NHMe (0.038 mL, 0.355 mmol) were combined in dimethyl sulfoxide (5 mL) in a glass pressure tube. The solution was purged with nitrogen, sealed, and heated in a 120° C. oil bath overnight. The crude reaction mixture was directly purified by preparative HPLC (C18 reversed phase, gradient elution 10% to 100% MeCN in water with 0.1% formic acid) to yield the desired product.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([O:66][CH3:67])=[C:62]([Cl:65])[CH:63]=2)[N:58]=[C:57]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][N:69]=2)[C:56]=1[CH3:74].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:65][C:62]1[CH:63]=[C:64]2[C:59](=[CH:60][C:61]=1[O:66][CH3:67])[N:58]=[C:57]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][N:69]=1)[C:56]([CH3:74])=[C:55]2[NH:47][C:46]1[C:41]([N:38]2[CH2:39][CH2:40][O:35][CH2:36][CH2:37]2)=[N:42][CH:43]=[C:44]([N:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[CH:45]=1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: COc1cc2nc(-c3ccccn3)c(C)c(Cl)c2cc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2nc(-c3ccccn3)c(C)c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c2cc1Cl
Temperature: 120 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of X-Phos (0.024 g, 0.050 mmol), 2,5-dimorpholinopyridin-3-amine (0.099 g, 0.38 mmol), 4,6-dichloro-7-methoxy-3-methyl-2-(pyridin-2-yl)-quinoline (0.10 g, 0.31 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.011 g, 0.013 mmol) in toluene (3.13 mL) was added sodium t-butoxide (0.075 g, 0.78 mmol). The reaction mixture was heated to 120° C. and stirred for 45 min. The reaction was then cooled to rt and diluted with water (25 mL). The mixture was extracted with EtOAc (2×10 mL) and DCM (10 mL). The organic layers were combined and washed with brine (20 mL) and dried over magnesium sulfate. The crude product was purified by column chromatography on basic alumina (0 to 50% EtOAc) to give the desired product 6-chloro-N-(2,5-di-4-morpholinyl-3-pyridinyl)-7-methoxy-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.72-8.79 (1H, m), 7.80-7.96 (3H, m), 7.63 (2H, br s), 7.37-7.45 (1H, m), 7.27 (1H, m), 6.79 (1H, br. s.), 6.27 (1H, m), 4.06 (3H, s), 3.93 (4H, t, J=4.6 Hz), 3.71-3.81 (4H, m), 3.24 (4H, br. s.), 2.92-3.00 (4H, m), 2.35 (3H, s). Mass Spectrum (ESI) m/e=547.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])=[C:6]2[N+:18]([O-])=O.[Cl-].[NH4+].C(OCC)(=O)C>C(O)C.[Fe]>[NH2:18][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][C:7]=1[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13]
Reactant: COc1ccc2[nH]c(C(=O)N(C)OC)c([N+](=O)[O-])c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc2[nH]c(C(=O)N(C)OC)c(N)c2c1

Procedure:
A mixture of 5-methoxy-2-(N-methoxy-N-methylamino)carbonyl-3-nitroindole (step 2, 110 mg, 0.39 mmol), ammonium chloride (11 mg, 0.20 mmol) and iron powder (115 mg, 1.97 mmol) in 70% aqueous ethanol (10 ml) was heated at reflux for 2 h, and then cooled and filtered through a pad of Celite. The pad was washed copiously with a mixture of ethanol/ethyl acetate (1:1 v/v) and the combined washing evaporated. The residue was diluted with ethyl acetate (50 ml), washed with saturated aqueous sodim bicarbonate (30 ml) and dried (Na2SO4). Removal of solvent gave product as an oil. tlc: Rf=0.5 (50% ethyl acetate in hexanes)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([C@H:12]1[CH2:16][O:15]C(C)(C)[O:13]1)[CH2:6][CH2:5]2.O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([C@H:12]([OH:13])[CH2:16][OH:15])[CH2:6][CH2:5]2
Reactant: CC1(C)OC[C@H]([C@H]2CCc3cc(F)ccc3O2)O1
Solvent: CC(=O)O
Solvent: O
Product: OC[C@@H](O)[C@H]1CCc2cc(F)ccc2O1
Temperature: 65 °C
Yield: 26 %

Procedure:
(R)-6-fluoro-3,4-dihydro-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2H-chromene (2.92 g, 11.6 mmol) was dissolved in acetic acid (24 ml) and demi water (9 ml). The reaction mixture was stirred vigorously and heated to 65° C. After 3 h at 65° C. the reaction mixture was cooled to 25° C. The solution was then concentrated in vacuo to obtain a vetrous oil. Chromatographic separation on silica of the crude, using a mixture of heptane:ethyl acetate 1:1 as eluent, furnished 0.64 g of (R)-1-((R)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethane-1,2-diol as a white solid (26% yield).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>C(=O)([O-])[O-].[Na+].[Na+]>[CH2:14]([O:13][C:11]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A solution of isonipecotic acid (5.0 g, 38.72 mmol) in 10% aqueous sodium carbonate (100 mL) was cooled to 0° C. and treated with benzyl chloroformate (7.93 g, 46.75 mmol). The resulting biphasic mixture was allowed to warm to room temperature over 2 h, at which time it became homogeneous. The mixture was washed with ether (2×50 mL), then was acidified to pH~2 by addition of concentrated hydrochloric acid. The aqueous solution was extracted with ether (2×100 mL). The organic extracts were washed with brine (50 mL), combined, dried (Na2 SO4), filtered and evaporated to afford the product as a clear oil which slowly crystallized on standing (9.64 g, 36.6 mmol, 95%).
Reaction SMILES: [CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19]([NH2:21])=O)=[CH:15][N:16]=1)=[CH:8]2.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[C:19]([CH2:18][CH2:17][C:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)(=[O:24])=[O:23])=[N:16][CH:15]=1)#[N:21]
Reactant: CN(c1cccc2cc(-c3ncc(CCC(N)=O)s3)[nH]c12)S(=O)(=O)c1cccs1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CN(c1cccc2cc(-c3ncc(CCC#N)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a mixture of 3-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)propanamide (1.32 g) and pyridine (15 mL) was added trifluoroacetic anhydride (0.90 mL) at 0° C. over 15 min. The reaction mixture was stirred at room temperature for 2 hr and concentrated. 10% Aqueous citric acid solution was added to the residue. The resulting crystals were collected by filtration, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (1.20 g, yield 95%) was obtained as yellow crystals from a fraction eluted with tetrahydrofuran-hexane (2:1, volume ratio). melting point 207-208° C.
Reaction SMILES: [N:1]1([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[S:17](Cl)(=[O:20])(=[O:19])[NH2:18]>C(#N)C>[N:1]1([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH2:12][CH2:13][O:14][S:17](=[O:20])(=[O:19])[NH2:18])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OCCCOc1ccc(-n2ccnc2)cc1
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Product: NS(=O)(=O)OCCCOc1ccc(-n2ccnc2)cc1
Reaction time: 20 h
Yield: 43 %

Procedure:
A solution of 9.0 g (0.041 mole) of 3-[4-(1H-imidazol-1-yl)phenoxy]propanol in 150 ml of acetonitrile was treated with a solution of one equivalent of sulfamoyl chloride in 13 ml of acetonitrile. The mixture was stirred for 20 hr. The reaction mixture was concentrated under vacuum and the residue was dissolved in water. The aqueous solution was filtered and the filtrate was basified to pH 8 with potassium carbonate. The mixture was extracted with ethyl acetate. The organic fraction was concentrated under a stream of nitrogen and the precipitate was collected and dried to give 5.2 g (43%) of tan powder, mp 105.0°-106.0° C.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[N:16]2)[CH2:10]1)(OC(C)(C)C)=O.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>ClCCl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[N:15]1([CH2:14][C@@H:11]2[CH2:12][CH2:13][C@H:9]([NH2:8])[CH2:10]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[N:16]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Cn2ncc3ccccc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@@H](Cn2ncc3ccccc32)C1

Procedure:
Deprotection of N1-BOC-(1S,3R)-3-(1H-indazol-1-ylmethyl)cyclopentan-1-amine (500 mg, 1.58 mmol), the less polar isomer, using TFA (3 ml) in dry dichloromethane (3 ml) as described in Example 1, Step 2 gave 341 mg of the amine as its TFA salt, which was used as such for the coupling reaction.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH2:2][CH3:3].[OH-].[Na+].[Br:13][CH2:14][CH2:15][CH2:16]Br>C(Cl)Cl.O.S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:13][CH2:14][CH2:15][CH2:16][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: CCCc1ccccc1O
Reactant: BrCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCc1ccccc1OCCCBr

Procedure:
The title compound was prepared according to the procedure of Example 7 using 2-n-propylphenol (30 g, 0.22 mol) in methylene chloride (400 ml), sodium hydroxide (18.8 g, 0.44 mol) in water (400 ml), 1,3-dibromopropane (100 g, 1 mol) and tetra-n-butylammonium bisulfate (80 g, 0.22 mol). Distillation of the crude product yielded 55 g (75%) of pure material, b.p. 85°-87° (0.1 mm Hg).
Reaction SMILES: Cl.Cl.[NH2:3][C@@:4]([CH3:16])([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:5]([OH:7])=[O:6].[CH3:17][CH2:18]O>>[NH2:3][C@@:4]([CH3:16])([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:5]([O:7][CH2:17][CH3:18])=[O:6]
Reactant: CCO
Reactant: COc1ccc([C@](C)(N)C(=O)O)cc1
Agent: Cl
Product: CCOC(=O)[C@@](C)(N)c1ccc(OC)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
HCl gas was bubbled through a solution of (S)-α-amino-4-methoxy-α-methyl-benzeneacetic acid, hydrochloride salt (2.0 g, 8.6 mmol) in EtOH (25 mL) at 4° C. The solution was stirred for 1 hour at 20° C. before being refluxed for 5 hours. After cooling, the solution was concentrated in vacuo. The resulting oil was dissolved in CH2Cl2, and washed with aq. NaHCO3 ; the aqueous phase was back-extracted with CH2Cl2. The combined organic fractions were washed with H2O, brine and dried over Na2SO4 prior to concentration to yield the title compound as a yellow oil (1.75 g, 91%).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:19])[CH2:18][O:17][CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C1COCC1.CCO.[H][H].[Pd]>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([OH:19])[CH2:16][O:17][CH2:18]2)=[CH:13][CH:14]=1
Reactant: OC1(c2ccc(N(Cc3ccccc3)Cc3ccccc3)cc2)COC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(C2(O)COC2)cc1
Yield: 127.6 %

Procedure:
To a stirred solution of 3-(4-(dibenzylamino)phenyl)oxetan-3-ol (1.5 g, 5.217 mmol, 1.0 eq) in THF (50 mL) and EtOH (50 mL) was added 10% Pd/C (300 mg) and the mixture was stirred in hydrogen atmosphere at 40 psi H2 for 5 h. The mixture was passed through celite, the filtrate concentrated under reduced pressure to get 3-(4-aminophenyl)oxetan-3-ol (1.1 g, 77%; TLC system: EtOAc/PE (7:3), Rf: 0.55).