Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2([CH2:9][O:10][C:11]3[CH:20]=[C:19]4[C:14]([C:15]([O:21][C:22]5[C:23]([F:32])=[C:24]6[C:28](=[CH:29][CH:30]=5)[NH:27][C:26]([CH3:31])=[CH:25]6)=[CH:16][CH:17]=[N:18]4)=[CH:13][C:12]=3[O:33][CH3:34])[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:39](C)=O.[Na+]>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH3:39])[C:6]2([CH2:9][O:10][C:11]3[CH:20]=[C:19]4[C:14]([C:15]([O:21][C:22]5[C:23]([F:32])=[C:24]6[C:28](=[CH:29][CH:30]=5)[NH:27][C:26]([CH3:31])=[CH:25]6)=[CH:16][CH:17]=[N:18]4)=[CH:13][C:12]=3[O:33][CH3:34])[CH2:7][CH2:8]2)[CH2:3][CH2:2]1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCC1(NCC2CC2)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCC1(N(C)CC2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound of Example 27 (50 mg) was mixed with HCHO (2 eq, 37% in H2O), NaBH(OAc)3 (2 eq) in DCM (5 ml) and stirred at RT for 3 hours. The reaction was evaporated and purified with silica gel column to give the titled product (20 mg). Mass: (M+1), 476
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.CON(C)[C:16]([C:18]1[CH:26]=[C:25]2[C:21]([C:22]([CH:28]([C:42]3[CH:50]=[CH:49][C:45]4[O:46][CH2:47][O:48][C:44]=4[CH:43]=3)[C:29]([NH:31][S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])=[O:30])=[CH:23][N:24]2[CH3:27])=[CH:20][CH:19]=1)=[O:17]>O1CCCC1>[O:46]1[C:45]2[CH:49]=[CH:50][C:42]([CH:28]([C:22]3[C:21]4[C:25](=[CH:26][C:18]([C:16]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=5)=[O:17])=[CH:19][CH:20]=4)[N:24]([CH3:27])[CH:23]=3)[C:29]([NH:31][S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=3)(=[O:34])=[O:33])=[O:30])=[CH:43][C:44]=2[O:48][CH2:47]1
Reactant: CON(C)C(=O)c1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C)cc3)c3ccc4c(c3)OCO4)cn(C)c2c1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(C(=O)c4ccccn4)ccc23)cc1
Temperature: -70 °C
Reaction time: 4 h

Procedure:
n-Butyllithium (0.32 ml of 2.5M solution in hexane) was added to a stirred solution of 2-bromopyridine (0.08 ml, 0.8 mmol) in anhydrous tetrahydrofuran (5 ml) at −70° C. under a nitrogen atmosphere. After 30 minutes a solution of N6-methoxy-N6,1-dimethyl-3-{1-(1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-1H-6-indolecarboxamide (the compound of Example 103, 200 mg, 0.36 mmol) in anhydrous tetrahydrofuran (2 ml) was added to the mixture at −70° C. The mixture was stirred at −70° C. for an additional 4 hours before being warmed to 0° C., and then quenched with the addition of water (5 ml). The mixture was acidified with acetic acid, and extracted with ethyl acetate (100 ml). The organic phase was separated and washed with brine, dried (magnesium sulphate) and the solvent was removed in vacuo. The residue was flash chromatographed using a gradient elution of a mixture of 90% hexane and 10% ethyl acetate, through to 100% ethyl acetate, to give the title compound (42 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[F:21][C:22]([F:35])([F:34])[O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:30]([C:27]1[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:34])[F:35])=[CH:29][CH:28]=1)(=[O:32])=[O:31])[CH:7]=[CH:6]2
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccc(OC(F)(F)F)cc2)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 4-(trifluoromethoxy)benzenesulfonyl chloride (29 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (6 mg, 21%) as a white solid. MS (ESI+) for C19H19F3N2O4S m/z 429 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24].S(=O)(=O)(O)O.[CH2:31](O)[CH3:32]>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:31][CH3:32])=[O:24]
Reactant: CCO
Reactant: CC1(C2CCCC2)Cc2cc(OCCCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCOc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Reaction time: 18 h

Procedure:
To a suspension of 4-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-oxy]butanoic acid (0.5 g, 0.0012 mole) in absolute ethanol (50 ml) is added conc. sulfuric acid and the mixture is refluxed for 1 hr., treated with 3 Å molecular sieves and stirred at 25° for 18 hours. The reaction mixture is treated with more conc. sulfuric acid (0.2 ml) refluxed for 1 hr, filtered and treated with solid potassium carbonate. The ethanol is distilled at reduced pressure to give ethyl 4-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]butanoate which is purified by chromatography on silica gel eluted with methylene chloride-tetrahydrofuran (100:1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[S:13])[NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:15][C:16](=O)[CH3:17]>C(O)C>[CH3:17][C:16]1[N:12]=[C:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[S:13][CH:15]=1
Reactant: CC(=O)CBr
Reactant: NC(=S)Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: Cc1csc(Cc2ccc([N+](=O)[O-])cc2)n1

Procedure:
A mixture of 2-(4-nitrophenyl)ethanethioamide (0.50 g), 1-bromo-2-propanone (0.43 g) and ethanol (20 mL) was heated under reflux for 1 hr. The reaction mixture was concentrated, and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and 4-methyl-2-(4-nitrobenzyl)-1,3-thiazole was obtained as pale-yellow crystals (0.37 g, yield 63%) from a fraction eluted with hexane-ethyl acetate (2:1-1:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 81-82° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[CH3:25][O:26][CH:27]1[CH2:30][NH:29][CH2:28]1>>[CH3:25][O:26][CH:27]1[CH2:30][N:29]([C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[O:21])[CH2:28]1
Reactant: COC1CNC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: Cl
Product: COC1CN(C(=O)c2ccc(OCc3c(-c4ccccc4)noc3C)nc2)C1
Yield: 61 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 3-methoxyazetidine hydrochloride instead of methylamine, to the title compound (75 mg, 61%) which was obtained as a light yellow oil. MS: m/e=380.3 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:10]([OH:14])=[CH:9][CH:8]=[CH:7][C:6]=2[CH:5]=1.Br[CH2:16][C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>CN(C)C=O.C(OC(=O)C)C>[NH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:14][CH2:16][C:17]2[S:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[CH:5]=1
Reactant: BrCc1nc2ccccc2s1
Reactant: Nc1ccc2c(O)cccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc2c(OCc3nc4ccccc4s3)cccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.9 %

Procedure:
Sodium hydride (1.05 g) is added to a cooled solution of 2-Amino-5-naphthol (4.18 g) in dimethylformamide (100 mL). Stir at room temperature 15 minutes and cool mixture. 2-Bromomethylbenzothiazole (6.00 g) is added and mixture to allowed to warm slowly and stir for 24 hours. Remove dimethylformamide in vacuo. Redilute with ethylacetate and absorb onto silica gel. Chromatograph (ethyl acetate/hexane) to give a brown solid (1.20 g, 15%) which was used directly in the next step., m.p. 141-143° C. 1H NMR (DMSO-d6, 400 MHz): d 5.43 (br s, 2H), 5.69 (s, 2H), 6.72 (d, 1H), 6.80 (s, 1H), 6.95 (d, 1H), 7.12-7.20 (m, 2H), 7.45 (t, 1H), 7.54 (t, 1H), 7.97 (d, 1H), 8.02 (d, 1H), 8.14 (d, 1H). MS [EI, m/z]: 306 [M]+. Anal. Calcd. for C18H14N2OS: C, 70.56; H, 4.61; N, 9.14. Found: C, 70.38; H, 4.42; N, 9.25.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:9][C:8]2=[O:19])=[CH:4][CH:3]=1.Cl[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=4)[CH2:15][CH2:14]3)=[N:9][C:8]2=[O:19])=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=c1nc(N2CCNCC2)ncn1Cc1ccc(Cl)cc1
Product: O=c1nc(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)ncn1Cc1ccc(Cl)cc1
Yield: 3.8 %

Procedure:
1-(4-chlorobenzyl)-4-(piperazin-1-yl)-1,3,5-triazin-2(1H)-one (31 mg, 0.10 mmol) synthesized in Reference Synthesis Example 9 and 2-chloro-5-trifluoromethylpyridine (18 mg, 0.10 mmol) in a similar manner to Synthesis Example 76 to obtain the title compound (1.7 mg, yield: 3.7%).
Reaction SMILES: [Br:1][C:2]1[N:6](C(OC(C)(C)C)=O)[C:5]2[CH:14]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[S:16][C:4]=2[C:3]=1[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[NH:6][C:5]2[CH:14]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[S:16][C:4]=2[C:3]=1[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(Br)n2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc2[nH]c(Br)c(C3CCCCC3)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A solution (0.1 M) of methyl 5-bromo-4-(tert-butoxycarbonyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (prepared as described in WO2005/023819) in CH2Cl2 was treated with trifluoroacetic acid (1:1). The reaction mixture was stirred at RT for 1 h. All volatiles were evaporated giving a residue that was purified by flash chromatography (PE:EtOAc, 7:3) giving the title compound (79%) as solid. 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 7.60 (s, 1H), 3.80 (s, 3H), 2.66-2.55 (m, 1H), 1.85-1.20 (m, 10H). MS (ES+) m/z: 342, 344 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[CH2:13][C:12]2[C:7](=[N:8][C:9](S(C)(=O)=O)=[N:10][CH:11]=2)[N:6]([CH3:18])[C:5]1=[O:19])([CH3:3])[CH3:2].[CH2:20]([N:22]([CH2:33][CH3:34])[CH2:23][CH2:24][O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)[CH3:21]>ClCCl.CO.C(O)(=O)C.O>[CH2:33]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([NH:30][C:9]2[N:8]=[C:7]3[N:6]([CH3:18])[C:5](=[O:19])[N:4]([CH:1]([CH3:3])[CH3:2])[CH2:13][C:12]3=[CH:11][N:10]=2)=[CH:31][CH:32]=1)[CH3:34]
Reactant: CC(C)N1Cc2cnc(S(C)(=O)=O)nc2N(C)C1=O
Reactant: CCN(CC)CCOc1ccc(N)cc1
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(C(C)C)C3)cc1
Temperature: 180 °C
Yield: 8.1 %

Procedure:
A mixture of 350 mg (1.2 mmol) of 3-isopropyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 500 mg (2.4 mmol) of 4-[2-(diethylamino)ethoxy]aniline was heated at 180° C. for 35 minutes and then cooled. The residue was subjected to column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was triturated in hexane, filtered off and dried to give 40 mg (8%) of 7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-3-isopropyl-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 154° C.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[N:8]=[C:7]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:6]([N+:15]([O-])=O)=[CH:5][CH:4]=1.C1N=CN([C:24](N2C=NC=C2)=[O:25])C=1>CO.[Pd]>[CH3:1][N:2]([CH3:18])[C:3]1[N:8]=[C:7]2[N:9]([CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:24]([OH:25])=[N:15][C:6]2=[CH:5][CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCC(CC)Nc1nc(N(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCC(CC)n1c(O)nc2ccc(N(C)C)nc21
Temperature: 25 °C
Yield: 57.4 %

Procedure:
To a solution of N6,N6-dimethyl-3-nitro-N2-(pentan-3-yl)pyridine-2,6-diamine (100 mg, 0.40 mmol) in MeOH (4 mL) was added a catalytic amount of Pd/C. The mixture was purged with hydrogen from a balloon fitted with a needle for 1 h. The resulting mixture was filtered through a pad of celite and concentrated in vacuo. The solid was then dissolved in THF (2 mL) and CDI (100 mg, 1.17 mmol) was added as a solid. After heating for 3 h, the reaction was cooled to room temperature. The excess CDI was quenched by the careful addition of water. The mixture was diluted with EtOAc and washed three times with water and once with brine. The solution was then dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (5%-25% EtOAc/hexanes) provided the title compound as a white solid (57 mg, 57%). m/z=249.2 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][C:23]1[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]#[N:30])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Reactant: N#Cc1ccccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccccc1C#N
Yield: 90.6 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.602 g, 2.25 mmol), α-bromo-o-tolunitrile (0.668 g, 3.41 mmol), KI (100 mg, 0.60 mmol), and DIPEA (0.80 mL, 4.59 mmol) in DMF (11 mL) was heated at 60° C. for 23 hours. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.78 g (91%) of 2-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzonitrile as a tan solid. 1H NMR (CDCl3) δ 1.63-1.73 (m, 3H), 2.02-2.07 (m, 1H), 2.26-2.38 (m, 2H), 2.48 (s, 6H), 3.69 (s, 2H), 4.12 (d, 2H, J=10.8 Hz), 6.83-6.89 (m, 3H), 6.99 (d, 1H, J=7.2 Hz), 7.19-7.26 (m, 3H), 7.64 (d, 1H, J=7.8 Hz), 8.27 (d, 2H, J=3.9 Hz). 13C NMR (CDCl3) δ 19.44, 25.53, 29.42, 52.72, 67.05, 109.86, 118.06, 122.19, 125.90, 130.68, 131.41, 131.54, 132.02, 138.18, 145.77, 147.23, 159.61; ES-MS m/z 383 (M+H). Anal. Calcd. For C25H26N4 C, 78.50; H, 6.852; N, 14.65. Found: C, 78.28; H, 6.93; N, 14.57.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=2)[NH:4][C:3]1=[O:14].S(Cl)(Cl)=O.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1.ClCCl>CN(C)C=O.O>[CH3:15][C:2]1([CH3:1])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)=[O:13])[CH:9]=2)[NH:4][C:3]1=[O:14]
Reactant: CC1(C)C(=O)Nc2ccc(C(=O)O)cc21
Reactant: COc1ccc(N)cc1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2ccc3c(c2)C(C)(C)C(=O)N3)cc1
Reaction time: 0.25 h

Procedure:
2.3 g. (10 mmole) 2,3-dihydro-3,3-dimethyl-2-oxo-(1H)-indole-5-carboxylic acid, 1 drop of dimethylformamide and 15 ml. thionyl chloride were heated to the boil under reflux for 30 minutes. The thionyl chloride was removed under a vacuum and the crude product was used without further purification. The crude product was dissolved in 20 ml. dichloromethane and added dropwise to a solution of 2.5 g. (20 mmol) p-anisidine in 50 ml. dichloromethane while cooling with ice. After 15 minutes, 50 ml. water were added thereto, the organic phase was separated off and the solvent removed under vacuum. The residue was purified by column chromatography (400 ml. silica gel 60, dichloromethane/methanol 20:1 v/v). The pure fractions were evaporated under vacuum, the residue was digested with diethyl ether, filtered off with suction and dried in a vacuum at 100° C. There was obtained 1.9 g. (61% of theory) of the title compound; m.p. 169-171° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH:25][CH:26]([C:31]1[S:35][C:34]([CH:36]=[O:37])=[N:33][CH:32]=1)[C:27]([OH:30])([CH3:29])[CH3:28].C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:36]([C:34]3[S:35][C:31]([CH:26]([OH:25])[C:27]([OH:30])([CH3:28])[CH3:29])=[CH:32][N:33]=3)=[O:37])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)(O)C(O)c1cnc(C=O)s1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(O)C(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1
Yield: 94.2 %

Procedure:
A mixture of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (0.35 g), 5-(1,2-dihydroxy-2-methylpropyl)-1,3-thiazole-2-carbaldehyde (0.21 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (27 mg), triethylamine (0.06 mL), tetrahydrofuran (4 mL) and ethanol (4 mL) was stirred with heating under reflux for 1 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, and the title compound (0.52 g, yield 95%) was obtained as a colorless oil from a fraction eluted with ethyl acetate. MS: 550 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-])=O)=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][OH:19]>[Ni].CO>[NH2:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH2:3][CH2:2][OH:1])[C:5]([C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][OH:19])=[CH:6]2
Reactant: CC(C)(CCO)c1cc2cc([N+](=O)[O-])ccc2n1CCO
Agent: [Ni]
Solvent: CO
Product: CC(C)(CCO)c1cc2cc(N)ccc2n1CCO
Yield: 25.9 %

Procedure:
A solution of 3-[1-(2-hydroxy-ethyl)-5-nitro-1H-indol-2-yl]-3-methyl-butan-1-ol (300 mg, 1.03 mmol) and Raney Nickel (200 mg,) in CH3OH (30 mL) was stirred for 5 h at room temperature under a H2 atmosphere. The catalyst was filtered through a celite pad and the filtrate was evaporated under vacuum to give a residue, which was purified by preparative TLC to afford 3-[5-amino-1-(2-hydroxy-ethyl)-1 H-indol-2-yl]-3-methyl-butan-1-ol (70 mg, 26%). 1 H NMR (300 MHz, CDCl3) δ 7.07(d, J=8.7 Hz, 1 H), 6.83(d, J. 2.1 Hz, 1 H), 6.62(dd, J=2.1, 8.4 Hz, 1 H), 6.15(s, 1 H), 4.47(t, J=5.4 Hz, 2 H), 4.07(t, J=5.4 Hz, 2 H), 3.68(t, ./.5.7 Hz, 2H), 2.16(t, J. 5.7 Hz, 2 H), 4.00-3.91(m, 4 H), 2.76(s, 2 H), 1.61(s, 6 H), 1.42(s, 6 H).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].[OH-].[K+]>C(O)C>[F:9][C:10]1[CH:18]=[C:17]([O:19][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(OCc2ccccc2)cc1F
Temperature: 60 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
62 g of benzyl chloride was added to a mixture of 73 g of 2-fluoro-4-hydroxy-benzoic acid, 55 g of potassium hydroxide and 300 ml of ethanol, and the resulting mixture was heated with stirring at 60° C. for 4 hours. 250 ml of the ethanol was distilled away, and 200 ml of water and 25 g of sodium hydroxide were added to the residue. The resulting mixture was stirred for 1 hour at 60° C. The reaction mixture was allowed to cool, and after addition of 200 ml of concentrated hydrochloric acid, it was further cooled. Solids formed were collected, filtered with heating using 600 ml of acetic acid, and then recrystallized as it is to obtain 98 g of 2-fluoro-4-benzyloxybenzoic acid having a clearing point of 167 to 169° C. A mixture of 59 g of 2-fluoro-4-benzyloxybenzoic acid and 70 ml of thionyl chloride was heated for 6 hours on a water bath maintained at 50° C. Excessive thionyl chloride was distilled away under reduced pressure. On cooling with water, solids were formed. These solids were dispersed in hexane and then filtered to obtain 61 g of solid. This was 2-fluoro-4-benzyloxybenzoic acid chloride. 36 g of 2-fluoro-4-benzyloxybenzoic acid chloride and 27 g of R-(-)-2-octanol were heated with stirring for 3 hours in an atmosphere of nitrogen. The reaction mixture was allowed to cool and then 200 ml of toluene was added. An organic layer was washed with saturated saline water, with 6 N hydrochloric acid, with saturated saline water, with a 2 N sodium hydroxide aqueous solution and then with saturated saline water to make it neutral. The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain 1'-methylheptyl 2-fluoro-4-benzyloxy-benzoate. The total of 1'-methylheptyl 2-fluoro-4-benzyloxybenzoate was subjected to hydrogenalysis in ethyl acetate by the use of a 2% palladium-carbon catalyst to obtain R-1'-methylheptyl 2-fluoro-4-hydroxy-benzoate.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC([O-])(C)C.[K+].[CH:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][C:30](Cl)=[O:31])=[CH:24][CH:23]=1>C1COCC1>[Si:1]([O:8][CH2:9][C@@H:10]1[CH2:11][CH2:12][C:13](=[O:15])[N:14]1[C:30]([O:29][CH2:28][C:25]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1)=[O:31])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CCC(=O)N1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
To a solution of (S)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one (48.5 g, 0.21 mol) in THF (100 mL) was added t-BuOK (30.8 g, 0.27 mol) at 0° C. The mixture was stirred at 0° C. for 30 min followed by addition of Cbz-Cl (40.4 mL, 0.27 mol) dropwise at 0° C. The resulting mixture was stirred at RT overnight, quenched with saturated NH4Cl, concentrated to a small amount, and diluted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-benzyl 2-((tert-butyldimethylsilyloxy)methyl)-5-oxopyrrolidine-1-carboxylate (70 g, 91%). LRMS (M+H−44) m/z 320.2.