Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.CCN(CC)CC.[Cl:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[CH:22][N:21]=1>C(O)C>[Cl:19][C:20]1[N:25]=[C:24]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]2)[CH:23]=[CH:22][N:21]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2ccnc(Cl)n2)CC1
Temperature: 80 °C
Reaction time: 0.13 h
Yield: 87.2 %

Procedure:
To a solution of ethyl piperidine-4-carboxylate (13.0 g, 82.69 mmol,) in ethanol (130 ml) were added Et3N (17.29 ml, 124 mmol) and 2,4-dichloropyrimidine (13.55 g, 90.96 mmol). After stirring for 8 minutes at 80° C., the solvent was removed under reduced pressure and the crude product was purified by normal phase chromatography, eluting with Heptane with 50% ethyl acetate to give compound ethyl 1-(2-chloropyrimidin-4-yl)piperidine-4-carboxylate (19.45 g) as a colourless oil.
Reaction SMILES: [C:1]([O:4][C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:27][Si:28]([CH3:31])([CH3:30])Cl>O1CCCC1>[C:1]([O:4][C@H:5]1[N:8]([Si:28]([CH3:31])([CH3:30])[CH3:27])[C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:18])([CH3:17])[CH3:19])([CH3:14])[CH3:15])[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1[Si](C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To an ice-cooled solution of 50g (0.174 mole) of (3R, 4R)-4-acetoxy-3-[(R)-1-t-butyldimethylsilyloxyethyl]-2 -azetidinone and 24.69 (0.244 mole) of triethylamine in 500 ml of tetrahydrofuran were added 26.5g (0.244 mole) of trimethylchlorosilane under a nitrogen stream. The reaction temperature was allowed to rise to room temperature and the reaction mixture was stirred for 2 hours. The precipitate was filtered off using a Celite (trade mark) filter aid. After the precipitate had been washed with ether twice, the filtrate and the washings were combined, and the solvent was evaporated. The residue was washed with ether to filter off the insoluble materials, Evaporation of the solvent from the filtrate gave 6.23 g (yield 100%) of the title compound as a semi-solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:23][S:24][CH2:25][CH2:26][O:27][C:28]([NH:30][C:31]1[NH:32][C:33](=[O:44])[C:34]2[N:35]=[CH:36][N:37]([CH2:40][C:41](O)=[O:42])[C:38]=2[N:39]=1)=[O:29]>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:41](=[O:42])[CH2:40][N:37]1[CH:36]=[N:35][C:34]2[C:33](=[O:44])[NH:32][C:31]([NH:30][C:28]([O:27][CH2:26][CH2:25][S:24][CH3:23])=[O:29])=[N:39][C:38]1=2)[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Reactant: CSCCOC(=O)Nc1nc2c(ncn2CC(=O)O)c(=O)[nH]1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cnc2c(=O)[nH]c(NC(=O)OCCSC)nc21
Yield: 81.8 %

Procedure:
The title compound (2.67 g, 75%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [2-N-(2-methylthioethoxycarbonyl)-guanin-9-yl]-acetic acid (1.64 g, 5 mmol) as per the procedure of Example 20.
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH:13]=[C:14]2[N:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=[N:16][C:15]2=[O:23])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1>C(O)C.CO>[C:3]1([CH2:13][CH:14]2[N:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=[N:16][C:15]2=[O:23])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=C1N=C2C=CC=CN2C1=Cc1cccc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: O=C1N=C2C=CC=CN2C1Cc1cccc2ccccc12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 137 mg (3.7 mmol) of sodium borohydride in 15 mL of ethanol is added a solution of 500 mg (1.8 mmol) of 3-[1-naphthalen-1-yl-methylidene]-imidazo[1,2-a]pyridin-2-one in 50 mL of methanol, dropwise at −78° C. After stirring for 10 min at −78° C., the reaction mixture is quenched with saturated aqueous ammonium chloride solution at −78° C. The product is extracted with dichloromethane. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][C@@H:20]([CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][C@@H:20]([CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)[C@@H](N)Cc1cccc2ccccc12
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-3-(1-naphthyl)propionate hydrochloride (Bachem), the title compound was prepared as a solid (mp=103-130° C.). The reaction was monitored by tlc (Rf=0.8 in 5% MeOH/methylene chloride) and the product was purified by flash column chromatography using 6% MeOH/methylene chloride as the eluent.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:12].C(=O)(O)[O-].[Na+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(O)C>[CH2:22]([O:21][C:19]([NH:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:12])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N[C@@H]1Cc2ccccc2C[C@H]1O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(N[C@@H]1Cc2ccccc2C[C@H]1O)OCc1ccccc1
Reaction time: 4 h

Procedure:
To a solution of trans 3-amino-2-hydroxy-1,2,3,4-tetrahydronaphthalene (2.2 g, 72% pure) in ethanol (135 mL) stirring at room temperature under nitrogen was added sodium bicarbonate (2.2 g) and benzyl chloroformate (2.12 mL). After 4 h, the reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography eluting with a step-wise gradient of 30-70% ethyl acetate in hexane to provide the title compound (2.0 g) as a white solid.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2[S:29][C:28]([O:30][C@@H:31]3[CH:38]4[CH2:39][N:34]5[CH2:35][CH:36]([CH2:40][CH:32]3[CH2:33]5)[CH2:37]4)=[N:27][N:26]=2)[CH:22]=[N:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47]([OH:50])(=[O:49])=[O:48])=[CH:43][CH:42]=1.[C:52]1([CH3:62])[CH:57]=[CH:56][C:55]([S:58]([OH:61])(=[O:60])=[O:59])=[CH:54][CH:53]=1.N1C=C(C2SC(O[C@@H]3C4CN5CC(CC3C5)C4)=NC=2)C=N1.N>>[C:41]1([CH3:51])[CH:42]=[CH:43][C:44]([S:47]([OH:50])(=[O:48])=[O:49])=[CH:45][CH:46]=1.[C:52]1([CH3:62])[CH:53]=[CH:54][C:55]([S:58]([OH:61])(=[O:59])=[O:60])=[CH:56][CH:57]=1.[NH:21]1[CH:22]=[C:23]([C:25]2[S:29][C:28]([O:30][C@@H:31]3[CH:32]4[CH2:33][N:34]5[CH2:35][CH:36]([CH2:37][CH:38]3[CH2:39]5)[CH2:40]4)=[N:27][N:26]=2)[CH:24]=[N:20]1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cc(-c3nnc(OC4C5CC6CC4CN(C6)C5)s3)cn2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Agent: c1n[nH]cc1-c1cnc(OC2C3CC4CC2CN(C4)C3)s1
Product: c1n[nH]cc1-c1nnc(OC2C3CC4CC2CN(C4)C3)s1

Procedure:
The free base of the title compound was prepared from the product of Example 54A (100 mg, 0.18 mmol) according to Method L, and then converted to the p-toluenesulfonate salt using the procedure of Method H: 1H NMR (300 MHz, methanol-D4) δ ppm 1.99 (d, J=13.6 Hz, 2H), 2.21 (s, 1H), 2.32 (s, 2H), 2.36 (s, 3H), 2.73 (s, 2H), 3.52-3.81 (m, 6H), 5.52 (s, 1H), 7.23 (d, J=8.1 Hz, 2H), 7.71 (d, J=8.1 Hz, 2H), 8.09 (br. s, 2H), MS (DCI/NH3) m/z=304 (M+H)+. Anal. Calcd. for C14H17N5OS.C7H8O3S: C, 53.03; H, 5.30; N, 14.73. Found: C, 52.48; H, 5.03; N, 14.46.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[NH:5][C:4]2=[N:15][CH:16]=[CH:17][C:3]=12.[I:18]N1C(=O)CCC1=O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:11])[CH3:12])[NH:5][C:4]2=[N:15][CH:16]=[C:17]([I:18])[C:3]=12
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)c2ccnc-2[nH]1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1nc(Cl)c2c(I)cnc-2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
4-Chloro-2-trimethylacetamido-pyrrolo[2,3-d]pyrimidine (9a, 10.9 g, 43.24 mmol) was dissolved in anhydrous THF (120 mL) under nitrogen. After the addition of N-iodosuccinimide (10.7 g, 47.56 mmol), the mixture was stirred at RT for 1 h. The solvent was then removed in vacuo. The residue dissolved in EtOAc (100 mL) and washed with 1 M sodium thiosulfate (3×100 mL). Column chromatography purification (2% MeOH in DCM, isocratic) yielded 9b (12.9 g).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[C:13]([CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH:29]([F:31])[F:30])[OH:21])=[N:14][C:15]([S:18][CH3:19])=[N:16][CH:17]=1.C(N(CC)CC)C>ClCCl.O>[Cl:11][C:12]1[C:13]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH:29]([F:30])[F:31])=[O:21])=[N:14][C:15]([S:18][CH3:19])=[N:16][CH:17]=1
Reactant: CSc1ncc(Cl)c(C(O)c2ccccc2OC(F)F)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ncc(Cl)c(C(=O)c2ccccc2OC(F)F)n1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
A solution of 78 mg of DMSO in 0.5 ml of dichloromethane is added slowly, under argon, to a solution of 75 mg of oxalyl chloride in 2 ml of dichloromethane, cooled to −78° C. After 20 min at −78° C., a solution of 308 mg of [5-chloro-2-(methylsulfanyl)pyrimidin-4-yl][2-(difluoromethoxy)phenyl]methanol 6 in 2 ml of dichloromethane is added. After 1 h 30 at −78° C., 182 mg of triethylamine are slowly added and the mixture is left to return to ambient temperature for 30 min. The mixture is then poured into water and extracted three times with dichloromethane. The organic phases are dried over magnesium sulfate, filtered, and then concentrated under vacuum so as to obtain 303 mg of [5-chloro-2-(methylsulfanyl)pyrimidin-4-yl][2-(difluoromethoxy)phenyl]methanone 7 in the form of a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:24][N:25]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26]1.C1CCN2C(=NCCC2)CC1>CN1C(=O)CCC1>[NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:30][CH:27]2[CH2:28][CH2:29][N:25]([CH3:24])[CH2:26]2)[CH:12]=3)[CH:7]=1
Reactant: CN1CCC(N)C1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(Cl)cc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NC3CCN(C)C3)cc21
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A solution of Example A3 (500 mg, 1.42 mmol), 1-methyl-pyrrolidin-3-ylamine (170 mg, 1.7 mmol) and DBU (383 mg, 2.84 mmol) in NMP (5 mL) was heated with a microwave at 160° C. for 2 h. After cooling to RT, the mixture was purified by silica gel chromatography to yield 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(1-methylpyrrolidin-3-ylamino)-1,6-naphthyridin-2(1H)-one (500 mg, 85% yield) as a yellow oil.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]([NH2:19])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1COCC1>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17](=[S:29])[NH2:19])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)n1ncc(C(N)=O)c1-c1ccc(F)cc1
Solvent: C1CCOC1
Product: CC(C)(C)n1ncc(C(N)=S)c1-c1ccc(F)cc1
Yield: 64.7 %

Procedure:
A solution of the compound (4.00 g, 15.31 mmol) obtained in step 3 and Lawesson's reagent (6.19 g, 15.31 mmol) in THF (50 mL) was stirred at 50° C. for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (solvent gradient; 2→65% ethyl acetate/hexane) to give 1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazole-4-carbothioamide (2.75 g, 9.91 mmol, 65%) as a pale-yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:35]([CH2:37][NH2:38])[OH:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:38][CH2:37][CH2:35][OH:36])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.32 (1H, m), 8.56 (1H, s), 7.16 (2H, dd, J=9, 6 Hz), 7.03 (2H, t, J=9 Hz), 6.97 (1H, s), 4.93 (2H, s), 4.11 (2H, s), 3.83 (2H, t, J=5 Hz), 3.62 (2H, q, J=5 Hz), 3.50 (2H, t, J=6 Hz), 3.44 (2H, t, J=5 Hz), 1.69-1.58 (6H, m); HRMS calcd for C25H27FN4O5+H+: 483.2044. Found: 483.2060.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[N:7]([CH3:10])[C:8]=1[CH3:9])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl>CN(C)C=O>[C:1]([C:4]1[N:5]=[C:6]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:24][CH:26]3[O:28][CH2:27]3)=[CH:15][CH:16]=2)[N:7]([CH3:10])[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: ClCC1CO1
Reactant: CC(=O)c1nc(-c2ccc(O)cc2)n(C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1nc(-c2ccc(OCC3CO3)cc2)n(C)c1C
Reaction time: 20 h

Procedure:
A mixture of 11.5 g of 4-acetyl-1,5-dimethyl-2-(4-hydroxyphenyl)-1H-imidazole, 13.8 g of potassium carbonate, 7.0 g of epichlorohydrin and 120 ml of dimethylformamide is stirred for 20 hours in a bath at 60°-70°. The insoluble material is filtered off, the filtrate is concentrated by evaporation and the residue is divided between ethyl acetate and water. From the organic phase there is obtained, by concentration by evaporation, an oil which is chromatographed on silica gel with ethyl acetate. 4-acetyl-1,5-dimethyl-2-[4-(2,3-epoxypropoxy)-phenyl]-1H-imidazole is obtained from the first six fractions eluted in the form of a yellow oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(CBr)cc1

Procedure:
N-Bromosuccinimide (1.51 g, 8.509 mmol) was added to a solution of 1-methyl-4-nitrobenzene (1.2 g, 7.735 mmol) in carbon tetrachloride. 70% benzoyl peroxide (cat. 120 mg) was added to the mixture at room temperature. The mixture was refluxed. After 24 h the mixture was extracted with ethyl acetate, dried over magnesium sulfate. Evaporation of the ethyl acetate and purification by column chromatography yielded 1-(bromomethyl)-4-nitrobenzene.
Reaction SMILES: [N:1]([CH:4]([CH2:7][OH:8])[CH2:5][OH:6])=[N+:2]=[N-:3].C([C:11](CC)(CC)[C:12]([O-])([O-])[O-:13])C.O.CCOC(C)=O>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:12]([O:6][CH2:5][CH:4]([N:1]=[N+:2]=[N-:3])[CH2:7][OH:8])(=[O:13])[CH3:11]
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: [N-]=[N+]=NC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCC(CO)N=[N+]=[N-]
Reaction time: 0.67 h
Yield: 57.3 %

Procedure:
2-Azidopropane-1,3-diol 23 (10.46 g, 89.3 mmol) was dissolved in CH2Cl2 (450 mL) and treated with a catalytic amount of p-toluene sulfonic acid monohydrate (340 mg, 1.8 mmol) and triethylorthoacetate (24.4 mL, 134 mmol) at room temperature for 1 hr. After the formation of the orthoester was complete, a stoichiometric amount of water (2.4 mL, 134 mmol) was added to the mixture. The mixture was then stirred for 40 min and then concentrated in vacuo. Purification of the residue on a silica gel cartridge using EtOAc:Hex as the eluent (5% EtOAc to 100% EtOAc) afforded 8.14 g (57% yield) of 24 as a clear, colorless oil. 1H NMR (CDCl3, 400 MHz), δ: 2.45 (1H, br s), 2.12 (3H, s), 3.63-3.78 (3H, 4.20-4.30 (2H, m).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][C:21]2([C:27]([O:29][CH3:30])=[O:28])[O:26][C:24](=[O:25])[CH2:23][CH2:22]2)=[CH:12]1.C(C1C=CC(S([N:43]=[N+:44]=[N-:45])(=O)=O)=C(C(C)C)C=1C(C)C)(C)C.C(O)(=O)C>C1COCC1>[N:43]([CH:23]1[CH2:22][C:21]([CH2:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][CH:12]=2)([C:27]([O:29][CH3:30])=[O:28])[O:26][C:24]1=[O:25])=[N+:44]=[N-:45]
Reactant: COC(=O)C1(Cc2c[nH]c3ccccc23)CCC(=O)O1
Reactant: CC(C)c1ccc(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C1(Cc2c[nH]c3ccccc23)CC(N=[N+]=[N-])C(=O)O1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 63.9 %

Procedure:
To a solution of LHMDS (1.0 M, 24.2 mL, 24.2 mmol) in THF was added indole lactone 11 (3.00 g, 11 mmol) in freshly distilled THF (33 mL) at -78° C. The light yellow solution was stirred for 40 min, and triisopropylbenzenesulfonyl azide (3.40 g, 11 mmol) in 33 mL dry THF was added at -78° C. via syringe. The reaction mixture was stirred for 20 min before quenching with acetic acid (49.5 mmol, 2.83 mL). The reaction mixture was allowed to warm to room temperature over 30 min before being diluted with saturated NH4C1 solution. This solution was stirred for 5 min and extracted with EtOAc (2×75 mL). The combined organic layers were dried (MgSO4), and the solvent was removed under reduced pressure. The crude oil was flash chromatographed on silica gel (1:2, EtOAc-hexanes eluant) to afford 2.21 g (64%) of pure azido lactone 12 as a mixture of diastereomers (3:2; SS/RR:SR/RS). A sample was crystallized from ethyl acetate/hexanes: mp. 110-112° C., SS/RR recemate; 1H NMR (300 MHz, CDC13) δ 2.19 (dd, 1H, J=14.0, 7.3 Hz), 2.63 (dd, 1H, J=14.0, 9.3 Hz), 3.34 (dd, 1H, J=9.0, 2.6 Hz), 3.39 (ABq, 2H, J=15.3 Hz), 3.84 (s, 3H), 7.10 (d, J=2.4 Hz), 7.14-7.24 ((m, 2H), 7.37 (d, 1H, J=8.3 Hz), 7.63 (d, 1H, J=7.6 Hz), 8.32 (brs 1H, D2O Exchangeable).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl[CH2:34][C:35](=[O:37])[CH3:36].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl-].[NH4+]>CC(C)=O>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([O:32][CH2:34][C:35](=[O:37])[CH3:36])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(O)cn3)[nH]2)cc1)C1CC1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Yield: 64 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-ol (0.052 g) in acetone (5 mL) were added chloroacetone (0.01 mL), potassium carbonate (18 mg) and potassium iodide (2 mg), and the mixture was heated under reflux for 11 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-100:0, volume ratio) to give the title compound (0.038 g, yield 64%) as a colorless amorphous solid. MS: 509 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16])[C:6](N(OC)C)=[O:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[C:15]([F:16])([F:17])[F:18])[CH:6]=[O:7]
Reactant: COc1cc(C(=O)N(C)OC)ccc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C=O)ccc1C(F)(F)F
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-methoxy-N-methoxy-N-methyl-4-(trifluoromethyl)benzamide (2.63 g) in dry tetrahydrofuran (26 ml) was added lithium aluminum hydride (380 mg) at −40° C. under nitrogen atmosphere. After 1 hour of stirring at 5° C., 2N sodium hydroxide was added to the mixture. The insoluble materials were removed by filtration through Celite® and washed with ethyl acetate. The filtrate and washing were combined and evaporated under reduced pressure to give crude 3-methoxy-4-(trifluoromethyl)benzaldehyde as a colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:37][CH2:36][C:11]2[N:12]([CH3:35])[C:13]3[CH:14]=[C:15]([N:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=5)=[CH:21][C:20]4=[O:34])[CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=O)(C)(C)C.[ClH:38]>CO.CCOCC>[ClH:33].[ClH:38].[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][O:25][C:22]2[CH:23]=[CH:24][N:19]([C:15]3[CH:16]=[CH:17][C:18]4[C:10]5[CH2:9][NH:8][CH2:37][CH2:36][C:11]=5[N:12]([CH3:35])[C:13]=4[CH:14]=3)[C:20](=[O:34])[CH:21]=2)=[CH:32][CH:31]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5)cc4=O)cc31)CNCC2
Reaction time: 3 h
Yield: 71 %

Procedure:
tert-Butyl-7-(4-(4-chlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (143 mg, 0.275 mmol) was dissolved in MeOH (1 mL) and 2 N HCl in Et2O (5 mL) was added. The reaction was allowed to proceed for 3 h. The resulting precipitate was collected by filtration and washed with Et2O to provide the title compound (95 mg, 71%) as a yellow solid: mp 305-310° C. dec; 1H NMR (500 MHz, DMSO-d6) δ 9.54 (br s, 2H), 7.57 (m, 2H), 7.51 (s, 5H), 6.99 (d, J=7.8 Hz, 1H), 6.12 (dd, J=7.8, 2.7 Hz, 1H), 5.99 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.33 (br s, 2H), 3.68 (s, 3H), 3.52-3.48 (m, 2H), 3.12-3.08 (m, 2H); ESI MS m/z 420 [M+H]+; HPLC (Method B) 97% (AUC), tR=13.99 min.