Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:6]([OH:8])=O)#[N:2].[NH2:21][C@@H:22]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@H:23]([OH:42])[CH2:24][N:25]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=1)[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:6]([NH:21][C@@H:22]([CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C@H:23]([OH:42])[CH2:24][N:25]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=1)[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:8])#[N:2]
Reactant: CCCN(CCC)C(=O)c1cc(C#N)cc(C(=O)O)c1
Reactant: COc1cccc(CN(C[C@@H](O)[C@@H](N)Cc2ccccc2)C(=O)OC(C)(C)C)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)c1cc(C#N)cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CN(Cc2cccc(OC)c2)C(=O)OC(C)(C)C)c1
Reaction time: 65 h

Procedure:
To a mixture of 3-cyano-5-[(dipropylamino)carbonyl]benzoic acid (IX/XXXII, PREPARATION 7, 0.086 g, 0.314 mmol) and tert-butyl (2R,3S)3-amino-2-hydroxy4-phenylbutyl(3-methoxybenzyl)carbamate (XXXV, EXAMPLE 584, 0.126 g, 0.314 mmol) in dichloromethane (0.3 mL) is added diethylcyanophosphonate (0.062 g, 0.330 mmol) and triethylamine (0.032 g, 0.316 mmol). The mixture is stirred at 20–25 degrees for 65 hours and then partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic phase is separated and dried over sodium sulfate and concentrated. The residue is chromatographed (silica gel, 20 mL; methanol/dichloromethane, 5/95) to give several mixed fractions, which are combined and rechromatographed (silica gel; acetone/hexane, 20/80) to give the title compound, MS (ESI+) for C35H48N4O6 M/z 657.6 (M+H)+=657.6; (M+Na)=679.5 and (M—C4H9O2)=557.5.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7](OCC)=[O:8].[Li+].[BH4-].CO>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:18])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:7][OH:8]
Reactant: CCOC(=O)C(C)(CCCCBr)c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Product: CC(CO)(CCCCBr)c1ccccc1
Yield: 84.4 %

Procedure:
According to the procedure given for the synthesis of 206e, 205d (52.0 g, 166.0 mmol) was reacted with LiBH4 (5.4 g, 247.9 mmol) and methanol (8.2 g, 255.9 mmol) in CH2Cl2 (180 mL) to afford 206d (38.0 g, 84%) as an oil. 1H NMR (CDCl3): δ 7.5-7.1 (m, 5H), 3.60 (d, 1H, J=10.8), 3.53 (d, 1H, J=10.8), 3.34 (t, 2H, J=7.0), 1.90-1.78 (m, 3H), 1.62-1.26 (m, 3H), 1.35 (s, 3H), 1.14 (m, 1H). 13C NMR (CDCl3): δ 144.4, 128.4, 126.5, 126.1, 72.4, 43.2, 37.4, 33.5, 33.3, 22.5, 21.4.
Reaction SMILES: C(=O)(OCCCl)[O:2][CH:3]([CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:4]Cl.C(OCC(O)CCl)(C)(C)C.ClC(OCCCl)=O>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.C(Cl)CCl>[CH2:6]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])[CH:3]1[O:2][CH2:4]1
Reactant: CC(C)(C)OCC(CCl)OC(=O)OCCCl
Agent: CC(C)(C)OCC(O)CCl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: O=C(Cl)OCCCl
Solvent: ClCCCl
Product: CC(C)(C)OCC1CO1

Procedure:
Following the procedure of Example 14, 3-tert-butoxy-1-chloro-2-propyl 2-chloroethyl carbonate (from the reaction of 3-tert-butoxy-1-chloro-2-propanol with 2-chloroethyl chloroformate) is heated in the presence of tetrabutylphosphonium bromide to produce tert-butyl glycidyl ether and ethylene dichloride as the principal reaction products.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([S:26][CH3:27])[C:16]([N:17]([CH2:22][CH:23]4[CH2:25][CH2:24]4)[CH2:18][CH:19]4[CH2:21][CH2:20]4)=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.C(OCC)(=O)C.[CH3:36][N:37](C)C=O>[Zn]>[CH:19]1([CH2:18][N:17]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[C:16]2[C:15]([S:26][CH3:27])=[N:14][N:13]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([C:36]#[N:37])=[CH:3][C:4]=4[O:28][CH3:29])=[CH:9][CH:10]=[CH:11][C:12]=23)[CH2:21][CH2:20]1
Reactant: COc1cc(Br)ccc1-c1cccc2c(N(CC3CC3)CC3CC3)c(SC)nn12
Reactant: CN(C)C=O
Agent: [Zn]
Solvent: CCOC(C)=O
Product: COc1cc(C#N)ccc1-c1cccc2c(N(CC3CC3)CC3CC3)c(SC)nn12
Temperature: 95 °C
Reaction time: 12 h

Procedure:
After dissolving N-[7-(4-bromo-2-methoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine (60 mg) in N,N-dimethylformamide (0.26 mL), zinc cyamide (31 mg) and tetrakis (triphenylphosphine)palladium(0) complex (23 mg) were added, the mixture was heated and stirred at 95° C. for 12 hours and then cooled to room temperature, and ethyl acetate was added. After filtering out the precipitated insoluble portion, extraction was performed with ethyl acetate. The obtained organic layer washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:8) to obtain the title compound (32 mg) as a yellow oil.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)[N:17]=1)[CH:10]=[C:9]2[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.Br[CH2:39][CH2:40][CH2:41][OH:42].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13]([CH:12]=[C:11]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=4)[N:17]=3)[CH:10]=[C:9]2[N:32]2[CH2:33][CH2:34][N:35]([CH2:39][CH2:40][CH2:41][OH:42])[CH2:36][CH2:37]2)=[CH:14][CH:15]=1
Reactant: COc1cccc(CNc2nccc(-c3cc(N4CCNCC4)c4cc(OC)ccc4c3)n2)c1
Reactant: OCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cccc(CNc2nccc(-c3cc(N4CCN(CCCO)CC4)c4cc(OC)ccc4c3)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
A mixture of 4-(6-methoxy-4-(piperazin-1-yl)naphthalen-2-yl)-N-(3-methoxybenzyl)pyrimidin-2-amine tris hydrochloride salt (1.0 g, 1.78 mmol), 3-bromopropan-1-ol (250 mg, 1.80 mmol), potassium carbonate (1.23 g, 8.91 mmol) and acetonitrile (20 ml) was stirred for 16 hours at room temperature. The mixture was diluted with water (100 ml) and extracted with dichloromethane (3×50 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (24 g) using a gradient of ethyl acetate-hexanes to afford 3-(4-(7-methoxy-3-(2-((3-methoxybenzyl)amino)pyrimidin-4-yl)naphthalen-1-yl)piperazin-1-yl)propan-1-ol 193 as a yellow solid (600 mg, 66%). 400 M Hz 1H NMR (DMSO-d6) δ: 8.35 (d, J=5.2 Hz, 1H), 8.29 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.80 (bm, 2H), 7.42 (s, 1H), 7.23 (m, 3H), 6.99 (bm, 2H), 6.78 (dd, J=2.4 and 8.4 Hz, 1H), 4.55 (m, 3H), 3.91 (s, 3H), 3.71 (s, 3H), 3.50 (m, 3H), 3.06 (bm, 6H), 2.73 (bm, 3H), 1.67 (m, 2H); LCMS[M+H]: 514.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:37].[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41][NH2:42].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:42][CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:37]
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CN(C)CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
To the solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide (30 mg, 0.055 mmol) in dichloromethane (3.0 mL) were added N,N-dimethyl-1,2-ethanediamine (12.2 μL, 0.11 mmol) and triethylamine (15.6 μL, 0.11 mmol). The reaction mixture was stirred at room temperature for 16 hours then was concentrated, redissolved in DMSO (0.5 mL), filtered and applied to the reverse phase HPLC to afford the titled compound 16.9 mg (54%). LC-MS m/z 565 (M+H)+; 1H-NMR (MeOD) 2.20 (s, 3H), 2.33 (m, 7H), 2.81 (s, 2H), 3.26 (m, 1H), 4.13 (m, 1H), 4.43 (s, 1H), 7.17 (m, 3H), 7.50 (m, 3H), 8.01 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([CH:13]=[O:14])[N:10]=[CH:9]2)=[N:6][CH:7]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9]2)=[N:6][CH:7]=1
Reactant: O=Cc1cn(-c2ccc(Br)cn2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cn(-c2ccc(Br)cn2)cn1
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
To a suspension of 1-(5-bromopyridin-2-yl)-1H-imidazole-4-carbaldehyde (730 mg, 2.90 mmol) in MeOH (10 mL) at room temperature was added NaBH4 (134 mg, 3.53 mmol). The mixture was stirred for 30 min, during which time the suspension became clear. The solvent was removed in vacuo. The residue was partitioned between H2O and EtOAc. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give (1-(5-bromopyridin-2-yl)-1H-imidazol-4-yl)methanol as a solid (520 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:17][N:18]([CH2:20][CH2:21]O)[CH3:19]>>[CH3:17][N:18]([CH2:20][CH2:21][O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9](=[O:10])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:19]
Reactant: CN(C)CCO
Reactant: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)OCCN(C)C

Procedure:
Following General Procedure BC above, and using N-(3-chlorophenyl-acetyl)alanine (from Example BD above) and 2-(N,N-dimethyl amino) ethanol (Aldrich), the title compound can be prepared. The reaction was monitored by tlc on silica gel and purification was by liquid chromatography using 0.1:2:0.79 NH4OH:EtOH:CHCl3 as the eluant.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:28])=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[CH:11][C:10]([O:24][CH3:25])=[C:9]([O:26][CH3:27])[CH:8]=2)(=[O:3])[CH3:2].[Br:29]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([C:4]1[C:5]([CH2:28][Br:29])=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[CH:11][C:10]([O:24][CH3:25])=[C:9]([O:26][CH3:27])[CH:8]=2)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2c(C(C)=O)c(C)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(-c2c(C(C)=O)c(CBr)nc3cc(OC)c(OC)cc23)cc1OC
Yield: 67 %

Procedure:
A mixture of 3-acetyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-methylquinoline (8.5 g), N-bromosuccinimide (5. mg) , 2,2'-azobis(isobutyronitrile) (1.46 g) and carbon tetrachloride (500 ml) was stirred under reflux for 40 minutes. The reaction mixture was cooled, and then the insoluble material was filtered off. The filtrate was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethyl acetate (20:1, v/v) gave 3-acetyl-2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline (6.85 g, 67%). This compound was recrystallized from ethyl acetate-hexane to give colorless prisms, mp. 181°-182° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.[F:14][C:15]([F:27])([F:26])[C:16]1[CH:17]=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1>>[CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH:13][S:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:14])([F:26])[F:27])[CH:17]=3)(=[O:24])=[O:23])=[N:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(COCC2CC2)cn1
Product: O=S(=O)(Nc1ccc(COCC2CC2)cn1)c1cccc(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 5-cyclopropylmethoxymethyl-pyridin-2-ylamine (0.051 g) and 3-(trifluromethyl)-benzenesulfonyl chloride (0.077 g) as a crystalline white solid (0.062 g). MS (ESI−): 385.0 ([M−H]−)
Reaction SMILES: [NH2:1]N1C2C=NC=CC=2C2C1=CC(Cl)=CC=2.N1C=CC=CC=1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>C1COCC1>[C:23](=[O:24])([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:1]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nn1c2cnccc2c2ccc(Cl)cc21
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 224 %

Procedure:
A cold (3° C. to 5° C.) solution of the product of example 15 (30 mg, 0.14 mmol) and pyridine (0.014 ml, 0.17 mmol) in THF (0.7 ml) was treated with phenyl chloroformate (0.018 ml, 0.145 mmol). After stirring at RT for 2 h, the reaction was partitioned in ethyl acetate and buffer (pH 7.2). The organic layer was dried (brine, Na2SO4) and concentrated to give 43 mg of phenyl carbamate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]C(OC(C)(C)C)=O)=[C:19]([CH3:31])[CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[ClH:33]>O1CCOCC1.C(OCC)C>[ClH:33].[CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([CH3:31])[CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)OC(C)(C)C)c(C)c1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1ccc(N)c(C)c1)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of N-(benzyloxycarbonyl)-4-[(1,1-dimethylethoxy)carbonyl]amino-3-methyl-L-phenylalanine methyl ester (4.52 mmol, 2 g) in dioxane (12 mL) was added 4N hydrochloric acid in dioxane (48 mmol, 2 mL) at room temperature and the solution was stirred for approximately 2 h as a white precipitate was formed. The solids were diluted with diethyl ether, the mother liquor was decanted and the residue was dried first on a rotary evaporator and then under high vacuum to afford 1.487 g (87% yield) of N-(benzyloxycarbonyl)-4-amino-3-methyl-L-phenylalanine methyl ester hydrochloride salt as an amorphous yellow solid. FAB-HRMS m/e calcd for C19H22N2O4 (M+H) 343.0142, found 343.0144.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[C:17]2[C:4]=1[C@H:5]1[C@H:14]([CH2:15][S:16]2(=[O:25])=[O:24])[C@:13]2([CH3:26])[C@H:8]([C:9]([CH3:28])([CH3:27])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1.[CH3:29][N:30](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.CN>CN(C=O)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:20]=[C:19]([C:21]([NH:30][CH3:29])=[O:22])[CH:18]=[C:17]2[C:4]=1[C@H:5]1[C@H:14]([CH2:15][S:16]2(=[O:25])=[O:24])[C@:13]2([CH3:26])[C@H:8]([C:9]([CH3:28])([CH3:27])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1
Reactant: COc1cc(C(=O)O)cc2c1[C@@H]1CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1cc(OC)c2c(c1)S(=O)(=O)C[C@H]1[C@H]2CC[C@H]2C(C)(C)CCC[C@]12C
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.7 %

Procedure:
A mixture of (1R,10S,11S,16S)-3-methoxy-11,15,15-trimethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-5-carboxylic acid (61) (0.35 g, 0.83 mmol), HATU (0.61 g, 1.7 mmol), N-methylmorpholine (0.18 mL, 2.5 mmol), methylamine (2 M in THF, 1.04 mL, 2.08 mmol), THF (10.0 mL) and DMF (2.0 mL) in a sealed tube was stirred at room temperature for 18 h. The THF was evaporated and the residue was quenched with water. The resulting solid was collected by filtration. The crude product was purified by flash chromatography on silica gel (Hexanes/EtOAc, 1:1) to yield (1R,10S,11S,16S)-3-methoxy-N,11,15,15-tetramethyl-8,8-dioxo-8λ6thiatetracyclo[8.8.0.02,7.011,16]-octadeca-2,4,6-triene-5-carboxamide (0.26 g, 74%) (Compound No. 62) as a white solid. 1H NMR (CDCl3): δ 8.77 (s, 1H), 8.07 (s, 1H), 7.60 (s, 1H), 6.59 (m, 1H), 3.52 (m, 1H), 3.37 (m, 1H), 3.24 (m, 1H), 3.05 (d, 3H), 2.32 (d, 1H), 1.65-1.10 (m, 13H), 0.97 (s, 3H), 0.88 (s, 3H), 0.84 (s, 3H). MS m/z 420 (C23H33NO4S+H+).
Reaction SMILES: [O:1]([C:8]1[CH:28]=[CH:27][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH2:25][NH2:26])[CH:22]=[CH:23][CH:24]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:36]1C[CH2:39][CH2:38][CH2:37]1>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=2)[CH2:25][NH:26][C:37](=[O:36])[CH:38]=[CH2:39])=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: NCc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Solvent: CCN(CC)CC
Product: C=CC(=O)NCc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Yield: 6 %

Procedure:
N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)acrylamide was prepared from (3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine, triethylamine and tetrahydrofuran using Method G (6% yield). HPLC: 96%, RT=4.127 min. MS: m/z=423 [M+H]+, RT=3.22 min. 1H-NMR (DMSO-d6) δ 9.14 (s, 1H), 9.02 (d, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 8.09 (d, 1H), 7.93 (t, 1H), 7.87-7.84 (m, 3H), 7.73 (d, 2H), 7.62-7.58 (m, 3H), 7.51-7.50 (m, 3H), 6.77 (dd, 1H), 6.67 (d, 1H), 6.03 (d, 1H), 5.02 (d, 2H).
Reaction SMILES: [F:1][C:2]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][C:8]([O:10]C)=[O:9])=[O:5].[OH-].[Li+].Cl>CO.O>[F:1][C:2]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5]
Reactant: COC(=O)CNC(=O)c1cccc(F)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CNC(=O)c1cccc(F)c1F
Reaction time: 8 h

Procedure:
To a solution of methyl [(2,3-difluorobenzoyl)amino]acetate (0.250 g, 1.1 mmol) in methanol (7 mL) were added lithium hydroxide (0.053 g, 2.2 mmol) and water (3 mL). The reaction mixture was allowed to stir overnight. The mixture was diluted with water (20 mL) and acidified with 1N HCl (5 mL). The product was partitioned into DCM/methanol (4:1). The organic layer was dried over sodium sulfate and the solvent removed to give [(2,3-difluorobenzoyl)amino]acetic acid which was used in the next step without purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:11]1([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Brc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-n2ccc3ccccc32)cc1
Yield: 20.2 %

Procedure:
A mixture of 17.57 g (0.15 mole) of indole, 23.55 g (0.15 mole) of bromobenzene, 21 g of anhydrous potassium carbonate, 0.75 g of CuO, and 30 mL of DMF was stirred and heated under reflux for 43 hours. The cooled mixture was diluted with 200 mL of H2O and extracted with 150 mL of ether. The extract was washed with H2O (2×50 mL) and 50 mL of brine and dried over MgSO4. The oil was chromatographed on the solvent left 35.7 g of brown oil. The oil was chromatographed on a 1100 g column of silica gel. The column was eluted with 25% CH2Cl2 -Skellysolve B and 200 mL fractions were collected. The fractions were assayed by silica gel tlc (1×4") (25% CH2Cl2 -Skellysolve B). Fractions 15-22 were combined giving 5.86 g (20%) of 1-phenylindole as a yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[N:19]O)[C:10]=2[CH:9]=[CH:8][CH:7]=1>C(O)C.O1CCCC1.[Ni]>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([NH2:19])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1ncc[nH]1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: NC1c2ccccc2-c2c(-c3ncc[nH]3)cccc21
Reaction time: 3 h

Procedure:
Work in an autoclave as in Stage 3 in Example 5, starting from 449 mg of equimolecular mixture of the Z and E isomers of 4-(1H-imidazol-2-yl)-fluoren-9-one oxime, obtained in the preceding stage, in a mixture of 25 mL of ethanol and 25 mL of tetrahydrofuran, in the presence of Raney nickel, under an initial hydrogen pressure of 1 bar, at 60° C. for 3 hours. After filtration of the catalyst on Celite, concentration of the filtrate at reduced pressure and purification by making into a paste with diisopropyl oxide, we obtain 367 mg of 4-(1H-imidazol-2-yl)-9H-fluorene-9(R,S)-amine, in the form of a white powder, with the following characteristics:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH2:8]([C:11]1[C:19]([OH:20])=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]([CH2:21][CH2:22][NH:23][C:24](=[O:27])[CH2:25][CH3:26])[CH2:14][NH:15]2)[CH:9]=[CH2:10].O>C(O)=O>[CH2:8]([C:11]1[C:19]([OH:20])=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]([CH2:21][CH2:22][NH:23][C:24](=[O:27])[CH2:25][CH3:26])[CH2:14][N:15]2[CH:1]=[O:3])[CH:9]=[CH2:10]
Reactant: C=CCc1c(O)ccc2c1C(CCNC(=O)CC)CN2
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: O
Product: C=CCc1c(O)ccc2c1C(CCNC(=O)CC)CN2C=O
Reaction time: 0.17 h
Yield: 46 %

Procedure:
Formic acid (3.3 g, 71.7 mmol) and acetic anhydride (7.32 g, 71.7 mmol) was mixed under ice-cooling and the mixture was stirred for 10 minutes. To the mixture was added a solution of N-[2-(4-allyl-2,3-dihydro-5-hydroxyindol-3-yl)ethyl]propionamide in formic acid (10 mL). The mixture was stirred for 1 hour under ice-cooling and poured into water. The product was extracted with 10% methanol/ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, brine and water, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1) to afford the title compound (yield 2.0 g, 46% from N-[2-(4-allyl-5-hydroxyindol-3-yl)ethyl]propionamide).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:11]=[CH:12][C:13]([N+:25]([O-:27])=[O:26])=[C:14]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=1.[H-].[Na+]>CN1CCCC1=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:10]2[CH:11]=[CH:12][C:13]([N+:25]([O-:27])=[O:26])=[C:14]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NCc1cc(Oc2ccc(Cl)nc2)ccc1[N+](=O)[O-]

Procedure:
The reaction and post-treatment were carried out according to Example (1a) using 6-chloropyridin-3-ol (10 g, 77 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (19 g, 66 mmol), sodium hydride (56%, 3.1 g, 77 mmol) and N-methylpyrrolidinone (80 mL) to obtain the title compound.