Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[OH:6].[H-].[Na+].[F:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([O:25][CH3:26])[C:17]=1[CH2:18]Br.Cl>CN(C)C=O.O>[Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([O:6][CH2:18][C:17]2[C:20]([O:25][CH3:26])=[CH:21][CH:22]=[C:23]([F:24])[C:16]=2[F:15])=[C:4]([OH:12])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(O)c(O)cc1Cl
Reactant: COc1ccc(F)c(F)c1CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)c(F)c1COc1cc([N+](=O)[O-])c(Cl)cc1O
Reaction time: 0.17 h
Yield: 97.5 %

Procedure:
To a solution of 4-chloro-5-nitrocatechol (10.4 g) in N,N-dimethylformamide (55 mL) was added sodium hydride (55%, 5.04 g) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added N,N-dimethylformamide (11 mL), followed by adding a solution of 2,3-difluoro-6-methoxy-benzyl bromide (14.3 g) in N,N-dimethylformamide (22 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes, and then stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water. The mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=7/3−1/1) to give the title compound (18.5 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].O[CH2:22][CH2:23][NH:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C1(C)C(C)=CC=CC=1>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4].O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH2:22][CH2:23][NH:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:19])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCCCCCCCCCCCC(=O)NCCO
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Agent: [Ti+4]
Agent: CCCC[O-]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCCCCCCC(=O)NCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
A mixture of 30.6 g (0.11 mole) 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid, 32.6 g (0.1 mole) N-(2-hydroxyethyl)stearamide, 0.8 g Tyzor TBT, and 100 ml xylene was refluxed for six hours. The water (1.8 ml) was trapped in a Stark & Dean trap. The solution was filtered through Microcel (trademark, synthetic calcium silicate) and the solvent was removed by vacuum stripping. The title compound (51 g) was recrystallized from acrylonitrile. It melted at 52°-55° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].O>CN1CCCC1=O>[CH2:17]([O:16][C:14]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)CNc1ccc(O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)CN(C(=O)OCc1ccccc1)c1ccc(O)cc1
Reaction time: 0.67 h
Yield: 75 %

Procedure:
N-(4-hydroxyphenyl)glycine (55.0 g, 0.330 mol) was dissolved in 275 mL of N-methylpyrrolidone in a 1 L round-bottomed flask. Benzyl chloroformate (50.1 mL, 0.352 mol) was added with stirring over a 40 min period and then stirred at ambient conditions for 18 h. Deionized water was added until slightly turbid and then stored at 4° C. for 24 h. The product was isolated and recrystallized in warm ethanol, dried in vacuum oven at 40° C. overnight (yield 75%, mp=196-198° C.). 1H-NMR (500 MHz, DMSO-d6) δ 12.80 (s, 1H, COOH), 9.50 (s, 1H, phenol), 7.58-6.95 (m, 7H, aryl), 6.74 (s, 2H, aryl), 5.10 (d, J=21.9, 2H, —CH2-benzyl), 4.22 (d, J=21.7, 2H, N—CH2-).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)=[C:4]([F:26])[C:3]=1[F:27].[C:28](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:28][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:5]4[C:4]([F:26])=[C:3]([F:27])[C:2]([Cl:1])=[C:7]([F:8])[C:6]=4[F:9])=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH2:15][CH2:16][C:17]1=[O:22]
Reactant: CC(C)(C)O
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3c(F)c(F)c(Cl)c(F)c3F)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4c(F)c(F)c(Cl)c(F)c4F)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(4-chloro-2,3,5,6-tetrafluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (43 mg, 0.12 mmol), 0.3 mL of t-butanol, and potassium t-butoxide (40 mg, 0.36 mmol). Methyl iodide (0,022 mL, 0.36 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 30 mg (66%) of the title compound as an off-white solid. mp 150°-151°. FDMS: m/e=412 α[D]589 =+68.57 (c=0.12, chloroform).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[N:10]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]#[N:52])[C:11]2[C:16]([C:17]=1[CH2:18][N:19]1[C:25](=[O:26])[C@@H:24]([NH:27][C:28](=[O:40])[C@@H:29]([N:31](C)[C:32](=O)OC(C)(C)C)[CH3:30])[CH2:23][O:22][C:21]3[CH:41]=[CH:42][CH:43]=[CH:44][C:20]1=3)=[CH:15][CH:14]=[CH:13][CH:12]=2>C(Cl)Cl>[Cl:8][C:9]1[N:10]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]#[N:52])[C:11]2[C:16]([C:17]=1[CH2:18][N:19]1[C:25](=[O:26])[C@@H:24]([NH:27][C:28](=[O:40])[C@@H:29]([NH:31][CH3:32])[CH3:30])[CH2:23][O:22][C:21]3[CH:41]=[CH:42][CH:43]=[CH:44][C:20]1=3)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: C[C@@H](C(=O)N[C@H]1COc2ccccc2N(Cc2c(Cl)n(-c3ccccc3C#N)c3ccccc23)C1=O)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@H]1COc2ccccc2N(Cc2c(Cl)n(-c3ccccc3C#N)c3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.7 %

Procedure:
TFA (5 mL) was added to a solution of tert-butyl (S)-1-((S)-5-((2-chloro-1-(2-cyanophenyl)-1H-indol-3-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (130 mg, 207 μmol, Eq: 1.00) in DCM (5 mL). The mixture was stirred at RT for 16 h, then concentrated. Sat. NaHCO3 was added to the residue and the mixture was extracted with DCM. The combined organic extracts were concentrated and the residue purified by preparative TLC to give the title compound (50 mg, 43%) as a white solid. MS m/z 529 (MH+)
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])[CH:2]=[CH2:3].[NH2:14][C:15]1[C:16]([CH2:24][CH2:25][CH3:26])=[N:17][N:18]([CH3:23])[C:19]=1[C:20]([NH2:22])=[O:21]>ClCCl.N1C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[C:16]([CH2:24][CH2:25][CH3:26])=[N:17][N:18]([CH3:23])[C:19]=1[C:20]([NH2:22])=[O:21])=[O:8])[CH:2]=[CH2:3]
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Reactant: C=CCOc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOc1ccccc1C(=O)Nc1c(CCC)nn(C)c1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
A solution of 2-allyloxybenzoyl chloride (3.93 g, 0.02 mol) in dichloromethane (20 ml) was added dropwise to a stirred, partial solution of 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide (3.64 g, 0.02 mol) in pyridine (50 ml), and the resulting mixture stirred at room temperature overnight in a dry atmosphere. The solvent was evaporated under vacuum and the residue partitioned between dichloromethane (50 ml) and saturated aqueous sodium carbonate solution (50 ml). The organic layer was separated and the aqueous layer exhaustively extracted with further dichloromethane. The combined organic solutions were washed with 2M Hcl (3×30 ml), then brine (1×30 ml), and dried (Na2SO4). After filtration and evaporation under vacuum of the filtrate, the crude product was crystallised from ethyl acetate to give the title compound (4.525 g, 66%), m.p. 132-134° C. Found: C, 63.49; H, 6.42; N, 16.33. C18H22N4O3 requires C, 63.14; H, 6.48; N, 16.36%.
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:11][CH:10]=2)[CH2:6]1)(=O)[CH2:2][CH3:3].B.C1COCC1.C(OCC)(=O)C>C1COCC1>[CH2:1]([N:5]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:11][CH:10]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCC(=O)N1CC(c2ccc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cc2)C1
Agent: B
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cc2)C1
Yield: 53.2 %

Procedure:
Following the same procedure as described in Example 47.2, N-[4-(1-propionyl-azetidin-3-yl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide (170 mg, 0.39 mmol) in THF (20 ml) was then treated with 1M BH3.THF (3.9 ml). The crude material was chromatographied (ethyl acetate) to afford the title compound (86 mg, 52%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1.[O-]CC.[Na+]>C(O)C>[O:16]=[C:6]1[N:5]2[CH:17]=[CH:18][S:19][C:4]2=[N:3][C:2](/[CH:1]=[CH:20]/[C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[C:7]1[C:8]1[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=1
Reactant: O=Cc1cccnc1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C#N)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(-c2c(/C=C/c3cccnc3)nc3sccn3c2=O)cc1
Yield: 57 %

Procedure:
The title compound was prepared by condensation of Intermediate 4 (350 mg, 1.309 mmol) with nicotinaldehyde (196 mg, 1.833 mmol) in presence of sodium ethoxide (178 mg, 2.618 mmol) in ethanol (15 ml) according to the procedure outlined in Example 9 to give 266 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 6.88 (d, J=15.6 Hz, 1H), 7.30-7.38 (m, 1H), 7.50-7.58 (m, 3H), 7.84-7.93 (m, 4H), 8.02 (d, J=4.8 Hz, 1H), 8.47 (d, J=3.9 Hz, 1H), 8.70 (s, 1H); ESI-MS (m/z) 357.32 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].[OH:10]O.O>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[C:4]([OH:10])=[O:5])[CH3:2]
Reactant: CCCCC(CC)CO
Reactant: OO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: CCCCC(CC)C(=O)O
Temperature: 40 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 2-ethyl hexanol (8.7 mmol) in CH2Cl2 (10 ml), RuCl3H2O (0.014 mmol) and tetra butyl ammonium bromide (0.2 mmol) were added. The mixture was heated at 40° C. and 30% H2O2 (v/v) (3 ml) was added dropwise. After 1 hours the reaction was complete. Water is added, the organic phase was separated, dried over sodium sulphate and evaporated under reduced pressure to give the crude product of the title that was purified by flash chromatography (pure CH2Cl2) obtaining 0.8 g of the desired product. Yield 65%.
Reaction SMILES: Cl.Cl.[C:3]([O:7][C:8]([N:10]([C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[C:11]1[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:38])=[CH:33][CH:32]=1.C1COCC1>CCN(CC)CC>[C:37]([C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:26]2[CH2:27][CH2:28][C@@H:24]([N:10]([C:8]([O:7][C:3]([CH3:4])([CH3:5])[CH3:6])=[O:9])[C:11]3[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=3)[CH2:25]2)=[CH:36][CH:35]=1)(=[O:38])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(Cc3ccc(C(=O)c4ccccc4)cc3)C2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a mixture of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate dihydrochloride (150 mg), [4-(bromomethyl)phenyl](phenyl)methanone (143 mg), and THF (3.5 mL) was added Et3N (0.168 mL). After stirring for 2 hours at room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-{6-[[(3R)-1-(4-benzoylbenzyl)-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylate (149 mg).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(Cl)Cl.[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=1>C(N(CC)CC)C>[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23]([NH:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(NC(=O)c1ccc(C)cc1)C(=O)OCC
Yield: 91.2 %

Procedure:
Diethyl aminomalonate hydrochloride (20.5 g) was suspended into 180 ml of methylene chloride, and 29.4 g of triethylamine was added while cooling with ice-cold water. After 30-minute-stirring, 15 g of p-toluoyl chloride was added dropwise, and the mixture was stirred for 24 hours at room temperature. The reaction solution was washed with water, dilute hydrochloric acid, and water, dried over anhydrous magnesium sulfate and concentrated. To the residue was added isopropyl ether, and the resultant crystals were collected by filtration and dried to provide 25.9 g of the objective compound as white crystal. M.p. 101-102° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=O)[O:13][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12>C(O)(=O)C>[C:2]1([N:1]2[C:11](=[O:12])[C:10]3=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]3[C:8]2=[O:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1ccccc1

Procedure:
The reaction of aniline 3.8 g (0.041 mol) with phthalic anhydride 4.0 g (0.041) mol in 100 ml of refluxing glacial acetic acid for 3 hours, followed by precipitation from water, filtration and vacuum drying at 120° C., afforded an 8.2 g (91%) yield of product, m.p. 205°-9° C. (from ethanol). Lit. reports m.p. 210° C. ("Dict. Org. Cpds", 5, 2740(1965), Oxford Univ. Press, N.Y.). Anal. Calcd. for C14H9NO2 : C, 75.33; H, 4.06. Found: C, 75.10; H, 4.17%. Ir(KBr): 1765, 1700, and 1375 cm-1 (imide).
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.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:21])=[CH:22][CH:23]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: C1COCCN1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCOCC2)cn1
Yield: 67 %

Procedure:
As described for example 12, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) was converted using morpholine instead of 2,2,2-trifluoroethylamine to the title compound (SiO2, heptane:ethyl acetate=80:20 to 20:80, 165 mg, 67%) which was obtained as a white solid. MS: m/e=380.3 [M+H]+.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@H:15]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]([C@:23]34[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:24]3[C@@H:25]3[C@@:38]([CH3:41])([CH2:39][CH2:40]4)[C@@:37]4([CH3:42])[C@@H:28]([C@:29]5([CH3:46])[C@@H:34]([CH2:35][CH2:36]4)[C:33]([CH3:44])([CH3:43])[C@@H:32]([OH:45])[CH2:31][CH2:30]5)[CH2:27][CH2:26]3)=[O:22])[CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:59]1(=[O:66])[O:65][C:63](=[O:64])[CH2:62][CH2:61][CH2:60]1>C(OCC)(=O)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@H:15]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]([C@:23]34[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:24]3[C@@H:25]3[C@@:38]([CH3:41])([CH2:39][CH2:40]4)[C@@:37]4([CH3:42])[C@@H:28]([C@:29]5([CH3:46])[C@@H:34]([CH2:35][CH2:36]4)[C:33]([CH3:44])([CH3:43])[C@@H:32]([O:45][C:59](=[O:66])[CH2:60][CH2:61][CH2:62][C:63]([OH:65])=[O:64])[CH2:31][CH2:30]5)[CH2:27][CH2:26]3)=[O:22])[CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCC(Cc5ccccc5)CC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C1CCCC(=O)O1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCC(Cc5ccccc5)CC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CCCC(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-N-((1R,3S)-3-((4-benzylpiperidin-1-yl)methyl)cyclopentyl)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamide (Example 32, 0.24 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.32 g, 0.48 mmol) and glutaric anhydride (1.3 ml) were added and the contents were refluxed for about 16 hours and completion of the reaction monitored by TLC. The reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, washed with water followed by brine solution, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.1 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.82-0.95 (m, 17H) 1.13-3.01 (m, 48H); 3.05-3.12 (m, 4H), 3.13-3.54 (m, 2H), 4.18-4.21 (m, 1H), 4.45-4.17 (m, 1H), 4.58 (s, 1H), 4.72 (s, 1H); 6.28-6.30 (m, 1H), 7.11-7.13 (m, 2H), 7.14-7.22 (m, 1H), 7.24-7.29 (m, 2H); ES Mass: [M+] 825 (100%); HPLC: 90%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[CH:18]=[CH:19][CH:20]=[N:21][C:22]=3[C:23]([O:38]C(C3C=CC=CC=3)C3C=CC=CC=3)=[C:24]3[C:28](=[O:29])[N:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:26][C:25]=23)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:27]2[C:28](=[O:29])[C:24]3[C:23]([OH:38])=[C:22]4[C:17]([CH:18]=[CH:19][CH:20]=[N:21]4)=[C:16]([C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[O:15])[C:25]=3[CH2:26]2)=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c3c(c(OC(c4ccccc4)c4ccccc4)c4ncccc24)C(=O)N(Cc2ccc(F)cc2)C3)CC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2c(c(C(=O)N3CCNCC3)c3cccnc3c2O)CN1Cc1ccc(F)cc1
Temperature: 25 °C
Yield: 445.8 %

Procedure:
Carboxamide 229 (0.0108 g, 0.0153 mmol) was dissolved in 1 mL of dichloromethane. To this was added 0.4 mL of triethylsilane and 0.2 mL of trifluoroacetic acid. Stirred at room temperature and after ten minutes complete by TLC. Concentrated off volatiles, azeotroped with toluene to give crude. Then dissolved in 0.6 mL dichloromethane, 0.6 ml trifluoroacetic acid. Stirred at room temperature for one hour. Concentrated off volatiles, azeotroped with toluene to give crude. Triturated twice with 1:1 diethyl ether/hexanes to give 7-(4-fluoro-benzyl)-9-hydroxy-5-(piperazine-1-carbonyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 230 (0.039 g, 0.0682 mmol, 100%.) 1H NMR (CD3SOCD3) δ 98.97 (s, 2H), 8.32 (d, 1H), 7.74 (s, 1H), 7.36 (dd, 2H), 7.19 (dd, 2H), 4.86 (d, 1H), 4.58 (d, 1H), 4.42 (d, 1H), 4.34 (d, 1H), 3.9-2.90 (m, 8H.) 19F NMR: −74.202 MS: 421 (M+1), 419 (M−1)
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:20]N1C(=O)CCC1=O.[CH2:28](O)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH2:37]>C1COCC1>[Cl:20][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH2:37]
Reactant: C=CCCCCCCCCO
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCCCCCCCCCl
Reaction time: 0.08 h
Yield: 80 %

Procedure:
To a flame-dried round-bottomed flask was added PPh3 (1.1 equiv, 27.5 mmol, 7.21 g) and THF (65 mL). N-chlorosuccinimide (1.1 equiv, 27.5 mmol, 3.67 g) was dissolved in THF (50 mL) and added dropwise. The mixture was stirred for 5 min, and 9-decen-1-ol (1 equiv, 25 mmol, 3.91 g) was added dropwise in THF (30 mL). After 9 h, the volatile components of the reaction were evaporated and hexanes (100 mL) and H2O (50 mL) were added. The liquid was decanted and the resulting solid was washed with hexanes. The aqueous layer was collected and extracted with hexanes (2×50 mL). The combined organic layers were washed sequentially with bleach (30 mL) and brine (50 mL). The crude product was filtered through a pad of silica (which was washed with ˜400 mL of hexanes) and concentration in vacuo to afford 10-chlorodecene (3.48 g, 20 mmol, 80%), which was deemed pure by NMR and used without further purification. TLC Rf=0.87 (5% EtOAc/Hex); 1HNMR (400 MHz): δ 5.84 (ddt, 1H, J=17.4, 10.3, 6.7 Hz), 5.02 (ddd, 1H, J=17.4, 2.0, 3.6 Hz), 4.93-4.98 (m, 1H), 3.56 (t, 2H, J=6.5 Hz), 2.02-2.12 (m, 2H), 1.74-1.84 (2H), 1.27-1.50 (10H); 13CNMR (100 MHz): δ 139.2, 114.2, 45.2, 33.8, 32.7, 29.3, 29.0, 28.88, 28.85, 26.88.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13](=[O:18])[NH:14][CH:15]3[CH2:17][CH2:16]3)[CH:10]=[CH:9][C:8]=2[CH3:19])[N:5]=[CH:4][C:3]=1[C:20]([OH:22])=O.[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[NH2:30].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[NH:30][C:20]([C:3]1[CH:4]=[N:5][N:6]([C:7]2[CH:12]=[C:11]([C:13](=[O:18])[NH:14][CH:15]3[CH2:17][CH2:16]3)[CH:10]=[CH:9][C:8]=2[CH3:19])[C:2]=1[NH2:1])=[O:22]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)O)c1N
Reactant: CC1CCCCC1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)NC2CCCCC2C)c1N
Yield: 68.7 %

Procedure:
A solution of 5-amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-1H-pyrazole-4-carboxylic acid (21 mg), 2-methylcyclohexylamine (10 mg), EDCI (28 mg) and HOBt (12 mg) in DMF (0.75 ml) was reacted at room temperature for 24 h. Water (4 ml) was added and the solution was extracted with ethyl acetate (3 mL×2). The organic phase was then washed with water (3 mL), dried over Na2SO4 and evaporated. The residue was purified by preparative TLC plate to give the desired product 5-amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-1H-pyrazole-4-carboxylic acid (2-methylcyclohexyl)-amide (19 mg, 70%). HPLC (4 minute gradient) tR 2.34 min; MS m/z 396.31 [M+H].