Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:21]([CH2:29][CH3:30])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18](O)=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:64][C@:65]1([C:70]([NH:72][S:73]([CH:76]2[CH2:78][CH2:77]2)(=[O:75])=[O:74])=[O:71])[CH2:67][C@H:66]1[CH:68]=[CH2:69]>ClCCl>[CH:76]1([S:73]([NH:72][C:70]([C@@:65]2([NH:64][C:18]([C@@H:13]3[CH2:14][C@@H:15]([OH:17])[CH2:16][N:12]3[C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[C@H:21]([CH2:29][CH3:30])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])=[O:19])[CH2:67][C@H:66]2[CH:68]=[CH2:69])=[O:71])(=[O:75])=[O:74])[CH2:78][CH2:77]1
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Reactant: C=CCCC(C)C[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(C)C[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of (2S,4R)-1-((2S,3R)-2-(tert-butoxycarbonylamino)-3-ethyl-5-methylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.3 g, 3.05 mmole) in dichloromethane (50 mL) was added HATU (1.15 g, 3.05 mmole) followed by DIPEA (1.6 mL, 9.13 mmole) at room temperature. The reaction mass was stirred at the same temperature for 10 min. (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide (1.22 g, 3.05 mmole) was added to the reaction mass and the mixture was stirred at room temperature for 1 h. The reaction mass was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous Na2SO4; filtered; then concentrated under reduced pressure to get the crude compound. The crude compound was purified by silica gel chromatography (6% methanol in chloroform) to get 1.7 g (87%) of tert-butyl (2S,3R)-1-((2S,4R)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-hydroxypyrrolidin-1-yl)-3-ethyl-5-methyl-1-oxonon-8-en-2-ylcarbamate as a white solid. MS: MS m/z 639.55 (M++1).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:22][CH2:21][C:12]3[NH:13][C:14]4[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=4[C:11]=3[CH2:10]2)=[CH:5][CH:4]=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[CH2:33])=[CH:28][N:27]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:22][CH2:21][C:12]3[N:13]([CH2:33][CH2:32][C:29]4[CH:28]=[N:27][C:26]([CH3:25])=[CH:31][CH:30]=4)[C:14]4[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=4[C:11]=3[CH2:10]2)=[CH:7][CH:8]=1
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(c1ccc(C(F)(F)F)cc1)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(c2ccc(C(F)(F)F)cc2)C1

Procedure:
The title compound is prepared from a mixture of 2-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH2:14][CH2:15][O:16][CH3:17])[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)=[O:21].O>CC#N>[CH3:17][O:16][CH2:15][CH2:14][N:4]1[C:5](=[O:13])[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:2]([NH:29][C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:20](=[O:21])[CH3:19])=[CH:28][CH:27]=2)[C:3]1=[O:18]
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)C1=O
Reactant: CC(=O)Nc1ccc(N)cc1
Solvent: CC#N
Solvent: O
Product: COCCN1C(=O)C(Nc2ccc(NC(C)=O)cc2)=C(c2ccccc2)C1=O
Temperature: 140 °C
Yield: 45.6 %

Procedure:
3-Chloro-1-(2-methoxyethyl)-4-phenyl-1H-pyrrole-2,5-dione (0.26 mmol, 70 mg) and 4-aminoacetanilide (0.53 mmol, 79 mg) was dissolved in dry CH3CN (2 mL) and the reaction mixture was subjected twice to microwave heating single node 140° C. for 10 min. 0.3 mL Water was added and the reaction mixture was purified using HPLC (57% 0.1M ammonium acetate buffer: 43% CH3CN→100% CH3CN, 20 mL/min) to give 45 mg (45%) of the title compound. 1H NMR (400 MHz, CD3CN) δ 8.17 (bs, 1H), 7.78 (bs, 1H), 7.24-7.09 (m, 5H), 7.04-7.00 (m, 2H), 6.73-6.68 (m, 2H), 3.73 (t, J=5.7 Hz, 2H), 3.59 (t, J=5.7 Hz, 2H), 3.33 (s, 3H), 2.01 (s, 3H).
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][NH2:13])=[N:3]1.[F:14][C:15]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:16]=1[CH2:17][C:18]1[O:22][N:21]=[C:20]([C:23](O)=[O:24])[CH:19]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][NH:13][C:23]([C:20]2[CH:19]=[C:18]([CH2:17][C:16]3[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:15]=3[F:14])[O:22][N:21]=2)=[O:24])=[N:3]1
Reactant: NCCc1n[nH]c2ccccc12
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1n[nH]c2ccccc12)c1cc(Cc2cc(F)ccc2F)on1
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.1 %

Procedure:
A mixture of 2-(1H-indazol-3-yl)ethanamine hydrochloride (0.040 g; 0.202 mmol), 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.053 g; 0.223 mmol) N,N-diisopropylethylamine (0.87 mL; 0.506 mmol) and HATU (0.84 g; 0.223 mmol) in DMF (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with sodium hydrogen sulphate, sodium carbonate and brine. The organic layer was dried and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 1 to 10% methanol in dichloromethane) and by preparative HPLC method 4 to yield 0.007 g (9%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([C:13]1[CH:20]=[C:19]([CH3:21])[C:16]([C:17]#[N:18])=[C:15]([CH3:22])[CH:14]=1)=[O:12].[H-].[Na+].[CH3:25]I>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:13]1[CH:14]=[C:15]([CH3:22])[C:16]([C:17]#[N:18])=[C:19]([CH3:21])[CH:20]=1)=[O:12]
Reactant: CI
Reactant: COc1ccc(CC(=O)c2cc(C)c(C#N)c(C)c2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C(C)C(=O)c2cc(C)c(C#N)c(C)c2)c(Cl)c1

Procedure:
In analogy to Example 1, step 2, 4-[2-(2-chloro-4-methoxy-phenyl)-acetyl]-2,6-dimethyl-benzonitrile was reacted with sodium hydride and methyl iodide to give the title compound as an orange oil. MS (m/e)=328.3 [M+H+].
Reaction SMILES: N[C@@H](C(C)C)C(C1C=CC=CC=1)(C1C=CC=CC=1)O.B.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:36]3[CH:37]=[C:38]4[O:43][CH2:42][O:41][C:39]4=[CH:40][C:35]=3[CH2:34][C:33]([CH3:44])=[N:32][N:31]=2)=[CH:26][CH:25]=1)([O-:23])=[O:22]>C(Cl)Cl.C1COCC1.C(O)C>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([C:30]2[C:36]3[CH:37]=[C:38]4[O:43][CH2:42][O:41][C:39]4=[CH:40][C:35]=3[CH2:34][CH:33]([CH3:44])[NH:32][N:31]=2)=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: CC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C1)OCO3
Agent: B
Agent: CC(C)[C@H](N)C(O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClCCl
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1)OCO3
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A solution of (S)-(-)-2-amino-3-methyl-1,1-diphenylbutan-1-ol (4.75 g) in dry methylene chloride was cooled to -70° C. and treated with a solution of borane in THF (1.8M, 9.5 ml) over a 20 minute period under an atmosphere of dry nitrogen. The resulting solution was gradually warmed to 0° C. and allowed to stand overnight at 4° C. This mixture was treated with a solution of 1-(4-nitrophenyl)-4-methyl-7.8-methylenedioxy-5H-2,3-benzodiazepine (5.0 g) in dry methylene chloride (100 ml) at room temperature over a period of about 1 hour. The resulting solution was allowed to stand at room temperature for seven days. The reaction was quenched by the addition of 10% sodium carbonate (15 ml). The resulting phases were separated, and the organic layer washed with water (2×50 ml), dried ever sodium sulfate, and concentrated in vacuo to give a yellow crystalline solid. This solid was suspended in ethanol (50 ml), filtered, and dried to give 4.47 g of the title compound. Proton NMR spectroscopy using a shift reagent (Eu(hfc)3) shows the product as 90:10 mixture of enantiomers. This material was dissolved in hot ethyl acetate (24 ml) and allowed to stand at room temperature overnight. The crystalline precipitate was separated by filtration, washed with ethyl acetate (3×5 ml), and dried to give 2.87 g of the title compound. Proton NMR spectroscopy using a shift reagent (Eu(hfc)3) shows this material to have an enantiomeric purity of more than 98%. Melting point 171°-172.5° C.
Reaction SMILES: C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.[C:14]([NH:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1)(=[O:34])[CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]=[CH:25][CH2:26][CH:27]=[CH:28][CH2:29][CH:30]=[CH:31][CH2:32][CH3:33].CCN(CC)CC.[CH:51]([C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH:60]([CH3:62])[CH3:61])[C:55]=1[N:63]=[C:64]=[O:65])([CH3:53])[CH3:52]>C1COCC1>[C:14]([NH:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH:41][C:64]([NH:63][C:55]2[C:54]([CH:51]([CH3:52])[CH3:53])=[CH:59][CH:58]=[CH:57][C:56]=2[CH:60]([CH3:62])[CH3:61])=[O:65])=[CH:38][CH:37]=1)(=[O:34])[CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]=[CH:25][CH2:26][CH:27]=[CH:28][CH2:29][CH:30]=[CH:31][CH2:32][CH3:33]
Reactant: CCC=CCC=CCC=CCC=CCC=CCCCC(=O)Nc1ccc(CN)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC=CCC=CCC=CCC=CCC=CCCCC(=O)Nc1ccc(CNC(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 87.7 %

Procedure:
This compound was subjected to TLC analysis [silica gel plate, developing solvent:CHCl3 -MeOH-H2O (90:10:1)]. As a result, a single spot was obtained by the detection with iodine and a 0.2% ninhydrin reagent. The obtained 4-(N-5,8,11,14,17-eicosapentaenoylamino)benzylamine (813 mg, 2 mmol) and Et3N (204 mg, 2 mmol) were dissolved in anhydrous THF (10 ml), and 2,6-diisopropylphenyl isocyanate (406 mg, 2 mmol) was added. The mixture was reacted for about 2 hours under cooling in a nitrogen stream, and concentrated under reduced pressure. The obtained concentrate was dissolved in a small amount of CHCl3 and applied to an SiO2 (800 g) column activated with CHCl3 in advance, which was followed by elution with CHCl3 (600 ml) and CHCl3 -MeOH (98:2, 800 ml) in this order. The objective fractions were recovered from the obtained eluate fractions based on TLC analysis as an index, and concentrated to give the objective compound (1.07 g, yield 88%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][C:8]=1[CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH3:2].[H-].[Na+].[CH3:29]I>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:29])=[CH:9][C:8]=1[CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH3:2]
Reactant: CCOC(=O)COc1ccc(NC(=O)OC(C)(C)C)cc1CCCOC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(N(C)C(=O)OC(C)(C)C)cc1CCCOC
Reaction time: 1 h

Procedure:
To 2.21 g (6.01 mmol) of the above prepared [4-tert-butoxycarbonylamino-2-(3-methoxy-propyl)-phenoxy]-acetic acid ethyl ester, dissolved in 18 ml of abs. DMF, was added at 0° C. 0.313 g of NaH (60% in mineral oil, 1.3 eq.). 5 min later, 0.75 ml (2 eq.) of MeI was added and the reaction allowed to proceed for 10 min at 0° C. and for 1 h at ambient temperature. Pouring onto crashed ice/aqueous 10% KHSO4, twofold extraction with EtOAc, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/EtOAc=8/2), yielded 1.55 g of the title compound as light yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[S:5][C:6]3[C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=[C:9]([O:16][CH3:17])[C:7]=3[N:8]=2)[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:24][C:25]1[C:29]([NH2:30])=[C:28]([CH3:31])[O:27][N:26]=1>CN(C)C=O.ClCCl.C(N(CC)CC)C>[CH3:24][C:25]1[C:29]([NH:30][C:13]([C:12]2[C:6]3[S:5][C:4]([CH:1]4[CH2:2][CH2:3]4)=[N:8][C:7]=3[C:9]([O:16][CH3:17])=[CH:10][CH:11]=2)=[O:15])=[C:28]([CH3:31])[O:27][N:26]=1
Reactant: Cc1noc(C)c1N
Reactant: COc1ccc(C(=O)O)c2sc(C3CC3)nc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2c(C)noc2C)c2sc(C3CC3)nc12
Yield: 24.3 %

Procedure:
Starting from 2-cyclopropyl-4-methoxybenzothiazole-7-carboxylic acid (0.20 g), oxalyl chloride (0.11 ml), dichloromethane (30 ml) and dimethylformamide (1 drop), followed by 3,5-dimethylisoxazol-4-amine (0.20 g), triethylamine (0.22 ml) and dichloromethane (30 ml). Purification by flash chromatography (eluent 50% ethyl acetate/heptane) yielded the title compound as a white solid (0.067 g). TLC Rf 0.33 (ethyl acetate); Mpt 196-197° C.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1(O)[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11]>O1CCOCC1>[CH3:1][CH2:2][C@H:3]1[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[C:14](=[CH:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13]3)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Solvent: C1COCCO1
Product: CC[C@H]1C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Temperature: 90 °C

Procedure:
Camptothecin (500 mg, 1.44 mmol) was suspended in 1,4-dioxane (10 mL) and added Lawsson's reagent (290.5 mg, 0.72 mmol). The reaction mixture was then heated to 90° C. for 10 hours under an inert atmosphere. The resultant homogeneous reaction mixture was then concentrated, organic portion was taken up in chloroform (25 mL) and the aqueous fraction was repeatedly extracted with chloroform (25 mL×3). The combined organic portion was then concentrated to get the title compound in the crude form. The crude product was then flash chromatographed over a bed of florisil using 10% chloroform in methanol to furnish the desired product in 40% yield in diastereomeric mixture.
Reaction SMILES: CC([NH:5][S:6]([C:9]1[C:17]2[CH2:16][S:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)C>FC(F)(F)C(O)=O.CCCCCC.C(OCC)(=O)C>[CH2:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[C:17]=2[CH2:16][S:15]1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc2c1CSC2
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1cccc2c1CSC2
Yield: 58.8 %

Procedure:
A solution of 3.0 g of 1,3-dihydro-N-(1,1-dimethylethyl)benzo[c]thiophene-4-sulfonamide in 50 ml of trifluoroacetic acid was stirred at ambient temperature for 4 hours. The brown solution was concentrated in vacuo. 1-Chlorobutane was added to the resulting brown oil and the mixture concentrated in vacuo. Repeating this procedure gave an oil which on trituration with 1-chlorobutane gave a brown solid. Purification of the crude reaction product by chromatography, using hexane/ethyl acetate (3:2) as eluent gave 1.4 g of 1,3-dihydrobenzo[c]thiophene-4-sulfonamide as a pale yellow solid, m.p. 146°-148°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]([CH3:19])[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[C:20]([BH3-])#N.[Na+].C(O)=O.C=O>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]([CH3:19])[CH:13]1[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][CH2:14]1
Reactant: COc1ccc([N+](=O)[O-])cc1N(C)C1CCNCC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O=CO
Product: COc1ccc([N+](=O)[O-])cc1N(C)C1CCN(C)CC1
Temperature: 27.5 °C
Reaction time: 0.08 h

Procedure:
To a 250 mL three neck round bottom flask added 2-Methoxy-5-nitro-N-methyl-N-(piperidin-4-yl) phenylamine (1.93 grams, 7.33 mmol) obtained at step (III), followed by the addition of methanol (20 mL) and stirred at 25-30° C. for 5 minutes. Added sodium cyanoborohydride (0.548 grams, 8.80 mmol) and formic acid (1.08 mL, 22.01 mmol) and stirred the reaction mass for 10 minutes. The reaction mass was cooled to 0-5° C. in an ice bath and added formaldehyde (1.46 mL, 14.6 mmol, 30-50%) through syringe. Clear solution was obtained. The reaction mass was further stirred for 6 hours at 20-25° C. After completion of reaction (thin layer chromatography), solvent was distilled off under reduced pressure. To the residual oily mass, added water (100 mL) and basified to pH: 8 using saturated solution of sodium bicarbonate. The product was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine solution (100 mL) and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure to obtain 1.96 grams of dark yellow colored oily mass.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([O:12][CH3:13])[N:9]=[C:8]([CH2:14][NH:15][C:16]([NH:18]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=S)[CH:7]=1)=[O:5])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1>C1(C)C=CC=CC=1>[NH:18]=[C:16]1[N:9]2[C:10]([O:12][CH3:13])=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][C:8]2=[CH:14][NH:15]1
Reactant: CCOC(=O)c1cc(CNC(=S)NC(=O)OCC2c3ccccc3-c3ccccc32)nc(OC)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(OC)n2c(=N)[nH]cc2c1
Reaction time: 8 h
Yield: 15.7 %

Procedure:
1.17 g (2.38 mmol) of N-(4-ethoxycarbonyl-6-methoxypyridin-2-ylmethyl)-N′-(fluoren-9-ylmethyloxycarbonyl)thiourea (20e) were treated with 491 mg (2.38 mmol) of DCC in 25 ml of toluene and refluxed for six hours. After standing overnight at RT, the mixture was freed from the solvent and the residue was chromatographed on silica gel (heptane/ethyl acetate 75:25→ethyl acetate/methanol 90:10), it being possible to isolate 88 mg of the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C@@H:8]([C@@H:14]1[C@@:18]2([CH3:35])[C@@H:19]([OH:34])[CH2:20][C@@H:21]3[C@@:26]4([CH3:32])[CH2:27][CH2:28][C@@H:29]([OH:31])[CH2:30][C@H:25]4[CH2:24][C@@H:23]([OH:33])[C@H:22]3[C@@H:17]2[CH2:16][CH2:15]1)[CH2:9][CH2:10][C:11](O)=[O:12]>C1COCC1>[OH:31][C@@H:29]1[CH2:28][CH2:27][C@@:26]2([CH3:32])[CH:25]([CH2:24][C@@H:23]([OH:33])[C@@H:22]3[C@@H:21]2[CH2:20][C@H:19]([OH:34])[C@@:18]2([CH3:35])[C@H:17]3[CH2:16][CH2:15][C@@H:14]2[C@H:8]([CH3:7])[CH2:9][CH2:10][CH2:11][OH:12])[CH2:30]1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CCCO)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Yield: 87.6 %

Procedure:
To a suspension of LiAlH4 (3.85 g, 100 mmol) in dry THF (100 mL) at 0° C. was added dropwise a solution of cholic acid (15.03 g, 35 mmol) in dry THF (200 mL) with vigorous stirring under nitrogen atmosphere. The reaction mixture was then heated to reflux with stirring for overnight. Upon completion, the reaction was carefully quenched with saturated aqueous NH4Cl solution at RT. Then the mixture was acidified with IN HCl to pH 1˜2. The precipitate was collected via filtration and washed with water and acetone to give the product (12.1 g, 88%) as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=1[C:12](=[O:23])[NH:13][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:15]=O.P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=1[C:12]1[O:23][CH:15]=[C:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:13]=1
Reactant: COC(=O)c1cc(C(=O)NC(C=O)c2ccccc2)c(SC)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(-c2nc(-c3ccccc3)co2)c(SC)s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 25.9 %

Procedure:
To a cooled (0° C.) solution of 465 mg (1.33 mmol) methyl 5-methylthio-4-[N-(2-oxo-1-phenylethyl)carbamoyl]thiophene-2-carboxylate (as prepared in the previous step) in 6 mL of anhyd DMF was added 186 μL (2.00 mmol) of phosphorus oxychloride. After stirring for 14 h at room temperature, the mixture was treated with 10 mL of saturated NaHCO3 and concentrated to dryness under high vacuum. The resulting residue was partitioned between 80 mL of EtOAc and 60 mL of water. The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic phases washed with brine (60 mL), and dried over Na2SO4. The resulting 406 mg of amber-colored solid was recrystallized from CH2Cl2—Et2O to remove the majority of a polar impurity as a cream-colored solid. The remaining mother liquors were chromatographed on a 10 g silica SPE column (Waters Sep-Pak) with a gradient of 40-100% CH2Cl2-hexane and the resulting residue triturated with Et2O-hexane (2:1)) to afford the title compound as a light beige solid (114 mg, 26%). 1H-NMR (300 MHz, CDCl3) δ8.24 (s, 1H), 7.93 (s, 1H), 7.83 (m, 2H), 7.43 (m, 2H), 7.33 (m, 1H), 3.91 (s, 3H), and 2.72 (s, 3H). Mass spectrum (ESI) calcd. for C16H13NO3S2: 332.0 (M+H). Found: 332.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.CC(C)([O-])C.[K+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[CH3:26].Cl>CS(C)=O.O>[CH3:1][O:2][C:3]1[C:4](=[O:9])[N:5]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[CH3:26])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: COc1ccc[nH]c1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cccn(-c2ccc([N+](=O)[O-])cc2C)c1=O
Temperature: 80 °C

Procedure:
28.5 g (228 mol) of 3-methoxypyridin-2(1H)-one are dissolved in 850 ml of dimethyl sulfoxide and admixed at RT with 31 g (273 mmol) of potassium tert-butoxide. The suspension is stirred at RT for 30 min, before 35 g (228 mmol) of 1-fluoro-2-methyl-4-nitrobenzene are added, and the reaction solution is heated to 80° C. for 20 h. The mixture is then cautiously diluted with 1 l of water and brought to pH 1-2 with 1N hydrochloric acid. The solution is extracted repeatedly with dichloromethane. The combined organic extracts are washed with water and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid is washed with a little tert-butyl methyl ether, filtered off and dried under reduced pressure. This affords 42.8 g (72% of theory) of the desired compound.