Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:38])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([S:12][C@@H:13]1[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:31])[O:15][CH2:14]1)[CH3:11].[H-].[Na+].[CH2:41]([O:44][P:45]([O:51][CH2:52][C:53]1[C:54]([C:58](Cl)=[O:59])=[CH:55][O:56][CH:57]=1)([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])[CH:42]=[CH2:43]>>[CH2:48]([O:47][P:45]([O:51][CH2:52][C:53]1[C:54]([C:58]([O:38][C@:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([CH2:32][N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[C@H:10]([S:12][C@@H:13]2[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=3[F:31])[O:15][CH2:14]2)[CH3:11])=[O:59])=[CH:55][O:56][CH:57]=1)([O:44][CH2:41][CH:42]=[CH2:43])=[O:46])[CH:49]=[CH2:50]
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: C=CCOP(=O)(OCC=C)OCc1cocc1C(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: C=CCOP(=O)(OCC=C)OCc1cocc1C(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1
Yield: 70 %

Procedure:
According to a similar procedure to that described in Example 13-(2), 4-[(1E,3E)-4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-1,3-butadienyl]-3-fluorobenzonitrile (690.5 mg, 1.27 mmol) described in Reference example 1, sodium hydride (55% dispersion in mineral oil; 66.5 mg, 1.52 mmol), and crude 4-[[bis(allyloxy)phosphoryl]oxymethyl]-3-furoyl chloride were reacted, and the reaction mixture was worked up to afford, after extraction, the title compound as a crude oil. The crude product was subjected to chromatography on a silica gel (30 g) column (eluent; ethyl acetate:hexane=2:1˜9:1) to afford the title compound (740.8 mg, 70% yield) as a colorless amorphous solid.
Reaction SMILES: N[C:2]1[CH2:3][O:4][C:5]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:6]=2[S:7][C:8]=1[C:9]#[N:10].Cl.[Cl-].[NH4+].C([OH:22])C>>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:5]2[O:4][CH2:3][C:2](=[O:22])[CH:8]([C:9]#[N:10])[S:7][C:6]=2[CH:11]=1
Reactant: CCO
Reactant: COc1ccc2c(c1)SC(C#N)=C(N)CO2
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc2c(c1)SC(C#N)C(=O)CO2
Reaction time: 0.5 h

Procedure:
In 60 ml of ethanol is suspended 6.0 g of 3-amino-7-methoxy-2H-1,5-benzoxathiepin-4-carbonitrile, and 18 ml of concentrated hydrochloric acid is added to the suspension, followed by stirring at 80° C. to 90° C. for 30 minutes. After the reaction mixture is cooled, ammonium chloride, which separates out, is filtered off, and the filtrate is concentrated under reduced pressure. The residue is recrystallized from ethyl acetate-hexane to give colorless prisms of 7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carbonitrile. Yield of 5.1 g, m.p. of 132°-133° C.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:16]2[C@H:17]3[C@H:26]([CH2:27][CH2:28][C@:13]2([CH2:14][CH3:15])[C:12](=[O:30])[CH2:11]1)[C@@H:25]1[C:20](=[CH:21][C:22](=[O:29])[CH2:23][CH2:24]1)[CH2:19][CH2:18]3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31]OC(OC)(C)C>>[C:1]([O:9][C@@H:10]1[C@H:16]2[C@H:17]3[C@H:26]([CH2:27][CH2:28][C@:13]2([CH2:14][CH3:15])[C:12](=[O:30])[CH2:11]1)[C@@H:25]1[C:20]([CH:21]=[C:22]([O:29][CH3:31])[CH2:23][CH2:24]1)=[CH:19][CH2:18]3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(C)(C)OC
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(=O)c1ccccc1)CC2=O
Product: CC[C@]12CC[C@H]3[C@@H](CC=C4C=C(OC)CC[C@@H]43)[C@@H]1[C@@H](OC(=O)c1ccccc1)CC2=O

Procedure:
Analogously to Direction II(b), 7.8 g of 15α-benzoyloxy-18-methyl-4-estrene-3,17-dione is reacted with dimethoxypropane and worked up, thus obtaining 6.8 g of 15α-benzoyloxy-3-methoxy-18-methyl-3,5-estradien-17-one as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[NH2:31][C@H:32]1[CH2:37][CH2:36][CH2:35][C@@H:34]([NH:38][C:39](=[O:42])[O:40][CH3:41])[CH2:33]1.[OH-].[Li+]>C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:31][C@H:32]4[CH2:37][CH2:36][CH2:35][C@@H:34]([NH:38][C:39](=[O:42])[O:40][CH3:41])[CH2:33]4)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Reactant: COC(=O)N[C@@H]1CCC[C@H](N)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)N[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 130 °C

Procedure:
5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridine, 19b, (2.04 g, 4.39 mmol) and methyl N-[(1R,3S)-3-aminocyclohexyl]carbamate (0.60 g, 3.14 mmol) were suspended in THF (16 mL) and heated in the microwave to 130° C. for 20 minutes. Lithium hydroxide (15.67 mL of 1M solution, 15.67 mmol) was added, and the resulting mixture was heated in the microwave for 20 min at 130° C. The resulting solution was diluted with water (150 mL) and ethyl acetate (200 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (100 mL) and t organic layers were combined, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography (40-100% EtOAc/hexanes) followed by treatment of the pure fractions with 4N HCl in dioxane to provide the hydrochloride of compound, 570, as an off white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=1.[CH2:26]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH3:27]>O1CCOCC1>[CH2:26]([C:28]1[N:29]([CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=3[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=2)[CH:30]=[CH:31][N:32]=1)[CH3:27]
Reactant: CC(C)Cc1cc(-c2cccc(CBr)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: CCc1ncc[nH]1
Solvent: C1COCCO1
Product: CCc1nccn1Cc1cccc(-c2cc(CC(C)C)sc2S(=O)(=O)NC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 3-(3-bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (70 mg, 0.158 mmol; see Example 1(e)) in dioxane (2.0 mL) was added 2-ethylimidazole (45.4 mg, 0.473 mmol) and the reaction mixture was stirred for 1 h at 80° C. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography using MeOH:CH2Cl2 (6:94) as eluent to give the sub-title compound in 85% yield as a colourless syrup (61.2 mg, 0.134 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].S(=O)(=O)(O)O>CC(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH2:11][C:12](=[O:13])[CH2:17][CH2:18]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(C2CCC3(CC2)OCCO3)cc1Cl
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C1CCC(c2ccc(F)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 8-(3-chloro-4-fluorophenyl)-1,4-dioxaspiro[4.5]decane (401.7 mg, 1.484 mmol) in acetone (6 ml) was added 1M sulfuric acid (24 ml, 24 mmol). The reaction was stirred vigorously at room temperature for 18 hours, and then diluted with EtOAc (100 mL) and washed with water (3×50 mL), saturated NaHCO3 (2×50 mL), and brine (2×50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to afford 4-(3-chloro-4-fluorophenyl)cyclohexanone. 1H NMR (500 MHz, CDCl3): δ 7.06-7.28 (m, 3H), 3.00 (m, 1H), 2.49-2.52 (m, 4H), 2.19-2.23 (m, 2H), 1.85-1.93 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:12][S-:13].[Na+]>CN(C=O)C>[CH3:12][S:13][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([NH2:5])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cccc(N)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
20 g of 3-chloro-2-nitroaniline are dissolved in 230 ml of dry DMF. The mixture was cooled to 0° C. and sodium methanethiolate (10 g) was added portionwise. The mixture was stirred for 2 h at 20° C. The solvent was evaporated in vacuo and the residue taken up in water and EA (200 ml each). The aqueous layer was extracted with EA, and the combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography (300 g silica gel; cyclohexane/EA, gradient from 100:0 to 50:50). 8.3 g of the title compound were obtained as a red solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)=[CH:24][CH:23]=2)(=[O:20])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid was prepared starting from 1-benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester (2.11 g, 4.1 mmol) dissolved in TB:methanol (3:1 150 ml) and 10 N NaOH (20 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.11 g (56%); white solid; mp 201° C.; MS: 485.9 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[CH3:19])[NH2:15]>>[NH2:15][C:14]1[CH:13]=[C:12]([O:11][CH3:10])[C:18]([CH3:19])=[CH:17][C:16]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: COc1cc(N)ccc1C
Reactant: O=Cc1ccccc1Cl
Product: COc1cc(N)c(C(=O)c2ccccc2Cl)cc1C

Procedure:
(2-amino-4-methoxy-5-methylphenyl)-(2-chlorophenyl)-methanone (Xz) was prepared by reacting 2-chlorobenzaldehyde with 0.0226 moles of 3-methoxy-4-methyl aniline in a manner analogous to Example 1. MH+/Z=276.
Reaction SMILES: [CH2:1]([N:8](C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C@H:9]([C:22]([OH:24])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCCC1.CN(C=O)C>>[CH2:1]([NH:8][C@H:9]([C:22]([OH:24])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](C(=O)O)N(Cc1ccccc1)C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NCc1ccccc1)C(=O)O
Reaction time: 0.33 h

Procedure:
Fmoc protected amino acid 48 (1.0 g, 1.79 mmol) was treated with a solution of piperidine/DMF (9 mL, 5% v/v) and stirred for 20 min then concentrated to dryness and used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([C:18](OCC)=[O:19])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH2:18][OH:19])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc2c(-c3ccc(C)cc3)nccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2nccc3c(CO)cccc23)cc1
Yield: 60.4 %

Procedure:
1-(4-Methylphenyl)-5-ethoxycarbonylisoquinoline (14.5 g) was dissolved in 200 ml of anhydrous tetrahydrofuran, and with stirring under cooling, lithium aluminum hydride (suspended in 100 ml of tetrahydrofuran) was added dropwise. The mixture was stirred at room temperature for 1 hour. Water and a 20% aqueous solution of sodium hydroxide were added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was filtered through Celite. The filtrate was concentrated, and the residue was recrystallized from benzene to afford 7.5 g of 1-(4-methylphenyl)-5-hydroxymethylisoquinoline as colorless needles.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]3[CH:18]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.C(OCC)(=O)C.[Ni]>[N:11]1[C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:18][N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=12
Reactant: O=[N+]([O-])c1ccc(-c2cn3ccccc3n2)cc1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(-c2cn3ccccc3n2)cc1

Procedure:
4.50 g (18.8 mmol) 2-(4-Nitro-phenyl)-imidazo[1,2-a]pyridine and 0.45 g Raney-Nickel are stirred at RT under hydrogen (50 psi) in 50 mL ethanol and 50 mL ethyl acetate. The mixture is filtered and the solvent is evaporated.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:29]([CH2:31][NH2:32])[OH:30].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(C(C)C)C(C)C>>[OH:30][CH2:29][CH2:31][NH:32][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:27])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: NCCO
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCO)ccc21
Yield: 24.4 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethyl)-amide (27 mg) was prepared by following General Procedure N starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), ethanolamine (15 mg), DPPA (53 uL), and DIEA (43 uL). LC/MS: m/z 452.9. 1H NMR (DMSO-d6, 400 MHz): δ 8.37 (s, 1H), 8.07 (s, 1H), 7.91 (s, 1H), 7.81-7.56 (m, 2H), 7.46 (d, 1H), 7.34 (d, 1H), 4.72 (s, 1H), 3.64 (s, 3H), 3.58-3.48 (m, 2H), 3.40-3.32 (m, 2H), —NH proton signal was not observed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.CO.[BH4-].[Na+]>C1COCC1.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCN(S(C)(=O)=O)CC2)ccc1[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(N2CCN(S(C)(=O)=O)CC2)ccc1N

Procedure:
1-[3-(Methyloxy)-4-nitrophenyl]-4-(methylsulfonyl)piperazine (1.09 g, 3.46 mmol) was suspended in 5 mL THF and 10 mL MeOH in a 100 mL round bottom flask. Nickle(II)chloride hexahydrate (0.247 g, 1.04 mmol) was added followed by slow addition of NaBH4 (0.392 g, 10.38 mmol). TLC analysis indicated reaction complete after addition of NaBH4. Reaction mixture was adsorbed on SiO2 and purified via column chromatography using a gradient of 0-10% MeOH in DCM. Fractions were combined and rotovapped to give the title compound of step B. (0.925 g, 3.24 mmol, 93%); MS (ESI): 285 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[CH:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:14][C:13]=2[CH:12]=[CH:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>[Cu].C(Cl)(Cl)Cl>[Br:8][C:4]1[CH:3]=[C:2]([N:14]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:21]3[CH:9]=[N:10][CH:11]=[CH:12][C:13]2=3)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: c1ccc2c(c1)[nH]c1ccncc12
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: Brc1cccc(-n2c3ccccc3c3cnccc32)c1
Temperature: 180 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
Another reaction vessel was charged with 17.2 ml of 1,3-dibromobenzene, 6.0 g of 5H-pyrido[4,3-b]indole, 1.1 g of copper powder, 9.9 g of potassium carbonate, and 0.6 ml of dimethyl sulfoxide, followed by heating and stirring at 180° C. for 4 hours. After cooling to room temperature, 50 ml of chloroform was added thereto, the insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (carrier: silica gel, eluent: hexane/chloroform) to obtain 7.1 g (yield 62%) of 5-(3-bromophenyl)-5H-pyrido[4,3-b]indole as a white powder.
Reaction SMILES: COC[C@H](O)C.[Cl:7][C:8]1[N:13]=[C:12]([O:14][C@@H:15]([CH3:19])[CH2:16][O:17][CH3:18])[C:11]([Cl:20])=[CH:10][N:9]=1>>[Cl:7][C:8]1[N:13]=[C:12]([O:14][C@H:15]([CH3:19])[CH2:16][O:17][CH3:18])[C:11]([Cl:20])=[CH:10][N:9]=1
Reactant: COC[C@H](C)Oc1nc(Cl)ncc1Cl
Agent: COC[C@@H](C)O
Product: COC[C@@H](C)Oc1nc(Cl)ncc1Cl

Procedure:
From (R)-1-methoxypropan-2-ol, reacted in an analogous manner to the preparation of intermediate 91. (UPLC-MS 7) tR 1.02; ESI-MS 237.1 and 239.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[CH:18]=[CH:17][C:11]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:8]1[CH:18]=[CH:17][C:11]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20]
Reactant: CN(C)CCN
Reactant: CN(C)C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: CN(C)CCNc1ccc(C(=O)N(C)C)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 16.5 h

Procedure:
N,N-Dimethylethylenediamine (2.10 ml) was added to 4-chloro-N,N-dimethyl-3-nitrobenzamide (2.140 g) and the mixture was stirred for 16.5 hours at 100° C. The reaction mixture, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated, thereby yielding the entitled compound (2.638 g) as orange solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:10][C:11]2[O:12][C:13]3[C:19]([NH2:20])=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH:31]=O.C([BH3-])#N.[Na+]>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:10][C:11]2[O:12][C:13]3[C:19]([NH:20][CH2:31][C:27]4[NH:26][CH:30]=[CH:29][N:28]=4)=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ncc[nH]1
Reactant: COc1ccc(Cc2nc3cccc(N)c3o2)cc1OC1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1ccc(Cc2nc3cccc(NCc4ncc[nH]4)c3o2)cc1OC1CCCC1
Yield: 31.4 %

Procedure:
By employing a procedure similar to that in Example 33 and using 2-(3-cyclopentyloxy-4-methoxybenzyl)-7-aminobenzoxazole (1.3 g, 0.0038 mol), imidazole-2-carboxaldehyde (0.54 g, 0.0056 mol) and sodium cyanoborohydride (0.38 g, 0.0060 mol), a yellow oil was obtained after workup. The oil was triturated with a 50:50 blend of hexane in ether and the solid product (0.5 g) which was obtained, was separated by filtration. This solid could be recrystallized from ethanol (1 g/14 ml) to give the title compound as white crystals, mp 179-180° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>CO>[NH:11]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][N:3]=1)[NH2:12]
Reactant: CCc1cnc(Cl)nc1
Reactant: NN
Solvent: O
Solvent: CO
Product: CCc1cnc(NN)nc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To a solution of 2-chloro-5-ethylpyrimidine (0.31 g, 2.2 mmol) in MeOH (5 mL) was added hydrazine monohydrate (1.0 mL, 20.6 mmol). After stirring for 16 h at 50° C., the solution was cooled to room temperature and purified by reverse phase HPLC to give 0.24 g (80%) of the title compound as a white solid. MH+139.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)=[CH:8]2)=[O:4].[OH-].[Na+].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH2:49]([O:51][C:52](=[O:57])[CH2:53][CH2:54][CH2:55][NH2:56])[CH3:50].CCN(C(C)C)C(C)C>CCOC(C)=O.C(Cl)Cl.C1COCC1.CO>[CH2:49]([O:51][C:52](=[O:57])[CH2:53][CH2:54][CH2:55][NH:56][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)=[CH:8]2)=[O:4])[CH3:50]
Reactant: COC(=O)c1ncc2c(cc(-c3cccc(OC)c3)c(=O)n2Cc2ccccc2)c1O
Reactant: CCOC(=O)CCCN
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)CCCNC(=O)c1ncc2c(cc(-c3cccc(OC)c3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (60 mg, 0.14 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. overnight, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. To the residue were then added HOBt (32 mg, 0.23 mmol), CH2Cl2 (3 mL), and EDC (50 mg, 0.26 mmol), and the resulting mixture was stirred for 10 min. 4-Amino-butyric acid ethyl ester HCl salt (39 mg, 0.23 mmol) and Hunig's base (0.1 mL, 0.52 mmol) were added, and the mixture was stirred for 48 h. The mixture was diluted with EtOAc and washed with 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-50% EtOAc/hexanes+1% AcOH) to give 38 mg of the title compound. MS: (+) m/z 516.37 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19])[C:6]([O:8]C)=[O:7].[OH-].[Li+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(N2CCCCC2=O)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1N1CCCCC1=O

Procedure:
Prepared analogously to Example 39d from methyl 3-methoxy-4-(piperidin-2-on-1-yl)-benzoate and lithium hydroxide in ethanol.
Reaction SMILES: C[C@@H]([C@@H]1[C@@]2(C)[C@@H](O)C[C@@H]3[C@@]4(C)CC[C@@H](O)C[C@H]4C[C@@H](O)[C@H]3[C@@H]2CC1)CCC(O)=[O:6].[CH2:30]1[CH2:35][CH2:34][CH:33]([N:36]=[C:37]=[N:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:32][CH2:31]1.ON1C(=O)CCC1=O>CN(C=O)C>[C:37]([NH:36][CH:33]1[CH2:32][CH2:31][CH2:30][CH2:35][CH2:34]1)([NH:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:6]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
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: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C

Procedure:
To cholic acid (2 gm, 4.9 mmol) in anhydrous DMF (20 mL), under argon at room temperature, are added DCC (1 gm, 4.9 mmol) and N-hydroxysuccinimide (0.56 gm, 4.9 mmol). The reaction mixture is stirred at room temperature. Dicyclohexylurea starts forming after about 45 min. After 3.5 hours, the dicyclohexylurea is filtered, and the reaction mixture is concentrated under vacuum (using a vacuum pump) overnight to remove DMF. The residue is triturated with Et2O, and the precipitate is filtered. The precipitate is taken up in CH3CN, and the precipitate (left over dicyclohexylurea) is again filtered. Quantitative yield of product is obtained (2.5 gm). TLC (5% MeOH/EtOAc) Rf 0.26. 1HNMR (MeOH-d4): δ(ppm)=0.65 (s, 3H, 10axial CH3); 0.84 (s, 3H, 13axial CH3); 0.97 (d, 3H, CH3 on side chain); 2.78 (s, 4H, NHS protons).