Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]([CH3:11])[CH2:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[Na+].[I-:27]>C(Cl)Cl.CC(C)=O>[I:27][CH2:9][CH2:8][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11]
Reactant: C[C@H](CCO)c1ccccc1
Reactant: [I-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: C[C@H](CCI)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A solution of 900 mg (6.0 mmol) of 3-(R)-phenylbutan-1-ol (from EXAMPLE 104, Step A) and 3.0 mL (18.0 mmol) of DIEA in 10 mL of CH2Cl2 was treated with 0.7 mL (9.0 mmol) of methanesulfonyl chloride and the resulting mixture was stirred at rt for 1 h. The reaction was quenched with H2O and 50 mL of 1.0 N HCl. The quenched mixture was extracted 3× with CH2Cl2. The organic extracts were washed with sat'd NaCl, dried over Na2SO4, filtered and the filtrate concentrated. A mixture of the residue and 9.0 g (60.0 mmol) of NaI in 10 mL of acetone was heated at reflux for 2 h. The reaction mixture cooled and concentrated. The residue was diluted with H2O and extracted 3× with CH2Cl2. The extracts were washed with sat'd NaCl, dried over Na2SO4, filtered and the filtrate concentrated. The residue was purified by flash chomatography on 50 g of silica eluting with 0-20% EtOAc/hexanes (v/v) to give 1.4 g (90%) of the title compound: 1H NMR (500 MHz) δ 1.31 (d, J=6.9, 31), 2.10-2.14 (2H), 2.87-2.92 (m, 1H), 2.96-3.01 (m, 1H). 3.11-3.15 (m, 1H), 7.22-7.35 (5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([N-]C(C)C)(C)C.[Li+].C(=O)=O.COC1C2OC3C(=CC=CC=3)C(C(O)=O)C=2C=CC=1.C(Cl)(=O)[C:48]([Cl:50])=[O:49]>O1CCCC1.C1(C)C=CC=CC=1.CN(C=O)C>[CH3:1][O:2][C:3]1[C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]([C:48]([Cl:50])=[O:49])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1Oc1ccccc1C2
Reactant: O=C(Cl)C(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: COc1cccc2c1Oc1ccccc1C2C(=O)O
Agent: O=C=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cccc2c1Oc1ccccc1C2C(=O)Cl

Procedure:
(RS)-4-Methoxy-9H-xanthene-9-carbonyl chloride was prepared according to general methods described in WO 9706178. 4-Methoxy-xanthene [J.Med.Chem., 32(10), 2357(1989)] was deprotonated with lithium diisopropylamide in tetrahydrofuran followed by treatment with carbon dioxide. The resulting (RS)-4-methoxy-9H-xanthene-9-carboxylic acid (white solid and MS: m/e=256.0 (M+)) was chlorinated with oxalyl chloride in toluene/DMF and yielded after evaporation of the reagent and solvents, the crude acid chloride, which was directly used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:30])[C:16]([NH:18][C@H:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([OH:29])=[CH:24][CH:25]=3)[CH2:20]2)=O)=[CH:11][C:10]=1[CH2:31][CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(CCO)(CCO)CCO.O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:30])[CH2:16][NH:18][C@H:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([OH:29])=[CH:24][CH:25]=3)[CH2:20]2)=[CH:11][C:10]=1[CH2:31][CH2:32][O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CCc2ccc(O)cc2C1)[C@H](O)c1ccc(OCc2ccccc2)c(CCOCc2ccccc2)c1
Solvent: O
Solvent: OCCN(CCO)CCO
Solvent: C1CCOC1
Product: Oc1ccc2c(c1)C[C@@H](NC[C@H](O)c1ccc(OCc3ccccc3)c(CCOCc3ccccc3)c1)CC2
Yield: 65.3 %

Procedure:
(-)-(2R)-2-[4-Benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-hydroxy-N-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (low polarity isomer) (1.08 g) was dissolved in 20 ml of tetrahydrofuran, 438 μl of borane-dimethylsulfide complex was added to the solution, and the mixture was heated under reflux for 3 hours. Then, a solution of 1.14 g of triethanolamine in 1 ml of tetrahydrofuran was added and the mixture was again heated under reflux for 6 hours. After cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was evaporated under reduced pressure and the resulting residue was recrystallized from ethyl acetate to give 687 mg of (-)-(1R)-1-[4-benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylamino)ethanol having a melting point of 147 to 150° C.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([NH:13][NH2:14])=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[CH:20](OC)(OC)OC>>[C:1]1([S:7]([CH2:10][C:11]2[O:12][CH:20]=[N:14][N:13]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(OC)OC
Reactant: NNC(=O)CS(=O)(=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cc1nnco1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To 1.73 g (8.07 mmol) of benzenesulfonyl-acetic acid hydrazide were added 20 mL of trimethyl orthoformate and 1.26 g (8.07 mmol, 1 eq) of phosphorous oxychloride. The reaction mixture was stirred one hour at RT, and concentrated under reduced pressure. Column chromatography on silica gel with EtOAc/hexane 2:1 yielded 930 mg (52%) of 2-benzenesulfonylmethyl-[1,3,4]oxadiazole as a white solid, MS: 225 (MH+).
Reaction SMILES: C1(C2SC(C(N)C)=CC=2)C=CC=CC=1.Cl.O1CCOCC1.[C:22]1([C:28]2[S:32][C:31]([CH:33]([NH:35][S:36]([CH2:38][CH:39]([CH3:41])[CH3:40])=[O:37])C)=[CH:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[C:22]1([C:28]2[S:32][C:31]([CH:33]=[N:35][S:36]([CH2:38][CH:39]([CH3:41])[CH3:40])=[O:37])=[CH:30][CH:29]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)CS(=O)NC(C)c1ccc(-c2ccccc2)s1
Agent: CC(N)c1ccc(-c2ccccc2)s1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)CS(=O)N=Cc1ccc(-c2ccccc2)s1
Reaction time: 2 h
Yield: 53.5 %

Procedure:
1-(5-Phenyl-thiophen-2-yl)ethylamine (Isomer 2, Preparation 171) Add 4N hydrogen chloride in dioxane (1.112 mL, 4.449 mmol) to a stirred solution of N-[1-(5-phenylthiophen-2-yl)ethyl]-2-methylpropanesulfinamide (Isomer 2) (684 mg, 2.225 mmol) in methanol (10 mL) at room temperature. Stir for 2 h and remove the solvent in vacuo to obtain a solid that was washed with ethyl ether. Dissolve the solid in DCM and wash with saturated aqueous NaHCO3. Dry the organic phase over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate (347 mg, 77% yield).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:21]1[S:25][CH2:24][CH2:23][S:22]1.[CH:26](OCC)([O:30][CH2:31][CH3:32])OCC.[C:36]1(C)C=CC(S(O)(=O)=O)=CC=1>>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:21]1[S:22][CH2:23][CH2:24][S:25]1.[CH2:26]([O:30][CH:31]=[CH2:32])[CH3:36]
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1SCCS1
Product: C=COCC

Procedure:
To 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(1,3-dithiolan-2-yl)-1H-pyrazole-3-carbonitrile (0.30 g, 0.71 mmol) in triethyl orthoformate (4.45 g, 29.70 mmol) was added p-toluenesulfonic acid (18 mg). The resulting mixture was heated up to 100 C for 1.5 hr. It was then cooled and then concentrated. The resulting viscous liquid was diluted with dichloromethane (20 mL). The organic layer was washed with saturated sodium bicarbonate, brine, and then dried over sodium sulfate to provide, upon concentration, a yellow oil (0.35 g, 0.72 mmol); 19F-NMR: −63.698.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:20][N:21](C(OC(C)(C)C)=O)[CH3:22])[CH2:10][N:11](C(OC(C)(C)C)=O)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C.N.CO>C(Cl)Cl>[CH2:1]([O:8][CH:9]([CH2:20][NH:21][CH3:22])[CH2:10][NH:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CC(CN(C)C(=O)OC(C)(C)C)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CNCC(CNC)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
To a solution of 2-benzyloxy-N,N′-bis(t-butoxycarbonyl)-N,N′-dimethyl-1,3-propanediamine (73.0 mg, 0.17 mmol) in methylene chloride (2.0 mL) was added a 4.0 M solution of hydrogen chloride in ethyl acetate (1.0 mL, 4.0 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, ethanol (5.0 mL) was added to the residue, and the resulting mixture was concentrated under reduced pressure. An approx. 10% solution of ammonia in methanol (2.0 mL, approx. 12 mmol) was added to the residue, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield the title compound as a colorless oil (35.0 mg, yield: 98%).
Reaction SMILES: [CH:1]([C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=O.Cl.[C:38]([CH2:43][NH:44][NH2:45])([O:40][CH2:41][CH3:42])=[O:39]>O1CCCC1.O>[S:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[CH2:29][C:28]([NH:27][CH:26]1[C:25](=[O:36])[N:7]2[C:8]([C:9]([O:11][CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:10])=[C:3]([CH:1]=[N:45][NH:44][CH2:43][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:4][S:5][C@H:6]12)=[O:35]
Reactant: CCOC(=O)CNN
Reactant: O=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CNN=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 48 h
Yield: 69.8 %

Procedure:
To a solution of diphenylmethyl 3-formyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate (155 mg) in tetrahydrofuran (15 ml) is added a solution of carbethoxymethylhydrazine hydrochloride (69 mg) in water (2.5 ml), and the mixture is kept at room temperature for 2 days. The crystals obtained by concentration of the reaction mixture are collected by filtration, washed with ether and water, and dried to give diphenylmethyl 7-(2-thienylacetamido)-3-(2-carbethoxymethylhydrazono)methyl-3-cephem-4-carboxylate (129 mg). m.p. 70°-75° C. Yield: 69%. IR: νmaxNujol 3270, 1780, 1745, 1670; 1540cm-1. NMR: δd 6-DMSO (60MHz) 1.435 (6Hz) 3H, 3.52ABq (24; 17Hz) 2H, 3.48s2H, 3.60s2H, 4.17 quintet (6Hz) 2H, 4.95d(5Hz)1H, 5.70dd(8;4Hz)1H, 6.67-7.63m16H, 8.03s1H. [ α]D24.5 - 144° (c=0.340, CHCl3).
Reaction SMILES: C(O)(=O)C.[CH3:5][C@H:6]1[CH2:11][NH:10][C@H:9]([CH3:12])[CH2:8][N:7]1[C@@H:13]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1)[C:14]1[CH:26]=[CH:25][C:17]([C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1.[C:34]([C:37]1[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=1)([OH:36])=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH2:21]([N:20]([CH2:23][CH3:24])[C:18]([C:17]1[CH:25]=[CH:26][C:14]([C@H:13]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[N:7]2[C@@H:6]([CH3:5])[CH2:11][N:10]([CH2:41][C:40]3[CH:43]=[CH:44][C:37]([C:34]([OH:36])=[O:35])=[CH:38][CH:39]=3)[C@H:9]([CH3:12])[CH2:8]2)=[CH:15][CH:16]=1)=[O:19])[CH3:22]
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)NC[C@@H]2C)cc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)N(Cc3ccc(C(=O)O)cc3)C[C@@H]2C)cc1
Yield: 88.4 %

Procedure:
Glacial acetic acid (0.635 mL, 11.1 mmol) was added to a solution of 4-[(R)-((2S,5R)-2,5-dimethyl-1-piperazinyl)-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide (1.98 g, 5 mmol) and 4-carboxybenzaldehyde (1.50 g, 10 mmol) in anhydrous tetrahydrofuran (35 mL. While stirring briskly, sodium triacetoxyborohydride (2.12 g, 10 mmol) was added in 50-100 mg portions, allowing effervescence to subside after each addition. The reaction was monitored for absence of starting material by HPLC. After stirring at room temperature for 16 hours, more 4-carboxybenzaldehyde (0.75 g, 5 mmol), acetic acid (0.318 mL, 5 mmol), and sodium triacetoxyborohydride (1.06 g, 5 mmol) was added. After stirring an additional 4 hours, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (50 mL) and 3 M hydrochloric acid (10 mL). The layers were separated and the organic layer was extracted again with 3 M hydrochloric acid (5×10 mL). The aqueous solution was adjusted to pH 4.5-5 with saturated aqueous sodium carbonate solution and extracted with methylene chloride (3×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to yield 4-{(2R, 5S)-4-[(R)-(4-diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl]-2,5-dimethyl-1-piperazinyl-methyl}benzoic acid as a brittle white foam (2.34 g). The product showed a single peak on HPLC (Zorbax RX-C8, 4.6 mm×25 cm, isocratic 40% 0.01 M NH4OAc in MeOH, 3 min; linear gradient to 100% MeOH, 45 min; isocratic MeOH, 5 min; 1.0 mL/min; λobs=210 nm, Rt=13.75 min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:22]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>ClCCl>[C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:22]=1)(=[O:32])[CH3:31]
Reactant: Nc1ccc2snc(NCCNC(=O)c3ccccn3)c2c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2snc(NCCNC(=O)c3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
N-(2-(5-Aminobenzo[d]isothiazol-3-ylamino)ethyl)picolinamide (95 mg, 0.30 mmol) was dissolved in anhydrous dichloromethane (5 mL) with triethylamine (50 μL, 0.36 mmol). The solution was cooled on an ice-water bath and a solution of acetyl chloride (26 μL, 0.36 mmol) in dichloromethane (0.5 mL) was added dropwise. The reaction mixture was allowed to stir for 2.5 h while warming to room temperature. The solution was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, then dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to yield N-(2-(5-acetamidobenzo[d]isothiazol-3-ylamino)ethyl) picolinamide as a white solid. 1H NMR (300 MHz, CDCl3): 8.48 (d, 1H), 8.30 (s, 1H), 8.20 (d, 1H), 7.80 (t, 1H), 7.52 (s, 1H), 7.42 (m, 1H), 7.31 (d, 1H), 7.18 (s, 1H), 6.82 (d, 1H), 3.70 (m, 2H), 3.50 (m, 2H), 2.20 ppm (s, 3H). MW=355 confirmed by LC-MS, tr=9.35 min (Method Y) MH+=356.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]1([NH:15]C2C=CC=CC=2)C=CC=CC=1.[S-]C#N.BrBr>>[NH2:15][C:9]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Nc1ccccc1S
Agent: BrBr
Agent: N#C[S-]
Product: Nc1nc2ccccc2s1

Procedure:
If the desired 2-amino benzenethiol 8-scheme 3 is not commercially available it can be synthesized by reaction of the phenyl aniline with the thiocyanate anion in the presence of an oxidant(like bromine) to produce the 2-aminobenzthiazole 7-scheme 3. This thiazole can then be hydrolyzed to the desired 2-aminobenzenethiol 8-scheme 3 with a strong base like NaOH in a protic solvent (i.e., EtOH).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:12]C2C=CC=CC=2)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.O.Cl.[NH3:21]>C(Cl)Cl>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]2)=[C:4]([C:4]2[C:3]([NH2:12])=[C:2]([CH3:1])[CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[CH:9]3)[C:3]=1[NH2:21]
Reactant: Cc1cc2ccccc2cc1Nc1ccccc1
Reactant: N
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: Cc1cc2ccccc2c(-c2c(N)c(C)cc3ccccc23)c1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
At 50° C., 3.1 g (20 mmol) of 3-methyl-2-naphthylamline, 6.5 g (40 mmol) of FeCl3 and 80 mL of H2O were stirred for 2 hours. To the reaction mixture was added 2 mL of concentrated hydrochloric acid at room temperature. The mixture was stirred at room temperature for 10 minutes. To the reaction mixture were added 20 mL of methylene chloride and 20 mL of a saturated aqueous ammonia solution. After vigorous stirring at room temperature, the reaction mixture was filtered over Celite and the filtrate was washed with methylene chloride. The organic layer was concentrated by distilling off the solvent under reduced pressure. The residue was purified by Florisil (trade name) and then by chromatography on a silica gel column (hexane/ethyl acetate=4/1 to 3/1). By recrystallization from hexane-chloroform, 0.76 g (yield: 24%) of 3,3′-dimethyl-1,1′-binaphthyl-2,2′-diamine was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=O.[C:19]([O:26][CH3:27])(=[O:25])[CH2:20][CH2:21][C:22]([CH3:24])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:27][O:26][C:19](=[O:25])[CH2:20][C:21]1[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:22]=1[CH3:24]
Reactant: Nc1sc2c(c1C(=O)c1cccnc1)CCCC2
Reactant: COC(=O)CCC(C)=O
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1cccnc1)CCCC3
Yield: 39.1 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(pyridin-3-yl)methanone (0.362 g; 1.4 mmol), methyl levulinate (0.198 mL; 1.54 mmol), chlorotrimethylsilane (0.717 mL; 5.6 mmol) in DMF (5.6 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.193 g (39%) of the title compound as a yellow solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[CH2:35][C:36]([OH:38])=O.CCN(C(C)C)C(C)C.[F:48][C:49]1[CH:50]=[C:51]([CH2:56][CH:57]([C:59]2[N:60]=[CH:61][S:62][C:63]=2[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=2[CH3:70])[NH2:58])[CH:52]=[C:53]([F:55])[CH:54]=1>CN(C=O)C>[F:48][C:49]1[CH:50]=[C:51]([CH2:56][CH:57]([NH:58][C:36](=[O:38])[CH2:35][C:29]2[C:28]3[C:32](=[CH:33][CH:34]=[C:26]([OH:25])[CH:27]=3)[NH:31][CH:30]=2)[C:59]2[N:60]=[CH:61][S:62][C:63]=2[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=2[CH3:70])[CH:52]=[C:53]([F:55])[CH:54]=1
Reactant: O=C(O)Cc1c[nH]c2ccc(O)cc12
Reactant: Cc1ccccc1-c1scnc1C(N)Cc1cc(F)cc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1scnc1C(Cc1cc(F)cc(F)c1)NC(=O)Cc1c[nH]c2ccc(O)cc12
Reaction time: 0.17 h

Procedure:
HATU (40 mg, 0.105 mmol) was added to a solution of 2-(5-hydroxy-1H-indol-3-yl)acetic acid (19.2 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 13D (33.1 mg, 0.1 mmol) in 0.2 mL of DMF was added to the reaction. The reaction was stirred for 2 hours. LC/MS shows desired product. Purified reaction mixture on prep reverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined pure fractions as determined by LC/MS and lyophilized to provide the desired product. 1H NMR (400 MHz, DMSO) δ 10.46 (s, 1H), 9.18 (s, 1H), 8.31 (d, J=8.2 Hz, 1H), 7.35-7.15 (m, 2H), 7.05 (t, J=7.1 Hz, 2H), 6.94 (dd, J=10.2, 5.8 Hz, 2H), 6.75 (t, J=7.2 Hz, 2H), 6.59-6.35 (m, 3H), 3.38 (s, 2H), 3.01 (d, J=7.5 Hz, 2H), 1.81 (s, 3H). MS (m/z) 504 [M+H]+.
Reaction SMILES: [CH3:1][NH:2]C(C1N(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)N=CN=1)=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:43]=2[CH2:44][N:45]2[C:49]([C:50]([O:52]C)=O)=[CH:48][C:47]([CH3:54])=[N:46]2)=[CH:31][CH:30]=1.CN>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:43]=2[CH2:44][N:45]2[C:49]([C:50]([NH:2][CH3:1])=[O:52])=[CH:48][C:47]([CH3:54])=[N:46]2)=[CH:31][CH:30]=1
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Reactant: COC(=O)c1cc(C)nn1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: CN
Product: CNC(=O)c1cc(C)nn1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to the procedure described for compound 68 from 3 methyl 1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-3-methyl-1H-pyrazole-5-carboxylate and methylamine. M/e+ 380 for C20H19ClN5O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.29 (d, J=6.6 Hz, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.8 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.23 (m, 1H), 6.82 (t, J=6.9 Hz, 1H), 6.66 (s, 1H), 6.05 (s, 2H), 3.84 (s, 3H), 2.19 (s, 3H) 1.57 (s, 1H), ppm;
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[CH3:12][C@:13]12[CH2:23][CH2:22][C@@H:21]3[CH2:24][C@:18]1([O:19][C:20]3([CH3:26])[CH3:25])[C:17]([CH2:27][CH2:28][CH2:29][OH:30])=[CH:16][CH2:15][CH2:14]2.CCOCC>C(Cl)Cl>[CH3:12][C@:13]12[CH2:23][CH2:22][C@@H:21]3[CH2:24][C@:18]1([O:19][C:20]3([CH3:25])[CH3:26])[C:17]([CH2:27][CH2:28][CH:29]=[O:30])=[CH:16][CH2:15][CH2:14]2
Reactant: CC1(C)O[C@]23C[C@H]1CC[C@]2(C)CCC=C3CCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)O[C@]23C[C@H]1CC[C@]2(C)CCC=C3CCC=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
300 mg (1.39 mmol) of PCC was added to a solution of 100 mg (0.38 mmol) of (1R,6S,9R)6,10,10-trimethyl-2-(3-hydroxypropyl)-11-oxatricyclo[7.2.1.01,6]dodec-2-ene from example 12 in 15 ml of methylene chloride and the reaction mixture was stirred at room temperature for 3 hours, then was added 15 mL of ether. After filtration, the filtrate was concentrated to give 90 mg of crude product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][C:3]=1[C:9]1[N:13]2[C:14]3[C:19]([N:20]=[C:21]([CH3:22])[C:12]2=[C:11]([CH3:24])[N:10]=1)=[CH:18][CH:17]=[C:16](F)[CH:15]=3.F[C:26]1C=C(Cl)C=CC=1[N+]([O-])=O>>[CH3:24][C:11]1[N:10]=[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:26])[N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:20]=[C:21]([CH3:22])[C:12]=12
Reactant: Cc1nc(-c2cc(Cl)ccc2Cl)n2c1c(C)nc1ccc(F)cc12
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Product: Cc1ccccc1-c1nc(C)c2c(C)nc3ccccc3n12
Yield: 62 %

Procedure:
3,4-Dimethyl-1-(2-methylphenyl)imidazo[1,5-a]quinoxaline was synthesized in a manner similar to 1-(2,5-dichlorophenyl)-8-fluoro-3,4-dimethyl-imidazo[1,5-a]quinoxaline starting with 2-fluoro-4-chloronitrobenzene. A white solid was recovered (0.07 g) 62% yield. MS (ES) m/z 288.1 [M+1]+
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].IC.CCCCCC.CCOC(C)=O>CN(C=O)C.O>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH:4]=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1c(O)cc(Cl)cc1Cl
Agent: [K+]
Solvent: CCCCCC
Solvent: CI
Solvent: O
Product: COc1cc(Cl)cc(Cl)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a stirred solution of 2,4-dichloro-6-hydroxybenzaldehyde (1.85 g; 9.7 mmol) in 20 mL DMF at ambient temperature was added solid potassium carbonate (1.47 g; 10.6 mmol), and the resulting yellow mixture was stirred at ambient temperature. After 30 minutes, iodomethane (5.5 g; 38.7 mmol) was added, and the resulting mixture was stirred in an oil bath set to 50° C. After 10 minutes, the reaction was determined to be complete by thin layer chromatography (90/10 hexane/EtOAc). After a total of 30 minutes the mixture was cooled to ambient temperature and diluted with 200 mL water. After stirring for a few minutes, the precipitate that formed was collected by filtration, washed with water, and dried under vacuum to give 1.93 g of 2,4-dichloro-6-methoxybenzaldehyde as an off-white powder.