Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[CH:10]([O:12][CH2:13][CH2:14][OH:15])[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1)[CH3:34].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1C=CC=CC=1.CCCCCCC>[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:15][CH2:14][CH2:13][O:12][CH:10]2[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][S:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]2=3)=[CH:41][CH:40]=1)[CH3:34]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: OCCOC1c2ccccc2CSc2ccccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCCC
Solvent: c1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCOC2c3ccccc3CSc3ccccc32)cc1)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.7 %

Procedure:
Under a nitrogen atmosphere, 2-(6,11-dihydrodibenzo[b,e]thiepin-11-yloxy)-ethanol (340 mg, 1.25 mmol), tributylphosphine (280 mg, 1.37 mmol) and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (330 mg, 1.37 mmol) were successively dissolved in dry benzene (10 mL). Solid azodicarboxylic dipiperidine (ADDP) (350 mg, 1.37 mmol) was added under stirring at 0° C. to the solution. After 10 min, the reaction mixture was brought to room temperature and the stirring was continued for 16 h. Heptane (10 mL) was added to the reaction mixture and dihydro-ADDP separated out was filtered off. After evaporation of the solvent the product was purified chromatography eluting with ethyl acetate/heptane (1:4) to give 460 mg (75%) of the title compound: 1H NMR (300 MHz, CDCl3) δ1.15 (t, 3H), 1.25 (t, 3H), 2.95 (d, 2H), 3.30-3.40 (m, 1H), 3.55-3.65 (m, 1H), 2.85 (t, 2H), 3.95 (t, 1H), 4.10-4.22 (m, 4H), 4.5-5.1 (bs, 1H), 5.60-5.75 (bs, 1H), 6.82 (d, 2H), 7.05-7.50 (m, 1OH).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([NH2:22])=[O:21])[C:3]1=[O:23].[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:33](ON1C(=O)CCC1=O)=[O:34]>CN(C)C=O>[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:33]([NH:1][C@H:2]1[C@@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([NH2:22])=[O:21])[C:3]1=[O:23])=[O:34]
Reactant: NC(=O)CN1C(=O)[C@@H](N)[C@@H](c2ccccc2)Cc2ccccc21
Reactant: O=C(ON1C(=O)CCC1=O)c1cc2ccccc2[nH]1
Solvent: CN(C)C=O
Product: NC(=O)CN1C(=O)[C@@H](NC(=O)c2cc3ccccc3[nH]2)[C@@H](c2ccccc2)Cc2ccccc21
Yield: 102.7 %

Procedure:
By conducting the reaction and treatment in the same manner as in Example 12 using 0.2 g of cis-3-amino-2-oxo-4-phenyl-2,3,4,5-tetrahydro-1H-1-benzazepine 1-acetamide and 0.1 g of succinimido 2 indolecarboxylate dissolved in 5 ml of dimethylformamide and recrystallization from a mixed solvent of ethanol and isopropyl alcohol, 0.18 g of cis-3-(2-indolecarboxamido)-2-oxo-4-phenyl-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetamide 1/2 isopropyl alcohol adduct is obtained, m.p. 204°-216° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[N:4]=[C:5]([S:39][CH3:40])[C:6]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][Si](C(C)C)(C(C)C)C(C)C)[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[CH3:1][O:2][C:3](=[O:41])[N:4]=[C:5]([S:39][CH3:40])[C:6]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([OH:28])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1ccc(OC)c(O[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1ccc(OC)c(O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.4 %

Procedure:
After dissolving 3.52 g of {2-(4-methoxy-3-triisopropylsilanyloxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 50 ml of THF, 6.49 ml of TBAF (1.0 M, THF solution) was added and the mixture was stirred at room temperature for 15 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.88 g, isomeric mixture) as a light yellow solid.
Reaction SMILES: [ClH:1].C(OCC)C.[CH3:7][O:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C>>[ClH:1].[ClH:1].[CH3:7][O:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH2:14]
Reactant: COCCNCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: COCCNCCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15.5 ml of a 2 N solution of hydrogen chloride in diethyl ether (31 mmol, 10 equivalents) were added to 750 mg of tert-butyl {2-[(2-methoxyethyl)amino]ethyl}carbamate (Example 165A, purity about 90%, 3.1 mmol, 1 equivalent), and the mixture was stirred at RT overnight. The solvent was decanted off, the residue was triturated three times with diethyl ether and the product obtained in this manner was dried under reduced pressure. This gave 482 mg (82% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C:10](=O)[CH3:11])[CH:5]=[CH:4][N:3]=1.[C:14]1([CH3:22])[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1.Cl.C(N(CC)CC)C>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:22])=[CH:15][CH:16]=3)[N:21]=[C:10]([CH3:11])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CC(=O)CC(=O)c1ccnc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccc(-n2nc(C)cc2-c2ccnc(Cl)c2)cc1
Temperature: 25 °C
Yield: 52 %

Procedure:
A mixture of 1-(2-chloro-4-pyridinyl)-1,3-butanedione (7 g, 35.25 mmol), paratolylhydrazine.HCl (6.13 g, 38.78 mmol) and triethylamine (5.41 mL, 38.78 mmol) in methanol (100 mL) was heated to reflux overnight. The resulting dark colored solution was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, and dried over magnesium sulfate. After filtration, the solution was concentrated to give a brown solid. The solid was purified by column chromatography (silica gel, 2:8 EtOAc/hexane) to yield the titled product (3.6 g, 52%) as a crystalline light brown solid. MP: 100.07° C. Anal. Calc'd for C16H14N3Cl: C, 67.72, H, 4.97, N, 14.81. Found: C 67.40, H, 4.89, N, 14.59.
Reaction SMILES: C([O-])(=O)C.[NH4+].[C:6]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH:13]([CH2:18][CH3:19])[CH2:12]1)([O:8][CH2:9][CH3:10])=[O:7].C([BH3-])#[N:21].[Na+]>CO>[NH2:21][CH:14]1[CH2:15][CH2:16][N:11]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:12][CH:13]1[CH2:18][CH3:19]
Reactant: [BH3-]C#N
Reactant: CCOC(=O)N1CCC(=O)C(CC)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(N)C(CC)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ammonium acetate (33 g) was added to the stirred solution of 1-carbethoxy-3-ethyl-4-piperidinone (8.2 g, 41 mmol) in methanol (125 ml) and stirring was continued for 3 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (2.5 g, 39 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 6 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish crude 4-amino-1-carbethoxy-3-ethylpiperidine, which was used as such in the next step.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])=[N:7][C:6]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=O)[O:26]C4C=CC=CC=4)=[CH:20][CH:19]=3)=[N:5][C:4]=2[CH2:3]1.[CH:34]1([NH2:38])[CH2:37][CH2:36][CH2:35]1>>[CH:34]1([NH:38][C:25]([NH:24][C:21]2[CH:20]=[CH:19][C:18]([C:6]3[N:7]=[C:8]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]4[CH3:17])[C:9]4[CH2:10][N:2]([CH3:1])[CH2:3][C:4]=4[N:5]=3)=[CH:23][CH:22]=2)=[O:26])[CH2:37][CH2:36][CH2:35]1
Reactant: NC1CCC1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc2c1CN(C)C2
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CCC3)cc2)nc2c1CN(C)C2

Procedure:
Method as described for example 51 using intermediate 10 and cyclobutanamine as starting materials. Purified by prep. LCMS (high pH).
Reaction SMILES: Br[C:2]1[C:18]([O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][C:9]=3[CH3:14].C([Sn](CCCC)(CCCC)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[C:7](=[O:15])[N:6]([CH3:16])[C:5]1[CH:17]=[C:18]([O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:22][CH:23]([CH3:25])[CH3:24])[C:2]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)=[CH:3][C:4]2=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(Br)cc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(-c3ccccn3)cc21
Temperature: 120 °C
Yield: 62.2 %

Procedure:
To a solution of (S)-tert-butyl (1-((9-bromo-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (100 mg, 0.193 mmol) in 1,4-dioxane (2 mL) was added 2-(tributylstannyl)pyridine (85 mg, 0.231 mmol) and Pd(PPh3)4 (11.14 mg, 9.64 μmol). The reaction mixture was degassed for 30 min and heated to 120° C. for 1 h in a microwave. The reaction mixture was cooled and diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (3% methanol in chloroform) to afford (S)-tert-butyl (1-((4,6-dimethyl-5-oxo-9-(pyridin-2-yl)-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (50 mg, 0.120 mmol, 62% yield) as a pale yellow solid which was carried on without further purification LC/MS (ESI) m/e 517.7 [(M+H)+, calcd for C30H37N4O4 517.3]; LC/MS retention time (method E): tR=1.19 min.
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([C:24]([OH:26])=O)[CH2:7]1)(=[O:4])=[O:3].[OH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(#N)C>[OH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][N:33]([C:24]([C@@H:8]2[CH2:7][C@@H:6]([O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][N:9]2[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])=[O:26])[CH2:32][CH2:31]1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: OCCN1CCNCC1
Solvent: CC#N
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 40 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
584 mg of N,N'-carbonyldiimidazole were added to a solution of 1.16 g of trans-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-L-proline in 10 ml of dry acetonitrile, and the resulting mixture was stirred at 40° C. for 1 hour. 586 mg of 1-(2-hydroxyethyl)piperazine were then added to the mixture, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 35 minutes. The solvent was then removed by distillation under reduced pressure, and the residue was purified in a similar manner to that described in step 54(a)(ii), to give 930 mg of the title compound, as a powder. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the product were identical with those of the compound obtained as described in step 54(a)(ii) above.
Reaction SMILES: Cl.[F:2][CH:3]([F:29])[O:4][C:5]1[CH:6]=[C:7]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:16]=2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1.C=O.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:29][CH:3]([F:2])[O:4][C:5]1[CH:6]=[C:7]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([N:23]3[CH2:24][CH2:25][N:26]([CH3:32])[CH2:27][CH2:28]3)[CH:16]=2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCNCC1
Agent: C=O
Agent: Cl
Agent: [Na+]
Product: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCN(C)CC1

Procedure:
The compound was prepared by reaction of 3-difluoromethoxy-N-[4-methoxy-3-(piperazin-1-yl)-phenyl]-benzenesulfonamide hydrochloride (compound of example 1) with aqueous formaldehyde and sodium triacetoxyborohydride as described for example 5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([NH2:11])[CH:5]=1.C(N(CC)CC)C.[CH2:20]([O:27][CH2:28][C:29](Cl)=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([NH:11][C:29](=[O:30])[CH2:28][O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:5]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: COC(=O)c1ccc(Cl)c(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)c(NC(=O)COCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 31 %

Procedure:
A solution of carbonic acid monobenzyl ester (3.50 g, 21.0 mmol) in the 50 ml of DCM and 0.50 ml of DMF was cooled to −78° C. followed by addition of oxalyl chloride (11.79 ml, 105 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. After the completion of the reaction mixture (TLC monitoring), concentrated it to give 2-benzyloxyacetyl chloride (3.0 g, 96%). To an ice cold solution of 3-amino-4-chloro-benzoic acid methyl ester in 10 ml of DCM was added triethylamine (2.47 ml, 17.78 mmol) followed by addition of 2-benzyloxyacetyl chloride (3.0 g, 17.78 mmol) in 10 ml of DCM. The reaction mixture was stirred at 25° C. for 12 hr. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (5:95) as the eluent to provide the title compound (1.70 g, 31%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH:12]([OH:17])[CH2:13][CH2:14][CH2:15]O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH:12]3[CH2:13][CH2:14][CH2:15][O:17]3)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2cc(C(O)CCCO)oc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: COc1cccc2cc(C3CCCO3)oc12
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A solution of 1-(7-methoxybenzofuran-2-yl)-butane-1,4-diol (0.88 g) was treated with p-toluenesulfonic acid monohydrate (10 mg) and 3 Å molecular sieves in dichloromethane (10 ml) at ambient temperature. After stirring for 1 hour the solvent was removed in vacuo. The residue was purified by column chromatography on silica eluting with 20% ethyl acetate in hexane to give the title compound as a yellow oil (0.58 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl-].[NH4+]>O1CCCC1.O.[Zn]>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Nc2ncccc2N)cc1F
Reaction time: 0.17 h
Yield: 110.9 %

Procedure:
Zinc dust (14.3 g, 219 mmol) was added to a stirring mixture of N-(3-fluoro-4-methylphenyl)-3-nitropyridin-2-amine (C1) (6.78 g, 27.4 mmol) and ammonium chloride (11.7 g, 219 mmol) in tetrahydrofuran (55 mL) and water (55 mL), which caused the temperature of the mixture to rise to 45° C. The reaction mixture was stirred for 10 minutes, and then filtered through a pad of Celite, rinsing with ethyl acetate. The organic layer from the filtrate was further diluted with ethyl acetate, washed with aqueous ammonium chloride solution and with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to afford the product as a black solid (6.6 g), the bulk of which was taken directly to the following step. LCMS m/z 218.1 [M+H]+. 1H NMR (400 MHz, CDCl3), characteristic product peaks: δ 7.84 (dd, J=4.9, 1.6 Hz, 1H), 7.01 (dd, J=7.6, 1.6 Hz, 1H), 6.82 (br dd, J=8, 2 Hz, 1H), 6.77 (dd, J=7.6, 4.9 Hz, 1H), 2.20 (d, J=2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=1.[CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[C:18]=1[N:26]=[C:27]=[O:28])([CH3:16])[CH3:15].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:24])[CH3:25])[C:18]=1[NH:26][C:27]([NH:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:6]=1)=[O:28])[CH3:15]
Reactant: Nc1nnn(Cc2ccccc2)n1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1cccc(C(C)C)c1NC(=O)Nc1nnn(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
5-Amino-2-benzyltetrazole (1.55 g, 8.84 mmol) was dissolved in 20 mL methylene chloride after which 2,6-diisopropylphenyl isocyanate (2.25 mL, 10.6 mmol) and 1.5 mL triethylamine was added. The mixture was stirred at room temperature for 4 days then quenched with 5 mL 2N sulfuric acid and extracted with 50 mL ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium carbonate, dried over magnesium sulfate, filtered, and evaporated, leaving a white solid which was recrystallized from ethyl acetate/ether to give the title compound, m.p. 180-181° C.
Reaction SMILES: [CH2:1]([C:7]([OH:9])=[O:8])[C@H:2]([OH:6])[C:3]([OH:5])=[O:4].O.[C:11]1(C)[CH:16]=CC(S(O)(=O)=O)=C[CH:12]=1>COC(OC)(C)C>[CH3:12][C:11]1([CH3:16])[O:6][C@@H:2]([CH2:1][C:7]([OH:9])=[O:8])[C:3](=[O:5])[O:4]1
Reactant: O=C(O)C[C@H](O)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC1(C)OC(=O)[C@H](CC(=O)O)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 2757.9 %

Procedure:
Step A To a suspension of L-(−)-malic acid (Aldrich) (10.3 g, 77 mmol) in 2,2-dimethoxypropane (20 mL) was added p-toluenesulfonic acid monohydrate (0.4 g). The reaction mixture was stirred at room temperature for 30 min. The mixture was partitioned between water and dichloromethane. The organic layer was separated, the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated to give ((S)-2,2-dimethyl-5-oxo-[1,3]dioxolan-4-yl)-acetic acid as a white solid (10.1 g, 75%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:5]=[CH:4][N:3]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1)([O-:16])=[O:15].C([O-])([O-])=O.[Na+].[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CC([O-])=O.CC([O-])=O.[Pd+2].COCCOC>[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:22]2[CH:21]=[C:20]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[CH:19]=[CH:18][C:17]=2[N+:14]([O-:16])=[O:15])[CH:7]=1)#[CH:9]
Reactant: CC1(C)OB(c2cc(N3CCCCC3)ccc2[N+](=O)[O-])OC1(C)C
Reactant: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: COCCOC
Product: C#Cc1ccnc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])c1
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
A degassed mixture of 2-chloro-4-((trimethylsilyl)ethynyl)pyridine 24a, boronic ester 1.1e, 4.9 mL of 2 M aqueous Na2CO3, and 12 mL of DME was treated with 45 mg of XPHOS and 11 mg of Pd(OAc)2. The mixture was stirred at 75° C. for 1.5 h. The solvent was evaporated at reduced pressure and the residue was dissolved in 100 mL of dichloromethane. The solution was washed with water and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel chromatography eluting with a 0-20% gradient of EtOAc in CH2Cl2 to give 275 mg of product. MS (ESI, m/z) 308.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[CH:9][N:10]([C:11]3[S:15][C:14]([C:16]([O:18]C)=O)=[C:13]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:31])([F:30])[F:29])[CH:12]=3)[C:4]=2[CH:3]=1.[NH3:32]>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[CH:9][N:10]([C:11]3[S:15][C:14]([C:16]([NH2:32])=[O:18])=[C:13]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:30])([F:31])[F:29])[CH:12]=3)[C:4]=2[CH:3]=1
Reactant: COC(=O)c1sc(-n2cnc3cnc(Cl)cc32)cc1OCc1ccccc1C(F)(F)F
Reactant: N
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3cnc(Cl)cc32)cc1OCc1ccccc1C(F)(F)F
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 140 mg of methyl 5-(6-chloro-1H-imidazo[4,5-c]pyridin-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate and 20 ml of a saturated solution of ammonia in methanol were stirred in a microwave vial at 120° C. for 4 h in the microwave cavity. The reaction mixture was concentrated to half of the volume. The solid that precipitated after standing was collected and recrystallized from acetonitrile to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:47])[CH2:3][CH2:4][NH:5][C:6]([C@:8]12[CH2:43][CH2:42][C@@H:41]([CH:44]([CH3:46])[CH3:45])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:40])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)=[O:7].ClC1C=C(C=CC=1)C(OO)=[O:53]>C(Cl)Cl>[C:34]([C:33]1[CH:38]=[CH:39][C:30]([C:17]2[C:18]([CH3:29])([CH3:28])[C@H:19]3[C@:14]([CH3:40])([CH2:15][CH:16]=2)[C@@H:13]2[C@:22]([CH3:27])([C@@:23]4([CH3:26])[C@H:10]([CH2:11][CH2:12]2)[C@H:9]2[C@H:41]([CH:44]([CH3:46])[CH3:45])[CH2:42][CH2:43][C@:8]2([C:6]([NH:5][CH2:4][CH2:3][N+:2]([O-:53])([CH3:1])[CH3:47])=[O:7])[CH2:25][CH2:24]4)[CH2:21][CH2:20]3)=[CH:31][CH:32]=1)([OH:36])=[O:35]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(C2=CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)NCCN(C)C)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Solvent: ClCCl
Product: CC(C)[C@@H]1CC[C@]2(C(=O)NCC[N+](C)(C)[O-])CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 3 h
Yield: 49.9 %

Procedure:
To a mixture of methyl 4-((1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)ethylcarbamoyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (20 mg, 0.031 mmol) in DCM (2 mL) was added 3-chlorobenzoperoxoic acid (13.90 mg, 0.062 mmol) at −78° C. The reaction mixture was stirred for 3 hours. LCMS indicated the formation of desired product and consumption of the starting material. The reaction mixture was quenched with distilled water, extracted with DCM (3×2 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as an yellow oil (10 mg, 49%). LCMS: m/e 661.49 (M+H)+, 2.79 min (method 1).