Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11](=O)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:13])[CH:8]=2)[O:3]1.[H-].[Na+].[CH3:17][CH2:18][O:19][C:20]([CH2:22]P(OCC)(OCC)=O)=[O:21].P([O-])([O-])([O-])=O>O1CCCC1>[CH2:18]([O:19][C:20]([CH2:22][C:11]1[C:2]([CH3:14])([CH3:1])[O:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([F:13])=[CH:6][CH:5]=2)=[O:21])[CH3:17]
Reactant: CC1(C)Oc2ccc(F)cc2CC1=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1=Cc2cc(F)ccc2OC1(C)C
Reaction time: 0.5 h

Procedure:
While stirring at from 0° to 5°, a solution of 5.7 g (29 mmol) of 2,2-dimethyl-6-fluoro-3-oxo-chroman in 100 ml of absolute tetrahydrofuran is added dropwise within a period of 30 minutes to a suspension of 1.69 g (35 mmol) of sodium hydride dispersion (55% in mineral oil), which has been substantially freed of mineral oil beforehand by repeated washing with n-hexane, in 100 ml of absolute tetrahydrofuran. The mixture is then stirred at from 0° to 5° for 30 minutes and then a solution of 7.9 g (35 mmol) of phosphonoacetic acid triethyl ester of the formula (H5C2O)2P(=O)CH2C(=O)OC2H5 in 70 ml of absolute tetrahydrofuran is added dropwise thereto within a period of 30 minutes at from 0° to 5°. The reaction mixture is stirred for a further 30 minutes at from 0° to 5° and then for 16 hours at room temperature and then poured into 700 ml of cold phosphate buffer solution (pH=6). The resulting mixture is extracted with diethyl ether. The combined organic phases are washed in succession with phosphate buffer solution (pH=7) and water, dried over sodium sulfate and concentrated by evaporation. The resulting red oil is chromatographed on 400 g of silica gel (0.040-0.063 mm) with toluene as eluant, yielding 5.76 g (75% of the theoretical yield) of 3-ethoxycarbonylmethyl-2,2-dimethyl-6-fluoro-2H-chromene in the form of an orange-coloured oil.
Reaction SMILES: [CH:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22](=[O:36])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:17][CH2:16]2)=[O:12])=[C:5]([CH3:37])[CH:4]=1)=O.C(O)(=O)C.[NH2:42][CH2:43][C@@H:44]([C:53]1[CH:54]=[CH:55][C:56]([OH:62])=[C:57]([NH:59][CH:60]=[O:61])[CH:58]=1)[O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47].CO>C1(C)C=CC=CC=1>[Si:46]([O:45][C@H:44]([C:53]1[CH:54]=[CH:55][C:56]([OH:62])=[C:57]([NH:59][CH:60]=[O:61])[CH:58]=1)[CH2:43][N:42]=[CH:1][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22](=[O:36])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:17][CH2:16]2)=[O:12])=[C:5]([CH3:37])[CH:4]=1)([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47]
Reactant: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1C=O
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c(NC=O)c1
Solvent: CC(=O)O
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1C=NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(NC=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.7 %

Procedure:
To a 250 mL round-bottom flask was added biphenyl-2-ylcarbamic acid 1-[2-(4-formyl-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (7.1 g, 14.2 mmol) and N-{5-[(R)-2-amino-1-(tert-butyldimethylsilanyloxy)ethyl]-2-hydroxyphenyl}formamide acetic acid salt (5.8 g, 15.6 mmol). Methanol (100 mL) was added to form a slurry and this mixture was stirred at 45° C. to 50° C. under nitrogen for 1 hour. The mixture was then cooled to room temperature and toluene (50 mL) was added and the solvent was removed on a rotary evaporator at temperature ranging from 35° C. to 45° C. Toluene (50 mL) was added to the residue and the solvent was removed to provide biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(tert-butyldimethylsilanyloxy)-2-(3-formylamino-4-hydroxyphenyl)ethylimino]methyl}-2,5-dimethyl-phenylcarbamoyl)ethyl]piperidin-4-yl ester (12 g) as a yellow-orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.Cl.[N+:18]([C:21]1[CH:22]=[C:23]([NH:27][NH2:28])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].S(=O)(=O)(O)O>CO>[OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](=[N:28][NH:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)[C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: NNc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Product: O=[N+]([O-])c1cccc(NN=C(c2ccc(O)cc2)c2ccc(O)cc2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
A solution of 4,4′-dihydroxybenzophenone (0.32 g, 1.5 mmol) in 10 mL of methanol was added to a solution of 3-nitrophenylhydrazine hydrochloride (0.43 g, 2.25 mmol), concentrated sulfuric acid (0.3 mL) in 10 mL of methanol at 50° C. It was stirred at 50° C. for additional 2 h. The reaction mixture was concentrated and diluted with 20 mL of water. The precipitates were separated by filtration and washed with 3% aqueous NaHCO3 and water. The crude product was recrystallized from ethanol to give 0.4 g (77% yield) of the desired compound as a yellow solid, mp 160-162° C. 1H NMR (300 MHz, d6-DMSO): δ6.71 [d, 2H, J=8.8 Hz, Ar—H], 6.91 [d, 2H, J=8.1 Hz, Ar—H], 7.07 [d, 2H, J=8.8 Hz, Ar—H], 7.27 [d, 2H, J=8.8 Hz, Ar—H], 7.40 [dd, 1H, J=J2=8.1 Hz, Ar—H], 7.49 [d, 1H, J=8.1 Hz, Ar—H], 7.61 (dd, 1H, J1=8.4 Hz, J2=2.2 Hz, Ar—H], 7.99 [d, 1H, J=2.2 Hz, Ar—H], 9.25 [s, 1H, NH], 9.78 and 9.62 [s, 1H, OH].
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([CH2:23][CH:24]=O)=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[N:4]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[N:3]=1.[CH3:34][NH:35][CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.CCO>[CH3:34][N:35]([CH3:36])[CH2:24][CH2:23][C:21]1[CH:20]=[CH:19][N:18]2[C:14]([C:12]([NH:11][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[C:2]([CH3:1])=[N:3][N:4]4[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=3)=[O:13])=[CH:15][N:16]=[C:17]2[CH:22]=1
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(CC=O)ccn45)cccc32)n1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(CCN(C)C)ccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
A solution of N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxamide (33 mg, 0.068 mmol) and dimethylamine (0.34 mL, 0.68 mmol) in 1.4 mL of a 1:1 MeOH/EtOH mixture was treated at ambient temperature with excess (10 equivalents) sodium triacetoxyborohydride. The reaction mixture was stirred overnight at ambient temperature. Another 10 equivalents of sodium triacetoxyborohydride were added, and stirring was continued for a few more hours. The reaction mixture was quenched with an equal volume of saturated, aqueous sodium bicarbonate, and extracted with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, concentrated, and subjected to preparative thin-layer chromatography on silica, with an 8% MeOH-2% 7N NH3/MeOH/DCM mixture as eluent, to afford 6.6 mg of desired product. MS (ES+APCI) m/z=468 (M+H) detected.
Reaction SMILES: [C:1]([N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][CH:23]=[N:24][C:25]=2[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:40][C:41]1[O:42][C:43](=[O:57])[C:44]2[C:49]([C:50]=1[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[CH:48][CH:47]=[CH:46][CH:45]=2.O>CN(C=O)C>[O:57]=[C:43]1[C:44]2[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:50]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[C:41]([CH2:40][N:29]([C:25]2[N:24]=[CH:23][N:22]=[C:21]3[C:26]=2[N:27]=[CH:28][N:20]3[C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[O:42]1
Reactant: CC(C)(C)OC(=O)Nc1ncnc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=c1oc(CBr)c(-c2ccccc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1oc(=O)c2ccccc2c1-c1ccccc1)c1ncnc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
tert-Butyl 9-trityl-9H-purin-6-ylcarbamate (63.6 mg, 0.133 mmol) in DMF (0.1 ml) was added to a suspension of 50% dispersion in mineral oil NaH (5.33 mg, 0.133 mmol) in DMF (0.1 ml) at 0° C. 3-(bromomethyl)-4-phenyl-1H-isochromen-1-one (intermediate C1, 35 mg, 0.111 mmol) in DMF (0.2 ml) was added and the resulting mixture was allowed to warm to RT. The reaction mixture was then poured into water and extracted with EtOAc. The collected organic phases were dried and concentrated under reduced pressure and the resulting crude (80 mg) was used in the next step without any further purification and characterization.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)C)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:3]=1>[OH-].[Na+]>[ClH:1].[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([NH:10][C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]([NH:8][CH3:9])[N:5]=2)(=[O:12])=[O:13])=[CH:15][CH:16]=1
Reactant: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(NC(C)=O)cc2)n1
Agent: [Na+]
Agent: [OH-]
Product: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Product: Cl
Yield: 151.3 %

Procedure:
2.7 g (0.008 mol) of N-[4-(6-chloro-2-methylamino-pyrimidin-4-ylsulfamoyl)-phenyl]-acetamide were dissolved in 76 ml of 1N NaOH and boiled at reflux for 3 hours. The mixture was extracted with ethyl acetate, the aqueous phase was saturated with sodium chloride and the residual ethyl acetate was distilled off on a rotary evaporator. Then, the aqueous phase was made acid with 3N HCl and the precipitate which separated was filtered off under suction. After drying there were obtained 2.12 g (89%) of 4-amino-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide hydrochloride (1:1.9) as white crystals; MS (ISN): me/e=312 (C11H11ClN5O2S-).
Reaction SMILES: CC(OC[C:6]1[C:19]2[C:14](=CC=CC=2)[C:13]([CH2:20][O:21]C(C)=O)=[C:12]2[C:7]=1C=CC=C2)=O.C(Cl)(=[O:32])C1C=CC=CC=1>>[C:20]([OH:21])(=[O:32])[C:13]1[CH:12]=[CH:7][CH:6]=[CH:19][CH:14]=1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: O=C(Cl)c1ccccc1
Product: O=C(O)c1ccccc1

Procedure:
Preferred acylation agents are acetic, propanoic, benzoic, monochloroacetyl, and dichloroacetyl anhydride, also benzoyl chloride.
Reaction SMILES: [CH:1](=O)[C:2]([CH3:4])=[O:3].[NH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1.C1(C)C=CC(S([CH:27]([N+:35]#[C-:36])[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH2:16]([O:15][C:13]([N:10]1[CH2:9][CH2:8][CH:7]([N:6]2[C:1]([C:2](=[O:3])[CH3:4])=[C:27]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[N:35]=[CH:36]2)[CH2:12][CH2:11]1)=[O:14])[CH3:17]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: [C-]#[N+]C(c1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2C(C)=O)CC1
Reaction time: 0.17 h

Procedure:
To a solution of pyruvaldehyde (40% w/w solution in water, 6.6 mL, 7.8 g, 0.058 mol) in DMSO (100 mL) at ambient temperature was added ethyl 4-aminopiperidinecarboxylate (10 g,, 0.058 mol). After 10 min, α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (8.4 g, 0.029 mol) and K2CO3 (8.0 g, 0.058 mol) were added. After stirring for 18 h, the solution was partition between EtOAc and 3N HCl and the organic phase was washed with 3N HCl. The combined aqueous layers were neutralized with solid K2CO3 and extracted twice with EtOAc. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to give a brown oil which solidified upon standing. Flash chromatography eluting consecutively with 33%, 50% and 67% EtOAc in hexanes followed by trituration with ether afforded the title compound as a white solid; yield 3.5 g (23%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:11][CH2:10]1
Reactant: Brc1ccccn1
Reactant: O=[N+]([O-])c1ccc(OC2CCNCC2)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(OC2CCN(c3ccccn3)CC2)c(Cl)c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
To a suspension of 3-chloro-4-(piperidin-4-yloxy)nitrobenzene (3.00 g) obtained in reference example 8 in pyridine (30 ml) was added 2-bromopyridine (1.25 ml) at room temperature, and the resulting mixture was stirred at 150° C. for 16 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:2) as the eluent to afford the title compound (0.80 g, yield: 20%) as a yellow solid.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:13]=[CH:12][N+:11]([O-])=[C:10]([CH3:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([C:22]#[N:23])(C)C.CN(C)C(Cl)=O.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:9]=[C:10]([CH3:15])[N:11]=[C:12]([C:22]#[N:23])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C#N
Reactant: Cc1cc(C(C)(C)O[SiH2]C(C)(C)C)cc[n+]1[O-]
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C(C)(C)O[SiH2]C(C)(C)C)cc(C#N)n1
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
To a stirred solution of 4-(tert-butyl-dimethyl-silanyloxymethyl)-2-methyl-pyridine 1-oxide (11.2 g, 44 mmol) in dichloromethane (100 ml) at room temperature, was added trimethylsilyl cyanide (7.1 ml, 53.2 mmol). After 15 min., dimethylcarbamyl chloride (4.8 ml, 53.2 mmol) was added and the stirring was continued for 24 hr. The mixture was then cooled in an ice bath and saturated aqueous sodium bicarbonate solution (100 ml) was added. After 1 hr., organic layer was separated, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether:hexane (1:1)) to afford 8.8 g (76%) of 4-(tert-butyl-dimethyl-silanyloxymethyl)-6-methyl-pyridine-2-carbonitrile as a white solid. 1H NMR (200 MHz, CDCl3) δ 0.11 (6H, s), 0.94 (9H, s), (3H, s), 2.52 (3H, s), 4.67 (2H, s), 6.97 (1H, d, J=6.7 Hz), 7.08 (1H, s), 8.10 (1H, d, J=6.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[CH:17]([CH3:35])[C:18]([C:24]1[CH:25]=[CH:26][C:27]2[O:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]=2[CH:34]=1)([OH:23])[C:19]([F:22])([F:21])[F:20].[CH3:36][O:37][C:38]([C:40]1[CH:45]=[CH:44][C:43](Br)=[CH:42][N:41]=1)=[O:39]>>[CH3:36][O:37][C:38]([C:40]1[CH:45]=[CH:44][C:43]([C:6]2[CH:5]=[CH:4][C:3]([CH:17]([CH3:35])[C:18]([OH:23])([C:24]3[CH:25]=[CH:26][C:27]4[O:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]=4[CH:34]=3)[C:19]([F:22])([F:20])[F:21])=[C:2]([Cl:1])[CH:7]=2)=[CH:42][N:41]=1)=[O:39]
Reactant: CC(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: COC(=O)c1ccc(Br)cn1
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)cn1

Procedure:
The title compound was prepared in analogy to Example 186, step 2 from 5-{2-[2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1-hydroxy-1-trifluoromethyl-propyl}-3-methyl-3H-benzooxazol-2-one (obtained in Example 186, step 1) with methyl-5-bromopyridine-2-carboxylate [CAS Reg. No. 29682-15-3]. MS (m/e)=521.2 [M+H+].
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:29])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[N:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH3:2].[NH2:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:10]2[C:9](=[O:29])[CH:8]=[CH:7][C:6]3[N:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:12][C:11]2=3)[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ncc(C#N)cc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N
Product: N#Cc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 139.7 %

Procedure:
To a solution of 1,1-dimethylethyl {1-[2-(7-cyano-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl]-4-piperidinyl}carbamate (0.411 g, 1.03 mmol) in DCM (16 ml) was added TFA (9 ml) and the reaction stirred at rt for 1 h. The solution was evaporated, dissolved in MeOH and passed through a column of Amberlyst A21 basic resin. The fractions containing the desired product were evaporated and the residue was subjected to column chromatography on silica gel using a DCM:MeOH:aq NH3 gradient to provide the desired compound (0.214 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:22]=[C:21]([CH3:36])[C:3]=1[C:4]([NH:6][C@H:7]([C:17]([O:19]C)=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:22]=[C:21]([CH3:36])[C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)NCc2cccc(O)c2)cc(Cl)c1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A mixture of N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-6-methylbenzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine, methyl ester (2.06 g, 3.9 mmol) in methanol (100 mL) and sodium hydroxide (0.31 g, 7.8 mmol) in water (2 mL) was stirred at room temperature overnight and then the solvents were evaporated. The residue was partitioned between water and ethyl acetate and the ethyl acetate layer was discarded. The aqueous layer was poured into 2 M HCl, and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, concentrated, and dried under high vacuum to give N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-6-methylbenzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine (1.50 g, 75%) as a white solid.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH:9]([OH:12])[CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:14]([CH3:31])[CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1.C([BH3-])#N.[Na+]>CO>[C:1]1([S:7][CH2:8][CH:9]([OH:12])[CH2:10][NH:11][CH:14]([CH3:31])[CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:29][CH:30]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: NCC(O)CSc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)CSc1ccccc1
Yield: 36.3 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 2.95 g of 3-phenylthio-2-hydroxypropylamine (prepared as described in Preparation 87), 3 g of 5-[4-(2-oxopropoxy)benzyl]thiazolidine-2,4-dione, 1.0 g of sodium cyanoborohydride and 100 ml of anhydrous methanol were used, to give 1.74 g of the title compound, melting at 176° C. to 177° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>[Pd]>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:9])([F:21])[F:22])=[CH:17][CH:16]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: [Pd]
Product: FC(F)(F)Oc1ccc(-c2cncc(Cl)n2)cc1

Procedure:
The compound was prepared by palladium-catalyzed arylation of 2,6-dichloropyrazine and 4-trifluoromethoxyphenyl boronic acid: mp 58-60° C.; 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.57 (s, 1H), 8.10 (d, J=9.0 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H); EIMS m/z 274 (M+).
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[CH:12]=[C:13]([C:17](O)=[O:18])[CH:14]=[CH:15][C:16]=3[C:8]=2[N:7]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=2)[CH:5]=1)(=[O:3])[NH2:2].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]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>[Cl:27][C:22]1[CH:21]=[C:20]([C:6]2[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:9]3[NH:10][C:11]4[CH:12]=[C:13]([C:17]([N:32]5[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]5)=[O:18])[CH:14]=[CH:15][C:16]=4[C:8]=3[N:7]=2)[CH:25]=[CH:24][C:23]=1[F:26]
Reactant: NC(=O)c1cc(-c2ccc(F)c(Cl)c2)nc2c1[nH]c1cc(C(=O)O)ccc12
Reactant: CN1CCNCC1
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: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4ccc(F)c(Cl)c4)nc23)CC1
Reaction time: 8 h

Procedure:
A mixture of 4-carbamoyl-2-(3-chloro-4-fluorophenyl)-5H-pyrido[3,2-b]indole-7-carboxylic acid 431D (55 mg, 0.143 mmol), 1-methylpiperazine (0.032 mL, 0.287 mmol), N,N-diisopropylethylamine (0.075 mL, 0.430 mmol) and HATU (109 mg, 0.287 mmol) in DMF (1 mL) was stirred for overnight. The mixture was concentrated and purified using preparative HPLC to give titled product. MS (ESI) m/z 466.16 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.82 (s, 1H), 8.62 (s, 1H), 8.53 (s, 1H), 8.50 (dd, 1H, J=7.1, 2.1), 8.34 (m, 2H), 7.99 (s, 1H), 7.79 (s, 1H), 7.62 (t, 1H, J=8.8), 7.28(d, 1H, J=8.0), 3.67 (bs, 4H), 2.37 (bs, 4H), 2.22 (s, 3H).
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42]C1N=NC(C)=CC=1)[CH2:4][CH2:3]2.Cl[C:51]1[N:52]=[N:53][CH:54]=[CH:55][CH:56]=1.[C:57](O)(C(F)(F)F)=O>>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([O:29][CH3:57])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][C:51]1[N:52]=[N:53][CH:54]=[CH:55][CH:56]=1)[CH2:4][CH2:3]2
Reactant: O=C(O)C(F)(F)F
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNc3ccc(C)nn3)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
Reactant: Clc1cccnn1
Product: C=C(C)[C@@H]1CC[C@]2(NCCNc3cccnn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 6 %

Procedure:
The title compound was prepared following a similar procedure as described for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(6-methylpyridazin-3-ylamino)ethylamino)-1-(prop-1-en-2-yl)-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)benzoic acid, except 3-chloropyridazine (0.011 g, 0.100 mmol) was used in place of 3-bromo-6-methylpyridazine. Purification of the crude mixture by reverse phase preparative HPLC using Prep HPLC Method 9 gave the title compound as a white glassy solid (4.9 mg, 6.0% yield) bis TFA salt. LCMS: m/e 665.5 (M+H)+, 2.40 min (method 11).