Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:13][C:14]([N:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([C@:22]([OH:35])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH2:17]1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+]=[N-].O>CO.[Pd]>[NH2:1][CH2:4][C@@H:5]([NH:13][C:14]([N:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([C@:22]([OH:35])([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH2:17]1)=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=O)N[C@H](CN=[N+]=[N-])Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=O)N[C@H](CN)Cc2ccccc2)C1
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
Crude (3R)-N-((S)-3-azido-1-phenylpropan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide (210.7 mg, 91% purity, 0.4 mmol) from the previous step was dissolved in MeOH (10 mL) and was added to 0.2 g of Pd/C previously wetted with a drop of H2O. After 3 vacuum/purge cycles using 12 torr vacuum and 14 psi H2, the reaction was stirred under an atmosphere of H2 at 14 psi for 30 minutes. The crude mixture was filtered through a plug of Celite and the solvent was removed. The resulting oil was dissolved in a minimal volume of 1:1 acetonitrile:H2O then separated by prep HPLC on a C-18 column using a gradient of 0.05% TFA in H2O and acetonitrile. Appropriate fractions were combined, made slightly basic with 1 N NaOH, and the solvent was removed at 50° C. and 150 torr. The residue was taken up in CH2Cl2 (50 mL) and 1 N NaOH (10 mL). The organic layer was dried (Na2SO4), decanted and stripped to afford (3R)-N-((S)-1-amino-3-phenylpropan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide (61.5 mg, 34% overall yield from (R)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbonyl chloride) as a clear colorless film. MS ESI +ve m/z 454 (M+1).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[C:33]([O:41][CH2:42][CH3:43])[CH:32]=4)[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:42]([O:41][C:33]1[CH:32]=[C:31]([C:23]2[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[N:26]=[C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[CH:20]=3)[N:22]=2)[CH:36]=[CH:35][C:34]=1[C:37]([F:40])([F:39])[F:38])[CH3:43]
Reactant: CCOc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4cccc(S(=O)(=O)NC(C)(C)C)c4)c3)n2)ccc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4cccc(S(N)(=O)=O)c4)c3)n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.8 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{4-[6-(3-ethoxy-4-trifluoromethylphenyl)-4-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide (0.24 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into saturated Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.17 g, 72%). MS (ISP) 569.2 [(M+H)+]; mp 223.5° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][C@@:8]([CH3:16])([C:12]([F:15])([F:14])[F:13])[C:9](O)=[O:10].[Br:17][C:18]1[CH:24]=[C:23]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:19]=1[NH2:20].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>ClCCl.CN(C=O)C>[Br:17][C:18]1[CH:24]=[C:23]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:19]=1[NH:20][C:9](=[O:10])[C@:8]([OH:7])([CH3:16])[C:12]([F:15])([F:14])[F:13]
Reactant: Nc1ccc(Sc2ccccc2)cc1Br
Reactant: C[C@@](O)(C(=O)O)C(F)(F)F
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@](O)(C(=O)Nc1ccc(Sc2ccccc2)cc1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.1 %

Procedure:
Oxalyl chloride (0.052 ml) was added to a stirred suspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (Method 9) (0.095 g) in dichloromethane (3 ml) containing DMF (1 drop). The mixture was stirred at ambient temperature for 2 hours and was then added to a solution of 2-bromo-4-phenylthioaniline (Method 17) (0.135 g) and 2,6-di-tert-butylpyridine (0.14 ml) in dichloromethane (5 ml) and stirred a further 3 hours. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-30% ethyl acetate/hexane to give the title compound (0.061 g) as a waxy solid. NMR: 1.59 (s, 3H), 7.25-7.50 (bm, 6H), 7.59 (s, 1H), 7.82 (bs, 1H), 7.98 (d,1H), 9.79 (s, 1H); MS: 420 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:23])[CH:21]=[CH2:22])[CH2:16][CH:15]=3)[S:13][C:6]=12.[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:23])[CH2:21][CH2:22][NH:35][CH2:34][CH2:33][O:32][CH3:31])[CH2:16][CH:15]=3)[S:13][C:6]=12
Reactant: C=CC(=O)N1CC=C(c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)CC1
Reactant: COCCN
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCCNCCC(=O)N1CC=C(c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)CC1
Yield: 44.5 %

Procedure:
A solution of the compound 98 (171.0 mg, 0.4 mmol) and 2-methoxyethanamine (0.14 mL, 1.62 mmol) in THF (98.1 mL) was stirred overnight at room temperature. It was then diluted with DCM, washed with aqueous sodium bicarbonate and water. The organic phase was extracted with 1N HCl, the aqueous acidic phase was basified by addition of 1N NaOH (pH˜11) and extracted with DCM. The DCM extract was dried over anhydrous sodium sulphate and concentrated under reduced pressure affording title compound 99 (89.0 mg, 45% yield) as cream foam. MS (m/z): 501.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:17]=[C:18]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([F:34])=[C:30](F)[CH:31]=3)[C:26](=[O:35])[N:25]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:24]2=[O:44])[CH:19]=[CH:20][C:21]=1[F:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([F:34])=[C:30]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH:31]=3)[C:26](=[O:35])[N:25]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:24]2=[O:44])[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: O=c1c2cc(F)c(F)cc2n(-c2ccc(F)c(Cl)c2)c(=O)n1OCc1ccccc1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3-c2ccc(F)c(Cl)c2)CC1
Yield: 85.3 %

Procedure:
Using General Method 4, the reaction of N-methylpiperazine (0.12 mL, 1 mmol), triethylamine (0.14 mL, 1 mmol), and 1-(3-chloro-4-fluorophenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example D-1, 0.14 g, 0.32 mmol) provided 0.14 g of the title compound as a solid.
Reaction SMILES: [CH:1]([NH2:3])=[O:2].[H-].[Na+].C(OC([C:11]1[N:15]2[CH:16]=[C:17]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=4)=[N:23][N:22]4[CH2:32][CH2:33][CH2:34][C:21]=34)[CH:18]=[CH:19][C:14]2=[N:13][CH:12]=1)=O)C>CN(C=O)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:31][C:27]1[N:26]=[C:25]([C:24]2[C:20]([C:17]3[CH:18]=[CH:19][C:14]4[N:15]([C:11]([C:1]([NH2:3])=[O:2])=[CH:12][N:13]=4)[CH:16]=3)=[C:21]3[CH2:34][CH2:33][CH2:32][N:22]3[N:23]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1cnc2ccc(-c3c(-c4cccc(C)n4)nn4c3CCC4)cn12
Reactant: NC=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2nn3c(c2-c2ccc4ncc(C(N)=O)n4c2)CCC3)n1
Temperature: 155 °C
Yield: 99 %

Procedure:
Add formamide (36 mL) to a suspension of sodium hydride (2.04 g, 60% dispersion in mineral oil, 51.1 mmol) and 6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (3.6 g, 9.29 mmol) in DMF (15 mL) over 10 min. Heat at 155° C. for 40 min, cool, dilute with ethyl acetate, and carefully dilute with saturated aqueous sodium bicarbonate. Filter any un-dissolved solid and wash with ethyl acetate. Concentrate the remaining organic layer and adsorb onto a 1:1 mixture of SiO2 and Celite®. Flash chromatography using ethyl acetate methanol mixtures followed by trituration of the combined lots in diethyl ether gives the titled compound (3.32 g, 99%) as a white solid. TOF MS ES+ exact mass calculated for C10H9IN2O2 (p+1): m/z=359.1620 Found: 359.1617.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39])[NH2:32]>>[CH3:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:31]1[N:32]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:28][N:30]=1
Reactant: Cc1ccccc1C(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: Cc1ccccc1-c1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 33 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-2-methylbenzenecarboximidamide were reacted according to the General Method 1. Yield: 14 mg (13% of theory)
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].[N+:7]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13]Br)([O-:9])=[O:8].P([O-])([O-])([O-])=O>CN(C=O)C.O>[N+:7]([C:10]1[CH:11]=[C:12]([CH2:13][O:3][CH2:2][CH2:1][OH:4])[CH:15]=[CH:16][CH:17]=1)([O-:9])=[O:8]
Reactant: OCCO
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(COCCO)c1
Reaction time: 0.5 h
Yield: 358 %

Procedure:
Ethylene glycol (7.18 g) in anhydrous DMF (50 ml) was treated at 0° under nitrogen with sodium hydride (60% dispersion in mineral oil, 1.85 g) and the mixture stirred for 30 min. 3-Nitrobenzyl bromide (5.00 g) was added and the mixture was warmed to 200 over 1 h and stirred for a further 15 h. Phosphate buffer (pH 6.5, 100 ml) and water (100 ml) were added and the product was extracted with EtOAc (2×150 ml). The combined organic layer was washed with water (2×200 ml) and dried (Na2SO4). Solvent evaporation in vacuo gave a residue that was purified by Biotage. Elution with EtOAc-PE (1:1 then 2:1) followed by solvent evaporation in vacuo gave the title compound (16.34 g) HPLC RT=1.554 min. TSP+ve 215 (MNH4)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].C([Li])CCC.[Br:17]C(Cl)(Cl)C(Br)(Cl)Cl.O>O1CCCC1>[Br:17][C:10]1[N:5]2[N:4]=[C:3]([CH2:1][CH3:2])[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: CCc1cc2ccccn2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc2cccc(Br)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a solution of 2-ethylpyrazolo[1,5-a]pyridine (80 mg) dissolved in tetrahydrofuran (1 mL) was added n-butyllithium (1.6M hexane solution: 0.58 mL) dropwise at −78° C. under a nitrogen stream, and the reaction mixture was further stirred for 30 minutes at the same temperature. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (196 mg) in tetrahydrofuran (0.5 mL) was added dropwise to the reaction mixture, and stirring was continued for 30 minutes. After raising the temperature to room temperature and adding water to the reaction mixture, extraction was performed with ethyl acetate and the organic extract was washed with water and brine. The obtained organic extract was dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (90 mg) was obtained as a light brown oil from the n-hexane:ethyl acetate (20:1) fraction.
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([O:8][CH2:9][CH2:10][NH2:11])([O-:7])=[O:6].[O:12]=[C:13]1[NH:17][CH:16]([C:18](O)=[O:19])[CH:15]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[S:14]1>>[N+:5]([O:8][CH2:9][CH2:10][NH:11][C:18]([CH:16]1[CH:15]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[S:14][C:13](=[O:12])[NH:17]1)=[O:19])([O-:7])=[O:6]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C1NC(C(=O)O)C(c2cccnc2)S1
Solvent: O=[N+]([O-])O
Product: O=C1NC(C(=O)NCCO[N+](=O)[O-])C(c2cccnc2)S1

Procedure:
A procedure similar to that described in Example 1 was repeated, but using 300 mg of N-(2-nitrooxyethyl)-amine nitrate and 330 mg of 2-oxo-5-(3-pyridyl)thiazolidine-4-carboxylic acid, to obtain 140 mg of the title compound as colorless crystals, melting at 139°-140° C. (after recrystallization from ethanol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8]Br.[CH3:11][N:12]([CH3:20])[C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]([CH3:20])[CH3:11])=[CH:14][CH:15]=1
Reactant: CN(C)c1ccc(S)cc1
Reactant: COC(=O)C=CC=CCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C=CC=CCSc1ccc(N(C)C)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To a solution of 6-bromo-hexa-2,4-dienoic acid methyl ester (1.15 g, 5.6 mmol) and 4-dimethylamino-benzenethiol (0.86 g, 5.6 mmol) in tetrahydrofuran (30 mL) was added dropwise triethylamine (1.6 mL, 11.4 mmol) under an atmosphere of argon. The mixture was stirred at 20° C. for 30 minutes, then filtered. The filtrate was concentrated under reduced to pressure and the residue was dissolved in ethyl acetate (100 mL). This solution was washed with saturated aqueous sodium hydrogen carbonate (50 mL), demineralised water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a yellow oil that was purified by column chromatography (9:1 to 7:3 60-80° C. petroleum ether:diethyl ether, all eluant containing 1% triethylamine by volume). The solid was recrystallised from diethyl ether/petroleum ether to give the title compound (1.0 g, 64%) as a white solid, mp 68-70° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[O:16])[NH:14][CH2:13][CH:12]([CH2:17][NH:18][C:19]([N:21]=[N+]=[N-])=[O:20])[N:11]3[CH:24]=2)[CH:5]=[CH:6][CH:7]=1.[OH-:25].[Na+]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[O:16])[NH:14][CH2:13][CH:12]([CH2:17][NH:18][C:19]([NH:21][CH2:17][CH:12]4[N:11]5[CH:24]=[C:8]([C:4]6[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=6)[CH:9]=[C:10]5[C:15](=[O:25])[NH:14][CH2:13]4)=[O:20])[N:11]3[CH:24]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NC(=O)NCC1CNC(=O)c2cc(-c3cccc(Cl)c3)cn21
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCC1CNC(=O)c2cc(-c3cccc(Cl)c3)cn21)NCC1CNC(=O)c2cc(-c3cccc(Cl)c3)cn21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Step b 71 mg (0.206 mmol) of {[7-(3-chlorophenyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl]methyl}carbamic azide were dissolved in 10 ml of dry THF, NaOH 1N (2 ml) was added and the mixture was stirred at room temperature for 30 minutes. The reaction was diluted with EtOAc and extracted with water, the organic layer was mixed with HCl 2N (5 ml) for 10 minutes, and then discarded; the aqueous solution was brought to pH 10 with NaOH 23% (10 ml) and portioned between EtOAc (10 ml) and THF (10 ml). The organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure to give the title compound 50 mg (89%) as a light yellow solid.
Reaction SMILES: Br[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C1COCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[O:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: O=c1c(Br)coc2ccccc12
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1c(-c2ccc(F)cc2)coc2ccccc12
Yield: 22.5 %

Procedure:
Prepared according to general procedure using 3-bromochromone (338 mg, 1.5 mmol), 4-fluorophenylboronic acid (231 mg, 1.65 mmol), K2CO3 (622 mg, 4.5 mmol), PdCl2(PPh3)2 (45 mg, 0.045 mmol), THF (3 mL) and water (1.5 mL). Purified by flash column chromatography (SiO2, 10% EtOAc/Hex) to afford afford 37 (81 mg, 23%) as a white solid. Analytical data for isoflavone 37: 1H NMR (500 MHz, CDCl3) δ 8.34 (d, J=9 Hz, 1H), 8.04 (s, 1H), 7.72 (app t, J=9 Hz, 1H), 7.58-7.56 (m, 2H), 7.52 (d, J=8.5 Hz, 1H), 7.47 (app t, J=8 Hz, 1H), 7.16 (app t, J=9 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 176.5, 164.0, 162.0, 156.5, 153.2, 134.0, 131.0, 128.0, 126.7, 125.6, 124.8, 118.3, 115.8; LCMS: Mass calculated for C15H9FO2, [M+H]+, 241. Found 241.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.Cl>O.C(O)C>[ClH:1].[OH:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[NH:18][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Nc1cccc(O)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Oc1cccc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1
Temperature: 25 °C

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol), 3-aminophenol (32 mg, 0.290 mmol), and 2N HCl (150 μl) in water:ethanol (2:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature and the resulting crystals was filtered, washed with water, with water:ethanol (2:1) and dried to give a tan crystals (22 mg, 30%). 1H NMR (DMSO-d6): 10.17 (s, 1H), 9.36 (d, J=1.5 Hz, 1H), 8.72–8.66 (m, 2H), 7.66–7.62 (m, 1H), 7.20 (s, 1H), 7.10 (d, J=7.8 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 7.04 (s, 1H), 7.01 (s, 1H), 6.45–6.41 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:15])=[CH:6][C:7]([CH3:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[S:3])[NH2:2].[CH3:16]I>O1CCCC1>[NH:2]=[C:1]([S:3][CH3:16])[C:4]1[C:5]([CH3:15])=[CH:6][C:7]([CH3:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc(C(N)=S)c(C)cc1C
Reactant: CI
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=N)SC)c(C)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-carbamothioyl-2,4-dimethylbenzoate (compound 130.1, 3.10 g, 12.5 mmol, 1.00 equiv, 90%) in tetrahydrofuran (30 mL) was added CH3I (3.95 g, 27.8 mmol, 2.00 equiv) and the resulting mixture was stirred overnight at 25° C. The organic layer was washed with 2×30 mL of Na2S2O4 (aq.) and 1×30 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. This resulted in 2.10 g (64%) of methyl 5-(imino(methylthio)methyl)-2,4-dimethylbenzoate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:19])[N:4]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[CH:6][C:7]=1Cl.[CH3:20][NH2:21].O>CS(C)=O>[Cl:1][C:2]1[C:3](=[O:19])[N:4]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[CH:6][C:7]=1[NH:21][CH3:20]
Reactant: CN
Reactant: CC1(C)CC(n2ncc(Cl)c(Cl)c2=O)CC(C)(C)C1
Solvent: O
Solvent: CS(C)=O
Product: CNc1cnn(C2CC(C)(C)CC(C)(C)C2)c(=O)c1Cl
Temperature: 100 °C
Yield: 34.1 %

Procedure:
4,5-Dichloro-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one (0.3 g, 1.475 mmoles) was dissolved in DMSO (20 mL) and a 40% aqueous solution of methylamine (0.6 mL, 1.7 mmoles) was added with stirring. Heated at 100° C. overnight. Allowed to cool and then poured into water. A solid precipitated out and was filtered off. Purified using a silica cartridge eluted with ethyl acetate:isohexane (3:7) to give the product as a cream solid (150 mg). 1H NMR (300 MHz CDCl3) 7.65 (s, 1H), 5.35 (m, 1H), 4.7 (brs, 1H), 3.05 (d, 3H, J=5 Hz), 1.55 (m, 4H), 1.3 (m, 1H), 1.15 (m, 1H), 1.15 (s, 6H), 0.95 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([CH2:22][NH:23][CH3:24])=[C:10]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][CH3:21])[CH2:16][CH2:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[C:1]([O:5][C:6]([C:8]1[C:9]([CH2:22][NH:23][CH3:24])=[C:10]([C@H:14]2[CH2:15][CH2:16][C@H:17]([N:20]([C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([Cl:25])=[CH:27][CH:28]=3)[CH3:21])[CH2:18][CH2:19]2)[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CNCc1c(C(=O)OC(C)(C)C)cccc1[C@H]1CC[C@H](NC)CC1
Product: CNCc1c(C(=O)OC(C)(C)C)cccc1[C@H]1CC[C@H](N(C)C(=O)c2ccc(Cl)cc2)CC1

Procedure:
from trans-4-(3-tert.butoxycarbonyl-methylaminomethylphenyl)-N-methylcyclohexylamine and 4-chlorobenzoylchloride. Melting point: 134°-135° C.
Reaction SMILES: Cl.[C:2]([CH2:5][CH2:6][CH2:7][CH:8]1[C:20]2[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH2:11][CH2:10][N:9]1[CH2:21][CH3:22])([OH:4])=[O:3].[CH3:23]O>>[CH3:23][O:3][C:2]([CH2:5][CH2:6][CH2:7][CH:8]1[C:20]2[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH2:11][CH2:10][N:9]1[CH2:21][CH3:22])=[O:4]
Reactant: CCN1CCc2c([nH]c3ccccc23)C1CCCC(=O)O
Reactant: CO
Agent: Cl
Product: CCN1CCc2c([nH]c3ccccc23)C1CCCC(=O)OC
Yield: 90 %

Procedure:
10 ml of methanol and 3 ml of 10% methanolic hydrogen chloride were added to 2.86 g of 1,2,3,4-tetrahydro-1-(3-carboxypropyl)-2-ethyl-β-carboline, and the mixture was refluxed for 2 hours. After the reaction was completed, the mixture was concentrated to one third volume. The concentrated mixture was alkalified with an aqueous saturated sodium bicarbonate solution, and then extracted with benzene. The extract was washed with water, dried and evaporated to remove solvent. 2.70 g of 1,2,3,4-tetrahydro-1-(3-methoxycarbonylpropyl)-2-ethyl-β-carboline were obtained. Yield: 90%
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]3)=[O:23])=[CH:17][CH:16]=4)=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([C:13]3[N:14]([C:39]4[CH:38]=[CH:37][CH:36]=[C:35]([C:34]([F:45])([F:44])[F:33])[CH:40]=4)[C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22]([N:24]3[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH2:29]3)=[O:23])=[CH:17][CH:16]=4)=[O:12])[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC5(CC4)OCCO5)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC4(CC2)OCCO4)n3-c2cccc(C(F)(F)F)c2)CC1
Yield: 55 %

Procedure:
The title compound was synthesized in analogy to example 66, from (1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 196), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (55%).