Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:9][C:10]([NH:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])=[O:11].O>CN(C)C=O>[CH3:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:20])[C:13]=1[NH:12][C:10](=[O:11])[CH2:9][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C)c1NC(=O)Cn1ccnc1
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
A mixture of 6.0 g of a 60% oil dispersion of sodium hydride in 90 ml of dimethylformamide was stirred and heated at 50° C. during the portionwise addition of 10.32 g of imidazole. After stirring for 20 minutes, 15.0 g of 2-chloro-N-(2,6-dimethylphenyl)acetamide was added and heating was continued for an additional 30 minutes. Water was added and the reaction mixture was evaporated to dryness. The residue was dissolved in 2N hydrochloric acid, washed with ether, made strongly basic with excess sodium hydroxide and the product was extracted with dichloromethane. The combined organic layers were dried with sodium sulfate and evaporated to give 14 g of N-(2,6-dimethylphenyl)-1H-imidazole-1-acetamide, mp 160°-162° C.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)=[CH:4][N:3]=[CH:2]1.C([Li])CCC.CON(C)[C:31](=[O:43])[CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1>C1COCC1.CCCCCC>[CH3:42][O:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][O:33][CH2:32][C:31]([C:2]2[S:1][C:5]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)=[CH:4][N:3]=2)=[O:43])=[CH:36][CH:37]=1
Reactant: COc1ccc(COCC(=O)N(C)OC)cc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cncs3)ncnc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(COCC(=O)c2ncc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)s2)cc1
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
To a solution of 4-(1,3-thiazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (2.12 g, 6.38 mmol) in THF (70 mL) at −78° C. was added 2.5 M n-butyllithium in hexane (3.06 mL) slowly dropwise. After stirring for 30 minutes, N-methoxy-2-[(4-methoxybenzyl)oxy]-N-methylacetamide (2.29 g, 9.56 mmol) was added. The reaction was continued for 30 minutes following the addition, at −78° C., then the cooling bath was removed and the reaction was quenched with saturated ammonium chloride and extracted with ether. The extracts were dried with sodium sulfate and concentrated in vacuo. The crude mixture was purified by flash column chromatography (ethyl acetate/hexanes) to afford desired product (2.16 g, 66%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[CH:28]=[C:29]([OH:34])[CH:30]=[CH:31][C:32]=1[F:33].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:26][C:27]2[CH:28]=[C:29]([OH:34])[CH:30]=[CH:31][C:32]=2[F:33])=[O:19])[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: Nc1cc(O)ccc1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)c1cc(NC(=O)Nc2cc(O)ccc2F)n(-c2ccccc2)n1
Temperature: 50 °C
Yield: 58.9 %

Procedure:
To a stirred suspension of phenyl 3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared as described in example 153A) (335 mg, 1 mmol) and 3-amino-4-fluorophenol (127 mg, 1 mmol) in acetonitrile (15 mL) at rt, was added DBU (0.3 mL, 2 mmol). The mixture was heated at 50° C. for 1 h. The reaction mixture was cooled to rt, concentrated under reduced pressure, and the residue purified via silica gel column chromatography to afford 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-hydroxyphenyl)urea (217 mg, 59%) as a solid. LC-MS (ESI) m/z 369 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9]1)=[O:7].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:29]=2[C:30]([NH:32][CH2:33][C:34]#[CH:35])=[O:31])[C:24]([Cl:41])=[CH:23][N:22]=1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([NH:19][C:21]3[N:26]=[C:25]([NH:27][C:28]4[C:29]([C:30](=[O:31])[NH:32][CH2:33][C:34]#[CH:35])=[CH:36][CH:37]=[CH:38][C:39]=4[F:40])[C:24]([Cl:41])=[CH:23][N:22]=3)=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9]1)=[O:7]
Reactant: COCCOC(=O)N1CCCOc2cc(N)ccc21
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OCCOC)ncc1Cl

Procedure:
The title compound was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 2-methoxy-ethyl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 1410. Product isolated as a white foam (70 mg, 44%). LCMS (me/) 569 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.47-9.36 (m, 1H), 9.24-9.15 (m, 1H), 9.05-8.95 (m, 1H), 8.19 (s, 1H), 7.57-7.41 (m, 3H), 7.33-7.23 (m, 1H), 7.14-7.05 (m, 1H), 6.93 (d, 1H, J=8.7 Hz), 4.23-3.87 (m, 6H), 3.67-3.49 (m, 2H), 3.46-3.37 (m, 1H), 3.36-3.26 (m, 2H), 3.23-3.14 (m, 2H), 3.11 (t, 1H, J=2.4 Hz), 1.97-1.84 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.C([Li])CCC.CCCCCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>C(OCC)C>[CH3:8][C:5]1[CH:4]=[CH:3][C:2]([B:20]([OH:25])[OH:21])=[CH:7][N:6]=1
Reactant: Cc1ccc(Br)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1ccc(B(O)O)cn1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 5-bromo-2-methyl-pyridine (992 mg, 5.8 mmol) in diethyl ether (5 mL) was slowly added n-butyl lithium in hexane (1.4 M, 5 mL, 7 mmol) at −78° C. over a span of 10 minutes under nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 90 minutes. At this time, tri-isopropyl borate (1.30 g, 6.9 mmol) was slowly added, and the resulting mixture was allowed to warm to room temperature and stirred for an additional 90 minutes. The reaction was quenched with 5% aqueous sodium hydroxide solution (6 mL) at 0° C. and was extracted with diethyl ether (25 mL×4). The pH of the aqueous solution was adjusted to about 7 by the slow addition of 2N hydrochloric acid. The aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-methyl-5-pyridinylbronic acid, which was used without further purification.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:12]=[CH:11][C:9]([OH:10])=[C:8]([CH2:13][CH2:14][CH3:15])[C:7]=2[OH:16])=O)[CH2:3]C1.[NH2:17][OH:18].Cl.C([O-])(=O)C.[Na+]>CO.O>[CH:4]1([CH:6]2[C:12](=[N:17][OH:18])[CH:11]=[C:9]([OH:10])[C:8]([CH2:13][CH2:14][CH3:15])=[C:7]2[OH:16])[CH2:1][CH2:3]1
Reactant: NO
Reactant: CCCc1c(O)ccc(C(=O)C2CC2)c1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCC1=C(O)C(C2CC2)C(=NO)C=C1O

Procedure:
A solution of 4-cyclopropylcarbonyl-2-(n-propyl)resorcinol (1.0 g, 4.54 mmole) in methanol (10 mL) was treated with hydroxylamine.HCl (1.58g, 22.7 mmole) and sodium acetate (1.86g, 22.7 mmole) and the mixture refluxed for 7 hours. The cooled mixture was poured into water and extracted 3× with ethyl acetate. The combined extracts were washed with water (2×), 10% sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo to give a solid. The crude product was chromatographed on silica gel eluting with methylene chloride followed by methanol:methylene chloride (5:95) to afford the title compound. NMR (CDCl3); δ 0.89 (m, 2H); 0.94 (t, 3H); 1.10 (m, 2H); 1.76 (m, 1H); 2.61 (t, 2H); 6.35 (d, 1H); 7.41 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.Cl.CO>O>[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]2=[O:12])=[CH:17][CH:16]=1
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: CN(C)c1ccc(C=O)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: CN(C)c1ccc(C=C2CCc3cc(O)ccc3C2=O)cc1
Temperature: 25 °C
Yield: 48.9 %

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and 4-dimethylaminobenzaldehyde 0.97 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for 1.5 hours and cooled to room temperature, and water 400 ml was added. The precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for six hours under reduced pressure to obtain the desired compound 0.885 g.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:15][O:16][CH:17]([O:21][CH3:22])N(C)C>>[CH3:15][O:16][CH:17]([O:21][CH3:22])[CH:10]1[CH2:9][CH:8]([CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:14][CH2:13][CH2:12][NH:11]1
Reactant: c1cn(CCC2CCCNCC2)cn1
Reactant: COC(OC)N(C)C
Product: COC(OC)C1CC(CCn2ccnc2)CCCN1
Temperature: 100 °C

Procedure:
A mixture of hexahydro-4-[2-(1H-imidazol-1-yl)ethyl]-1H-azepine (6.0 g, 0.031 M) and dimethylformamide dimethylacetal (33 ml) was heated at 100° C. for 4 hrs. The reaction was stripped to dryness to give hexahydro-4-[2-(1H-imidazol-1-yl)ethyl]-1H-azepine carboxaldehyde dimethylacetal. The solution of the hexahydroazepine carboxaldehyde dimethylacetal in methylene chloride (40 ml) was added to the mixture of 6-aminopenicillanic acid (5.7 g, 0.026 M) and diisopropylethylamine (3.15 ml) in methylene chloride (150 ml) at 0° C. and stirred at 0° C. for 1 hr, room temperature for 3 hrs. The solvent was removed and water (100 ml) was added. After being washed with ether, the aqueous solution, acidified to pH 3, was purified on Sephadex LH 20 columns to give [2S-(2alpha,5alpha,6beta)]-6-[[4-[hexahydro[2-(1H-imidazol-1 -yl)ethyl]-1H-azepin-1-yl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 1.2 molar hydrochloride hydrate (diastereomers) (4.0 g, 32% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]([O:20]C)=O)[CH:12]=2.[NH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[NH:22][C:18]([C:13]1[CH:12]=[C:11]2[C:16]([CH:17]=[C:9]([C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:1][C:2]=3[CH3:7])[NH:10]2)=[CH:15][CH:14]=1)=[O:20]
Reactant: COC(=O)c1ccc2cc(-c3c(C)cccc3C)[nH]c2c1
Reactant: Nc1ccc2ccccc2n1
Product: Cc1cccc(C)c1-c1cc2ccc(C(=O)Nc3ccc4ccccc4n3)cc2[nH]1

Procedure:
The title compound was prepared from methyl 2-(2,6-dimethylphenyl)-1H-indole-6-carboxylate and 2-aminoquinoline analogous to Example 3-6. 1H NMR (DMSO-d6, 400 MHz) δ 11.60 (s, 1H), 11.01 (s, 1H), 8.40 (s, 2H), 7.95 (d, J=7.83 Hz, 1H), 7.89 (d, J=8.46 Hz, 1H), 7.80 (d, J=9.60 Hz, 1H), 7.74 (t, 1H), 7.65 (d, J=8.34 Hz, 1H), 7.52 (t, 1H), 7.28 (m, 1H), 7.19 (d, J=7.45 Hz, 1H), 6.44 (s, 1H), 2.15 (s, 6H). MS (m/z) 392.2 (M+1).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=O)[O:4][C:2]2=[O:3].N1C=CC=C[CH:14]=1>>[CH3:14][C:5]1[O:4][C:2](=[O:3])[C:1]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: c1ccncc1
Product: Cc1nc2ccccc2c(=O)o1
Temperature: 45 °C
Yield: 86 %

Procedure:
The isatoic anhydride and pyridine were combined in a round bottomed, 3-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, dropping funnel and drying tube. The isatoic anhydride suspension was heated to 45° C and the acetic anhydride was added over a period of 30 minutes. Carbon dioxide evolution occurred during the addition of the acetic anhydride. The reaction mixture was heated to 90° C for 1.5 hours. The evolution of carbon dioxide stopped. The reaction mixture was concentrated under reduced pressure (15 mm. of Hg). The residue was crystallized from 100 ml of cyclohexane to give 42 parts by weight (86% yield) of 2-methyl-4H-3,1-benzoxazine-4-one with m.p. 79°-81° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.[Li+].[CH3:17][CH:18]([N-]C(C)C)C.C(I)C>C1COCC1>[CH2:17]([CH:10]([CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:4]=1)[C:11]([OH:13])=[O:12])[CH3:18]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCC(Cc1cccc(C(F)(F)F)c1)C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1 eq. of 3-(3-trifluoromethylphenyl)propionic acid was converted, in THF and at -78° C., into the dianion using 2 eq. of LDA (stirring for 30 min. at -78° C., then 30 min. at RT). 2 eq. of ethyl iodide were then added at -78° C. and the mixture was subsequently stirred at RT. Acidic working-up using 2N HCl and purification by chromatography yielded 2-ethyl-3-(3-trifluoromethylphenyl)-propionic acid.
Reaction SMILES: [NH3:1].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]=[C:10]=[S:11])#[N:3]>O1CCOCC1>[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH2:1])=[S:11])#[N:3]
Reactant: N
Reactant: N#CCCCCCN=C=S
Solvent: C1COCCO1
Product: N#CCCCCCNC(N)=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0.5M solution of ammonia in dioxane (80 ml) at 10° C. was added 5-cyanopentyl isothiocyanate (5 g) and the solution was stirred at room temperature overnight. TLC of the reaction mixture still showed the presence of some starting material. Additional ammonia in dioxane (40 ml) was added and the solution was stirred for a further 6 hours. At this stage, the reaction was found to be complete as judged by TLC analysis. The solvent was then removed on a rotary evaporator and to the residue was added methyl tert-butyl ether (40 ml). The mixture was then heated on steam bath briefly (the solid did not dissolve) then cooled to give the required product as a colorless crystalline material (5 g), m.p. 69-71° C.
Reaction SMILES: C[C:2]1[C:3]([C:7]([OH:9])=O)=[CH:4][S:5][CH:6]=1.B.C1C[O:14][CH2:13]C1.CO>C1COCC1>[CH3:13][O:14][C:2]1[C:3]([CH2:7][OH:9])=[CH:4][S:5][CH:6]=1
Reactant: C1CCOC1
Reactant: Cc1cscc1C(=O)O
Agent: B
Solvent: CO
Product: COc1cscc1CO
Yield: 99.9 %

Procedure:
4-Methylthiophene-3-carboxylic acid (158 mg, 1.00 mmol) was reduced with BH3-THF (1.0M in THF, 3.0 mL, 3.0 mmol) in THF (2 mL) at room temperature and treated with MeOH to give (4-methoxy-thiophen-3-yl)-methanol as an oil (144 mg, 100%) after work-up.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>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.COCCOC.CCO>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:19][CH2:20]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(Cl)nncc2c1
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(-c3ccccc3Cl)nncc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
A mixture of 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (0.11 g, 0.327 mmol), 2-chlorophenylboronic acid (51 mg, 329 μmol), 5 mL DME/EtOH (4:1), 0.5 mL 2M K2CO3 and tetrakis(triphenylphosphine)palladium (20mg) was stirred at 90° C. for 1 h. The reaction mixture was cooled to RT. The crude product was purified via flash chromatography (silica gel) with 2% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give the crude compound (120 mg) as a yellow solid. The compound was further purified by HPLC by dissolving the crude product in methanol (˜20 mg/mL) and injecting at a rate of about 0.500 mL per injection onto the Gilson preparatory HPLC. Pure product fractions were collected, combined, basefied with sodium bicarbonate (saturated, aqueous), extracted with CH2Cl2, separated, dried over sodium sulfate, and concentrated via rotary evaporation to give pure title compound (28.8 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10].[NH3:15]>O1CCCC1>[NH2:15][C:13]([NH:12][S:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1])(=[O:10])=[O:11])=[O:14]
Reactant: N
Reactant: O=C=NS(=O)(=O)c1cccc(Cl)c1Cl
Solvent: C1CCOC1
Product: NC(=O)NS(=O)(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10.0 g of 2,3-dichlorobenzenesulfonyl isocyanate in 200 mL of dry tetrahydrofuran was cooled to 0° C. and treated with 5.0 mL of anhydrous liquid ammonia, added in a dropwise manner at a rate that maintained the temperature between 0° and 10° C. The resultant white mixture was allowed to warm to room temperature and was stirred overnight. The precipitate was collected by filtration, dissolved in 250 mL of water, and acidified with concentrated hydrochloric acid to yield a white solid. Filtration and air drying gave 7.0 g of the title compound, m.p. 197°-200° C.; NMR (DMSO-d6): δ6.0-6.8 (br s, 2H), 7.6 (t, 1H), 7.8-8.1 (m, 2H), 11.1 (br s, 1H); IR (nujol): 1690 cm-1.
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[S:12][C:11](=[O:14])[NH:10][C:9]=2[C:8]([OH:15])=[CH:7][CH:6]=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][O:27][CH2:28][CH2:29][S:30]([CH2:33][CH2:34][C:35](O)=[O:36])(=[O:32])=[O:31])=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[OH:15][C:8]1[C:9]2[NH:10][C:11](=[O:14])[S:12][C:13]=2[C:5]([CH2:4][CH2:3][NH:2][C:35](=[O:36])[CH2:34][CH2:33][S:30]([CH2:29][CH2:28][O:27][CH2:26][CH2:25][C:22]2[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=2)(=[O:31])=[O:32])=[CH:6][CH:7]=1
Reactant: NCCc1ccc(O)c2[nH]c(=O)sc12
Reactant: O=C(O)CCS(=O)(=O)CCOCCc1ccc([N+](=O)[O-])cc1
Agent: Br
Product: O=C(CCS(=O)(=O)CCOCCc1ccc([N+](=O)[O-])cc1)NCCc1ccc(O)c2[nH]c(=O)sc12

Procedure:
Following the general method outlined in Example 20c) using 7-[2-aminoethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-one hydrobromide and 3-[2-[2-[4-nitrophenyl]ethoxy]ethylsulphonyl]propanoic acid [Example 13a)] gave the subtitled compound after purification by chromatography over silica using 8% ethanol in dichloromethane as eluant.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[N:14]=[N:15][N:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:17]=3)[CH:12]=[C:6]2[C:5]=1[NH:24][C@H:25]1[C@@H:29]([CH2:30][CH3:31])[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]1)(=[O:3])[NH2:2].Cl.O1CCOCC1>ClCCl>[CH2:30]([C@H:29]1[CH2:28][NH:27][CH2:26][C@H:25]1[NH:24][C:5]1[C:6]2[N:7]([CH:10]=[C:11]([C:13]3[N:14]=[N:15][N:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:17]=3)[CH:12]=2)[N:8]=[CH:9][C:4]=1[C:1]([NH2:2])=[O:3])[CH3:31]
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cn(-c4ccccc4)nn3)cc12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cn(-c4ccccc4)nn3)cc12
Temperature: 25 °C
Yield: 106.4 %

Procedure:
To a solution of (3S,4S)-tert-butyl 3-((3-carbamoyl-6-(1-phenyl-1H-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (41 mg, 0.079 mmol) in dichloromethane (1 mL) was added 4N HCl in 1,4-dioxane (0.198 mL, 0.794 mmol). The solution was stirred at room temperature. After stirring 2 h, the reaction is complete. Concentration afforded a tan solid as the hydrochloride salt of the title compound (35 mg, 99% yield). MS (ES+) m/z: 417.1 (M+H). LC retention time: 2.776 min (analytical LCMS Method J).
Reaction SMILES: [CH3:1][P:2]1(=[O:21])[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+].FC1[CH:37]=[CH:38][C:39]([N+:44]([O-:46])=[O:45])=[C:40]([O:42][CH3:43])[CH:41]=1>C(Cl)Cl>[CH3:43][O:42][C:40]1[CH:41]=[C:14]([N:11]2[CH2:10][CH2:9][CH:8]([N:5]3[CH2:4][CH2:3][P:2](=[O:21])([CH3:1])[CH2:7][CH2:6]3)[CH2:13][CH2:12]2)[CH:37]=[CH:38][C:39]=1[N+:44]([O-:46])=[O:45]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCP(C)(=O)CC2)CC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCC(N3CCP(C)(=O)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 85.1 %

Procedure:
To a stirring solution of tert-butyl 4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidine-1-carboxylate (178 mg, 0.563 mmol) in CH2Cl2 (2 mL) was added trifluoroacetic acid (0.5 mL). After 20 min, the solution was concentrated and the resulting residue was redissolved in DMF (2 mL). Potassium carbonate (160 mg, 1.16 mmol) was added portionwise to the stirring solution followed by 5-fluoro-2-nitroanisole (158 mg, 0.930 mmol). The reaction mixture was heated to 50° C. After 2 h, the reaction mixture was concentrated and the residue was purified by silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) to afford the compound as a bright yellow solid (176 mg, 86% yield).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35]C[C@@H]5CCCO5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].O1C[CH2:49][CH2:48][C@H:47]1[CH2:51]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH:47]([CH3:51])[CH2:48][CH3:49])[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: NC[C@@H]1CCCO1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)NCc1cc(F)cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Yield: 50.6 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 2-butanamine (37 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 27.7 mg of the title compound (50.6%).