Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[Cl:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]([CH3:32])[C:19]([C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27](=[O:29])[N:26]([CH3:30])[C:25]=2[CH:31]=1)=[O:20].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]([CH3:32])[C:19]([C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27](=[O:29])[N:26]([CH3:30])[C:25]=2[CH:31]=1)([OH:20])[C:2]([F:4])([F:3])[F:1]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc(C(C)C(=O)c2ccc3oc(=O)n(C)c3c2)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(C)C(O)(c2ccc3oc(=O)n(C)c3c2)C(F)(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
Trifluoromethyltrimethylsilane (2M in THF, 6.33 mL) was added at 0° C. to a solution of 5-[2-(2-chloro-4-methoxy-phenyl)-propionyl]-3-methyl-3H-benzooxazol-2-one (1.99 g) in THF (30 mL) followed by the addition of tetrabutylammonium fluoride trihydrate (363 mg). Stirring was continued for 2.5 hours at 0° C. More tetrabutylammonium fluoride (1M in THF, 4.60 mL) was added to the reaction mixture and stirring was continued for 30 minutes at r.t. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, CH2Cl2:MeOH=100:0 to 99:1) to give the title compound as a colorless foam (2.0 g, 80%). MS (m/e)=416.3 [M+H+].
Reaction SMILES: [NH2:1][C@H:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.CC(O)=O>[CH2:9]([NH:1][C@H:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCC[C@H](C)N
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCC[C@H](C)NCc1ccccc1
Temperature: 0 °C
Reaction time: 28 h

Procedure:
A sample of 0.15 mL (1 mmol) of (S)-(+)-2-aminoheptane ((S)-44) 0.1 mL (1 mmol) of benzaldehyde and 0.1 mL of HOAc were combined in 10 mL of CH2Cl2 and cooled to 0° C., then added 650 mg (3 mmol) of sodium triacetoxyborohydride in one portion. The reaction mixture was stirred under argon at room temperature for 28 hours. The mixture was diluted with 10 mL of dichloromethane, cooled in an ice bath and 20 mL of 5% NaOH (in water) was added. Fractions were separated, organics were dried (Na2SO4) and evaporated to 154 mg (70%). 1H NMR (CDCl3) 600.88 (m, 3H), 1.08 (d, 3H J=6.6 Hz), 1.19-1.37 (m, 6H), 1.41-1.67 (m, 2H), 3.62-3.77 (m, 1H), 3.75 (p, 2H, J=12 Hz), 7.17-7.41 (m, 5H); MS (APCI+) m/z (rel): 206 (100); [α]D=+7.8° (c=1.0, MeOH).
Reaction SMILES: [CH3:1][N:2]([CH2:30][CH3:31])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[N:17]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[C:16](=[O:29])[CH2:15][S:14]1.[H][H]>C(O)C.[Pd]>[CH3:1][N:2]([CH2:30][CH3:31])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[N:17]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=2)[C:16](=[O:29])[CH2:15][S:14]1
Reactant: [H][H]
Reactant: CCN(C)CCCOc1ccccc1C1SCC(=O)N1CCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCN(C)CCCOc1ccccc1C1SCC(=O)N1CCc1ccc(N)cc1

Procedure:
A suspension of 10 parts of 2-[2-[3-(methylethylamino)propoxy]phenyl]-3-[2-(4-nitrophenyl)ethyl]-4-thiazolidinone (see Example 19) in 100 ml of ethanol is treated with 1 part of 5% palladium on carbon and placed under 3 atmospheres of gaseous hydrogen. The mixture is shaken until one equivalent of hydrogen is consumed, filtered and the solvent evaporated under reduced pressure to give the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1>CN(C)C(=O)C.O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:18][CH:19]2[CH2:21][CH2:20]2)[C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CC2CC2)C(=O)C1
Reaction time: 18 h
Yield: 99.9 %

Procedure:
Sodium hydride (60% dispersion in oil) (0.40 g, 10.0 mmol) was added portionwise over 10 min to a solution of 3-oxopiperazine-1-carboxylic acid tert-butyl ester (1.00 g, 5.0 mmol) in N,N-dimethylacetamide (10 ml). The mixture was stirred for 30 min before addition of bromomethylcyclopropane (1.45 ml, 15.0 mmol) and then stirred for a further 18 h. The mixture was diluted with water (100 ml) and extracted with EtOAc (2×100 ml). The combined organic extracts were washed with brine (50 ml), dried over MgSO4 and evaporated to give 4-cyclopropylmethyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester (1.27 g, 100%) as a yellow oil. This oil was dissolved in dichloromethane and hydrogen chloride bubbled through the reaction (2×10 min). The solvent was evaporated to give 1-cyclopropylmethylpiperazin-2-one.HCl (0.95 g, 100%) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[CH2:7][S:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.[CH3:21][C:22]([C:33]1[CH:37]=[C:36]([NH2:38])[O:35][N:34]=1)([C@@H:24]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH3:25])[CH3:23].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl.C1COCC1>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[CH2:7][S:8][C:9]([CH3:14])([CH3:13])[C:10]([NH:38][C:36]1[O:35][N:34]=[C:33]([C:22]([CH3:21])([C@@H:24]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[CH3:25])[CH3:23])[CH:37]=1)=[O:12]
Reactant: C[C@H](OC1CCCCO1)C(C)(C)c1cc(N)on1
Reactant: CC(C)(SC[C@H]1COCCO1)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H](OC1CCCCO1)C(C)(C)c1cc(NC(=O)C(C)(C)SC[C@H]2COCCO2)on1
Temperature: 60 °C
Yield: 85.3 %

Procedure:
Activation of 145 mg (0.58 mmol) of 2-{[(2R)-1,4-dioxan-2-ylmethyl]sulfanyl}-2-methylpropanoic acid as its acid chloride is achieved by treatment with oxalyl chloride (0.1 mL, 1.16 mmol) and DMF (1 drop) in DCM (15 mL) at room temperature for 16 h. The solvent is removed under reduced pressure and the crude acid chloride is dissolved in anhydrous THF (5 mL) and added to a solution of 147 mg (0.58 mmol) of 3-[(3S)-2-methyl-3-(oxan-2-yloxy)butan-2-yl]-1,2-oxazol-5-amine and N,N-diisopropylethylamine (0.30 mL, 1.73 mmol) in THF (10 mL). The reaction is heated to 60° C. for 18 h. After cooling to room temperature, the reaction mixture is concentrated under reduced pressure. The residue is diluted with DCM (20 mL) and washed with saturated aqueous NaHCO3 solution (10 mL). The organic layer is dried (MgSO4), filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography (silica, eluent: heptanes, 0-30% ethyl acetate) to afford 226 mg of 2-{[(2R)-1,4-dioxan-2-ylmethyl]sulfanyl}-2-methyl-N-{3-[(3S)-2-methyl-3-(oxan-2-yloxy)butan-2-yl]-1,2-oxazol-5-yl}propanamide of 63% purity. This intermediate is taken on in the next step without further purification. Yield: 54%, ES-MS: m/z 479 [M+Na]
Reaction SMILES: Br[C:2]1[C:3](=[O:14])[CH:4]2[CH:9]([C:10]=1[O:11][CH3:12])[CH:8]1[O:13][CH:5]2[CH2:6][CH2:7]1.[CH2:15]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH2:24][CH3:25])[C:18]=1B(O)O)[CH3:16].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:24]([C:19]1[CH:20]=[C:21]([CH3:23])[CH:22]=[C:17]([CH2:15][CH3:16])[C:18]=1[C:2]1[C:3](=[O:14])[CH:4]2[CH:9]([C:10]=1[O:11][CH3:12])[CH:8]1[O:13][CH:5]2[CH2:6][CH2:7]1)[CH3:25]
Reactant: CCc1cc(C)cc(CC)c1B(O)O
Reactant: COC1=C(Br)C(=O)C2C3CCC(O3)C12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1C1=C(OC)C2C3CCC(O3)C2C1=O

Procedure:
A mixture of (1RS, 2SR,6RS,7SR)-4-bromo-5-methoxy-10-oxatricyclo[5.2.1.02,6]dec-4-en-3-one (0.315 g, 1.2 mmol), 2,6-diethyl-4-methylphenylboronic acid (0.35 g, 1.8 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (20 mg, 0.048 mmol), palladium (II)acetate (5.5 mg, 0.024 mmol) and potassium phosphate (0.51 g, 2.4 mmol) are heated in degassed toluene at 95° C. for 24 hours. The reaction mixture is partitioned between dichloromethane and water, and the organic phase is dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-4-(2,6-diethyl-4-methylphenyl)-5-methoxy-10-oxatricyclo[5.2.1.02,6]dec-4-en-3-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=O)[C:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:7]2[CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.B.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:7]2[CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1c(CCCOc2cccc3ccccc23)c2cccc(Br)c2n1CC(=O)N1CCOCC1
Agent: B
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CCCOc2cccc3ccccc23)c2cccc(Br)c2n1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of EXAMPLE 77A (0.15 g) in THF (10 mL) was added 1M BH3.THF (1.8 mL). The mixture was stirred at room temperature for 16 hours, quenched with methanol (5 mL) and concentrated. The concentrate was dissolved in ethanol (40 mL) and treated with 12N HCl (0.5 mL). After stirring for three hours, the mixture was concentrated, and the concentrate was purified by preparative reverse phase HPLC (Zorbax SB, C-18, 30% to 100% acetonitrile/water/0.1% TFA).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([CH3:10])=[C:8]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]2)[CH:7]=[CH:6][N:5]=1.Cl[C:22]1[S:23][C:24]([C:27]#[N:28])=[CH:25][N:26]=1>C1COCC1>[C:18]([N:15]1[CH2:14][CH2:13][N:12]([CH2:11][C:8]2[CH:7]=[CH:6][N:5]=[C:4]([NH:3][C:22]3[S:23][C:24]([C:27]#[N:28])=[CH:25][N:26]=3)[C:9]=2[CH3:10])[CH2:17][CH2:16]1)(=[O:20])[CH3:19]
Reactant: N#Cc1cnc(Cl)s1
Reactant: CC(=O)N1CCN(Cc2ccnc(N)c2C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1CCN(Cc2ccnc(Nc3ncc(C#N)s3)c2C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (60% dispersion, 14 mg, 0.35 mmol) was stirred in 1 mL anhydrous THF. 1-[4-(2-Amino-3-methyl-pyridin-4-ylmethyl)-piperazin-1-yl]-ethanone (0.039 g, 0.157 mmol) was added followed, after 10 min by the addition of 2-chloro-thiazole-5-carbonitrile (0.027 g, 0.19 mmol). The reaction was stirred at RT for 30 min then was heated to reflux. After 2 h an additional 0.010 g NaH (0.25 mmol) was added. After 1 h the reaction was cooled to RT and quenched with water. The pH was adjusted to 7 with 1M HCl and the mixture was extracted 3× with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase HPLC to provide the pure titled compound. TFA salt: 1H NMR (CD3OD) δ8.37 (d, 1H, J=5.1 Hz), 8.08 (s, 1H), 7.19 (d, 1H, J=5.1 Hz), 4.45 (s, 2H), 3.81 (bs, 4H), 3.35 (s, 4H), 2.47 (s, 3H), 2.15 (s, 3H). MS [M+H]+=357.3.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O[C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:25]=1.P(CCCC)(CCCC)CCCC>C1COCC1>[F:22][C:2]([F:21])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([CH:15]([O:20][C:26]3[CH:25]=[CH:24][CH:36]=[CH:35][C:27]=3[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCCCC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CCOC(=O)COc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCCC(Oc1ccccc1OCC(=O)OCC)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 26.9 %

Procedure:
To a solution of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (99 mg, 0.32 mmol) in dry THF (6.4 mL) at 0° C. (ice/water bath) under nitrogen was added ethyl (4-hydroxyphenoxy)acetate (63 mg, 0.32 mmol) followed after 1 minute by ADDM (164 mg, 0.64 mmol) in one portion. The resulting orange slurry was stirred for 2 minutes and then treated with nBu3P (159 μL, 0.64 mmol) drop-wise over 1 minute. The resulting pale yellow/orange mixture was then allowed to warm slowly to rt over 69 hours. The cloudy mixture was then reduced under vacuum and the residue purified by SPE (silica) eluting with cyclohexane:EtOAc (gradient 100:1 to 1:1) to give the title compound (42 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[OH:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>>[OH:22][CH:23]1[CH2:24][CH2:25][N:26]([C:29]2[CH:37]=[CH:36][C:32]([C:33]([NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][CH:21]=3)[N:6]=[CH:5]4)=[O:34])=[CH:31][CH:30]=2)[CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Reactant: CCOC(=O)c1ccc(-n2ncc3cc(N)ccc32)cc1
Product: CCOC(=O)c1ccc(-n2ncc3cc(NC(=O)c4ccc(N5CCC(O)CC5)cc4)ccc32)cc1

Procedure:
Compound 1030 was prepared according to the procedure described in Scheme IV from ethyl 4-(5-amino-1H-indazol-1-yl)benzoate and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C28H28N4O4: 485.21; found: 485.09.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[Li][CH:10](CC)[CH3:11].C(OCC)(=O)C.[NH4+].[Cl-]>C1COCC1.CO>[CH3:10][C:11]1[NH:1][C:2]2=[CH:3][N:4]=[CH:5][CH:6]=[C:7]2[CH:8]=1
Reactant: Cc1ccncc1N
Reactant: [Li]C(C)CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc2ccncc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.2 %

Procedure:
To a stirred solution of 3-Amino-4-picoline (7 g, 64.8 mmol) in anhydrous THF (200 mL), sec-BuLi (150 mL, 1.3M in cyclohexane, 194 mmol) was added dropwise over 20 minutes at −78° C. The solution was warmed to room temperature and stirred at 3 hours. Ethyl acetate (2.3 g, 25.9 mmol) was added dropwise into the reaction at −78° C. and the mixture was stirred at the same temperature for 2 hours. Methanol (50 mL) was added dropwise into the reaction over 10 minutes. The mixture was warmed to room temperature and stirred for 1 hour. A half-saturated NH4Cl (250 mL) was added. The mixture was extracted with EA. The combined organic layers were washed with brine, dried and concentrated to afford the crude product. The crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate=10:1) to afford 2-methyl-1H-pyrrolo[2,3-c]pyridine (2.5 g, 73.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH:22]([CH3:24])[CH3:23].Cl>O1CCCC1>[CH3:23][CH:22]([N:10]1[C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=2[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:9]1)[CH3:24]
Reactant: CC(C)I
Reactant: O=c1[nH]nc(-c2cccc(Cl)c2)c2ncccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)n1nc(-c2cccc(Cl)c2)c2ncccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
To a suspension of 8- (3-chlorophenyl)pyrido [2,3 -d]pyridazin-5-one (0.33 g, 1.28 mmoles) in tetrahydrofuran (50 ml) was added sodium hydride (0.07 g, 1.53 mmoles). The mixture was stirred at room temperature for 30 minutes under an inert atmosphere. 2-Iodopropane (0.64 ml, 6.4 mmoles) was added and the mixture refluxed for 48 hours. The mixture was cooled and acidified by the addition of 50 ml of 1N HCl. The mixture was extracted with ethyl acetate (3×50 ml) and dried over magnesium sulfate. The solution was filtered and the solvent removed to yield the crude product. The product was purified by crystallization (ethyl ether/hexane) yielding 0.15 g of 6-(2-propyl)-8-(3-chlorophenyl)pyrido[2,3-d]pyridazin-5-one (39%), mp 80°-81° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[C:18]([NH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:20])[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:21][C:18](=[O:20])[CH3:19])[CH:27]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)o1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)Nc1cccc(-c2ccc(C(=O)N[C@H]3CN4CCC3CC4)o2)c1

Procedure:
Prepared by a method analogous to that described in Example 1 from (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and 3-(N-acetylamino)phenylboronic acid, using tetrakis(triphenylphosphine)palladium (0) and sodium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The product-containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M in diethyl ether) was added and the solution was evaporated. Recrystallisation from methanol/diethyl ether gave the hydrochloride salt of the title compound as a yellow solid; MS (ES+) 354 (MH+).
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C@:10]2([CH2:19][C@H:18]2[C:20]2[CH:28]=[C:27]3[C:23]([CH:24]=[N:25][N:26]3CC3C=CC=CC=3)=[CH:22][CH:21]=2)[C:9]1=[O:36])C1C=CC=CC=1.C1COCC1.CC([O-])(C)C.[K+]>CS(C)=O>[NH:26]1[C:27]2[C:23](=[CH:22][CH:21]=[C:20]([C@H:18]3[C@@:10]4([C:11]5[C:16](=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=5)[NH:8][C:9]4=[O:36])[CH2:19]3)[CH:28]=2)[CH:24]=[N:25]1
Reactant: Cc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3cnn(Cc4ccccc4)c3c1)C(=O)N2Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3cn[nH]c3c1)C(=O)N2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 100 mL flask charged with (1R,2S)-1′-benzyl-2-(1-benzyl-1H-indazol-6-yl)-5′-methylspiro[cyclopropane-1,3′-indolin]-2′-one (469 mg, 1 mmol) was added dry THF (2 mL) and the resulting mixture was stirred at 0° C. before KOtBu (1 M in THF, 18 mL, 18 mmol) was added over 2 min. After addition, the resulting mixture was stirred for 15 min at 0° C. and DMSO (1.85 mL) was added. Oxygen was bubbled through for 1 h and reaction turned from homogeneous to heterogeneous. LC-MS showed good conversion at 50 min. It was quenched with sat. NH4Cl. The above reaction was repeated on a larger scale using (1R,2S)-1′-benzyl-2-(1-benzyl-1H-indazol-6-yl)-5′-methylspiro[cyclopropane-1,3′-indolin]-2′-one (1.41 g, 3 mmol). After quenching with saturated NH4Cl, two reactions were combined, diluted with H2O and extracted with EtOAc (100 mL×2). Purification by Biotage Isolera (10-95% EtOAc in hexane) gave the title compound as a light solid (680 mg, 53%). 1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.46 (s, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.81 (d, J=7.6 Hz, 1H), 5.78 (s, 1H), 3.32 (t, overlapping with MeOH residue), 2.20-2.12 (m, 2H), 1.87 (s, 3H); MS ESI 290.1 [M+H]+, calcd for [C18H15N3O+H]+ 290.1.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C.O>C(Cl)Cl>[O:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][NH:12][S:8]([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:17][CH2:18]1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: NCCCN1CCOCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCCCN1CCOCC1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
4-Iodophenylsulphonyl chloride (3.03 g, 10 mmol) in DCM (30 ml) was added dropwise over 15 minutes to a solution of 4-(3-aminopropyl)morpholine (1.75 ml, 12 mmol) and triethylamine (1.7 ml, 12 mmol) in DCM (50 ml) cooled in an ice bath. The mixture was allowed to warm to ambient temperature and stirred for 15 minutes. Water (50 ml) was added and the phases separated. The organic layer was washed with water (50 ml) and brine (50 ml), dried (Chemelut column 1010) and evaporated to give the title compound (4.10 g, 100%) as a beige solid. NMR 1.70 (m, 2H), 2.43 (m, 6), 3.14 (t, 2H), 3.71 (m, 4H), 7.08 (s, 1H), 7.58 (d, 2H), 7.85 (d, 2H); m/z 411.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][O:4][N:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:31][C@H:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1>C(Cl)Cl.CN(C=O)C>[CH:32]1([NH:31][C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][CH:5]=2)=[O:9])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: N[C@@H]1CCCc2ccccc21
Reactant: Cc1nocc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nocc1C(=O)NC1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.5 %

Procedure:
To a solution of 3-Methyl-isoxazole-4-carboxylic acid (0.52 g, 4.06 mmol) in DCM (15 mL) and DMF (2 mL), was added HOBt (1.1 g, 8.14 mmol) and EDCI (0.896 g 4.67 mmol). The clear yellow solution was cooled to 0 C and allowed to stir under Ar for 15 minutes. To the solution was added (R)-1-Amino-1,2,3,4-tetrahydronaphthalene (0.73 mL, 5.04 mmol and the reaction mixture was allowed to slowly warm to ambient temperature and was stirred for overnight. Dilution with DCM (50 mL) was followed by aqueous extraction (NaHCO3 water, brine (50 mL), drying over MgSO4, filtration and removal of solvent in vacuo. Silica gel chromatography (0-25% Hexane:EtOAc) afforded the title compound (650 mg; 62.5%) as a sticky solid. 1H NMR (CDCl3) δ 1.88 (m, 3H), 2.12 (m, 1H), 2.51 (s, 3H), 2.81 (m, 2H), 5.32 (m, 1H), 5.99 (bd, 1H), 7.13 (m, 1H), 7.20 (m, 2H) 7.20 (m, 2H); 13C NMR (CDCl3) δ 11.22, 20.15, 29.41, 30.35, 47.93, 116.73, 126.72, 127.88, 128.88, 129.65, 136.25, 138.00, 158.45, 160.28. ESIMS: 257 (M+H) EA calc'd for C15H16N2O2: C, 70.29; H, 6.29; N, 10.93; found C, 70.61; H, 6.11; N, 11.09.