Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:8][C:9]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:16]([O:28][CH3:29])[CH:15]=1)=[S:12])=O.[C:36](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:29][O:28][C:16]1[CH:15]=[C:14]([N:13]2[C:3](=[O:2])[C:5]3[S:6][C:7]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:8][C:9]=3[N:10]=[C:11]2[S:12][CH3:36])[CH:19]=[CH:18][C:17]=1[O:20][CH2:21][CH2:22][N:23]1[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(=S)Nc1ccc(OCCN2CCCC2)c(OC)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(-n2c(SC)nc3cc(-c4ccccc4)sc3c2=O)ccc1OCCN1CCCC1
Yield: 50 %

Procedure:
This ester (300 mg, 0.56 mmol) and potassium carbonate (162 mg, 1.17 mmol) were suspended in dry DMF (5 ml) and treated with a solution of methyl iodide (83 mg, 0.59 mmol) in DMF (1 ml). When the addition was complete, the mixture was evaporated. The residue was purified by chromatography on silica gel (eluting with dichloromethane-methanol) giving the title compound in 50% yield;
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH2:13]([OH:16])[C:14]#[CH:15].N1CCOCC1>C1(C)C=CC=CC=1.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>[F:10][C:9]([F:12])([F:11])[O:8][C:4]1[CH:3]=[C:2]([C:15]#[C:14][CH2:13][OH:16])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCO
Reactant: FC(F)(F)Oc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: OCC#Cc1cccc(OC(F)(F)F)c1
Temperature: 80 °C
Yield: 80.2 %

Procedure:
To a solution of 1-iodo-3-(trifluoromethoxy)benzene (0.5 g, 1.73 mmol) in toluene (10 mL) was added prop-2-yn-1-ol (0.15 g, 2.62 mmol) and morpholine (0.5 mL). Then cuprous iodide (4 mg, 0.02 mmol) and bis(triphenylphosphine)palladium(II) chloride (14 mg, 0.02 mmol) were added to the mixture under nitrogen. The reaction was heated at 80° C. overnight. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:6 to 1:3) to give 3-(3-(trifluoromethoxy)phenyl)prop-2-yn-1-ol (0.3 g, 80.2%) as a yellow oil. LCMS retention time 1.552 min.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].S(Cl)(Cl)=O.[CH3:16]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: CO
Reactant: Cc1cc(C(=O)O)ccc1Br
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
To a solution of 4-bromo-3-methylbenzoic acid (Aldrich 532819, 30 g; 139.5 mmol) in MeOH (600 mL), under N2 was added dropwise thionyl chloride (40.5 mL; 558.0 mmol) over 10 min. The reaction mixture was stirred at RT for 12 hours. The solvents were concentrated and the crude residue was dissolved in EtOAc (700 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 (200 mL), water (200 mL), brine (200 mL), dried over MgSO4 and concentrated affording the title compound as an orange solid (31.3 g, 98%). 1H NMR (DMSO-d6, 300 MHz) δ 7.96-7.95 (m, 1H), 7.79-7.69 (m, 2H), 3.89 (s, 3H), 2.45 (s, 3H). HPLC (Method A) Rt 4.37 min (Purity: 96.4%).
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:31])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:13]3[C:18]([C:19]=2O)=[CH:17][C:16]([F:21])=[CH:15][N:14]=3)=O)CCCCC1.C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:41]>>[Cl:41][C:19]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([F:21])[CH:17]=2)[N:12]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:11](=[O:31])[C:10]=1[C:8]#[N:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(Cn2c(=O)c(C(=O)NC3CCCCC3)c(O)c3cc(F)cnc32)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2c(=O)c(C#N)c(Cl)c3cc(F)cnc32)cc1
Yield: 69 %

Procedure:
A solution of 6-fluoro-4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid cyclohexylamide (92) (7.46 g, 17.53 mmol) and triethylamine (6.1 mL, 43.83 mmol) was heated in neat POCl3 overnight at 90° C. The solution was cooled and the excess POCl3 was distilled under vacuum. The residue was suspended in saturated NaHCO3 solution, sonicated briefly and filtered. The solids were dissolved in dichloromethane, washed subsequently by saturated NaHCO3 solution, water and brine. The organic phase was dried over MgSO4 and evaporated to yield 4.2 g (69%) of 4-chloro-6-fluoro-1-(4-methoxybenzyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (94) as white solids. MP 195° C. 1H-NMR (DMSO-d6): δ 3.69 (s, 3H), 5.51 (s, 2H), 6.82 (d, J=8.8 Hz, 2H), 7.29 (d, J=8.8 Hz, 2H), 8.48 (dd, J=2.8, 8.4 Hz, 1H), 8.96 (d, J=2.8 Hz, 1H); EIMS m/z 344 (M+1).
Reaction SMILES: CN(C)[C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[C:9](CC)[CH:8]=[CH:7][C:6]=1NC1C=CC(C)=C(C(F)(F)F)C=1F.CC[OH:30]>[OH-].[Na+]>[C:5]1([CH2:4][C:3]([OH:26])=[O:30])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCc1ccc(Nc2ccc(C)c(C(F)(F)F)c2F)c(CC(=O)N(C)C)c1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1ccccc1
Temperature: 80 °C

Procedure:
A solution of the above 5-ethyl-2-(2′-fluoro-4′-methyl-3′-trifluoromethylanilino)phenylacetic acid N,N-dimethyl amide described in Example 3 (0.9 g, 2,4 mmol) in EtOH (25 mL) and 4N NaOH (12 mL) is heated to 80° C. overnight. After cooling, the reaction is concentrated under reduced pressure and diluted with ice cold EtOAc. The pH of the aqueous layer is adjusted to 1-2 with ice cold 2.5 N HCl. The separated organic layer is dried with Na2SO4 and concentrated to a solid. The solid is purified by trituration with an Et2O/hexane mixture to give the title acid, 5-ethyl-2-2′-fluoro-4′-methyl-3′-trifluoromethylanilino)phenylacetic acid.
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10]([NH:12][C@H:13]([CH3:20])[C@@H:14]([CH2:18][CH3:19])[C:15]([OH:17])=O)=[O:11])([CH3:8])([CH3:7])[CH3:6].Cl.[NH2:22][C@@H:23]([CH2:28][OH:29])[C:24]([O:26][CH3:27])=[O:25].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[C:5]([O:9][C:10]([NH:12][C@H:13]([CH3:20])[C@@H:14]([CH2:18][CH3:19])[C:15]([NH:22][CH:23]([CH2:28][OH:29])[C:24]([O:26][CH3:27])=[O:25])=[O:17])=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: COC(=O)[C@@H](N)CO
Reactant: CC[C@@H](C(=O)O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](C(=O)NC(CO)C(=O)OC)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDC (2.01 g, 10.51 mmol) was added in one portion to a solution of (2R,3R)-3-((tert-butoxycarbonyl)amino)-2-ethylbutanoic acid (1.62 g, 7.00 mmol), (S)-methyl 2-amino-3-hydroxypropanoate hydrochloride (1.64 g, 10.51 mmol), HOBT (1.61 g, 10.51 mmol) and triethylamine (3.42 ml, 24.51 mmol) in anhydrous dichloromethane (28.0 ml). The reaction mixture was allowed to stir at rt under a nitrogen atmosphere overnight before evaporating in vacuo. The residue was then taken up in ethyl acetate (50 mL) and washed with water (50 mL). The organic was then dried (MgSO4) and evaporated in vacuo. The residue was treated with MeOH to precipitate title compound (1.71 g, 74%) which was used immediately in the next reaction. 1H NMR (400 MHz, CCl3D) δ 6.56 (d, J=6.6 Hz, 1H), 4.68 (dt, J=7.2, 3.5 Hz, 1H), 4.09-3.98 (m, 2H), 3.98-3.91 (m, 1H), 3.86 (br. s., 1H), 3.81 (s, 3H), 1.83-1.67 (m, 1H), 1.67-1.52 (m, 1H), 1.44 (s, 9H), 1.18 (d, J=6.8 Hz, 3H), 0.96 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:35])[C:12]2[O:18][C:17]3[C:19]([Cl:31])=[CH:20][C:21]([N:23]([C:27](=[O:30])[CH2:28]Cl)[CH2:24][CH2:25]Cl)=[CH:22][C:16]=3[CH2:15][S:14](=[O:33])(=[O:32])[C:13]=2[CH:34]=1)=[O:8]>CN(C=O)C>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:35])[C:12]2[O:18][C:17]3[C:19]([Cl:31])=[CH:20][C:21]([N:23]4[CH2:24][CH2:25][N:4]([CH:1]5[CH2:3][CH2:2]5)[CH2:28][C:27]4=[O:30])=[CH:22][C:16]=3[CH2:15][S:14](=[O:32])(=[O:33])[C:13]=2[CH:34]=1)=[O:8]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCCl)C(=O)CCl)cc(Cl)c1O2
Reactant: NC1CC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(C4CC4)CC3=O)cc(Cl)c1O2
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Cyclopropylamine (0.082 mL, 1.18 mmol) was added to a solution of Example 57k (0.2 g, 0.39 mmol) in DMF (5 mL) and stirred at 50° C. for 1.5 h. The reaction mixture was concentrated to obtain the title compound which was purified using flash chromatography (silica gel, 1.5% methanol/chloroform). Yield: 0.135 g (71%); 1H NMR (CDCl3): δ 0.49 (m, 2H, CH2), 0.56 (m, 2H, CH2), 1.77 (m, 1H, CH), 2.70 (s, 3H, CH3), 3.01 (t, 2H, CH2), 3.82 (s, 2H, CH2), 3.67 (t, 2H, CH2), 3.92 (s, 3H, OCH3), 4.70 (s, 2H, CH2), 7.36 (s, 1H, Ar), 7.44 (d, 1H, Ar), 8.10 (s, 1H, Ar), 8.46 (d, 1H, Ar); MS: m/e (ES+) 491 (M+1).
Reaction SMILES: [O:1]=[C:2]([CH3:11])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[H-].[Na+].I[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1>[C:2]([CH:3]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])(=[O:1])[CH3:11]
Reactant: CCOC(=O)CCCCI
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCCCC(C(C)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 75.4 %

Procedure:
To a solution of tert-butyl 3-oxobutanoate (20.0 g) in tetrahydrofuran (200 mL) was added 60% sodium hydride in oil (556 g) portionwise over 20 minutes in an ice-water bath under N2. After 40 minutes, to the mixture was added ethyl 5-iodopentanoate (35.6 g) at the temperature. After 15 minutes, the mixture was stirred at ambient temperature. After 1 hour, the reaction mixture was heated at 50° C. for 24 hours. The cooled mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 1 L) eluting with hexane-ethyl acetate=50-1, 20-1, 10-1, and 8-1 to give 1-tert-butyl 7-ethyl 2-acetylheptanedioate (27.3 g, 75.4%) as colorless oil.
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[O:6][C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.Br[C:19]1[S:23][C:22]([C:24]#[N:25])=[N:21][N:20]=1>>[F:17][C:3]([F:2])([F:16])[C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[O:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:19]2[S:23][C:22]([C:24]#[N:25])=[N:21][N:20]=2)[CH2:8]1
Reactant: N#Cc1nnc(Br)s1
Reactant: FC(F)(F)c1ccccc1O[C@H]1CCNC1
Agent: Cl
Product: N#Cc1nnc(N2CC[C@H](Oc3ccccc3C(F)(F)F)C2)s1

Procedure:
The title compound was prepared according to the procedure described for Example 6, step 2 from (3S)-3-[2-(trifluoromethyl)phenoxy]-pyrrolidine hydrochloride and 5-bromo-1,3,4-thiadiazole-2-carbonitrile.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([NH2:18])=[N:14][NH:15]2)=[CH:11][CH:10]=1>C1(C)C(C)=CC=CC=1>[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([NH:18][C:1](=[O:7])[CH:2]=[CH:3][C:4]([OH:6])=[O:5])=[N:14][NH:15]2)=[CH:11][CH:10]=1
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1C
Product: O=C(O)C=CC(=O)Nc1n[nH]c2cc(Cl)ccc12
Temperature: 145 °C
Yield: 63.1 %

Procedure:
585 mg of preground maleic anhydride are added to 1 g of 6-chloro-1H-indazole-3-amine in 30 cm3 of ortho-xylene. The reaction medium is refluxed at 145° C. for ten minutes and then cooled in a water bath. The insoluble material is filtered off and washed successively with 2×25 cm3 of ethyl acetate and then with 2×25 cm3 of diisopropyl ether. The solid is then dried under reduced pressure (90 Pa; 50° C.) to give 1 g of 4-[(6-chloro-1H-indazol-3-yl)amino]-4-oxo-2-butenoic acid (Z form) in the form of yellow crystals melting at 230° C.
Reaction SMILES: Br[C:2]1[C:6]([CH3:8])([CH3:7])[O:5]/[C:4](=[C:9]2/[C:10](=[O:19])[NH:11][C:12]3[C:17]/2=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)/[CH:3]=1.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C=O)C.C(OCC)(=O)C>[F:18][C:14]1[CH:13]=[C:12]2[C:17](/[C:9](=[C:4]3\[O:5][C:6]([CH3:8])([CH3:7])[C:2]([N:26]4[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][OH:20])[CH2:24][CH2:25]4)=[CH:3]\3)/[C:10](=[O:19])[NH:11]2)=[CH:16][CH:15]=1
Reactant: OCCN1CCNCC1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1N1CCN(CCO)CC1
Temperature: 100 °C

Procedure:
A mixture of (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (95 mg, 0.29 mmol) and 1-(2-hydroxyethyl)piperazine (0.40 mL, 3.3 mmol) in 6 mL of DMF was heated in 100° C. bath for 2 hours. The mixture was cooled, diluted with ethyl acetate (60 mL), washed with brine (3×50 mL), and concentrated to give the crude product, which was purified by silica gel chromatography with 5-20% methanol in chloroform to give (3E)-6-fluoro-3-{4-[4-(2-hydroxyethyl)piperazin-1-yl]-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one as a grey solid. Yield: 73 mg, 67%.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[C:7]([CH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)([CH3:10])([CH3:9])[CH3:8].[NH4+].[Cl-]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[C:7]([CH:11]1[CH2:16][CH2:15][C:14](=[CH2:1])[CH2:13][CH2:12]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: CCOCC
Product: C=C1CCC(C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyltriphenylphosphonium bromide (17.4 g, 48.6 mmol) was placed in abs. diethyl ether (106 ml) under a nitrogen atmosphere. Potassium tert-butylate (5.0 g, 45.4 mmol) was slowly added at 0° C. After 30 min, 4-tert-butylcyclohexanone (5.0 g, 32.4 mmol) as a solution in diethyl ether (10 ml) was slowly added dropwise, again at 0° C. The reaction mixture was stirred overnight at RT. For working up, the reaction mixture was cooled in an ice bath and mixed with sat. aq. NH4Cl solution. The phases were separated and the aqueous phase was shaken out several times with diethyl ether. The combined organic phases were dried over magnesium sulphate and the solvent was removed under vacuum. After column chromatography (silica gel, hexane/EtOAc 2:1), the desired compound 1-tert-butyl-4-methylenecyclohexane was obtained as a colourless liquid (3.93 g, 80% of the theoretical amount).
Reaction SMILES: CS(C1C=CC(N2CCCC2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[N:37]1([C:20]2[CH:28]=[CH:27][C:26]([S:29]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)(=[O:31])=[O:30])=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(S(=O)(=O)N2CCCC2)ccc1Cl
Agent: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Product: O=C(O)c1cc(S(=O)(=O)N2CCCC2)ccc1N1CCOCC1
Yield: 34 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-(pyrrolidine-1-sulfonyl)-benzoic acid and morpholine and obtained in 34% yield. MS (m/e): 339.2 (MH−, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:12][C:13]([OH:15])=[O:14])[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cc(Cl)cc(Cl)c1
Temperature: 150 °C
Yield: 61.8 %

Procedure:
A mixture of 3,5-dichlorobenzaldehyde (15.0 g, 85.7 mmol), malonic acid (12.5 g, 120.2 mmol), and piperidine (5 mL) was heated at 100° C. for 2 h and at 150° C. for 1 h. The reaction was poured onto 3N HCl (200 mL) and the precipitate was removed via filtration. The product was purified by recrystallization (100 mL hot EtOH) to afford 3-(3,5-dichlorophenyl)-acrylic acid (11.5 g). 1H NMR (250 MHz, DMSO-d6) δ12.6 (bs, 1H), 7.83 (m, 2H), 7.64-7.51 (m, 2H), 6.72 (d, 1H).
Reaction SMILES: C1(S([C:10]2[N:11]=[N:12][C:13]([C:16]3[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=34)=[CH:14][CH:15]=2)(=O)=O)C=CC=CC=1.[OH-:31].[Na+].Cl>O1CCOCC1>[O:31]=[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=23)=[N:12][NH:11]1
Reactant: [OH-]
Reactant: O=S(=O)(c1ccccc1)c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 114.5 %

Procedure:
A mixture of 3-(3-phenylsulfonylpyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (20.0 g), sodium hydroxide solution (80 ml; containing 7.8 g of sodium hydroxide), and 1,4-dioxane (40 ml) was stirred for 2 hours under reflux. After being cooled to room temperature, the reaction mixture was acidified with 36% hydrochloric acid (15 ml). The precipitate formed was collected, washed with three 25 ml portions of water, and dried to give 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[ 1,5-a]pyridine (16.0 g). An analytical sample was prepared by recrystallization from ethyl acetate.
Reaction SMILES: [Li].[H-].O1CCCC1.[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1)#[N:9]>C(O)C>[NH2:9][CH2:8][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1
Reactant: N#Cc1ccccc1-n1cccc1
Agent: [H-]
Agent: [Li]
Solvent: CCO
Solvent: C1CCOC1
Product: NCc1ccccc1-n1cccc1

Procedure:
To a well stirred suspension of (0.05 mol) of lithium alumunium hydride in 100 ml of anhydrous tetrahydrofuran, (0.043 mole) of 1-(2-cyanophenyl)pyrrole were added by small portions. Then the mixture was maintained with stirring at room temperature for 18 hours. Addition of aqueous ethanol to destroy the excess lithium aluminium hydride, followed by filtration afforded a solution, which was then evaporated in vacuo. The residue was extracted with ethyl ether, the organic layer washed with water and dried over anhydrous sodium sulphate. Removal of the solvent under reduced pressure gave a crude product, which was purified by passing through an alumina column eluting with chloroform to give 1-(2-aminomethylphenyl)pyrrole.
Reaction SMILES: [O:1]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1[S:13](Cl)(=[O:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[Br:24]>>[Br:24][C:19]1[C:20]([CH3:23])=[N:21][O:22][C:18]=1[NH:17][S:13]([C:9]1[S:10][CH:11]=[CH:12][C:8]=1[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:15])=[O:14]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1sccc1Oc1ccccc1
Product: Cc1noc(NS(=O)(=O)c2sccc2Oc2ccccc2)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenoxythiophene-2-sulfonamide was prepared from 3-phenoxythiophene-2-sulfonyl chloride and 5-amino-4-bromo-3-methylisoxazole using the method described in Example 1. The product was recrystallized from acetonitrile/H2O to give a solid m.p. 121-123° C., 61% yield.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[O:4][C:5]([CH2:16][C:17]#[CH:18])=[CH:6][C:7]=1[CH2:8][O:9]C1CCCCO1.C1(C)C(S(O)(=O)=O)=CC=CC=1>CO>[F:20][C:2]([F:1])([F:19])[C:3]1[O:4][C:5]([CH2:16][C:17]#[CH:18])=[CH:6][C:7]=1[CH2:8][OH:9]
Reactant: C#CCc1cc(COC2CCCCO2)c(C(F)(F)F)o1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CO
Product: C#CCc1cc(CO)c(C(F)(F)F)o1
Temperature: 20 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
1.1 g of the product of Stage F were mixed in 25 ml of methanol and 50 mg of toluenesulfonic acid were added. The mixture was stirred at 20° C. for 2 hours and poured into ice-cold water and extracted with isopropyl ether. The extract was dried and the solvent was evaporated. The residue was chromatographed on silica (eluent: 7/3 hexane/ethyl acetate) to obtain 600 mg of the expected alcohol.
Reaction SMILES: [C:1](=[O:18])(ON1C(=O)CCC1=O)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[N+:20]([C:23]1[CH:24]=[C:25]([C@@H:29]([NH2:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21].CCN(C(C)C)C(C)C>C(Cl)Cl>[N+:20]([C:23]1[CH:24]=[C:25]([C@@H:29]([NH:31][C:1](=[O:18])[O:2][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:30])[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: C[C@H](N)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)OCc1ccccc1)c1cccc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 118.4 %

Procedure:
Benzyl 2,5-dioxopyrrolidin-1-yl carbonate (1.36 g, 5.5 mmol) was added to a solution of (S)-1-(3-nitrophenyl)ethanamine HCl (1 g, 4.95 mmol) in CH2Cl2 (70 mL) and DIEA (2.2 mL, 12.4 mmol) and the reaction mixture was stirred for 1 h. The mixture was diluted with CH2Cl2 (100 mL), washed with NaHCO3, brine, dried over Na2SO4 and concentrated in vacuo to yield 59A (1.76 g, 99%) as a white solid. MS (ESI) m/z 323.02 (M+Na)+.
Reaction SMILES: [N:1]([C@@H:4]([C@H:46]1[CH2:50][CH2:49][O:48][CH2:47]1)[C:5]([NH:7][C@@H:8]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28]C(OC)=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)=[O:6])=[N+]=[N-].N1C=CC=CC=1.Cl[C:58]([O:60][CH3:61])=[O:59]>CO.C(OCC)(=O)C.[Pd]>[CH3:61][O:60][C:58](=[O:59])[NH:1][C@@H:4]([C@H:46]1[CH2:50][CH2:49][O:48][CH2:47]1)[C:5](=[O:6])[NH:7][C@@H:8]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:9]([OH:38])[CH2:10][C@H:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:34])([CH3:35])[CH3:36])[NH:28][C:58](=[O:59])[O:60][CH3:61]
Reactant: COC(=O)Cl
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N=[N+]=[N-])[C@H]1CCOC1)C(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@H]1CCOC1
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of the product of Example 142A (0.038 g, 0.055 mmol) in a mixture of methanol (0.40 mL) and ethyl acetate (0.40 mL) was added 10% Pd on C (0.038 g), and the reaction was stirred under an atmosphere of hydrogen (balloon pressure) for 2 hours. The mixture was filtered through celite and the solvent was evaporated. The residue was dissolved in dichloromethane (0.40 mL) and pyridine (0.007 mL, 0.087 mmol) and methyl chloroformate (0.004 mL, 0.052 mmol) were added and the mixture was stirred at room temperature for 1 hour. The reaction was diluted with ethyl acetate and the organic layer was washed with dilute NaHCO3, and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with chloroform and ending with 5% methanol in ethyl acetate to give the title compound (0.017 g, 43% yield). 1H NMR (300 MHz, MeOH-d4), δ ppm 0.87 (s, 9 H), 1.51-1.66 (m, 4 H), 2.31-2.43 (m, 1 H), 2.66 (dd, J=13.4, 9.0 Hz, 1 H), 2.83-2.96 (m, 3 H), 3.44 (dd, J=6.4, 9.0 Hz, 1 H), 3.52 (s, 3 H), 3.55-3.85 (m, 5 H), 3.65 (s, 3 H), 3.91 (d, J=9.6 Hz, 1 H), 4.24-4.30 (m, 1 H), 4.34-4.42 (m, 1 H), 7.11-7.35 (m, 8 H), 7.78-7.90 (m, 4 H), 8.57 (m, 1 H).