Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[NH:17][CH:16]=[CH:15]2.Br[C:24]1C=C2C(=CC=1)C(=O)NC=C2C>>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[NH:17][CH:16]=[C:15]2[CH3:24]
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(=O)[nH]ccc3c2)c1
Reactant: Cc1c[nH]c(=O)c2ccc(Br)cc12
Product: COC(=O)c1ccc(C)c(-c2ccc3c(=O)[nH]cc(C)c3c2)c1

Procedure:
The sub-title compound was prepared by the method of intermediate 3 using the product of step i).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]2[CH:20]=[C:19]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[O:18][C:15]2=[CH:16][N:17]=1.Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][N:29]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O>O>[CH2:34]([C:31]1[CH:30]=[N:29][C:28]([N:24]2[CH2:25][CH2:26][CH:21]([C:19]3[O:18][C:15]4=[CH:16][N:17]=[C:12]([C:3]5[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=5[F:1])[CH:13]=[C:14]4[CH:20]=3)[CH2:22][CH2:23]2)=[N:33][CH:32]=1)[CH3:35]
Reactant: CS(=O)(=O)c1ccc(-c2cc3cc(C4CCNCC4)oc3cn2)c(F)c1
Reactant: CCc1cnc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC(c3cc4cc(-c5ccc(S(C)(=O)=O)cc5F)ncc4o3)CC2)nc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 5-(2-fluoro-4-methanesulfonyl-phenyl)-2-piperidin-4-yl-furo[2,3-c]pyridine (70 mg), 2-chloro-5-ethyl-pyrimidine (25 mg), N,N-diisopropyl-ethylamine (67 μL), and N,N-dimethylformamide (1 mL) is stirred at 120° C. for 4 h and then at 100° C. overnight. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 4:1→1:1) to give the title compound. LC (method 1): tR=1.18 min; Mass spectrum (ESI+): m/z=481 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N+:9]([O-])=[CH:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]=1
Reactant: COc1ccc2cc(-c3ccccc3)[n+]([O-])cc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2cc(-c3ccccc3)nc(Cl)c2c1

Procedure:
7-Methoxy-3-phenylisoquinoline-2-oxide (0.30 g) was reacted with phosphorus oxychloride (3 ml) at 110° C. for 2 hr. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and an aqueous solution of saturated sodium bicarbonate. The resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give 0.20 g of the title compound was obtained as a white solid.
Reaction SMILES: [C:1]12([O:18][CH2:17][CH2:16][O:15]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][C@@H:3]([C:11](OC)=[O:12])[CH2:2]2.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1.C(Cl)Cl>[C:1]12([O:15][CH2:16][CH2:17][O:18]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][C@@H:3]([CH:11]=[O:12])[CH2:2]2
Reactant: COC(=O)[C@@H]1Cc2ccccc2C2(C1)OCCO2
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C[C@@H]1Cc2ccccc2C2(C1)OCCO2
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a stirred solution of (R)-methyl 3′,4′-dihydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalene]-3′-carboxylate (4.7 g, 18.93 mmol) in toluene (50 mL) and DCM (12.50 mL) to these solution of DIBAL-H (22.72 mL, 22.72 mmol) was added drop-wise at −78° C. under argon, and the mixture was stirred for 2 h at this temperature. Reaction mixture was quenched with aqueous NH4Cl solution at −78° C. and allowed to RT, filtered through celite, diluted with water (25 mL) and extracted with DCM (2×25 mL), dried over Na2SO4, filtered and concentrated to get the title compound (4.1 g) as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][O:7][CH3:8])[C:3]([OH:5])=[O:4].C(OC(=O)C(C)(C)CO)C.C(Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][C:2]([CH3:9])([CH2:6][O:7][CH2:8][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([OH:5])=[O:4]
Reactant: COCC(C)(C)C(=O)O
Reactant: ClCc1ccccc1
Agent: CCOC(=O)C(C)(C)CO
Product: CC(C)(COCc1ccccc1)C(=O)O

Procedure:
The title compound was prepared following the procedure described in Intermediate 68 using 2,2-dimethyl-3-hydroxypropionic acid ethyl ester and benzyl chloride.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[SH:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:10]1[CH:9]=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([S:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[N:7]2
Reactant: COC(=O)c1ccccc1S
Reactant: Clc1ccc2nccn2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1Sc1ccc2nccn2n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 23 %

Procedure:
A mixture of 6-chloroimidazo[1,2-b]pyridazine (1536 mg, 10.0 mmol), methyl 2-mercaptobenzoate (1.788 mL, 13.0 mmol), potassium carbonate (4146 mg, 30.0 mmol) and N,N-dimethylformamide (20 mL) was stirred at 70° C. for 18 hr. To the reaction mixture was added methyl 2-mercaptobenzoate (0.963 mL, 7.0 mmol), and the mixture was stirred at 70° C. for 6 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate=90/10→20/80) and precipitated from diisopropyl ether to give the title compound (663 mg, 2.3 mmol, yield 23%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]1
Reactant: COc1ccc2c(c1C#CCCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1CCCCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.4 %

Procedure:
A solution of tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)but-3-ynyl]piperidine-1-carboxylate (0.0302 g, 0.0756 mmol) synthesized in Example B61, Step 3 in ethanol (5 mL) was added with 5% palladium/carbon (wetted with 50% water, 0.100 g), and the mixture was stirred at room temperature for 20 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)butyl]piperidine-1-carboxylate (0.0291 g, 95%).
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:5]=1.[OH-].[K+].O.Cl>C(O)C>[CH2:26]([O:25][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:3]([OH:40])=[O:2])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1OCCCCCCCCCCCCCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1OCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.2 %

Procedure:
A mixture of 35 g of product from Example 103, 7.5 g of potassium hydroxide, 30 ml of water and 500 ml of ethyl alcohol is heated at reflux for 24 hours. The reaction is then stirred at room temperature for 48 hours and acidified to pH 2 with concentrated hydrochloric acid. The mixture is concentrated in vacuo, diluted with water and extracted with chloroform. The combined organic layers are washed with saturated sodium chloride, dried and concentrated in vacuo to give 34.2 g of the desired product.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:36][CH2:35][C:11]3([CH2:16][CH2:15][N:14]([C:17]([C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]5)=[O:18])[CH2:13][CH2:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>CO>[CH2:24]1[C:25]2[C:21](=[CH:20][C:19]([C:17]([N:14]3[CH2:13][CH2:12][C:11]4([CH2:35][CH2:36][N:8]([C:5]5[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=5)[CH2:9][CH2:10]4)[CH2:16][CH2:15]3)=[O:18])=[CH:27][CH:26]=2)[CH2:22][NH:23]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C(=O)N3CCC4(CC3)CCN(c3ccncc3)CC4)cc2C1
Agent: Cl
Solvent: CO
Product: O=C(c1ccc2c(c1)CNC2)N1CCC2(CC1)CCN(c1ccncc1)CC2

Procedure:
1.25 M hydrogen chloride in methanol (7.1 ml, 8.92 mmol) was added at RT to a solution of tert-butyl 5-(9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)isoindoline-2-carboxylate (0.85 g, 1.78 mmol) in methanol (1 ml), and the reaction mixture was refluxed for 1 h. The solvent was removed in vacuo, the residue was taken up in a small amount of ethanol (2 ml), and diethyl ether (50 ml) was added. The mixture was then cooled for 30 min in an ice bath, and the resulting solid was filtered out, washed with diethyl ether and dried in vacuo. Yield: 0.74 g (92%).
Reaction SMILES: Cl.[C:2]([C:5]1[S:32][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:15]=3[O:16][C@@H:17]3[CH2:21][NH:20][C@H:19]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH2:18]3)[C:7]=2[C:6]=1[CH3:33])(=[O:4])[NH2:3].[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[C:2]([C:5]1[S:32][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:15]=3[O:16][C@@H:17]3[CH2:21][N:20]([S:35]([CH3:34])(=[O:37])=[O:36])[C@H:19]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH2:18]3)[C:7]=2[C:6]=1[CH3:33])(=[O:4])[NH2:3]
Reactant: CC(=O)OC[C@@H]1C[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)CN1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: CC(=O)OC[C@@H]1C[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)CN1S(C)(=O)=O

Procedure:
Prepared analogously to example 10.2 from acetic acid (2S,4S)-4-[2-(6-carbamoyl-5-methyl-thieno[2,3-d]pyrimidin-4-ylamino)-5-fluoro-phenoxy]-pyrrolidin-2-ylmethyl ester hydrochloride and methanesulfonyl chloride. Methansulfonyl chloride was added at 0° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:25])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[CH2:9][CH2:8]2)=[O:4].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>>[CH2:17]([N:11]1[C:12]2[C:7](=[C:6]([OH:25])[C:5]([C:3]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])=[N:14][C:13]=2[C:15]#[N:16])[CH2:8][CH2:9][C:10]1=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1nc(C#N)c2c(c1O)CCC(=O)N2Cc1ccccc1
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c1N(Cc1ccccc1)C(=O)CC2
Temperature: 25 °C
Yield: 70.1 %

Procedure:
A mixture of 1-benzyl-8-cyano-5-hydroxy-2-oxo-1,2,3,4-tetrahydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (102 mg, 0.30 mmol), glycine (3.02 g, 40 mmol) and NaOMe solution (61 mL, 30 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH about 2 with 4M HCl and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 80 mg of the title compound as an off-white solid. MS: (+) m/z 381.13 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.Cl.[CH3:27][C:28]1([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([N:31]2[CH2:32][CH2:33][C:28]([CH3:27])([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:29][CH2:30]2)=[O:10])=[N:4][CH:3]=1
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: CCOC(=O)C1(C)CCNCC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1(C)CCN(C(=O)c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromopyrimidine-2-carboxylic acid (0.150 g, 0.742 mmol) and DMF (1 drop, catalytic amount) in DCM (10 mL) was added dropwise oxalyl chloride (0.10 mL, 1.11 mmol.) at 0° C. under inert atmosphere and the mixture stirred at rt for 1 h. The solvent was evaporated under reduced pressure under an inert atmosphere and the residue taken up in THF (5 mL) followed by the addition of DIPEA (0.70 mL, 3.71 mmol) and ethyl 4-methylpiperidine-4-carboxylate hydrochloride (0.14 g, 0.89 mmol.) at 0° C. The resulting mixture was stirred at rt for 16 h. After completion of reaction (by TLC) the mixture was poured into ice cold water (100 mL), extracted with EtOAc (3×100 mL) and the combined organics washed with water and brine, dried over Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the crude residue purified on silica-gel eluting with 40% EtOAc in hexane to obtain the desired product as an off white semi-solid (0.10 g, 37% yield). MS: 358.01 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:13][C:14]1[CH:26]=[CH:25][C:17]([CH2:18][N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:1][C:2]1[C:3]([N:22]2[CH2:21][CH2:20][N:19]([CH2:18][C:17]3[CH:25]=[CH:26][C:14]([Cl:13])=[CH:15][CH:16]=3)[CH2:24][CH2:23]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCN(Cc3ccc(Cl)cc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (15 ml) was added 1-(4-chlorobenzyl)-piperazine (0.115 g, 0.55 mmol) followed by diisopropylethylamine (0.10 ml, 0.55 mmol). The reaction mixture was heated at 45° C. for 18 h, then allowed to cool to room temperature. The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.148 g, 70%); 1H-NMR (500 MHz, DMSO-d6) 3.05 (br s, 4H, piperazine N(CH2)2), 3.52 (s, 2H, NCH2), 7.02 (s, 2H, NH2), 7.34 (d, J=8.52 Hz, 2H) and 7.38 (d, 2H) (3,5-ArH and 2,6-ArH), 8.16 (s, 1H, 6-H); LC (Method B)-MS (ESI, m/z): Rt=2.92 min—426, 428, 430 [(M+H)+, BrCl isotopic pattern].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[C:36]1([CH2:42][S:43](Cl)(=[O:45])=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:42]([S:43]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1)(=[O:45])=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCN(S(=O)(=O)Cc6ccccc6)CC5)c4)cnn23)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 30 (Step 6) starting from N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and phenylmethanesulfonyl chloride. LCMS (M+H)+: m/z=639.2.
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[NH:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[N:27]=[C:28]=[O:29]>>[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[N:18][C:28]([NH:27][C:21]1[C:20]([CH3:19])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:26])=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc(C)c1N=C=O
Reactant: N=C1CCCN1Cc1ccccc1
Agent: F[B-](F)(F)F
Product: Cc1cccc(C)c1NC(=O)N=C1CCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The fluoroborate salt of 1-benzyl-2-iminopyrrolidine (6.55 g.; 0.025 mole) is converted to free base (4.36 g; 0.025 mole) in the usual manner. After drying over K2CO3, the benzene solution is filtered through diatomaceous earth and 3.68 g. (0.025 mole) of 2,6-dimethylphenylisocyanate is added. The reaction mixture is stirred at room temperature for 1 hour and then evaporated to dryness in vacuo to give an oily residue of 1-(1-benzyl-2-pyrrolidylidene)-3-(2,6-dimethylphenyl)urea which is dissolved in ether and converted to the hydrochloride salt. Recrystallizations from methanol yields the product, 1-(1-benzyl-2pyrrolidylidene)-3-(2,6-dimethylphenyl)urea HCl, m.p. = 185°-195° C. (dec.) EXAMPLE XXXIV
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][C@H:10]([NH2:12])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.O=C1CCC(=O)N1[O:29][C:30]([NH:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH:35]=[N:36][N:37]2C(OC)=O)=O.C(=O)(OC)N.[OH-].[Na+]>O.CO.CN(C=O)C>[NH:37]1[C:38]2[C:34](=[C:33]([NH:32][C:30]([NH:12][C@H:10]3[CH2:11][C@@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:8]=[CH:9]3)=[O:29])[CH:41]=[CH:40][CH:39]=2)[CH:35]=[N:36]1
Reactant: COC(=O)n1ncc2c(NC(=O)ON3C(=O)CCC3=O)cccc21
Reactant: N[C@@H]1C=C[C@H](c2ccccc2)C1
Agent: COC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccc2[nH]ncc12)N[C@@H]1C=C[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
A solution of Example 48C (455 mg, 2.86 mmol), DMF (8 mL), diisopropylethylamine (1.05 mL, 6.01 mmol), and methyl 4-((2,5-dioxopyrrolidin-1-yloxy)carbonylamino)-1H-indazole-1-carboxylate (prepared as in Org. Proc. Res. Dev., 2007, 950 mg, 2.86 mmol) was stirred at room temperature. After 15 minutes, LCMS showed complete conversion to methyl carbamate. Methanol (16 mL) and 50% aqueous sodium hydroxide (0.50 mL, 8.6 mmol) were added to the reaction mixture. After 10 minutes, LCMS showed complete conversion to product. Water (24 mL) was added dropwise, and the resulting white slurry was stirred at room temperature for 15 minutes. The slurry was filtered and washed with 1:1 MeOH/water (10 mL). The white solid was dried in a vacuum oven at 50° C. to provide the title compound (646 mg, 2.03 mmol, 71% over three steps). 1H NMR (300 MHz, DMSO-d6) δ 13.11-12.64 (m, 1H), 8.56 (s, 1H), 8.06 (d, J=0.9 Hz, 1H), 7.63 (d, J=7.4 Hz, 1H), 7.52-7.30 (m, 2H), 7.21 (m, 4H), 7.05 (d, J=8.3 Hz, 1H), 6.59 (d, J=8.1 Hz, 1H), 5.93 (s, 2H), 4.86 (q, J=7.8 Hz, 1H), 3.86 (t, J=7.3 Hz, 1H), 2.90 (dt, J=13.1, 8.2 Hz, 1H), 1.47-1.28 (m, 1H); MS (DCI) m/z 319 (M+H)+.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[CH2:14][C@@H:15]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@H:16]([C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=2[F:27])[CH2:17][CH:18]=1.O.NN.C(OCC)(=O)C.[OH-].[Na+]>C(Cl)Cl.CO>[NH2:3][CH2:12][C:13]1[CH2:14][C@@H:15]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[C@H:16]([C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=2[F:27])[CH2:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC(CN2C(=O)c3ccccc3C2=O)=CC[C@H]1c1cc(F)c(F)cc1F
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CC(CN)=CC[C@H]1c1cc(F)c(F)cc1F

Procedure:
A solution of Example 58A (650 mg, 1.07 mmol) in 3 mL each of CH2Cl2 and methanol was treated with hydrazine hydrate (336 μL). Ethyl acetate and 1N NaOH were added. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the title compound.
Reaction SMILES: C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.CC(C[C@H](NC(C)=O)C(N[C@H](C(N[C@H:37]([C:45]([OH:47])=[O:46])[CH2:38][CH2:39][CH2:40]N=C(N)N)=O)CC(C)C)=O)C.CCC(CO[C:59](C(N(CC[NH+](C)C)C)=O)([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1C=C[CH:63]=[CH:62][CH:61]=1)CC.[Cl-].[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](COP(OP(OCC([C@H](C(NCCC(NCCS)=O)=O)O)(C)C)(O)=O)(O)=O)[C@@H](OP(O)(O)=O)[C@H]1O.P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.CCCCCCCCCCCCOS([O-])(=O)=O.[Na+]>C1N(CCO)CCN(CCS(O)(=O)=O)C1.C(O)C(N)(CO)CO.Cl>[C:45]([OH:47])(=[O:46])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:71][CH2:70][CH2:69][CH2:68][CH2:67][CH2:66][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]
Reactant: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Reactant: CC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O
Agent: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCS
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: Cl
Product: CCCCCCCCCCCCCCCC(=O)O
Reaction time: 0.17 h

Procedure:
Soluble Shh was labeled with 3H-palmitic acid in a cell-free system using a modified version of a published procedure (24). A crude microsomal fraction from rat liver was prepared by subjecting a liver homogenate to sequential centrifugation at 3000×g for 10 min, 9000×g for 20 min, and 100,000×g for 30 min. The 100,000×g pellet was suspended in 10 mM HEPES pH 7.4, 10% sucrose and again centrifuged at 100,000×g for 20 min. The final pellet (derived from 10 g of liver) was suspended in 3 mL of 20 mM Tris-HCl pH 7.4, 150 mM NaCl, 1 mM EDTA, 10 μg/mL leupeptin, 0.15% Triton X-100, aliquoted, and stored at −70° C. Reactions containing 3 μg Shh, 1 μL of rat microsomes, 50 ng/mL Coenzyme A (Sigma), 0.3 mM ATP, 20 mM Tris-HCl pH 7.4, 150 mM NaCl, 1 mM EDTA, 10 μg/mL leupeptin, and 0.5 μCi-[9,10-3H]-palmitic acid (50 Ci/mmol; New England Nuclear) were performed at room temperature for 1 h. Reactions were stopped with reducing electrophoresis sample buffer, subjected to SDS-PAGE on a 10-20% gradient gel, and visualized by fluorography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23](OC)=[O:24])=[CH:13][C:12]=2[N:11]=1.[F:27][C:28]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:29]=1[NH2:30].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([NH:30][C:29]3[CH:31]=[C:32]([C:35]([F:36])([F:37])[F:38])[CH:33]=[CH:34][C:28]=3[F:27])=[O:24])=[CH:13][C:12]=2[N:11]=1
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c2nc(C)oc12
Reactant: Nc1cc(C(F)(F)F)ccc1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1nc2c(o1)c(C(=O)Nc1cc(C(F)(F)F)ccc1F)cc1nc(Nc3c(F)cccc3Cl)[nH]c12
Yield: 23 %

Procedure:
The title compound was prepared following the procedure as described for Example-185 using methyl 7-[(2-chloro-6-fluorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylate (Step-3 of Intermediate-56, 0.100 g, 0.266 mmol), 2-fluoro-5-trifluoromethylaniline (0.071 g, 0.125 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 2.72 (s, 3H), 7.41-7.47 (m, 3H), 7.63 (s, 2H), 7.76 (s, 1H), 8.54 (d, J=6.9 Hz, 1H), 9.45 (s, 1H), 9.92 (s, 1H), 11.71 (s, 1H); MS [M+H]+: 522.12.