Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:32])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.Cl[CH2:34][C:35](Cl)=[O:36].C(=O)([O-])O.[Na+].C(N(CC)CC)C.Cl.[F:51][C:52]1([F:58])[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>CN(C)C(=O)C>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:11]([C:6]2[N:7]=[CH:8][C:9]3[N:10]=[C:2]([NH:1][C:35](=[O:36])[CH2:34][N:55]4[CH2:56][CH2:57][C:52]([F:58])([F:51])[CH2:53][CH2:54]4)[S:3][C:4]=3[N:5]=2)[CH3:32])[CH:13]=1)=[O:31])([CH3:27])[CH3:28])#[N:30]
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(N)sc2n1
Reactant: O=C(Cl)CCl
Reactant: FC1(F)CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)CN3CCC(F)(F)CC3)sc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)(methyl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (152 mg, 343 μmol) produced in Example D5(i) in N,N-dimethylacetamide (4 mL) was added chloroacetyl chloride (68 μL, 858 μmol), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (10 mL), and the mixture was extracted with ethyl acetate (15 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (4 mL), triethylamine (143 μL, 1.03 mmol) and 4,4-difluoropiperidine hydrochloride (162 mg, 1.03 mmol) were added, and the mixture was stirred at 60° C. for 15 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (10 mL), and the mixture was extracted with ethyl acetate (15 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=40/60→20/80), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (127 mg, 61%) as pale-red crystals.
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][CH:6]=1)([OH:4])=[O:3].[CH2:32]([O:39][C:40]1[C:45]([CH:46]=O)=[CH:44][CH:43]=[CH:42][N:41]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH2:32]([O:39][C:40]1[C:45]([CH:46]=[CH:12][CH2:11][C:8]2[CH:7]=[CH:6][C:5]([C:2]([OH:4])=[O:3])=[CH:10][CH:9]=2)=[CH:44][CH:43]=[CH:42][N:41]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=Cc1cccnc1OCc1ccccc1
Reactant: O=C(O)c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CC=Cc2cccnc2OCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
(2-(4-Carboxyphenyl)ethyl)triphenylphosphonium bromide (10.9 g, 22.2 mmol) was suspended in THF (80 ml) and the flask was flushed with argon. Lithium bis(trimethylsilyl)amide (1M in THF, 48.8 ml) was added dropwise and the reaction stirred for 1 hour, becoming dark brown. A solution of 2-benzyloxy-3-pyridinecarbaldehyde (4.73 g, 22.2 mmol) in THF (20 ml) was added slowly. The reaction was stirred at ambient temperature for 18 hours (shielding from light alumimium foil). The reaction mixture was then partitioned between Et2O/water, the organic layer was washed with water and the aqueous layers were combined, acidified with HCl and extracted with EtOAc. The organic phase was dried (MgSO4) and evaporated and purified by colum chromtagraphy with MeOH/CH2Cl2 to give the title product.
Reaction SMILES: [CH3:1][C:2]1(C(O)=O)[CH:6]=[CH:5][N:4]([C:7]2[C:16]([F:17])=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)[NH:3]1.C[N:22](C=O)C.C(Cl)(=O)C(Cl)=O.[N-]=[N+]=[N-].[Na+]>C(Cl)Cl.O.O1CCOCC1>[CH3:1][C:2]1[CH:6]=[C:5]([NH2:22])[N:4]([C:7]2[C:16]([F:17])=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)[N:3]=1
Reactant: CC1(C(=O)O)C=CN(c2cc3ccccc3cc2F)N1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(N)n(-c2cc3ccccc3cc2F)n1
Reaction time: 2 h
Yield: 38 %

Procedure:
3-Methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acid (see Step 1, Example 4) (828 mg, 3.1 mmol) was dissolved in 20 mL dry DCM. To it were added 0.05 mL DMF and oxalyl chloride (0.81 mL, 9.3 mL). The mixture was stirred for 2 hrs. It was evaporated in vacuuo. The residue was dissolved in 30 mL dry dioxane. It was chilled in ice bath. To the stirred cold mixture was added dropwise a chilled solution of sodium azide (0.4 g, 6.2 mmol) in 2 mL water and 1 mL dioxane. Reaction was allowed for 1 hr. It was evaporated in vacuuo. The residue was taken into EtOAc and washed with water ×2. The organic phase was dried and concentrated in vacuuo. The organic residue was then dissolved in 30 mL DMF. To it was added 15 mL water. The mixture was refluxed for 2.5 hrs. It was concentrated in vacuuo and purified using flash column to give 3-methyl-1-(3-fluoro-2-naphthyl)-5-amino-1H-pyrazole (280 mg, 38% overall). Rf 0.45 (1:1 EtOAc:hexane). ES-MS: (M+H)+242.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:23]#[CH:24]>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([N:28]4[CH2:29][CH2:30][N:25]([CH2:22][C:23]#[CH:24])[CH2:26][CH2:27]4)=[O:18])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2.[CH:1]12[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH:10]1[C:11]1[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([N:28]3[CH2:29][CH2:30][N:25]([CH2:22][C:23]#[CH:24])[CH2:26][CH2:27]3)=[O:18])=[CH:13][CH:12]=1)[CH2:2]2
Reactant: C#CCN1CCNCC1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Product: C#CCN1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Product: C#CCN1CCN(C(=O)COc2ccc(C3C4CC5CC(C4)CC3C5)cc2)CC1
Yield: 178.9 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.13 g, 0.45 mmol) and 1-(prop-2-yn-1-yl)piperazine (0.056 g, 0.45 mmol) according to the example 1, which was given 2-(4-(adamantan-2-yl)phenoxy)-1-(4-(prop-2-yn-1-yl)piperazin-1-yl)ethanone as a white solid (0.158 g, 89.3% yield).
Reaction SMILES: C(O[C:4](=[O:10])[CH2:5][CH2:6][O:7][CH2:8][CH3:9])C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:21]1([NH:26][C:27]2[C:32]([CH:33]=O)=[CH:31][N:30]=[C:29]([S:35][CH3:36])[N:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1.C(OCC)(=O)C.O>[CH:21]1([N:26]2[C:27]3[N:28]=[C:29]([S:35][CH3:36])[N:30]=[CH:31][C:32]=3[CH:33]=[C:5]([CH2:6][O:7][CH2:8][CH3:9])[C:4]2=[O:10])[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Reactant: CCOCCC(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOCc1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 34.9 %

Procedure:
3-Ethoxy-propionic acid ethyl ester (12.31 g, 84.2 mmol) was dissolved in tetrahydrofuran (40 mL) to which LiHMDS (89 mL, 88.9 mmol, 1.0 M in THF) was slowly added. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (10.0 g, 42.2 mmol) was then added neat and the reaction mixture was stirred at ambient temperature for 17 hours then brought to reflux for 7 hours. The reaction mixture was diluted with ethyl acetate and water, the layers separated, the organic layer dried over MgSO4 and the solvent evaporated to give a crude oil. The crude product was dissolved in ethyl acetate and diluted with hexanes to give a precipitate, which was collected by filtration to give 8-cyclopentyl-6-ethoxymethyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as an off-white solid (4.70 g, 34.9%).1H NMR δ(400 MHz, CDCl3) 8.47 (s, 1H), 7.52 (t, J=1.5 Hz, 1H), 5.82 (m, 1H), 4.32 (d, J=1.7 Hz, 1H), 3.53 (q, J=7.1 Hz, 2H), 2.47 (s, 3H), 2.17 (m, 2H), 1.93 (m, 2H), 1.73 (m, 2H), 1.54 (m, 2H), 1.15 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.Br[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH3:25][C:23]1[CH:22]=[CH:21][C:5]2=[C:6]3[C:11](=[C:2]([NH2:1])[N:3]=[C:4]2[CH:24]=1)[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:18][CH:19]=1)=[CH:7]3
Reactant: BrCCN1CCOCC1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCN4CCOCC4)cc3)cc12

Procedure:
8-Methyl-2-(4-(2-morpholinoethoxy)phenethyl)benzo[f][1,7]naphthyridin-5-amine was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) following the procedure described for Example 139, but using 4-(2-bromoethyl)morpholine. 1H NMR (Acetone-d6): δ 8.78 (s, 1H), 8.72 (s, 1H), 8.30 (d, 1H), 7.46 (s, 1H), 7.17-7.24 (m, 3H), 6.85 (d, 2H), 4.08 (t, 2H), 3.56-3.62 (m, 4H), 3.45-3.53 (m, 2H), 3.24 (t, 2H), 3.07 (t, 2H), 2.73 (t, 2H), 2.52-2.56 (m, 2H), 2.49 (s, 3H). LRMS [M+H]=443.2
Reaction SMILES: [Cl-].[NH4+].NC(N)=S.[NH2:7][C@:8]1([NH:40][CH:41]=[O:42])[C:38](=[O:39])[N:10]2[C:11]([C:22]([O:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[C:12]([CH2:15]SC3SC=NN=3)[CH2:13][S:14][C@H:9]12>CN(C)C=O>[NH2:7][C@:8]1([NH:40][CH:41]=[O:42])[C:38](=[O:39])[N:10]2[CH:11]([C:22]([O:24][CH:25]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[C:12](=[CH2:15])[CH2:13][S:14][C@H:9]12
Reactant: N[C@]1(NC=O)C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nncs3)CS[C@@H]21
Agent: NC(N)=S
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C=C1CS[C@H]2N(C(=O)[C@]2(N)NC=O)C1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 0.08 h
Yield: 10 %

Procedure:
Powdered ammonium chloride (1.25 g) and powdered thiourea (0.5 g) were added to a solution of diphenylmethyl 7β-amino-7α-formamido-3-[(1,3,4-thiadiazol-2- yl)thiomethyl]ceph-3-em-4-carboxylate in N,N-dimethylformamide (20 ml) at ca. -10° C. (ice/acetone bath) with stirring. After 5 min activated (freshly acid washed) zinc powder (1.5 g) was added in four portions over 3 min. After 25 min the mixture was filtered through Kieselguhr and the residue washed with ethyl acetate and water. Ethyl acetate (100 ml) and water (100 ml) was added to the combined filtrate and washings. The organic phase was separated and the aqueous phase re-extracted with ethyl acetate (50 ml). The combined organic extracts were washed with water (×5), then brine (×1), and dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated. Purification by silica gel chromatography eluting with ethyl acetate/n-hexane furnished the title compound as a white foam (0.744 g; containing ca. 10% diphenylmethyl 7 β-amino-7α-formamido-3-methylceph-3-em).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:9]=2)=[CH:16][CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCNCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.7 %

Procedure:
To a solution of tert-butyl 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-piperidinecarboxylate (0.69 g, 1.4 mmol) in dry CH2Cl2 (25 ml) at 0° C. was added TFA (5 ml). The solution was stirred at room temperature for 20 hr and the solvent evaporated. NaOH solution (5N, 10 ml) was added and the resulting slurry was extracted with EtOAc (3×50 ml). Wash with brine (1×50 ml). Dry, filter and concentrate to leave a solid which was triturated with diethylether and filtered to leave 5-(4-phenoxyphenyl)-7-(4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (433258) as a white solid (500 mg, 91%). M.pt 209-211° C. Rf in 1:1 EtOAc : MeOH=0.1. 1H NMR (d6 DMSO, 250 MHz) 8.13 (1H, s), 7.36-7.48 (4H, m), 7.29 (1H, s), 7.04-7.16 (5H, m), 5.80 (2H, bs), 4.64 (1H, m), 3.10 (2H, m), 2.80 (1H, bs), 2.67 (2H, m), 1.94 (4H, m). Mass spec. C23H23ON5 (385.1902). IR (KBr disc): 3278, 1620, 1585, 1490, 1245 cm−1.
Reaction SMILES: CS([C:4]1[S:5][C:6]2[CH:12]=[C:11]([CH2:13][N:14]3[C:18]4=[N:19][CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:22]=[C:17]4[N:16]=[CH:15]3)[CH:10]=[CH:9][C:7]=2[N:8]=1)=O.CS(C1SC2C=C(CN3C4=NC=C(C(OC)=O)C=C4N=C3)C=CC=2N=1)(=O)=O.[NH2:54][C@@H:55]1[CH2:60][CH2:59][CH2:58][CH2:57][C@H:56]1[OH:61].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[OH:61][C@@H:56]1[CH2:57][CH2:58][CH2:59][CH2:60][C@H:55]1[NH:54][C:4]1[S:5][C:6]2[CH:12]=[C:11]([CH2:13][N:14]3[C:18]4=[N:19][CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:22]=[C:17]4[N:16]=[CH:15]3)[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: COC(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(S(C)=O)sc2c1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: COC(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(S(C)(=O)=O)sc2c1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 100 °C
Reaction time: 19 h

Procedure:
A 2:1 mixture of methyl 3-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate and methyl 3-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (360 mg) from Step 4 of this Example was dissolved in anhydrous DMA (10 mL), and (1R,2R)-(−)-2-aminocyclohexanol (322 mg, 2.79 mmol) and DIEA (360 mg, 2.79 mmol) were added. The reaction vessel was sealed and the mixture was heated with stirring at 100° C. for 19 h. LCMS indicated the reaction was not complete. To the reaction mixture was added additional (1R,2R)-(−)-2-aminocyclohexanol (100 mg, 0.870 mmol) and the reaction vessel was sealed and the mixture was heated at 100° C. for a further 15 h. After the reaction mixture was cooled to rt, one half of the reaction mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford methyl 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (19 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.96 (d, J=7.3 Hz, 1H), 8.76 (m, 1H), 8.54 (m, 1H), 7.99 (br s, 1H), 7.66 (d, J=7.2 Hz, 1H), 7.16-7.33 (m, 2H), 5.51 (br s, 2H), 4.76 (br s, 1H), 3.89 (s, 3H), 3.30-3.50 (m, 2H), 2.02 (m, 1H), 1.86 (m, 1H), 1.50-1.70 (m, 2H), 1.10-1.30 (m, 4H). LCMS (ESI) m/z 438 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH:12]=[CH:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CC(C)=O>[CH2:12]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[O:1][CH2:23][CH:22]=[CH2:21])[C:6]([O:8][CH3:9])=[O:7])[CH:13]=[CH2:14]
Reactant: CC=Cc1cc(C(=O)OC)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)OC)cc1CC=C
Yield: 87 %

Procedure:
A solution of 3.04 g (15.8 mmol) of methyl 4-hydroxy-3-propenylbenzoate (prepared by the procedure described in patent application WO91/11999) was refluxed with anhydrous potassium carbonate (4.37 g, 2 equiv) and allyl bromide (3.5 mL, 2.5 equiv) in acetone overnight. The mixture was filtered through celite and the filter cake was washed with acetone and dichloromethane. After removing the solvents, the resulting oil was distilled under high vacuum to give 3.2 g (87%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:14]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)C1
Yield: 96 %

Procedure:
1-Benzyloxycarbonyl-3-azetidinecarboxylic acid (from step (i); 9.3 g, 39.6 mmol) was dissolved in methanol (100 mL) and toluene (100 mL), and cooled to 0° C. A solution of 2M trimethylsilyldiazomethane in hexanes was then added dropwise until bubbling had ceased and the yellow colour persisted. Acetic acid was then added dropwise until the yellow colour disappeared. Concentration of the solution yielded the title compound as an oil (9.48 g, 38 mmol, 96%).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)[CH:19]=[CH:18][C:5]=1[NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)([O-])=O.CCN(C(C)C)C(C)C>[Pt].C1COCC1>[N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][O:22][C:20]1[CH:21]=[C:4]([NH2:1])[C:5]([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:10][CH:9]=2)=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1NCc1ccc(C(F)(F)F)cc1
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(OCc2ccc3ccccc3n2)ccc1NCc1ccc(C(F)(F)F)cc1
Reaction time: 16 h

Procedure:
To a 50 mL round-bottomed flask were added a stir bar, 2-nitro-4-(quinolin-2-ylmethoxy)-N-(4-(trifluoromethyl)benzyl)aniline (310 mg, 0.69 mmol), THF (6.9 mL), and DIPEA (60 μL, 0.3 mmol) followed by 5% platinum on carbon (15 mg, 0.08 mmol). The reaction vessel was evacuated and then placed under one atmosphere of hydrogen for 16 h. The mixture was then flushed with N2 and filtered through a pad of Celite. The Celite was then rinsed with additional THF (25 mL). The resulting solution was concentrated to dryness to afford the title compound which was used without further purification. MS (ESI): mass calcd. for C24H20F3N3O, 423.16; m/z found, 424.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](CC(CC=C)C#N)[CH:6]=[CH:5]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(O[CH2:28][CH3:29])(=O)C>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:3][CH:4]([CH2:5][CH:28]=[CH2:29])[CH2:8][NH2:7])=[CH:5]2
Reactant: CCOC(C)=O
Reactant: C=CCC(C#N)Cn1ccc2cc(C)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(CN)Cc1cc2cc(C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a stirred solution of 51 (8.82 g, 39.3 mmol) in THF (400 mL) at 0° C. was added LiAlH4 (4.77 g, 118 mmol). The mixture was stirred at room temperature overnight, then cooled to −78° C. and ethyl acetate (60 mL) was added followed by 10% NaOHaq (15 mL). The reaction was quenched by the addition of moister Na2SO4, filtered through celite, washed with EtOAc (3×100 mL) and MeOH (3×150 mL). Evaporation provided a residue, which was purified by silica gel flash chromatography to provide 52 as colorless oil. (3.52 g, 39% yield). H NMR (d6-DMSO) δ 7.34-7.27 (m, 3H), 6.93 (d, 1H, J=1.5 Hz & 8.3 Hz), 6.31 (d, 1H, J=3.0 Hz), 5.78 (m, 1H), 5.06-4.99 (m, 2H), 4.16 (dd, 1H, J=7.0 Hz & 14.2 Hz), 4.00 (dd, 1H, J=6.5 Hz & 14.2 Hz), 2.42 (t, 2H, J=4.5 Hz), 2.36 (s, 3H), 2.05 (m, 1 H), 1.98-1.90 (m, 2H). FABMS (+Ve) m/z 229 [MH+].
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][CH:12]1[CH2:21][CH2:20][CH:19]([CH3:22])[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]1=2.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CCCCCC>[CH3:11][CH:12]1[CH2:21][CH2:20][CH:19]([CH3:22])[C:18]2[NH:17][CH:16]([CH:8]=[O:9])[CH:15]=[CH:14][C:13]1=2
Reactant: CN(C)C=O
Reactant: CC1CCC(C)c2ncccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CCC(C)C2=C1C=CC(C=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
Phosphorus oxychloride (18.6 g, 0.12 mol) was added dropwise to 29.2 g (0.4 mol) of N,N-dimethylformamide under ice cooling. After stirring at room temperature for 30 minutes, the reaction mixture was cooled over ice bath, followed by the dropwise addition of 17.0 g (0.1 mol) of 5,8-dimethyl-5,6,7,8-tetrahydroquinoline. After stirring at room temperature for one hour, the reaction mixture was poured into ice water and neutralized with an aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue so obtained was subjected to chromatography on a silica gel column (developing solvent: 10% ethyl acetate/n-hexane), whereby 11.4 g of the title compound were obtained in the form of a reddish brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:21]=[C:22](S(C)(=O)=O)[C:23]=2[C:24](=[O:31])[NH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[N-:36]=[N+:37]=[N-:38].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[N:36]([C:22]1[C:23]([C:24](=[O:31])[NH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:11]2[N:10]=[CH:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]2[N:21]=1)=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)c1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of the compound obtained in Example 33 (1.5 g) in dimethylformamide (20 mL) was added sodium azide (1.11 g) and the mixture was stirred at 110° C. overnight. After cooling to room temperature, to the reaction mixture was a saturated brine and the mixture was stirred and extracted with ethyl acetate. The organic layer was washed with water and concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=80/20 to 30/70) to give 2-azido-6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(N-cyclopentylcarbamoyl)pyrazolo[1,5-a]pyrimidine (1.15 g, a yellow viscidity). To a solution of the product (870 mg) in tetrahydrofuran (16 mL) was added triphenylphosphine (896 mg) and the mixture was stirred at 40° C. for 1 hour. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; chloroform/methanol=100/0 to 97/3) to give 6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-triphenylphosphoranylidenamino-pyrazolo[1,5-a]pyrimidine (942 mg, yield: 58%) as a yellow solid MS (APCI)m/z; 726/728 M+H]+