Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([OH:28])=O)[N:9]=2)[CH:7]=1.Cl.[O:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:43]3[CH2:44][CH2:45][N:40]([CH2:39][C:35]4[O:34][CH:38]=[CH:37][N:36]=4)[CH2:41][CH2:42]3)=[O:28])[N:9]=2)[CH:7]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: c1coc(CN2CCNCC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cn(CC(=O)N2CCN(Cc3ncco3)CC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]-pyrimidine-3-amido]-1H-pyrazol-1-yl]acetic acid (100 mg, 0.22 mmol) in DMF (10 mL) was added 1-(1,3-oxazol-2-ylmethyl)piperazine hydrochloride (132 mg, 0.65 mmol), HATU (123 mg, 0.32 mmol), DIEA (139 mg, 1.08 mmol). The resulting solution was stirred at room temperature overnight. Water (50 mL) and DCM (30 mL) was added. Phases were separated. The aqueous phase was extracted with DCM (×2) and the organic layers combined. The organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XBridge BEH130 Prep C18 OBD Column, 19&#65533; 100 mm 5 um 13 nm; mobile phase, Water with 10 mM NH4HCO3 and ACN (28% ACN up to 38% in 6 min); Detector, UV 254/220 nm. This resulted in 68.2 mg (52%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(1,3-oxazol-2-ylmethyl)piperazin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as an off-white solid. LCMS (Method 25) [M+H]+=612.1, RT=1.70 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.7, 7.1 Hz), 8.69-8.67 (m, 2H), 8.30 (s, 1H), 8.09 (d, 1H, J=0.6 Hz), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=9.0 Hz), 7.28 (dd, 1H, J=4.2, 7.2 Hz), 7.18 (d, 1H, J=0.6 Hz), 7.01 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 3.76 (s, 2H), 3.54-3.48 (m, 4H), 2.45-2.42 (m, 4H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.[CH3:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([CH:20]1[CH2:24][CH2:23][CH2:22][NH:21]1)=O.O.[OH-].[Na+]>C1COCC1>[CH3:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[CH2:18][C@@H:20]1[CH2:24][CH2:23][CH2:22][NH:21]1
Reactant: C[C@@H]1CCCN1C(=O)C1CCCN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1
Temperature: 40 °C
Reaction time: 0.75 h

Procedure:
BOC proline (CAS 15761-394) and 2-(R)-Methyl-pyrrolidine hydrochloride (CAS 135324-85-5) are coupled in a manner substantially analogous to Procedure A in dichloromethane to give 2(S)-(2(R)-Methyl-pyrrolidine-1-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester. The material is deprotected by stirring in dichloromethane at 5-10° C. while trifluoroacetic acid (10 eq,) is added and then stirred at room temperature for 18 hours. Reaction is concentrated, is dissolved in H2O, pH is adjusted to 8-9 with K2CO3, and is extracted several times with CH2Cl2. The extracts are combined, dried (Na2SO4) and concentrated in vacuo to give (2(R)-Methyl-pyrrolidin-1-yl)-pyrrolidin-2-yl-methanone. A 1 M Lithium Aluminum Hydride/THF solution (3 eq.) is diluted with an equal volume of THF and stirred under N2 as a THF solution of (2(R)-methyl-pyrrolidin-1-yl)-pyrrolidin-2-yl-methanone is added dropwise, allowing the reaction to mildly exotherm. The reaction mixture is stirred at 40° C. for 45 minutes, then at room temperature 18 hours. The mixture is cooled in an ice bath and is quenched with H2O (3 eq.), 4 N NaOH (3 eq.), then H2O (9 eq.) while keeping reaction temperature less than 15° C. The mixture is stirred overnight, filtered and the precipitate is washed three times with THF. The filtrate and washes are combined and concentrated to give 2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 169.3 (M+H)+ The title compound is used as such or is purified by SCX chromatography or distillation.
Reaction SMILES: C(O[C:5](=[O:21])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C=C.CC1C2C(=CC=CC=2)C(C)=C2C=1C=CC1C2=CC=CC=1.[CH3:42][O:43][C:44]1[CH:65]=[CH:64][C:47]([C:48]([NH:50][C:51]([CH3:63])([CH3:62])[C:52]([N:54]2[CH2:58][CH2:57][CH2:56][CH:55]2C(O)=O)=[O:53])=[O:49])=[CH:46][CH:45]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.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>[CH2:14]([O:13][CH:8]1[CH:7]([NH:6][C:5]([CH:55]2[CH2:56][CH2:57][CH2:58][N:54]2[C:52](=[O:53])[C:51]([NH:50][C:48](=[O:49])[C:47]2[CH:46]=[CH:45][C:44]([O:43][CH3:42])=[CH:65][CH:64]=2)([CH3:63])[CH3:62])=[O:21])[CH2:11][C:10](=[O:12])[O:9]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc(C(=O)NC(C)(C)C(=O)N2CCCC2C(=O)O)cc1
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1c2ccccc2c(C)c2c1ccc1ccccc12
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(C(=O)NC(C)(C)C(=O)N2CCCC2C(=O)NC2CC(=O)OC2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.2 %

Procedure:
To a solution of (2-benzyloxy-5-oxo-tetrahydrofuran-3-yl)-carbamic acid allyl ester (40) (1.027 g, 3.5 mmol) in CH2Cl2 (20 ml) was added DMBA (543 mg, 3.48 mmol) and Pd(PPh3)4 (280 mg, 0.24 mmol) and the solution was stirred at room temperature under N2 for 20 minutes. A solution of 1-[2-(4-methoxy-benzoylamino)-2-methyl-propionyl]-pyrrolidine-2-carboxylic acid (818 mg, 2.45 mmol) in CH2Cl2 (5 ml) was added, followed by HOBT (0.534 g, 3.95 mmol) and EDC (738 mg, 3.84 mmol). The reaction was stirred at room temperature for 18 hours under N2. The solvent was evaporated, the crude material dissolved in EtOAc and washed with 0.5N NaHSO4 (2×), saturated NaHCO3 (2×) and brine and was dried over anhydrous Na2SO4, filtered and evaporated to give a yellow solid. Purification by flash column chromatography, eluting with ethyl acetate/hexanes (20/80 to 50/50%), gave the product as pale yellow solid (760 mg, 61% yield). 1H-NMR (500 MHz, CD3OD) δ 1.53 (d, 6H), 1.65-1.93 (m, 3H), 1.96-2.14 (m, 1H), 2.60 (dd, 0.1H), 2.77 (dd, 0.85H), 2.94 (dd, 0.85H), 3.04-3.11 (m, 0.2H), 3.42-3.52 (m, 1H), 3.57-3.67 (m, 1H), 3.84 (s, 3H), 4.38-4.76 (m, 3H), 4.84 (d, 1H), 5.64-5.70 (m, 1H), 6.96-7.03 (m, 2H), 7.23-7.43 (m, 5H), 7.78-7.97 (m, 2H). Analytical HPLC (C18 column) 13.32, 14.37 min. LC-MS (ES+) m/e=524.3 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([CH3:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[N:26][N:27](C(OC(C)(C)C)=O)[CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH:26]1[CH:25]=[C:24]([NH:23][C:2]2[N:7]=[C:6]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]3([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]3)[C:5]([CH3:22])=[CH:4][N:3]=2)[CH:28]=[N:27]1
Reactant: Cc1cnc(Cl)nc1CCc1ccccc1C1(C(N)=O)CC1
Reactant: CC(C)(C)OC(=O)n1cc(N)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cnc(Nc2cn[nH]c2)nc1CCc1ccccc1C1(C(N)=O)CC1
Temperature: 120 °C
Yield: 12 %

Procedure:
A mixture of 1-(2-(2-(2-chloro-5-methylpyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A40 (0.147 g, 0.465 mmol), tert-butyl 4-amino-1H-pyrazole-1-carboxylate (0.102 g, 0.559 mmol), Cs2CO3 (0.455 g, 1.40 mmol), Xantphos (0.011 g, 0.019 mmol) and Pd(OAc)2 (0.002 g, 0.009 mmol) in 1,4-dioxane (5 mL) was bubbled with N2 for 10 minutes before being heated in the microwave for 20 minutes at 120° C. The reaction mixture was cooled to room temperature, adsorbed onto silica, and purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 20-100% EtOAc in petroleum benzine 40-60° C., then 0-20% MeOH in EtOAc) to give a white solid. This solid was taken up in DCM and precipitated by the addition of cyclohexane. The suspension was sonicated for 10 minutes and the precipitate was isolated by vacuum filtration and washed with Et2O to give the title compound 46 as a white solid (0.021 g, 12%). LCMS-D: rt 2.98 min; m/z 363 [M+H]+.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[N:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[N:23][OH:24])=[CH:17][CH:16]=2)[CH:10]=[CH:9][CH:8]=1.[C:26]([C:28]1[C:29]([NH2:34])=[N:30][CH:31]=[CH:32][CH:33]=1)#[CH:27].C(N(CC)CC)C>O>[F:6][C:7]1[N:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]4[C:29]([NH2:34])=[N:30][CH:31]=[CH:32][CH:33]=4)[O:24][N:23]=3)=[CH:17][CH:16]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: ON=C(Cl)Cc1ccc(COc2cccc(F)n2)cc1
Reactant: C#Cc1cccnc1N
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(COc3cccc(F)n3)cc2)no1
Temperature: 50 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-(6-fluoro-pyridin-2-yloxymethyl)-phenyl)acetohydroximoyl chloride (200 mg, 0.679 mmol) described in Manufacturing Example 55-1-5 and 3-ethynyl-pyridin-2-ylamine (50 mg, 0.423 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (237 μL, 1.7 mmol) at room temperature, which was stirred for 2 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1→2:1) to obtain the title compound (59 mg, 23%).
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13]/[CH:14]=[C:15](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)\[CH3:16])[CH2:11][O:10]C1(C)C)=O)(C)(C)C.Cl>O1CCOCC1.C(OCC)(=O)C>[NH2:8][C@@H:12]([CH2:13]/[CH:14]=[C:15](/[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)\[CH3:16])[CH2:11][OH:10]
Reactant: C/C(=C\C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C/C(=C\C[C@H](N)CO)c1ccccc1
Reaction time: 8 h

Procedure:
To a stirred solution of (4S)-2,2-dimethyl-4-((E)-3-phenyl-but-2-enyl)-oxazolidine-3-carboxylic acid tert-butyl ester (1.15 g) in dioxane (10 ml) at room temperature was added a 4 M solution of hydrogen chloride in dioxane (17.4 ml solution) and stirring was continued at room temperature overnight. The mixture was taken up in ethyl acetate and washed sequentially with aqueous sodium hydroxide solution (1N), water and saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, heptane/dichloromethane gradient; eluant containing 1% aq. ammonia) to yield a yellow oil, (185 mg, 28%); MS (ISP): 192.1 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:27]([CH3:28])[CH2:26][CH2:25][N:13]3[C:14](=[O:24])[C:15]=2[O:16]CC2C=CC=CC=2)=[O:9])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:27]([CH3:28])[CH2:26][CH2:25][N:13]3[C:14](=[O:24])[C:15]=2[OH:16])=[O:9])=[CH:29][CH:30]=1
Reactant: CN1CCn2c1nc(C(=O)NCc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN1CCn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Yield: 82.5 %

Procedure:
A solution of N-(4-fluorobenzyl)-6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide (0.202 g, 0.495 mmol) in a mixture of ethyl acetate (150 ml) and ethanol (20 ml) at 25° C. was hydrogenated over 10% palladium on activated carbon (50 mg) and under one atmosphere of hydrogen for one hour to give 0.130 g (83% yield) of the title compound as white needles; mp 212° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.93 (3H, s, CH3), 3.63 (2H, t, J=8.6 Hz, CH2), 4.14 (2H, t, J=8.6 Hz, CH2), 4.59 (2H, d, J=6.0 Hz, NCH2), 7.07 (2H, m, aromatics), 7.33 (2H, m, aromatics), 7.89 (1H, broad t, NH), 11.57 (1H, s, OH). HRMS (ESI+) calculated for C15H16FN4O3 [M+H+]: 319.1206. found: 319.1191.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@:12]34[C:13]5[C:14]6[O:21][C@H:11]3[C@@H:10]([N:24]([O:36][CH3:37])[C:25](=[O:35])[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=3)[CH2:9][CH2:8][C@@:7]4([OH:38])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[OH:20])[CH2:3][CH2:2]1.[CH3:39][Si](C=[N+]=[N-])(C)C.C(N(C(C)C)CC)(C)C.CO>C(#N)C>[CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@:12]34[C:13]5[C:14]6[O:21][C@H:11]3[C@@H:10]([N:24]([O:36][CH3:37])[C:25](=[O:35])[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=3)[CH2:9][CH2:8][C@@:7]4([OH:38])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[O:20][CH3:39])[CH2:3][CH2:2]1
Reactant: CON(C(=O)Cc1ccc(Cl)c(Cl)c1)[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC#N
Product: COc1ccc2c3c1O[C@H]1[C@@H](N(OC)C(=O)Cc4ccc(Cl)c(Cl)c4)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Temperature: 25 °C
Reaction time: 13 h
Yield: 23.4 %

Procedure:
A mixture of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(N-methoxy-3,4-dichlorophenylacetamido)morphinan (197 mg, 0.35 mmol), trimethylsilyldiazomethane (10% solution in CH2Cl2, 0.57 g, 0.5 mmol), diisopropylethylamine (65 mg, 0.5 mmol), methanol (0.2 ml), and acetonitrile (2 ml) was stirred at room temperature for 13 h. After evaporation of the solvent, the residual oil was purified by preparative thin layer chromatography (1 mm thick plate, CH2Cl2 /MeOH: 10/1) to give 47 mg of amorphous solid. This was purified again by preparative thin layer chromatography (1 mm thick plate, CH2Cl2 /MeOH: 10/1) to give 25 mg of amorphous solid as desired product.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:11]=2[CH:12]([CH3:14])[CH3:13])[C:3]1=[O:22].[CH3:23][C:24]1[NH:28][N:27]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[C:11]([CH:12]([CH3:14])[CH3:13])=[C:7]([N:4]3[CH2:5][CH2:6][CH:2]([N:28]4[C:24]([CH3:23])=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[N:27]4)[C:3]3=[O:22])[CH:8]=[N:9]2)=[CH:16][CH:17]=1
Reactant: Cc1cc(C(F)(F)F)n[nH]1
Reactant: CC(C)c1c(N2CCC(Br)C2=O)cnn1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nn1C1CCN(c2cnn(-c3ccc(F)cc3)c2C(C)C)C1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
A mixture of 3-bromo-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.023 g, 0.063 mmol), 5-methyl-3-(trifluoromethyl)-1H-pyrazole (0.040 g, 0.27 mmol) and K2CO3 (0.060 g, 0.43 mmol) in DMF (1 mL) was stirred at 60° C. for 1 hr. It was then cooled to room temperature, quenched with water (30 mL) and extracted with EtOAc (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by flash chromatography (SiO2, 0˜100% EtOAc/hexanes gradient elution) to give the title compound (0.022 g, 80%). 1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 7.37 (dd, J=9.2, 4.8 Hz, 2H), 7.17 (dd, J=8.6, 8.6 Hz, 2H), 6.32 (s, 1H), 5.05 (dd, J=9.2, 5.6 Hz, 1H), 4.07 (m, 1H), 3.80 (m, 1H), 2.84-3.02 (m, 2H), 2.74 (m, 1H), 2.45 (s, 3H), 1.21 (d, J=7.6 Hz, 3H), 1.11 (d, J=6.8 Hz, 3H); MS: (ES) m/z calculated for C21H21F4N5O [M+H]+ 436.1. found 436.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[Cl-].[OH:13][NH3+:14].C([O-])(=O)C.[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:14][OH:13])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: ON=C1CCc2cc(Br)ccc21
Reaction time: 8 h
Yield: 95.2 %

Procedure:
5-Bromoindan-1-one (5.0 g) was dissolved in methanol. Hydroxylammonium chloride (2.5 g) and sodium acetate (2.9 g) were added to the solution at room temperature, and then stirred overnight. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic layers were combined, washed with water, and dried over anhydrous magnesium sulfate. The desiccant was filtered and separated, and then the solvent was evaporated off under reduced pressure to obtain 5-bromo-N-hydroxyindan-1-imine (5.1 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])[N:12]=1.[CH:29]([N:32](C(C)C)CC)(C)[CH3:30].BrCC#N>CS(C)=O>[NH2:17][C:15]1[C:14]([NH:18][CH2:30][C:29]#[N:32])=[C:13]([S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])[N:12]=[C:11]([S:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[N:16]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1nc(SCc2cccc(F)c2F)nc(SCc2cccc(F)c2F)c1N
Agent: N#CCBr
Solvent: CS(C)=O
Product: N#CCNc1c(N)nc(SCc2cccc(F)c2F)nc1SCc1cccc(F)c1F

Procedure:
A solution of the product of example 1 step a) (5.0 g), diisopropylethylamine (2.8 ml) and bromoacetonitrile (1.1 ml) in DMSO (50 ml) was heated at 100° C. for 5 hours. After cooling, the reaction mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic phase was dried over magnesium sulphate, filtered and evaporated to give a black oil which was purified by silica gel flash column chromatography, eluting with 10:1 dichloromethane:ethyl acetate, to give the subtitled compound as a pale orange solid (1.6 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.Cl.CN(C)[CH2:15][CH2:16]CN=C=N.O.ON1C2C=CC=CC=2N=N1.C(O)C>CN(C)C=O.O>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([O:9][CH2:15][CH3:16])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: CN(C)CCCN=C=N
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
5-Bromosalicylic acid (434 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg), 1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give ethyl 5-bromosalicylate (299 mg, yield 61%).
Reaction SMILES: O.[NH2:2][NH2:3].[NH2:4][C:5]1[C:10]([F:11])=[C:9](F)[N:8]=[C:7]([C:13]#[N:14])[C:6]=1[Cl:15]>C1COCC1.CS(C)=O.C(#N)C>[NH2:4][C:5]1[C:10]([F:11])=[C:9]([NH:2][NH2:3])[N:8]=[C:7]([C:13]#[N:14])[C:6]=1[Cl:15]
Reactant: NN
Reactant: N#Cc1nc(F)c(F)c(N)c1Cl
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CS(C)=O
Product: N#Cc1nc(NN)c(F)c(N)c1Cl
Temperature: 65 °C
Yield: 97.3 %

Procedure:
To a solution of hydrazine hydrate (3.9 g, 78 mmol) in THF (15 mL) and DMSO (10 mL) was added 4-amino-3-chloro-5,6-difluoropicolinonitrile (5 g, 26 mmol) as a solution in DMSO (5 mL). This solution was heated to 65° C. for 45 min, cooled and diluted with acetonitrile (30 mL) to precipitate the product as a light tan solid. This solid was dried under vacuum at 40° C. for 3 h to give 4-amino-3-chloro-5-fluoro-6-hydrazinopicolinonitrile (5.1 g, 98%): mp 215-220° C. dec; 1H NMR (400 MHz, DMSO-d6) 7.9 (br, 1H), 6.5 (br, 2H), 4.0 (br, 2H); 13C {1H} NMR (101 MHz, DMSO-d6) δ 149.34 (d, J=10.5 Hz, C6), 138.28 (d, J=11.6 Hz, C4), 133.81 (d, J=251.6 Hz, C5), 123.74 (d, J=5.3 Hz, C2), 115.87 (s, C3), 112.57 (s, CN); 19F NMR (376 MHz, DMSO-d6) δ −154.6; ESIMS m/z 203 ([M+H]+). Anal. Calcd for C6H5ClFN5: C, 35.75; H, 2.50; N, 34.74. Found: C, 35.97; H, 2.70: N, 35.01.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][CH2:7][CH2:6]2)[CH3:2]>C(Cl)Cl.O=[Mn]=O>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][CH:7]=[CH:6]2)[CH3:2]
Reactant: CCc1cc2c(cc1[N+](=O)[O-])NCC2
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCc1cc2cc[nH]c2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
To a solution of 5-ethyl-6-nitroindoline (1.9 g, 9.9 mmol) in CH2Cl2 (30 mL) was added MnO2 (4.0 g, 46 mmol). The mixture was stirred at ambient temperature for 8 h. The solid was filtered off and the filtrate was concentrated to dryness to give 5-ethyl-6-nitro-1H-indole (1.9 g).
Reaction SMILES: Cl.C(C1C=CC(C(N)=N)=CC=1)CCCCC.C(OC(=O)C(=COCC)C#N)C.CC[O-].[Na+].[OH-].[Na+].[C:35]([C:37]1[C:38](O)=[N:39][C:40]([C:43]2[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:45][CH:44]=2)=[N:41][CH:42]=1)#[N:36].P(Cl)(Cl)([Cl:58])=O>C(O)C>[Cl:58][C:38]1[C:37]([C:35]#[N:36])=[CH:42][N:41]=[C:40]([C:43]2[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:45][CH:44]=2)[N:39]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCc1ccc(-c2ncc(C#N)c(O)n2)cc1
Agent: CCCCCCc1ccc(C(=N)N)cc1
Agent: CCOC=C(C#N)C(=O)OCC
Agent: CC[O-]
Solvent: CCO
Product: CCCCCCc1ccc(-c2ncc(C#N)c(Cl)n2)cc1

Procedure:
The starting material can be obtained according to the procedure of A. R. Todd and F. Bergel, J. Chem. Soc. 1937, 365 by reaction of p-n-hexylbenzamidine hydrochloride with α-ethoxymethylene- α-cyanoacetic acid ethyl ester and sodium ethylate in ethanol and then with sodium hydroxide solution. The resulting 5-cyano-4-hydroxy-2-(4-n-hexylphenyl)-pyrimidine (melting point 204.4°-205.2° C) is treated with phosphorus oxychloride to give 4-chloro-5-cyano-2-(4n-hexylphenyl)-pyrimidine having a melting point of 80.3°-80.5° C.