Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8]Br)[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16](#[N:18])C>>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:16]#[N:18])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC#N
Reactant: Fc1cc(CBr)ccc1-c1ccccc1
Product: N#CCc1ccc(-c2ccccc2)c(F)c1

Procedure:
The crude monobromide prepared in Example 4 was refluxed with 100 ml of EtOH and 6.9 g (0.14 mol) of NaCN for one hour. Most of the EtOH was then removed in a rotary evaporator at reduced pressure and the resulting residue was partitioned between H2O and Et2O. The Et2O phase was dried over MgSO4 and concentrated to leave 19.3 g of brown semi-solid material. Analysis of this material by NMR showed that it contained the acetonitrile and only trace amounts of the monobromide. The crude acetonitrile material was stirred all night in petroleum ether and then filtered. The product was collected as 13.2 g of brown solid that contained about 5% of the starting material according to GC analysis. Concentration of the petroleum ether solution gave 4.9 g of orange liquid that contained mostly the starting material and some of the product acetonitrile. The yield of the 95% pure acetonitrile based on unrecovered fluoride (3) was about 70-80%.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[O:3][CH:2]([F:13])[F:1]
Reactant: O=C(O)c1ccccc1OC(F)F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1OC(F)F
Yield: 87 %

Procedure:
2.0 g of 2-difluoromethoxy-benzoic acid (10.6 mmol, 1.0 eq) were dissolved in MeOH (15 mL) and a catalytic quantity of sulfuric acid was added; the mixture was heated at reflux overnight. The solvent was then evaporated and the residue was dissolved in DCM and washed with saturated NaHCO3. The organic phase was dried and evaporated to give 1.9 g of title product (yield 87%).
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11].N1C2C(=CC=CC=2)C=CC=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCO>[CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C#CCCCCCCCCCO
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: C=CCCCCCCCCCO
Reaction time: 1 h
Yield: 101 %

Procedure:
A mixture of undec-10-yn-1-ol (0.84 g, 5.0 mmol), quinoline (0.13 ml), Lindlar's catalyst (100 mg, 17% w/w) and EtOH (20 mL) was hydrogenated in a Parr apparatus at 50 psi of H2 for 1 h. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo to dryness to give undec-10-en-1-ol (0.86 g, 100%) as a colorless oil, which was used in the next step without further purification: 1H NMR (300 MHz, CDCl3) δ 5.78 (1H, m), 4.92 (2H, m), 3.61 (2H, t, J=6.6 Hz), 2.01 (2H, m), 1.53 (3H, m), 1.21–1.40 (12H, m); 13C NMR (75 MHz, CDCl3) δ 139.43, 114.31, 63.24, 34.00, 32.98, 29.74, 29.61, 29.31, 29.11, 25.92.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[N+:12]([C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CC(C)=O>[S:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:3]1[CH2:2][O:21][C:17]1[CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: ClCc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc(OCc2nc3ccccc3s2)c1
Yield: 84 %

Procedure:
A mixture of 2-chloromethylbenzthiazole (17.6 g), 3-nitrophenol (13.2 g), cesium carbonate (30 g), sodium carbonate (10 g), potassium iodide (0.5 g) and acetone (600 ml) is heated at reflux overnight. The mixture is filtered and the resulting solution is partially concentrated. A crystalline solid forms which is filtered and dried giving 22.8 g (84% yield) m.p. 156°-157° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[CH:18]1([SH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([S:24][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=c1ccc2cc(OCCCCBr)ccc2[nH]1
Reactant: SC1CCCCC1
Product: O=c1ccc2cc(OCCCCSC3CCCCC3)ccc2[nH]1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p.: 198°-199° C.) and cyclohexyl mercaptan.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>CN(C=O)C>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([NH:12][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: c1cc(OCC2CO2)ccn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NCC(O)COc2ccncc2)CC1
Temperature: 80 °C
Reaction time: 48 h
Yield: 36.6 %

Procedure:
To a sealed tube was added 4-oxiranylmethoxy-pyridine (80 mg, 0.529 mmol) in 4 mL of DMF, followed by the addition of 4-amino-1-N-boc-piperidine (148 mg, 0.739 mmol). The reaction mixture was stirred at 80° C. for 48 h. The reaction mixture was concentrated in vacuo. The residue was loaded to a flash chromatography column. The column was eluted with 0–5% 2M NH3 in MeOH/CH2Cl2. The product fractions were collected and concentrated to afford 68 mg (36.6%) of 4-[2-hydroxy-3-(pyridin-4-yloxy)-propylamino]-piperidine-1-carboxylic acid tert-butyl ester as a light brown oil. (TLC: Rf=0.15, 5% 2M NH3 in MeOH/CH2Cl2, UV). ES+ 352.43 m/z (MH+)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)([CH3:41])[CH3:40]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:45]3[CH2:46][CH2:47][N:42]([CH:39]([CH3:41])[CH3:40])[CH2:43][CH2:44]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)N1CCNCC1
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(C)C)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-isopropyl-piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H49N4O2Cl2 [(M+H)+] 663.3227, observed 663.3228.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[S:17][C:15]=2[N:16]=1>>[Cl:10][C:11]1[N:12]=[C:13]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:14]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[S:17][C:15]=2[N:16]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 4-fluorobenzylamine with 2,4-dichloro-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-nitro-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[N+](C1N=CC2C(=CC=CC=2)N=1)([O-])=O>CO.[Pd]>[CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: CNc1ncnc2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Agent: O=[N+]([O-])c1ncc2ccccc2n1
Solvent: CO
Product: CNc1ncnc2ccc(N)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of methyl-(6-nitro-quinazolin-4-yl)-amine (0.16 g; see Synthesis of Certain Nitroquinazoline Derivatives Structurally Related to some Chemotherapeutic Agents, Botros, S., et. al., Egyptian Journal of Pharmaceutical Sciences, 13(1), 11-21, (1972) for a description of preparing the nitro-quinazoline) and Pd/C (10 wt %, 0.032 g) in 10 ml of MeOH was placed under H2 from a balloon and stirred at RT for 3 h, filtered through a pad of Celite®. Removal of the solvents afforded the title compound as an off-white solid. MS (MH+)=175.3; Calc'd for C9H10N4—174.20.
Reaction SMILES: Cl[CH:2]([CH2:8][C:9]1[CH:14]=[C:13]([N:15]2[C:19](=[O:20])[C:18]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]3[C:16]2=[O:25])[C:12]([F:26])=[CH:11][C:10]=1[Cl:27])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1CCN2C(=NCCC2)CC1.O>O1CCCC1>[Cl:27][C:10]1[CH:11]=[C:12]([F:26])[C:13]([N:15]2[C:19](=[O:20])[C:18]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]3[C:16]2=[O:25])=[CH:14][C:9]=1[CH:8]=[CH:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Cl)Cc1cc(N2C(=O)c3ccccc3C2=O)c(F)cc1Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCOC(=O)C=Cc1cc(N2C(=O)c3ccccc3C2=O)c(F)cc1Cl
Reaction time: 1.5 h
Yield: 69.6 %

Procedure:
In 20 ml of tetrahydofuran was dissolved 1.23 g of ethyl 2-chloro-3-(2-chloro-4-fluoro-5-phthalimidophenyl)propionate, and 0.69 g of 1,8-diazabicyclo[5.4.0]-7-undecene was slowly added thereto dropwise. After the addition, the stirring was continued at room temperature for 1.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform) to give 0.78 g of the title compound (No. 17 of Table 2).
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]([CH3:33])([CH3:32])[CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]([C:30]#[N:31])[C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[C:17]([O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:16]=2)=[O:11])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:30]([C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:23][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)[CH:16]=2)[C:21]([OH:22])=[C:12]([C:10]([NH:9][CH2:8][C:7]([CH3:33])([CH3:32])[C:6]([OH:34])=[O:5])=[O:11])[N:13]=1)#[N:31]
Reactant: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(OC3CCCCC3)ccc2c1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(OC3CCCCC3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.9 %

Procedure:
A mixture of 3-[(1-cyano-7-cyclohexyloxy-4-hydroxy-isoquinoline-3-carbonyl)-amino]-2,2-dimethyl-propionic acid tert-butyl ester (55 mg, 0.118 mmol) in (½) TFA/CH2Cl2 (3 mL) was stirred at room temperature for 3 h and concentrated. Residue was taken up with 30 mL of water and the resultant suspension was basified by 1 N NaOH to pH=9-10. The clear solution was then acidified by 1 N HCl to pH=3-4. Precipitate was collected and dried. Crude product was triturated with MeOH (3 mL). Solid was collected and dried in vacuo to provide the title compound 8.6 mg (0.02 mmol) in 18% yield. LC-MS ESI−: 410.00 (M−1)−.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[C:3]=1[CH3:27].[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[F:31][C:30]([F:33])([F:32])[C:28]([OH:34])=[O:29].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:3]=1[CH3:27]
Reactant: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Tert-Butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)piperazine-1-carboxylate (370 mg, 0.93 mmol) was dissolved in DCM (3.0 mL) and cooled to 0° C. TFA (0.50 mL, 6.5 mmol) was then added and the mixture was stirred for 2 h while warming to rt. The mixture was then concentrated and triturated with EtOAc. The slurry was filtered to give 4-chloro-5,7-difluoro-3-methyl-2-(piperazin-1-yl)quinoline 2,2,2-trifluoroacetate. Mass Spectrum (ESI) m/e=298.1 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][C:18](=O)[NH:17][C@@H:16]([CH:21]([CH3:23])[CH3:22])[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl.O.O1CCCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][NH:17][C@@H:16]([CH:21]([CH3:23])[CH3:22])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)[C@@H]1NC(=O)CN(Cc2ccccc2)C1=O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)[C@H]1CN(Cc2ccccc2)CCN1
Temperature: 0 °C
Yield: 42.9 %

Procedure:
To 100 mL tetrahydrofuran cooled to 0° C. were added 9 mL (8.9 mMol) lithium aluminum hydride (1.0 M in tetrahydrofuran) dropwise. To this was added dropwise a solution of 1.0 gm (4.06 mmol) 1-benzyl-2,5-dioxo-3(S)-isopropylpiperazine in 50 mL dichloromethane over 30 minutes. The reaction mixture was then heated at reflux over night. The reaction mixture was then cooled to 0° C. and was stirred vigorously while being treated sequentially with 1 mL water, 1 mL 5N sodium hydroxide, 2 mL water, and 5 gm sodium sulfate. After stirring for 30 minutes the reaction mixture was filtered and the filter cake washed with dichloromethane. The filtrate was concentrated under reduced pressure and the yellow waxy solid residue was subjected to silica gel chromatography, eluting with dichloromethane containing 0–3% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 0.38 gm (42%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](O)=[O:10])[CH2:5][CH2:4]1.O=S(Cl)Cl.C(Cl)Cl.C[N:22](C=O)C>>[F:1][C:2]([F:13])([F:12])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH2:22])=[O:10])[CH2:5][CH2:4]1
Reactant: CN(C)C=O
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: NC(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reaction time: 0.08 h

Procedure:
A mixture of trans-4-trifluoromethyl-cyclohexane-carboxylic acid (10.4 g, 53.1 mmol), SOCl2 (10 mL, 137 mmol), DCM (100 mL) and DMF (200 μl) is heated to reflux for 1.5 h and concentrated. The crude acid chloride is diluted with 100 mL THF and conc. NH3 (350 mL) is slowly added. It is stirred for 5 min and the mixture is concentrated and dried at 40°.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][N:11]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=[CH2:25])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][N:15]=1
Reactant: C=CCCCCCCBr
Reactant: CCCCCCCCc1cnc(-c2ccc(O)c(F)c2F)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C=CCCCCCCOc1ccc(-c2ncc(CCCCCCCC)cn2)c(F)c1F
Temperature: 25 °C

Procedure:
A suspension of 2-(2,3-difluoro-4-hydroxyphenyl)-5-octylpyrimidine (1.00 g, 3.07 mmol), 8-bromo-1-octene (0.59 g, 3.07 mmol) and cesium carbonate (1.99 g, 6.14 mmol) in acetone (70 ml) was heated under reflux for 18 h. The reaction mixture was cooled to room temperature, washed with water and the organic layer extracted in ethyl acetate/hexane (3 times, 1:1). The combined extracts were washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residues were purified by column chromatography [silica gel, eluted with hexane/ethyl acetate (4:1), Rf 0.30] and recrystallized from hexane to yield colorless crystals.
Reaction SMILES: C(S[C:4](=[O:20])[C@H:5]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH:6]([CH3:8])[CH3:7])C.[SiH](CC)(CC)CC>CC(C)=O.[Pd]>[CH2:13]([O:12][C:10](=[O:11])[NH:9][C@@H:5]([CH:4]=[O:20])[CH:6]([CH3:8])[CH3:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCSC(=O)[C@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: CC(C)=O
Product: CC(C)[C@H](C=O)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution containing (R)-2-benzyloxycarbonylamino-3-methyl-thiobutyric acid S-ethyl ester (5.2 g, 17.6 mmol) in acetone (100 mL) is added Pd-on-C (10%, 233 mg). The heterogeneous mixture is cooled to 0° C. and Et3SiH (8.4 mL, 53 mmol) is quickly added. After 30 min, the reaction mixture is filtered through a pad of celite and the clear filtrate is concentrated to a residue which is partitioned between hexane (200 mL) and acetonitrile (300 mL). The layers are separated and the ACN phase is washed once with hexane (100 mL) and then concentrated to afford crude (R)-(1-Formyl-2-methyl-propyl)-carbamic acid benzyl ester (4.13 g) which is used directly without further purification. 1H NMR (300 MHz, CDCl3) δ2.30 (m, 1H), 4.31 (m, 1H), 5.09 (s, 2H), 5.45 (br, 1H), 7.30-7.45 (m, 5H), 9.65 (s, 1H) ppm.
Reaction SMILES: [C:1](=[NH:20])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:21]([CH:23]([CH2:28][C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[N:33][CH:34]=1)[C:24](OC)=O)=[O:22].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:36][O:35][C:32]1[N:31]=[CH:30][C:29]([CH2:28][C:23]2[C:21](=[O:22])[N:20]=[C:1]([O:3][CH2:4][CH2:5][C:6]3[CH:7]=[CH:8][C:9]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=4)=[CH:10][CH:11]=3)[NH:2][CH:24]=2)=[CH:34][N:33]=1
Reactant: Cc1cccc(Oc2ccc(CCOC(=N)N)cc2)n1
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4cccc(C)n4)cc3)nc2=O)cn1
Temperature: 130 °C
Yield: 4.6 %

Procedure:
To the solution of 2-{4-[(6-methyl-2-pyridinyl)oxy]phenyl}ethyl imidocarbamate (200 mg, 0.737 mmol) and methyl 2-formyl-3-[2-(methyloxy)-5-pyrimidinyl]propanoate (182 mg, 0.811 mmol) in NMP (3 mL) was added K2CO3 (408 mg, 2.95 mmol). The mixture was heated with a microwave reactor at 130° C. for 1 h. Purification via MDAP then afforded the title compound (15 mg, 4.57% yield). LCMS: rt=2.54 min, [M+H+]=447
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][O:14][CH2:15][CH2:16][NH2:17]>>[CH3:13][O:14][CH2:15][CH2:16][NH:17][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COCCN
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Product: COCCNc1ccc([N+](=O)[O-])cc1OC

Procedure:
0.3 mol (56.2 g) of 4-chloro-3-methoxynitrobenzene in 170 ml of 2-methoxyethylamine is heated to reflux for 18 hours. The excess 2-methoxyethylamine is distilled off. The reaction medium is diluted with 300 g of ice-cold water.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:24][C:25]2[C:26]([CH3:32])=[N:27][N:28]([CH3:31])[C:29]=2[CH3:30])[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([C@H:14]3[CH2:18][O:17][C:16]4([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[O:15]3)[N:10]=2)=[N:6][CH:7]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].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.[SH:83][CH2:84][CH2:85][C:86]([O:88][CH3:89])=[O:87]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[O:15]1[C:16]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[O:17][CH2:18][C@@H:14]1[C:11]1[N:10]=[C:9]([NH:8][C:5]2[N:6]=[CH:7][C:2]([S:83][CH2:84][CH2:85][C:86]([O:88][CH3:89])=[O:87])=[CH:3][C:4]=2[O:24][C:25]2[C:26]([CH3:32])=[N:27][N:28]([CH3:31])[C:29]=2[CH3:30])[S:13][N:12]=1
Reactant: COC(=O)CCS
Reactant: Cc1nn(C)c(C)c1Oc1cc(Br)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: COC(=O)CCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2c(C)nn(C)c2C)c1
Temperature: 100 °C
Yield: 46.7 %

Procedure:
A sealed tube was charged with (S)—N-(5-bromo-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.550 g, 1.055 mmol), Pd2(dba)3 (0.06065 g, 0.1055 mmol), K3PO4 (0.5821 g, 2.742 mmol), Xantphos (0.1221 g, 0.2110 mmol), and degassed toluene (5 mL). Nitrogen was bubbled through the solution for 5 minutes. Methyl 3-mercaptopropanoate (0.1752 ml, 1.582 mmol) was added and the reaction was heated to 100° C. overnight. The reaction was cooled to ambient temperature, water was added and the reaction was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified over silica gel (50 to 100% ethyl acetate in hexanes) to afford (S)-methyl 3-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-ylamino)-5-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-3-ylthio)propanoate (0.276 g, 0.4923 mmol, 46.67% yield) as yellow oil.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1)[CH:2]([CH3:4])[CH3:3].Br[CH2:19][C:20]([O:22]C(C)(C)C)=[O:21]>>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:19][C:20]([OH:22])=[O:21])=[CH:7][C:8]=1[C:14]([F:15])([F:16])[F:17])#[N:11]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)CNc1ccc(C#N)c(C(F)(F)F)c1
Product: CC(C)CN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 70B using 4-(isobutylamino)-2-(trifluoromethyl)benzonitrile and 1,1-dimethylethyl bromoacetate: 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J=9.0 Hz, 1H), 6.90 (d, J=2.6 Hz, 1H), 6.72 (dd, J=9.0, 2.7 Hz, 1H), 4.19 (s, 2H), 3.26 (d, J=7.5 Hz, 2H), 2.04 (m, 1H), 0.97 (d, J=6.6 Hz,
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[NH2:14])[CH:7]=1.[N:17]1[N:21]2[CH:22]=[CH:23][CH:24]=[N:25][C:20]2=[C:19]([C:26](O)=[O:27])[CH:18]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[NH:14][C:26]([C:19]2[CH:18]=[N:17][N:21]3[CH:22]=[CH:23][CH:24]=[N:25][C:20]=23)=[O:27])[CH:7]=1
Reactant: O=C(O)c1cnn2cccnc12
Reactant: COc1ccc(Cl)cc1-c1c(N)cnn1C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cl)cc1-c1c(NC(=O)c2cnn3cccnc23)cnn1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A mixture of 5-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-amine (0.100 g, 0.421 mmol, 1 eq), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (77.2 mg, 0.473 mmol, 1.12 eq), 7-azabenzotriazol-1-yloxy-tris-(pyrrolidino)phosphonium hexafluorophosphate (269 mg, 0.519 mmol, 1.23 eq), N,N-diisopropylethylamine (0.15 mL, 0.86 mmol, 2.0 eq), and 4-dimethylaminopyridine (20.1 mg, 0.164 mmol, 0.39 eq) in 5.0 mL N,N-dimethylformamide was stirred at 50° C. for 2 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 82.2 mg (51%) of N-(5-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=383.0; 1H NMR (400 MHz, DMSO-d6) δ: 9.51 (s, 1H), 9.31 (d, 1H), 8.67 (d, 1H), 8.63 (s, 1H), 7.98 (s, 1H), 7.58 (d, 1H), 7.54 (s, 1H), 7.31 (d, 1H), 7.28 (d of d, 1H), 3.85 (s, 3H), 3.70 (s, 3H).