Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[C:7]([Cl:25])=[CH:6][CH:5]=1.Br[CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[Cl:3][C:4]1[C:12]2[N:11]([CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[C:7]([Cl:25])=[CH:6][CH:5]=1
Reactant: BrCCOc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(Cl)ccc(Cl)c3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3ccccc3)c3c(Cl)ccc(Cl)c23)CC1
Reaction time: 0.42 h
Yield: 79 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 51 mg, 1.3 mmol) was added to a solution of tert-butyl 7,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.30 g, 0.84 mmol) in DMF (5 mL). After 25 min, β-bromophenetole was added (0.23 mL). The reaction was quenched with saturated aqueous NH4Cl after 18 h and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40S) with heptane/EtOAc (9:1) to give 0.32 g (79%) of a white solid: mp 131.5-133.0° C.; 1H NMR (300 MHz, CDCl3) δ 6.96 (m, 3H), 6.81 (m, 2H), 4.92 (t, J=4.9 Hz, 2H), 4.27 (m, 2H), 3.80 (m, 2H), 3.67 (m, 2H), 3.52 (m, 2H), 3.18 (m, 2H), 1.49 (s, 9H); IR (diffuse reflectance) 1686, 1498, 1474, 1404, 1366, 1350, 1318, 1295, 1248, 1227, 1221, 1167, 1116, 788, 757 cm−1; MS (EI) m/z 474 (M+), 418, 376, 374, 339, 334, 332, 77, 57, 56, 55; Anal. Calcd for C25H28Cl2N2O3: C, 63.16; H, 5.94; N, 5.89; found: C, 63.13; H, 6.00; N, 5.89.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5](O)(=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[OH:2][CH2:1][CH2:3][NH:4][C:5](=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NCCO
Reactant: CCCCCCCCCCCC(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(=O)NCCO
Temperature: 140 °C

Procedure:
To a solution of 24 g (0.4 mole) ethanolamine in 100 ml toluene was added 40 g (0.2) lauric acid at 50° C. The mixture was refluxed for 6 hours. Toluene was gradually removed to increase the final pot temperature to 140° C. The distillate was collected in a Stark & Dean trap. The toluene was removed by vacuum stripping and the residue was crystallized from n-hexane. The title compound (44 g) thus obtained melted at 80°-84° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:16])[CH2:14]Br)[C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.[F-:36].[K+]>C(#N)C>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:16])[CH2:14][F:36])[C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)C1CCN(Cc2ccccc2)C1=O
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: O=C(CF)C1CCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
To a solution of 1-benzyl-3-(2-bromoacetyl)pyrrolidin-2-one (2.2 g, 7.43 mmol, Example 14) in acetonitrile (25 mL) was added 18-crown-6 (0.980 g, 3.72 mmol) and potassium fluoride (spray dried) (2.16 g, 37.2 mmol). The reaction mixture was immersed in an oil bath at 80° C. After 1 hour, the mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude residue was then purified by chromatography (99:1 dichloromethane/methanol then 98:2 dichloromethane/methanol) to afford the title compound (0.515 g): 1H NMR (CDCl3) δ 7.36-7.19 (m, 5H), 4.93 (m, 2H), 4.46 (m, 2H), 3.61 (m, 1H), 3.48 (m, 2H), 2.74 (m, 2H).
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[C:8]1([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[CH2:1]([NH:5][C:6]([NH:21][CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:16][CH2:17]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CCCCN=C=O
Solvent: ClCCl
Product: CCCCNC(=O)NC1CCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
Butyl isocyanate (33.9 g, 342 mmol) is added dropwise to a solution of 1-(phenylmethyl)-4-piperidinamine (65 g, 342 mmol) in methylene chloride (400 mL) at 0° C., and the mixture is stirred for 2 hr. The mixture is washed three times with water, dried over magnesium sulfate, and evaporated. Recrystallization of the residue from methylene chloride-hexane affords the title compound.
Reaction SMILES: [ClH:1].[CH2:2]([O:6][CH:7]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])[C@H:8]([CH2:25][CH2:26][CH2:27][NH:28][C:29](=[NH:31])[NH2:30])[NH:9][C:10](=[O:24])[C@H:11]([CH3:23])[NH:12]C(OCC1C=CC=CC=1)=O)[CH2:3][CH2:4][CH3:5].[H][H]>CO.[Pd]>[ClH:1].[CH2:2]([O:6][CH:7]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])[C@H:8]([CH2:25][CH2:26][CH2:27][NH:28][C:29](=[NH:30])[NH2:31])[NH:9][C:10](=[O:24])[C@H:11]([CH3:23])[NH2:12])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@H](C)N
Yield: 98 %

Procedure:
After N-benzyloxycarbonyl-L-alanyl-L-argininal dibutylacetal hydrochloride (0.45 g, 0.85 mmol) was dissolved in methanol (25 ml), palladium black (1 g) was added to the solution. The mixture was stirred at room temperature for 2 hours in a hydrogen flow. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated to give 0.33 g (97%) of L-alanyl-L-argininal dibutylacetal hydrochloride as oil.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][CH2:5][CH:6]([NH:8][C:9]([C:11]1[CH:12]=[C:13]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:14]=[C:15]([C:17](=[O:19])[CH3:18])[CH:16]=1)=[O:10])[CH3:7]>>[CH3:3][O:4][CH2:5][CH:6]([NH:8][C:9]([C:11]1[CH:12]=[C:13]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:14]=[C:15]([C:17](=[O:19])[CH2:18][Br:1])[CH:16]=1)=[O:10])[CH3:7]
Reactant: BrBr
Reactant: COCC(C)NC(=O)c1cc(C(C)=O)cc(-c2ccc(C)cc2)c1
Product: COCC(C)NC(=O)c1cc(C(=O)CBr)cc(-c2ccc(C)cc2)c1
Temperature: 45 °C

Procedure:
A solution of bromine (0.074 ml, 1.5 mmol) dissolved in CCI4 (2.0 ml) was added slowly to a stirred solution of 5-acetyl-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (325 mg, 1 mmol) in 3.0 ml of CCI4 at room temperature. The mixture was then heated to 45° C. for 14 hours. The solution was cooled and extracted with EtOAc, and the combined organic layers were washed with saturated aqueous Na2S2O3, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude 5-(2-bromo-acetyl)-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide was used for next step directly without further purification.
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:8])(=[NH:7])[CH3:6].C([N:16]1[CH2:22][CH2:21][CH:20](Br)[C:19](=O)[CH2:18][CH2:17]1)C1C=CC=CC=1>CO>[CH3:6][C:5]1[NH:8][C:19]2[CH2:18][CH2:17][NH:16][CH2:22][CH2:21][C:20]=2[N:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CCC1Br
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1nc2c([nH]1)CCNCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3 equivalents (4.463 g) of sodium methoxide are placed in MeOH at ambient temperature, 7.8 g of acetamidine-hydrochloride are added and the mixture is stirred for 30 min. Then 10 g of N-benzyl-5-bromohexahydro-4-azepinone are added. After another 30 minutes an additional 2 eq. (2.976 g) of sodium methoxide are added to the mixture which is refluxed for 11 hours. After cooling to ambient temperature the mixture is fully concentrated by evaporation in vacuo, the material remaining is triturated with about 140 ml of isopropanol, filtered and the filtrate is evaporated down again. The crude product is taken up in 50 ml of 1N K2CO3 solution and extracted 3× with 40 ml of CH2Cl2. The organic phases are dried with MgSO4, filtered off and evaporated to dryness. The residue is chromatographed over silica gel (CH2Cl2/MeOH=87:13 to 70:30). Yield: 1.7 g
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([OH:25])=O)[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:26].FC1C=CC=C(F)C=1NC(=O)NC1C=CC(C2C=C(C([NH:52][CH:53]([CH:58]([CH3:60])[CH3:59])[C:54]([O:56][CH3:57])=[O:55])=O)ON=2)=CC=1C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:52][CH:53]([CH:58]([CH3:60])[CH3:59])[C:54]([O:56][CH3:57])=[O:55])=[O:25])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:26]
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3c(F)cccc3F)c(C)c2)no1)C(C)C
Reactant: Cc1cc(-c2cc(C(=O)O)on2)ccc1NC(=O)Nc1ccc(F)cc1F
Product: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(F)cc3F)c(C)c2)no1)C(C)C

Procedure:
The title compound was prepared from 3-(4-(3-(2,4-difluorophenyl)ureido)-3-methylphenyl)isoxazole-5-carboxylic acid using the same procedure as described for preparation of the compound of step 8 of Example 98. The title compound was obtained in crude form.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1cnccc1NCc1ccc(F)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of 90 parts of 4-chloro-3-nitropyridine, 71 parts of 4-fluorobenzenemethanamine, 63 parts of sodium carbonate and 900 parts of N,N-dimethylacetamide (DMA) was stirred for 1 hour at 50° C. Water was added and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 106 parts (75%) of N-[(4-fluorophenyl)methyl]-3-nitro-4-pyridinamine; mp. 136.8° C. (5).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:19]2[C:18]([CH3:17])=[CH:22][N:21]=[CH:20]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cncn1-c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of p-nitrofluorobenzene (2 g, 14 mmol) in DMF (20 mL) was treated with potassium carbonate (8 g, 58 mmol) and 4-methylimidazole (1.2 g, 14 mmol). After refluxing for 18 h, the reaction mixture was cooled down and concentrated at reduced pressure. The residue was treated with water and the mixture was extracted with ethyl acetate and dried over magnesium sulphate. The organic layer was concentrated and the residue was purified by flash-chromatography (methanol/methylene chloride, 0.5:9.5) affording 1.8 g (62%) of p-nitro-4 (5)-methyl-imidazol-1-yl as 7:1 mixture of regioisomers.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([N+:18]([O-])=O)[C:10]=1[NH:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21](O)C>C(O)=O.[Fe]>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH3:21])[CH:12]=[N:18][C:13]=2[CH:14]=[C:15]([Br:17])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CNc1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O=CO
Product: Cn1cnc2cc(Br)cc(OCc3ccccc3)c21
Temperature: 90 °C

Procedure:
To a solution of 2-(benzyloxy)-4-bromo-N-methyl-6-nitroaniline 2.50 (770 mg, 2.25 mmol) in ethanol (12 mL) and formic acid (15 mL) was added iron (630 mg, 11.27 mmol) and heated at 90° C. at 4 h and LCMS shows still lot of starting material present. 500 mg of iron was added and the mixture was heated at 90° C. overnight. The reaction mixture was concentrated, diluted with water and acidified to pH˜7 with sat'd NaHCO3 and then the aqueous layer was extracted with EtOAc (3×). Combined organic layer were then washed successively with water and brine and dried over anhydrous magnesium sulfate. The residue was purified by flash column chromatography (SiO2, 100% EtOAc) to give 7-(benzyloxy)-5-bromo-1-methyl-1H-benzo[d]imidazole 2.51.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C1COCC1>[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([N:13]2[CH2:14][CH2:15][CH2:16][CH:11]([C:10]#[C:9][C:6]3[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=3)[CH2:12]2)=[O:32])=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Fc1ccc(C#CC2CCCNC2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(F)cc1)N1CCCC(C#Cc2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 24 h
Yield: 45 %

Procedure:
To a mixture of 3-(4-Fluoro-phenylethynyl)-piperidine hydrochloride (0.14 g, 0.58 mmol) in THF (2.3 ml, 0.5M) was added DIEA (0.5 ml, 2.92 mmol). The reaction mixture was cooled to 0° C. and 4-Fluoro-benzoyl chloride (0.139 g-0.87 mmol) was slowly added. The reaction was to go up to R.T and stirred for 24 h. The solution was concentrated and DCM was added following by HCl 1N. The aqueous phase was separated and organic phase was extracted twice with HCl 1N and twice with water, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (DCM/MeOH:98/2) to afford 0.86 mg (45%) of (4-Fluoro-phenyl)-[3-(4-fluoro-phenylethynyl)-piperidin-1-yl]-methanone as a brown oil. Rf=0.39 (DCM/MeOH:98/2); LCMS (Tr): 4.14 min (Method C); MS (ES+) gave m/z: 326.2;
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:2].[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>CS(C)=O>[C:1]([C:3]1([C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)#[N:2]
Reactant: BrCCCCCBr
Reactant: COC(=O)c1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc(C2(C#N)CCCCC2)c1
Yield: 66.9 %

Procedure:
Using methyl 3-(cyanomethyl)benzoate (1.5 g, 8.6 mmol), sodium hydride (60% in oil, 1.0 g, 26 mmol), 1,5-dibromopentane (3.0 g, 13 mmol) and dimethyl sulfoxide (30 mL) as starting materials and in the same manner as in Reference Example 31, the title compound (1.4 g, 68%) was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]([CH3:35])[C:25]2=[O:36])=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[O:8]CC1C=CC=CC=1.C(OCC)(=O)C>[Pd].C(O)C>[Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[N:26]([CH3:35])[C:25]2=[O:36])=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([OH:8])[CH:16]=[CH:17][CH:18]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(OCc4ccccc4)c3)c(Cl)cc2F)c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(O)c3)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.4 %

Procedure:
To 1.01 g of ([3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]methyl)benzene, were added 3 ml of ethyl acetate, 1 ml of ethanol and 50 mg of 10% palladium/carbon, and the mixture was stirred for 5 hours at room temperature under hydrogen atmosphere. The reaction system was purged with nitrogen, then, the reaction solution was filtrated through Celite, the filtrate was concentrated to obtain 0.68 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:21](OC)(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[SH:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:29]=[C:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[S:24][C:1]([C:3]2[CH:8]=[C:7]([CH:9]3[CH2:13][CH2:12][CH2:11][N:10]3[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=[CH:5][N:4]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccnc(C#N)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC1c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 61 %

Procedure:
tert-Butyl 2-(2-cyano-4-pyridyl)-1-pyrrolidinecarboxylate (1.6 g, 6.0 mmol) and methyl thiosalicylate (3.0 g, 18.3 mmol) were dissolved in toluene (10 ml), and triethylamine (5.0 ml, 35.8 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (1.5 g, 63%) as white crystals.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:16]3[CH2:21][N:20]([C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C(=O)C(C)(C)C)C3)cc1

Procedure:
Method as example 18 using 1-ethyl-3-(4-(4-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 14) and pivaloyl chloride as starting materials.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][N:6]([C:8]2([CH3:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:5]1)#[N:2].[NH:22]1[CH:26]=[C:25]([C:27]2[C:28]3[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:29]=3[N:30]=[CH:31][N:32]=2)[CH:24]=[N:23]1.N12CCCN=C1CCCCC2>C(#N)C>[C:1]([CH2:3][C:4]1([N:22]2[CH:26]=[C:25]([C:27]3[C:28]4[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:29]=4[N:30]=[CH:31][N:32]=3)[CH:24]=[N:23]2)[CH2:5][N:6]([C:8]2([CH3:21])[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)[CH2:7]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CC(=CC#N)C2)CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)CC1

Procedure:
A 2 L round bottom flask fitted with overhead stirring, septa and nitrogen inlet was charged with tert-butyl 4-[3-(cyanomethylene)azetidin-1-yl]-4-methylpiperidine-1-carboxylate (9.17 g, 0.0472 mol), 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (14.9 g, 0.0472 mol) and acetonitrile (300 mL). The resulting solution was heterogeneous. To the solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (8.48 mL, 0.0567 mol) portionwise via a syringe over 3 minutes at room temperature. The solution slowly became homogeneous and yellow in color. The reaction was allowed to stir at room temperature for 3 hours. The solution was concentrated on a rotovap to remove ˜150 mL of acetonitrile. After addition of 100 mL of EtOAc and 100 mL of 20% brine, the organic phase was separated. The aqueous layer was extracted with 150 mL of EtOAc. The combined organic phase was dried over MgSO4, filtered and concentrated to yield an orange oil. Purification by flash chromatography (150 grams of silica, 60% EtOAc/hexanes, loaded with CH2Cl2) yielded the title compound as a white foam. LC-MS: 607.2 (M+H)+.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:8]=[N:7][CH:6]=[C:5]([CH3:9])[N:4]=1.Cl[C:13]1[N:18]=[CH:17][C:16]2[CH:19]=[N:20][N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N:28]4[CH2:34][CH2:33][CH2:32][N:31]([CH:35]5[CH2:38][O:37][CH2:36]5)[CH2:30][CH2:29]4)[N:23]=3)[C:15]=2[CH:14]=1>CN(C)C(=O)C>[CH3:9][C:5]1[N:4]=[C:3]([C:13]2[N:18]=[CH:17][C:16]3[CH:19]=[N:20][N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N:28]5[CH2:34][CH2:33][CH2:32][N:31]([CH:35]6[CH2:38][O:37][CH2:36]6)[CH2:30][CH2:29]5)[N:23]=4)[C:15]=3[CH:14]=2)[CH:8]=[N:7][CH:6]=1
Reactant: Clc1cc2c(cn1)cnn2-c1cccc(N2CCCN(C3COC3)CC2)n1
Reactant: Cc1cncc([Sn](C)(C)C)n1
Solvent: CC(=O)N(C)C
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCN(C4COC4)CC3)n2)n1
Temperature: 150 °C
Yield: 20.4 %

Procedure:
A mixture of trimethyl-(6-methylpyrazin-2-yl)stannane (0.387 mmol; 99.3 mg), 6-chloro-1-[6-[4-(oxetan-3-yl)-1,4-diazepan-1-yl]-2-pyridyl]pyrazolo[4,3-c]pyridine (0.258 mmol; 99.2 mg), and Palladium(0)tetrakis(triphenylphosphine) (0.0258 mmol; 29.8 mg) in N,N-Dimethylacetamide (3 ml) was purged with argon. The reaction mixture was sealed in a Biotage pressure vial and heated at 150° C. under microwave for 45 min. The mixture filtered through Celite. The filtrate was concentrated and the residue was purified on silica eluted with 0 to 10% MeOH in DCM. The material was further purified by reverse phase HPLC to afford 240 as an off-white solid (23.3 mg, 20%). 1H NMR (400 MHz, DMSO) δ 9.66-9.61 (s, 1H), 9.47-9.44 (s, 1H), 9.33-9.30 (s, 1H), 9.06-9.03 (s, OH), 8.67-8.60 (m, 2H), 8.52-8.50 (s, 1H), 7.76-7.68 (td, J=8.1, 3.4 Hz, 2H), 7.25-7.20 (d, J=7.7 Hz, 1H), 7.17-7.13 (d, J=7.7 Hz, 1H), 6.66-6.59 (dd, J=8.3, 6.0 Hz, 2H), 4.55-4.46 (m, 3H), 4.41-4.33 (dt, J=15.0, 6.0 Hz, 3H), 3.98-3.86 (d, J=5.5 Hz, 4H), 3.81-3.73 (m, 2H), 3.67-3.60 (dt, J=11.7, 5.8 Hz, 2H), 2.67-2.63 (s, 2H), 2.62-2.59 (s, 3H), 2.41-2.36 (dd, J=11.3, 6.0 Hz, 3H), 2.05-1.93 (dt, J=18.5, 6.1 Hz, 3H); MS (ESI) m/z: 443.2 [M+H]+
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[CH2:5]([OH:19])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>[OH-].[K+]>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:19][CH2:3][CH2:2][CH2:1][OH:4]
Reactant: CC1CO1
Reactant: CCCCCCCCCCCCCCO
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCOCCCO

Procedure:
Propylene oxide was bubbled into 685 g of myristyl alcohol in the presence of potassium hydroxide catalyst until three moles of propylene oxide were added per mole of myristyl alcohol, thus obtaining a pale, yellow liquid (PPG 3 myristyl ether) as the major product.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[NH:13]2)=[O:11])=[CH:5][CH:4]=1.[CH:32](N(C(C)C)CC)(C)[CH3:33].C(I)C>CN(C)C=O>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[N:13]2[CH2:32][CH3:33])=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)N1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCI
Product: CCN1C(c2ccc(Cl)cc2)C(c2ccccc2)CN1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 60 °C

Procedure:
To 1.0 g (2.2 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-phenyl-2,3,4,5-tetrahydro-1H-pyrazole-1-carboxamide (Example 3) in 5 ml of dimethylformamide was added 0.5 ml (3.0 mmole) of diisopropylethylamine and 0.25 ml (3.0 mmole) of ethyl iodide. The mixture was heated at 60° C. for 18 hours and then partitioned between diethyl ether and water. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate. Filtration, concentration in vacuo, and chromatography on silica gel using diethyl ether and hexanes gave the expected compound, a foam. NMR 1.3 t 3H, 3.1 q 2H, 4.1 dd 1H, 4.3 dd 1H, 4.4 t 1H, 6.7 d 2H, 6.9 m 2H, 7.1 m 5H, 7.5 s 4H, 8.4 s 1H.