Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH3:13].[CH3:14][O:15][C:16]1[C:17]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.[O-]CC.[Na+]>C(O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1/[CH:13]=[CH:19]/[C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([O:15][CH3:14])[C:17]=1[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCOc1c(C=O)cccc1OC
Reactant: Cc1nc2ccccn2c(=O)c1Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCOc1c(/C=C/c2nc3ccccn3c(=O)c2Br)cccc1OC

Procedure:
The title compound was prepared from 3-bromo-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (1.20 g, 5.01 mmol) and 3-methoxy-2-(pentyloxy)benzaldehyde (1.22 g, 5.521 mmol) in the presence of sodium ethoxide (0.512 g, 7.52 mmol) in absolute ethanol (30 ml) as described in Intermediate 1 to give 625 mg of the product as a light yellow solid; 1H NMR (300 MHz, CDCl3) δ 0.92 (t, J=6.9 Hz, 3H), 1.40 (q, J=7.2 Hz, 2H), 1.51-1.59 (m, 2H), 1.85 (q, J=7.8 Hz, 2H) 3.87 (s, 3H), 4.01 (t, J=6.3 Hz, 2H), 6.91 (d, J=7.8 Hz, 1H), 7.05-7.11 (m, 2H), 7.33 (d, J=7.8 Hz, 1H), 7.60-7.71 (m, 3H), 8.40 (d, J=15.9 Hz, 1H), 8.96 (d, J=6.6 Hz, 1H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.O.Cl.[Fe]>[CH2:1]([NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1NCc1ccccc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccccc1NCc1ccccc1
Yield: 57.1 %

Procedure:
To a solution of benzyl-(2-nitro-phenyl)-amine (1068) (2.5 g, 10.43 mmol) in ethanol (150 mL) and water (10 mL) was added iron (8.7 g, 155.7 mmol) followed by 30 drops of concentrated HCl, and the resulting mixture was heated overnight at reflux. The reaction mixture was quenched with water, diluted with DCM and the layers were separated. The organic layer was washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated to give a brown oily residue. Further purification by column chromatography (SiO2, 20% ethyl acetate/hexanes) afforded N-benzyl-benzene-1,2-diamine (1069) as a dark yellow oil (1.18 g, 57%). 1H NMR (400 MHz, CDCl3)  7.41-7.24 (m, 5H), 6.82-6.67 (m, 4H), 4.32 (s, 2H), 3.56 (b, 3H, NH).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[F:9][C:10]1[C:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:14]([N+:23]([O-])=O)[CH:13]=[CH:12][C:11]=1[CH3:26]>O.C1COCC1>[F:9][C:10]1[C:15]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:14]([NH2:23])[CH:13]=[CH:12][C:11]=1[CH3:26]
Reactant: Cc1ccc([N+](=O)[O-])c(Oc2ccccc2)c1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(N)c(Oc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
A solution of sodium hydrosulfite (4.42 g, 21.45 mmol) in water (25 mL) was added dropwise to a solution of 2-fluoro-1-methyl-4-nitro-3-(phenyloxy)benzene (0.884 g, 3.58 mmol) in THF (10 mL). The mixture was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was evaporated and the residue was purified by chromatography (ethyl acetate:hexane) to give [3-fluoro-4-methyl-2-(phenyloxy)phenyl]amine (0.444 g, 51.4%) as a colorless oil, which crystallized after standing overnight. 1H NMR (400 MHz, chloroform-d) δ ppm 7.23-7.33 (m, 2H), 7.03 (t, 1H), 6.94 (d, 2H), 6.83 (t, 1H), 6.51 (dd, 1H), 3.40 (br. s., 2H), 2.18 (d, 3H). ES MS: m/z 217.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[C:7]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C(Br)C=C>CC#N.C1OCCOCCOCCOCCOCCOC1>[C:7]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:3][CH:2]=[CH2:1])=[CH:24][CH:23]=1)([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: O=C(NCCCCc1ccc(O)cc1)OCc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: C=CCBr
Solvent: CC#N
Product: C=CCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
Potassium tert-butoxide (1.7 g, 15.2 mmol) and 18-crown-6 (0.1 g, 0.3 mmol) were added to a solution of 29 (4.3 g, 14.3 mmol) in dry MeCN (80 mL) and the mixture was stirred for 20 min at room temperature. After this time, allyl bromide (1.2 mL, 14.3 mmol) in MeCN (10 mL) was added. The reaction mixture was stirred overnight at room temperature, then the precipitate was filtered off and washed with ethyl acetate. The organic fractions were combined, the solvent was removed at reduced pressure and the residue was purified twice by flash chromatography (silica gel, 1:1 ethyl acetate/hexanes) to provide compound 30 (3.4 g, 71%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.55 (m, 4H), 2.54 (t, 2H), 3.20 (m, 2H), 4.50 (d, 2H), 5.08 (s, 2H), 5.28 (d, 1H), 5.40 (d, 1H), 6.06 (m, 1H), 6.82 (d, 2H), 7.05 (d, 2H), 7.33 (s, 5H)
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[CH3:20])[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]3([CH3:24])[CH3:23])=[CH2:9])[CH:5]=[CH:6][CH:7]=1.C(N(CCCC)CCCC)CCC.[C]=O.[C:40]([O:43][CH2:44]C)(=[O:42])C>CO.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:20][C:19]1[C:10]([C:8]([C:4]2[CH:3]=[C:2]([C:40]([O:43][CH3:44])=[O:42])[CH:7]=[CH:6][CH:5]=2)=[CH2:9])=[CH:11][C:12]2[C:13]([CH3:24])([CH3:23])[CH2:14][CH2:15][C:16]([CH3:22])([CH3:21])[C:17]=2[CH:18]=1
Reactant: C=C(c1cccc(I)c1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CCCCN(CCCC)CCCC
Solvent: CO
Product: C=C(c1cccc(C(=O)OC)c1)c1cc2c(cc1C)C(C)(C)CCC2(C)C

Procedure:
A solution of 6-[1-(3-iodophenyl)vinyl]-1,1,4,4,7-pentamethyl-1,2,3,4-tetrahydronaphthalene (10.8 g, 25 mmol), palladium diacetate (650 mg, 2.9 mmol) and tributylamine (13.8 ml, 58 mmol) in methanol (300 ml) is heated for 3 h at 100° C. under a pressure of carbon monoxide (3 bar). After concentration on an evaporator under vacuum at 40° C., the oil obtained is diluted in ethyl acetate and washed three times with water. The product is purified by flash chromatography on a column of silica.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:8]([C:5]1[N:6]=[CH:7][C:2]([N:13]2[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)=[CH:3][CH:4]=1)#[N:9]
Reactant: N#Cc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)nc2)CC1
Temperature: 120 °C

Procedure:
5-Bromo-pyridine-2-carbonitrile (8 mmol), tert-butyl 1-piperazine-carboxylate (9.6 mmol), Pd(dppf)Cl2 (0.24 mmol), dppf (0.36 mmol) and sodium tert-butoxide (11.9 mmol) are mixed in toluene (12 mL) and purged with N2. The mixture is heated in a microwave reactor at 120° C. for 15 minutes, poured into saturated Na2CO3 solution and extracted with EtOAc. The combined extracts are washed with saturated aqueous NaCl and dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (2:1 hexanes/EtOAc) to give tert-butyl 4-(6-cyano-pyridin-3-yl)-piperazine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9](OCC)=[O:10])=O)=[CH:4][CH:3]=1.[CH3:16][NH:17][NH2:18]>C(O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]2[NH:18][N:17]([CH3:16])[C:9](=[O:10])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Reactant: CNN
Solvent: CCO
Product: Cn1[nH]c(-c2ccc(Cl)cc2)cc1=O
Temperature: 25 °C
Yield: 43.2 %

Procedure:
To a solution of ethyl 4-chlorobenzoylacetate (500 mg) in 4 ml of ethanol was added 202 mg of methylhydrazine and the resulting mixture was stirred over night at room temperature. The solvent was removed under reduced pressure and to the residue was purified by the use of silica gel column chromatography to give 199 mg of 3-(4-chlorophenyl)-1-methylpyrazoline-5-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CC(=O)c1ccc(CCBr)cc1
Product: CC(=O)c1ccc(CCN2CCN(c3ccc(Cl)cc3)CC2)cc1
Yield: 64 %

Procedure:
By the reaction of 1-(4-chlorophenyl)-piperazine with 4'-(2-bromoethyl)-acetophenone analogously to Example (41a), there is obtained 4'-{2-[1-(4-chlorophenyl)-piperazin-4-yl]-ethyl}-acetophenone. Yield 64% of theory; m.p. 141°-143° C. (recrystallised from ethyl acetate).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36](=[N:38]O)[NH2:37]>>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[N:38]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:28][N:37]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(=NO)c1ccccc1Cl
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccccc3Cl)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 38 mg (0.22 mmol, 1.1 eq.) of 2-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 56 mg (52% of theory)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH:17]1(B(O)O)[CH2:19][CH2:18]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:17]1([C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NCc1cccc(Br)c1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc(C2CC2)c1
Temperature: 100 °C
Yield: 93 %

Procedure:
To a solution of tert-butyl 3-bromobenzylcarbamate (572 mg, 2 mmol), cyclopropyl boronic acid (223 mg, 2.6 mmol), potassium phosphate (1.49 g, 7.0 mmol) and tricyclohexyl phosphine (56 mg, 0.2 mmol) in toluene (9 mL) and water (0.45 mL) under a nitrogen atmosphere was added palladium acetate (22 mg, 0.1 mmol). The mixture was heated at 100° C. for 3 h and then cooled to rt. Water (20 mL) was added and the mixture extracted with EtOAc (2×30 mL), the combined organic extracts were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. Crude product was purified by column chromatography (15% EtOAc in hexanes) afforded tert-butyl 3-cyclopropylbenzylcarbamate as a colorless oil in 93% yield. (3-cyclopropylphenyl)methanamine was then generated by removing the Boc protecting group by treatment with HCl (in methanol or dioxane) or trifluoroacetic acid in dichloromethane.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([Cl:22])[C:13]=1[NH:23][NH2:24]>CCO>[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:15]=[C:14]([Cl:22])[C:13]=1[N:23]1[C:1]([CH3:2])=[C:4]2[C:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)=[N:24]1
Reactant: CC(=O)C1CCCCC1=O
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CCO
Product: Cc1c2c(nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl)CCCC2
Yield: 67 %

Procedure:
2-Acetylcyclohexanone (0.12 mL, 1 mmol) and 2,6-dichloro-4-trifluoromethylphenylhydrazine (245 mg, 1 mmol) in EtOH (10 mL) was heated under reflux for 12 hr. EtOH was removed under reduced pressure and the product purified by flash chromatography on silica (10% EtOAc:Hexane): yield 67%. 1H NMR (CDCl3) δ 7.8 (s, 2H), 2.7 and 2.05 (m, 2H each), 2.05 (s, 3H), 1.9 (m, 4H); MS (M+) 349.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:19]3[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=3)=[N:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[NH:42]1[CH2:47][CH2:46][CH:45]([C:48]2[N:52]=[C:51]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=3)[NH:50][N:49]=2)[CH2:44][CH2:43]1.C(N(CC)CC)C.C(O)(=O)C>CN(C=O)C>[C:1]1([C:7]2[C:8]([C:19]3[CH:26]=[CH:25][C:22]([CH2:23][N:42]4[CH2:47][CH2:46][CH:45]([C:48]5[N:52]=[C:51]([C:53]6[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=6)[NH:50][N:49]=5)[CH2:44][CH2:43]4)=[CH:21][CH:20]=3)=[N:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2nc(-c3ccccn3)ncc2-c2ccccc2)cc1
Reactant: c1ccc(-c2nc(C3CCNCC3)n[nH]2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: c1ccc(-c2cnc(-c3ccccn3)nc2-c2ccc(CN3CCC(c4n[nH]c(-c5ccccn5)n4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-(5-Phenyl-2-pyridin-2-ylpyrimidin-4-yl)benzaldehyde (4-3; 0.011 g, 0.033 mmol), sodium triacetoxyborohydride (0.010 g, 0.049 mmol) and 2-(3-piperidin-4-yl-1H-1,2,4-triazol-5-yl)pyridine hydrochloride (0.022 g, 0.082 mmol) were stirred in 0.5 ml of anhydrous DMF. Triethylamine (0.014 ml, 0.098 mmol) and acetic acid (0.007 ml, 0.13 mmol) were added and the reaction was stirred at ambient temperature for 6 h. The reaction was quenched by the addition of 3 drops of water and the resulting solution was purified by reverse phase preparative chromatography. This afforded 5-phenyl-2-pyridin-2-yl-4-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)pyrimidine (4-4) as a trifluoroacetic acid salt. 1H NMR (CDCl3): δ 9.12 (s, 1H), 9.09 (d, 1H), 8.94 (d, 1H), 8.72 (d, 2H), 8.20 (m, 1H), 8.15 (m, 2H), 7.98 (s, 1H), 7.75 (d, 2H), 7.58 (m, 3H), 7.43 (m, 2H), 7.36 (m, 2H), 4.40 (s, 2H), 3.62 (m, 2H), 3.25 (m, 2H), 2.42 (m, 2H), 2.12 (m, 2H). m/z (m+1): 551.2
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4]2([C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH2:8][C:7]2([CH3:15])[OH:14])[O:3]1.CN(C)C1C=CC=CC=1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>>[C:25]([O:14][C:7]1([CH3:15])[CH2:8][CH2:9][CH2:10][C:11]([CH3:13])([CH3:12])[C:4]21[O:3][CH:2]([CH3:1])[CH2:6][CH2:5]2)(=[O:28])[CH2:26][CH3:27]
Reactant: CCC(=O)Cl
Reactant: CC1CCC2(O1)C(C)(C)CCCC2(C)O
Solvent: CN(C)c1ccccc1
Product: CCC(=O)OC1(C)CCCC(C)(C)C12CCC(C)O2
Yield: 62 %

Procedure:
2.17 g (0.01 M) of 2,6,10,10-tetramethyl-1-oxa-spiro[4.5]decan-6-ol -- isomer A; see Example 1 -- were treated with a mixture of 12.1 g (0.10 M) of N,N-dimethylaniline and 4.62 g (0.05 M) of propionyl chloride as indicated in Example 3 to give 1.7 g (63%) of the desired ester, b.p. 100°-110°/0.5 Torr.
Reaction SMILES: OC(C(F)(F)F)=O.Br[C:9]1[CH:10]=[C:11]2[C:18]3([O:22][N:21]([CH3:23])[C:20](=[NH:24])[NH:19]3)[CH2:17][CH:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:15][C:12]2=[CH:13][CH:14]=1.[C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:24][C:20]1[N:21]([CH3:23])[O:22][C:18]2([C:11]3[C:12](=[CH:13][CH:14]=[C:9]([C:37]4[CH:38]=[C:33]([CH:34]=[CH:35][CH:36]=4)[C:31]#[N:32])[CH:10]=3)[O:15][CH:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:17]2)[N:19]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN1OC2(CC(c3ccccc3)Oc3ccc(Br)cc32)NC1=N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN1OC2(CC(c3ccccc3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 100 °C
Yield: 27.4 %

Procedure:
To a solution of 6-bromo-2′-methyl-2-phenylspiro[chroman-4,5′-[1,2,4]oxadiazolidin]-3′-imine TFA salt (45 mg, 0.092 mmol), 3-cyanophenylboronic acid (20 mg, 0.14 mmol) and Cs2CO3 (60 mg, 0.18 mmol) in 1,4-dioxane (3 mL) and H2O (0.5 mL) in a 10 mL CEM microwave test tube was added PdCl2(PPh3)2 (10 mg). After degassing by purging with N2, the mixture was heated to 100° C. for 5 min in a CEM microwave reactor. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 3-(3′-amino-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (10 mg) as a TFA salt. MS ESI+ve m/z 397 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): 8.14-8.12 (m, 2H), 8.03 (d, J=8.4 Hz, 1H), 7.84-7.79 (m, 2H), 7.66 (t, J=8.0 Hz, 1H), 7.54-7.40 (m, 5H), 7.09 (d, J=8.8 Hz, 1H), 5.29 (d, 11.6 Hz, 1H), 3.34 (s, 3H), 2.75 (d, 14.0 Hz, 1H), 2.37 (dd, J=14.4, 13.2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH:28]([CH2:32][C:33]2[CH:43]=[CH:42][C:36]([O:37][CH2:38][C:39](O)=[O:40])=[CH:35][CH:34]=2)[S:27]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH:28]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:37][CH2:38][C:39]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([S:8][C:9]4[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:40])=[CH:42][CH:43]=2)[S:27]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: Cc1ccc(Sc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(Sc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)cc1
Yield: 86.9 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-methylthiophenoxy)phenyl]-N-methylcarbamate (1.93 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (3.01 g), diethyl cyanophosphonate (1.75 g), triethylamine (1.08 g) and anhydrous tetrahydrofuran (80 ml) and the reaction mixture was purified to give the desired product (2.96 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[N:10]([CH3:24])[C:11]2[C:16]([CH:17]=1)=[C:15]([O:18][CH3:19])[C:14]([O:20][CH3:21])=[C:13]([O:22][CH3:23])[CH:12]=2)(=O)=O.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:24][N:10]1[C:11]2[C:16](=[C:15]([O:18][CH3:19])[C:14]([O:20][CH3:21])=[C:13]([O:22][CH3:23])[CH:12]=2)[CH:17]=[C:9]1[CH2:8][CH2:7][CH2:6][N:25]1[CH2:30][CH2:29][N:28]([CH2:6][CH2:7][CH2:8][C:9]2[N:10]([CH3:24])[C:11]3[C:16]([CH:17]=2)=[C:15]([O:18][CH3:19])[C:14]([O:20][CH3:21])=[C:13]([O:22][CH3:23])[CH:12]=3)[CH2:27][CH2:26]1
Reactant: COc1cc2c(cc(CCCOS(C)(=O)=O)n2C)c(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc2c(cc(CCCN3CCN(CCCc4cc5c(OC)c(OC)c(OC)cc5n4C)CC3)n2C)c(OC)c1OC

Procedure:
2-(3-Methanesulfonyloxypropyl)-N-methyl-4,5,6-trimethoxyindole (160 mg) and piperazine (17 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.O.[NH2:24][NH2:25]>CCO>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[CH:5]=3)=[CH:15][CH:14]=2)[NH:25][N:24]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(NC3CCCC3)nc(N)n2)cc1F
Solvent: CCO
Solvent: O
Product: Nc1nc(NC2CCCC2)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 95 °C
Reaction time: 16 h
Yield: 49.3 %

Procedure:
In a 25 mL sealable tube was dissolved 4-[2-amino-6-(cyclopentylamino)-4-pyrimidinyl]-2-fluorobenzonitrile (0.476 g, 1.16 mmol) in EtOH (10 mL). Hydrazine monohydrate (1.14 mL, 23.1 mmol) was added, the vial was sealed, and the reaction mixture was stirred for 16 hours at 95° C. The reaction was cooled to room temperature and concentrated. The resulting yellow solid was dissolved in EtOH (2 mL). Water (8 mL) was added, and the resulting mixture was sonicated for 10 minutes. The resulting white precipitate was filtered and dried to afford the title compound (177 mg, 47%) as a white solid. LC-MS (ES) m/z=310 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.38-1.61 (m, 4H), 1.61-1.78 (m, 2H), 1.92 (m, 2H), 4.22 (bs, 1H), 5.37 (s, 2H), 5.97 (bs, 2H), 6.26 (s, 1H), 6.87 (bs, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.82 (s, 1H), 11.51 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH:11]=[C:10]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:9]2[CH3:23])=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O>C(Cl)Cl.[Al]>[Br:24][C:11]1[C:12](=[O:13])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]([CH3:23])[C:10]=1[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1c(CCc2ccc(F)cc2)cc(=O)n1-c1ccc(F)cc1
Agent: [Al]
Solvent: ClCCl
Product: Cn1c(CCc2ccc(F)cc2)c(Br)c(=O)n1-c1ccc(F)cc1
Reaction time: 24 h
Yield: 84.3 %

Procedure:
To a solution of 2-(4-fluoro-phenyl)-5-[2-(4-fluoro-phenyl)-ethyl]-1-methyl-1,2-dihydro-pyrazol-3-one (0.296 g) in methylene chloride (5 mL) was added N-bromosuccinimide (0.168 g). The reaction vessel was wrapped in aluminium foil and stirred for 24 hours. The solvent was evaporated in vacuo and the residue was dissolved in EtOAc and water. The phases were separated and the aqueous phase was extracted with more EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and reduced in vacuo to give a crude residue. Flash column chromatography over silica gel using ISCO combiflash chromatography and eluting with EtOAc/heptane afforded the desired 4-bromo-2-(4-fluoro-phenyl)-5-[2-(4-fluoro-phenyl)-ethyl]-1-methyl-1,2-dihydro-pyrazol-3-one (0.312 g) as a white solid. MS (ESI+): 395.0 ([M+H]+).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1.CN([CH:16]=[O:17])C.Cl>C(OCC)C>[CH3:6][O:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[CH:16]=[O:17]
Reactant: COc1ccsc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccsc1C=O

Procedure:
3-Methoxy-2-thiophenecarboxadlehyde was prepared by adding n-butyllithium (10.56 mmol, 2.5M solution in hexane)(Aldrich), without cooling, to a solution of 3-methoxythiophene (1 g,8.8 mmol) (Aldrich) in dry diethyl ether (5 mL) over a period of 5 min. The mixture was gently heated at reflux for 2 h at which time the organolithium compound was transferred, via cannula, to a solution of DMF (23 mmol) in diethyl ether (5 mL) which was cooled in an ice bath. The reaction was stirred at room temperature for 14 h, at which time 1N HCl (10 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (3×25 mL), and the combined organic extracts were dried over magnesium sulfate, and concentrated to yield 3-methoxy-2-thiophenecarboxaldehyde as a pale, yellow solid. The 3-methoxy-2-thiophenecarboxaldehyde was then added to ethynylmagnesium chloride (Aldrich) according to Method A above to yield 3-hydroxy-3-(3-methoxy-2-thiophenyl)-1-propyne. (Yield 151 mg, 0.9 mmol).