Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Li])CCC.[B:17](OC)([O:20]C)[O:18]C>O1CCCC1.CCCCCC>[CH:9]1([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([B:17]([OH:20])[OH:18])=[CH:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: COB(OC)OC
Reactant: Brc1ccc(CC2CC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(CC2CC2)cc1
Temperature: -70 °C

Procedure:
1-Bromo-4-(cyclopropylmethyl)benzene (2.11 g) was dissolved in anhydrous tetrahydrofuran (20 ml) and cooled to −70° C. under an argon atmosphere. A 1.25M solution of n-butyl lithium in hexane (8.8 ml) was added at such a rate that the temperature did not exceed −65° C. with stirring, which was maintained for a further 30 minutes. Trimethyl borate was added slowly keeping the temperature below −60° C. and the reaction mixture was stirred for a further 1.5 hours at −70° C. After warming to −5° C., the reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride (50 ml) and the organic phase was separated. The aqueous layer was extacted with ethyl acetate (2×30 ml) and combined organic phases were dried (MgSO4) and evaporated to give 4-(cyclopropylmethyl)phenylboronic acid (1.52 g); 1H NMR (d6-DMSO): 0.2 (d, 2H), 0.5 (d, 2H), 0.9-1.07 (m, 1H), 2.5 (partly obscured by DMSO), 7.2 (d, 2H), 7.7 (d, 2H); mass spectrum (−ve ESP) 175 (M−H)−.
Reaction SMILES: [C:1]1(=O)[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1([NH2:16])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1[NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:16]=1
Reactant: Nc1ccccc1N
Reactant: O=C1CCCCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: NCCCCCc1nc2ccccc2[nH]1

Procedure:
A mixture of 678 g (6 mols) of caprolactam, 865 g (8 mols) of o-phenylene diamine and 60 g of p-toluene sulphonic acid is melted in a nitrogen atmosphere, 108 g of water distilling off over a period of 6 hours at an internal temperature of 200° to 250°C. The reaction mixture is then subjected to fractional distillation under reduced pressure, giving 1003 g (82.4 % of the theoretical) of 2-(5'-aminopentyl)- benzimidazole with boiling point of 210° to 215°C at 0.05 Torr, and a melting point of 101°C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](C2OC3=CC=CC3=CC=2)[C:9]=1[NH:23][C:24](=[O:36])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=1)=O)(C)(C)C.[C:38]([OH:44])([C:40](F)(F)F)=O>C(Cl)Cl>[O:44]1[C:38]2[C:40]([CH:10]=[CH:11][CH:12]=2)=[CH:13][CH:8]=[C:9]1[CH:25]1[C:26]([C:28]2[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=2)[C:34]#[N:35])=[N:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:23][C:24]1=[O:36]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc3cccc-3o2)c1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccccc3NC(=O)C2c2ccc3cccc-3o2)c1

Procedure:
Prepared from {4-benzofuran-2-yl-2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example K28) (255 mg, 0.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (260 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1cccc(Cl)c1
Product: O=C(O)Cc1ccccc1Nc1cccc(Cl)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid was condensed with 3-chloroaniline to yield 2-[(3-chlorophenyl)amino]phenylacetic acid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][CH3:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]=[C:20]=[O:21])[CH:14]=1>>[CH3:12][N:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[CH:3]=[CH:4]2)[C:20]([NH:19][C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1)=[O:21]
Reactant: CNc1ccc2c(ccn2C)c1
Reactant: O=C=Nc1cccnc1
Product: CN(C(=O)Nc1cccnc1)c1ccc2c(ccn2C)c1
Yield: 45 %

Procedure:
The title compound was prepared from 1-methyl-5-methylamino-1H-indole (D15) and 3-pyridyl isocyanate (D4) using a procedure similar to that described for Example 2 Method B. The crude produce was obtained in 45% yield.
Reaction SMILES: I[C:2]1[N:3]([CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:4](I)=[C:5]([I:7])[N:6]=1.[Li]C(C)(C)C.O>C1COCC1>[I:7][C:5]1[N:6]=[CH:2][N:3]([CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:4]=1
Reactant: Ic1nc(I)n(CCN2CCCC2)c1I
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: Ic1cn(CCN2CCCC2)cn1
Yield: 96 %

Procedure:
To a solution of 2,4,5-triiodo-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazole (166) (1.75 g, 3.22 mmol) in THF (32 mL) at −78° C. was added tBuLi (7.57 mL, 12.88 mmol) dropwise over a period of an hour. The reaction mixture was poured into water, extracted with EtOAc, and the organic extract was separated, dried over Na2SO4, and concentrated in vacuo to give the title compound 167 (0.9 g, 96% yield) as a dark yellow syrup. 1H NMR (DMSO-d6) δ (ppm): 7.59 (s, 1H), 7.36 (s, 1H), 4.02 (m, 2H), 2.78 (m, 2H), 2.42 (m, 4H), 1.63 (m, 4H). MS (m/z): 292.1 (M+H).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]=[S:13])([F:4])[F:3].[CH2:14]([C:21]1[N:25]2[C:26]3[S:40][C:39]4[CH2:41][NH:42][CH2:43][CH2:44][C:38]=4[C:27]=3[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])=[N:29][CH2:30][C:24]2=[N:23][N:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCCl>[CH2:14]([C:21]1[N:25]2[C:26]3[S:40][C:39]4[CH2:41][N:42]([C:12](=[S:13])[NH:11][C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[C:2]([F:4])([F:3])[F:1])[CH2:43][CH2:44][C:38]=4[C:27]=3[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])=[N:29][CH2:30][C:24]2=[N:23][N:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Clc1ccccc1C1=NCc2nnc(Cc3ccccc3)n2-c2sc3c(c21)CCNC3
Reactant: FC(F)(F)c1ccccc1N=C=S
Solvent: ClCCCl
Product: FC(F)(F)c1ccccc1NC(=S)N1CCc2c(sc3c2C(c2ccccc2Cl)=NCc2nnc(Cc4ccccc4)n2-3)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 24 %

Procedure:
Trifluoromethylphenylisothiocyanate (0.56 g, 0.0027 mol) is added to a mixture containing 1-benzyl-6-(2-chlorophenyl)-7,8,9,10-tetrahydro-4H-pyrido[4′,3′;4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (0.8 g, 0.0018 mol) in anhydrous 1,2-dichloroethane (13 ml). The reaction medium is agitated at ambient temperature for 12 hours. The precipitate is filtered on frit then washed with isopropyl ether, with ethyl acetate then with isopentane and finally dried under vacuum. 0.28 g (24%) of final product is obtained in the form of a pale yellow coloured solid. Melting point: 239–240° C.
Reaction SMILES: CO[CH:3]=[CH:4][C:5](=[O:7])[CH3:6].[F:8][C:9]([F:19])([F:18])[C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][NH2:14]>>[F:8][C:9]([F:18])([F:19])[C:10]1[CH:11]=[C:12]([CH2:13][NH:14][CH:3]=[CH:4][C:5](=[O:7])[CH3:6])[CH:15]=[CH:16][CH:17]=1
Reactant: COC=CC(C)=O
Reactant: NCc1cccc(C(F)(F)F)c1
Product: CC(=O)C=CNCc1cccc(C(F)(F)F)c1

Procedure:
The title compound 66 is prepared according to the procedure reported in step A of Example 18 with 4-methoxy-3-buten-2-one (0.2 g, 2 mmol) and 3-trifluoromethylbenzylamine (0.35 g, 2 mmol) as reactants. Yellow oil. (Yield 0.48 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=2[NH:18][C:19]2[C:20]3[CH:28]=[C:27]([F:29])[C:26]([CH:30]([CH3:32])[CH3:31])=[N:25][C:21]=3[N:22]=[CH:23][N:24]=2)=[CH:4][CH:3]=1.[NH2:33][C:34]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([CH3:37])[CH2:35][OH:36]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:33][C:34]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([CH3:37])[CH2:35][OH:36])=[O:14])=[CH:11][C:10]=2[NH:18][C:19]2[C:20]3[CH:28]=[C:27]([F:29])[C:26]([CH:30]([CH3:31])[CH3:32])=[N:25][C:21]=3[N:22]=[CH:23][N:24]=2)=[CH:4][CH:3]=1
Reactant: CC(N)(CO)c1ccccc1
Reactant: CC(C)c1nc2ncnc(Nc3cc(C(=O)O)ccc3Sc3ccc(N)cc3)c2cc1F
Product: CC(C)c1nc2ncnc(Nc3cc(C(=O)NC(C)(CO)c4ccccc4)ccc3Sc3ccc(N)cc3)c2cc1F
Yield: 30 %

Procedure:
The title compound was prepared (yield 30%) by the procedure of Example 449I, substituting the product of Example 451D for the product of Example 449H. 1H-NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=7.0 Hz, 6H), 1.69 (s, 3H), 3.43-3.58 (m, 2H), 3.74 (dd, J=10.7, 5.9 Hz, 1H), 5.09 (t, J=5.9 Hz, 1H), 5.57 (br-s, 2H), 6.62 (d, J=8.5 Hz, 2H), 6.86 (d, J=8.5 Hz, 1H), 7.12 (d, J=8.5 Hz, 2H), 7.17 (br-t, J=7.0 Hz, 1H), 7.27 (t, J=7.0 Hz, 2H), 7.33 (br-d, J=7.0 Hz, 2H), 7.68 (dd, J=8.5, 1.5 Hz, 1H), 7.83 (d, J=1.5 Hz, 1H), 8.04 (s, 1H), 8.60 (s, 1H), 8.76 (d, J=10.3 Hz, 1H), 10.10 (s, 1H). MS ESI+ m/z: 583 (M+H), ESI− m/z: 581 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2nc3c(-c4ccncc4)c(-c4ccc(Cl)cc4)cnn3c2=O)cc1
Temperature: 65 °C
Yield: 20.5 %

Procedure:
A solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (96 mg, 0.3 mmol), prepared as described in Example 244, K2CO3 (82 mg, 0.59 mmol), and α-bromo-p-toluonitrile (70 mg, 0.356 mmol) in DMF (1 mL) was heated at 65° C. for 2.5 h. Using a similar procedure as described in Example 247, the crude product was obtained. The crude product was purified by reverse phase HPLC to give the title compound, 4-((7-(4-Chlorophenyl)-3-oxo-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl)methyl)benzonitrile (27 mg) as a yellow solid. HPLC RT: 2.45 min; M+H=439; 1H NMR (CDCl3): δ 8.63 (d, J=6.04 Hz, 2H), 8.21 (s, 1H), 7.63 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.2 Hz, 2H), 7.33 (m, 2H), 7.21 (m, 2H), 7.08 (m, 2H), 5.25 (2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:24]=[N:23][C:22]([N:25]2[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]2)=[CH:21][CH:20]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: Nc1ccc(N2CCC(O)C2)nc1
Product: O=C(c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC(O)C2)nc1)C1CC1
Yield: 51.6 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with 1-(5-aminopyridin-2-yl)pyrrolidin-3-ol (269 mg, 1.5 mmol) to afford the desired product (234 mg, 51%) as a yellow solid: ESI MS m/z 453 [C22H21BrN4O2+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[NH:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([SH:19])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]n(-c2ccccc2)c2cc(Br)ccc12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1C
Product: Sc1nn(-c2ccccc2)c2cc(Br)ccc12
Temperature: 130 °C
Reaction time: 1 h

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of 6-bromo-1-phenyl-1,2-dihydroindazol-3-one (7 g, 24.22 mmol, 1.00 equiv) in xylene (50 mL) and P2S5 (21.5 g, 96.85 mmol, 4.00 equiv). The resulting solution was stirred for 1 h at 130° C. in an oil bath. The solids were collected by filtration, washed with ethyl acetate (2×50 mL). The organic layer was washed with water (2×50 mL). The resulting mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 6-bromo-1-phenyl-1H-indazole-3-thiol as a brown solid. MS: 304 (MH+).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][C@H:9]([CH3:11])[CH2:8][CH2:7][C@H:6]1[C:12]([OH:14])=O)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[C:1]([O:4][C@H:5]1[CH2:10][C@H:9]([CH3:11])[CH2:8][CH2:7][C@H:6]1[C:12]([Cl:18])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@H](C)CC[C@H]1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1C[C@H](C)CC[C@H]1C(=O)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.8 %

Procedure:
To a solution of (1R,2S,4R)-2-Acetoxy-4-methyl-cyclohexanecarboxylic acid (109 mg, 0.54 mmol) in dichloromethane (2.7 ml) was added oxalyl chloride (545 μl, 1.09 mmol) followed by 1 drop of dimethylformamide. The reaction mixture was stirred for 4 h at room temperature. The solvents were then removed to obtain 119 mg (99%) of (1R,2S,4R)-2-Acetoxy-4-methyl-cyclohexanecarboxylic acid chloride.
Reaction SMILES: O=[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][C:4](OCCC)=[O:5].O.[NH2:17][NH2:18]>C(O)C>[C:10]1([C:2]2[CH2:3][C:4](=[O:5])[NH:18][N:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCOC(=O)CC(=O)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1CC(c2ccccc2)=NN1
Temperature: 80 °C
Yield: 84.7 %

Procedure:
To a solution of propyl 3-oxo-3-phenylpropanoate (10 g, 48.5 mmol) in ethanol (100 mL) was added hydrazine hydrate (9.71 g, 194 mmol) at room temperature. The reaction was heated to 80° C. for 2 h, cooled to room temperature and concentrated. The residue was crystallized from 20% ethyl acetate/hexane to give the title compound (6.58 g). LCMS m/z=161.08 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm, 2.32 (br, 2H), 7.32-7.78 (m, 5H), 12.1 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:29]1[N:34]=[CH:33][C:32]([CH:35]2[CH2:37][CH2:36]2)=[CH:31][N:30]=1>>[CH:35]1([C:32]2[CH:31]=[N:30][C:29]([N:23]3[CH2:22][CH2:21][C:20]4([CH2:19][C:18]5([O:17][C:14]6=[CH:15][N:16]=[C:11]([C:8]7[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=7)[CH:12]=[C:13]6[CH2:27]5)[CH2:26]4)[CH2:25][CH2:24]3)=[N:34][CH:33]=2)[CH2:37][CH2:36]1
Reactant: Clc1ncc(C2CC2)cn1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCN(c4ncc(C5CC5)cn4)CC3)C2)CC1

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt) and 2-chloro-5-cyclopropyl-pyrimidine following a procedure analogous to that described for Example 15. LC (method 3): tR=0.85 min; Mass spectrum (ESI+): m/z=508 [M+H]+.
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].C(N(CC)CC)C.[C:25]([C:27]1[S:31][C:30]([CH2:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:29][CH:28]=1)#[N:26]>C(#N)C>[C:1]([C:3]([C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:38]1[CH2:39][CH2:40][N:35]([CH2:34][CH2:33][CH2:32][C:30]2[S:31][C:27]([C:25]#[N:26])=[CH:28][CH:29]=2)[CH2:36][CH2:37]1)#[N:2]
Reactant: N#Cc1ccc(CCCN2CCNCC2)s1
Reactant: CC(C)C(C#N)(CCCI)c1ccc(C#N)s1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)C(C#N)(CCCN1CCN(CCCc2ccc(C#N)s2)CC1)c1ccc(C#N)s1
Temperature: 55 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
In acetonitrile (3 ml) was dissolved 200 mg (0.56 mmol) of 4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl iodide. To the mixture were added 78.0 μl (0.56 mmol) of triethylamine and 178 mg (0.76 mmol) of 1-[3-(5-cyano-2-thieny)propyl]piperazine, followed by stirring at 55° C. After 5 hours, the reaction solution was concentrated, and the residue was subjected to Cromatorex NH silica gel (ethyl acetate/hexane=1/2), to give 243 mg (0.52 mmol, 92.8%) of the title compound as a yellow syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[N:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(-c4ccccc4C)cc3c(=O)[nH]2)c1
Reactant: C1CCNC1
Product: Cc1ccccc1-c1cc2c(N3CCCC3)nc(-n3cc(C(=O)O)cn3)nc2cc1Cl

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-chloro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. for C23H20ClN5O2, 433.9
Reaction SMILES: Cl[C:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH2:3][CH2:4][CH3:5].[OH:23][N:24]=[C:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH:2]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH2:3][CH2:4][CH2:5][N:28]2[CH2:29][CH2:30][C:25](=[N:24][OH:23])[CH2:26][CH2:27]2)=[CH:14][CH:15]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: ON=C1CCNCC1
Reactant: CCCC(Cl)(OC1CCCCO1)c1ccc(C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1ccc(C(CCCN2CCC(=NO)CC2)OC2CCCCO2)cc1

Procedure:
58.4 g of 1-chloro 1-(4-tertbutylphenyl) 1-tetrahydro pyranyloxy butane in 200 ml ethanol are heated to reflux under stirring with 20 g 4-hydroxyimino piperidine and 20 g sodium carbonate. After 20 hours reflux, the solution is concentrated to dryness then taken up with water, extracted with dried methylene chloride and concentrated to dryness under vacuum 70.5 g of pure compound are thus produced. It is recrystallized from methanol to recover 40 g of a solid having a melting point of 150°-151° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[N:5][C:6]([N:19]([CH3:21])[CH3:20])=[C:7]([Cl:18])[N:8]=2)[N:3]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[Cl:18][C:7]1[N:8]=[C:9]2[C:4](=[N:5][C:6]=1[N:19]([CH3:21])[CH3:20])[N:3]=[C:2]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[N:11]=[C:10]2[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: CN(C)c1nc2nc(Cl)nc(N3CCSCC3)c2nc1Cl
Product: CN(C)c1nc2nc(N3CCNCC3)nc(N3CCSCC3)c2nc1Cl

Procedure:
This compound was prepared analogous to Example 1 from 2,6-dichloro-4-thiomorpholino-7-dimethylamino-pteridine and piperazine.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:16]2[C:10]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[N:9]1.[OH-].[Na+]>C1COCC1.CO>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:25])=[O:2])[N:9]=[C:10]3[C:16]=2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[CH:19][CH:20]=1
Reactant: COC(=O)CCCCn1nc2c(c1-c1ccc(Cl)cc1)CCNCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCCCn1nc2c(c1-c1ccc(Cl)cc1)CCNCC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.1 %

Procedure:
5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-pentanoic acid methyl ester (Example 82, 0.009 g) was dissolved in 1 mL of 9:1 THF/MeOH and treated with 2 mL of 1 M NaOH. After stirring at RT for 5 h, the solvent was removed in vacuo. The aqueous residue was acidified with 1 mL of 1 N HCl and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, concentrated, and dried on a vacuum line. The residue was then dissolved in 1 mL of 9:1 CH2Cl2/MeOH and treated with 3 mL of 1 N HCl in Et2O. After 4 h, the volatiles were removed in vacuo. The crude oil was purified by preparative TLC (9:1 CH2Cl2/2 M NH3 in MeOH) to afford 0.002 g of the title compound. MS (ESI): exact mass calculated for C18H22ClN3O2, 347.14. found, m/z 348.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.55-7.53 (m, 4H), 7.35-7.32 (m, 2H), 3.98 (t, J=7.0 Hz, 2H), 3.38-3.35 (m, 2H), 3.28-3.26 (m, 2H), 3.13-3.10 (m, 2H), 2.77-2.74 (m, 2H), 2.09-2.06 (m, 2H), 1.71-1.66 (m, 2H), 1.41-1.37 (m, 2H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19]>>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])=[C:3]([C:10]([F:13])([F:12])[F:11])[CH:4]=1)=[O:7]
Reactant: N#Cc1cccc(O)c1
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Product: N#Cc1cccc(Oc2ccc(C=O)cc2C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 4-fluoro-3-(trifluoromethyl)benzaldehyde and 3-hydroxybenzonitrile. LC-MS (ESI): m/z 290 [M−H]−; 1.69 min (ret time).
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[CH3:30][N:31]1[CH2:35][CH2:34][N:33]=[C:32]1[CH:36]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>O1CCCC1>[CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][N:27]([CH2:36][C:32]4[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=4)[CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:5]
Reactant: CN(c1cccc2cc(C3=NCC4(CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CN1CCN=C1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(c1cccc2cc(C3=NCC4(CCN(Cc5nccn5C)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.6 %

Procedure:
To a solution of N-methyl-N-[2-(1-thia-3,8-diazaspiro[4.5]dec-2-en-2-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (100 mg) and 1-methyl-4H-imidazole-2-carbaldehyde (33 mg) in tetrahydrofuran (3 ml) was added sodium triacetoxyborohydride (125 mg), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (14 mg, yield 12%) as colorless crystals from a fraction eluted with ethyl acetate. melting point 103° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:12][C:13]3[CH:26]=[CH:25][C:16]([O:17][CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=3)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:27](O)CC>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:12][C:13]3[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH2:23][CH3:27])=[O:20])=[CH:25][CH:26]=3)[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)Oc1ccc(Oc2cnc3cc(Cl)ccc3c2)cc1
Reactant: CCCO
Agent: O=S(=O)(O)O
Product: CCCOC(=O)C(C)Oc1ccc(Oc2cnc3cc(Cl)ccc3c2)cc1
Reaction time: 72 h

Procedure:
A mixture of ethyl 2-[4-(7-chloroquinolin-3-yloxy)phenoxy]propionate (500 mg), concentrated sulphuric acid (2 drops) and n-propanol (50 ml) was heated under reflux with stirring for 72 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and water. The organic layer was separated, dried over magnesium sulphate and evaporated to give n-propyl 2-[4-(7-chloroquinolin-3-yloxy)phenoxy]propionate as a pale brown oil which was characterised by its proton magnetic resonance spectrum (Table 3).