Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:15][C:4]2[CH:5]=[CH:6][C:7]3[CH2:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12][C:13]=3[C:3]=2[O:2]1.[CH3:16][O:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]([CH2:33][Cl:34])[CH2:27]2)=[CH:20][CH:19]=1>>[ClH:34].[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]([CH2:33][N:10]3[C:9](=[O:14])[CH2:8][C:7]4[CH:6]=[CH:5][C:4]5[O:15][CH2:1][O:2][C:3]=5[C:13]=4[CH2:12][CH2:11]3)[CH2:27]2)=[CH:35][CH:36]=1
Reactant: O=C1Cc2ccc3c(c2CCN1)OCO3
Reactant: COc1ccc(OCCCN2CCCCC(CCl)C2)cc1
Product: COc1ccc(OCCCN2CCCCC(CN3CCc4c(ccc5c4OCO5)CC3=O)C2)cc1
Product: Cl

Procedure:
Prepared from 6,7-methylenedioxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and N-[3-(4-methoxy-phenoxy)-propyl]-3-chloromethylhexahydro-azepine analogously to Example 2.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH:8]([NH:12]C(N)=O)[C:9]([OH:11])=[O:10].[OH-].[Na+].OP(O)(O)=O>O>[NH2:12][C@@H:8]([CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[C:9]([OH:11])=[O:10]
Reactant: NC(=O)NC(CC1CCCC1=O)C(=O)O
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@@H](CC1CCCC1=O)C(=O)O
Temperature: 28 °C
Reaction time: 20 h

Procedure:
3-(2-oxocyclopentyl)-2-ureidopropanoic acid (15.0 g, 0.07 mol) was suspended in water (90 mL) and the pH was adjusted to 7.3 with a 32% NaOH solution (8.30 g). Then, MnCl2 solution (3.75 mL, 500 mmol/L) was added and 60 g of wet cell slurry obtained according to ‘Expression of Hyu genes in Escherichia coli RV308’ (see above) was added. The reaction was stirred at 28° C. for 20 h and the pH was decreased to 4 or 6, depending on the conditions as used in Example 4, with 85% H3PO4. The reaction mixture was then centrifuged (12.000 rpm) and the clear liquid was separated from the remaining cell mass.
Reaction SMILES: [H-].[Na+].[C:3]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[N:18]([CH3:22])[C:17]3=[CH:23][C:24]([C:26]([O:28]CC)=[O:27])=[N:25][N:16]3[C:15](=[O:31])[C:14]=2[CH:13]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:33]>CN(C=O)C>[C:3]([N:11]([CH3:33])[C:12]1[CH:21]=[CH:20][C:19]2[N:18]([CH3:22])[C:17]3=[CH:23][C:24]([C:26]([OH:28])=[O:27])=[N:25][N:16]3[C:15](=[O:31])[C:14]=2[CH:13]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: CCOC(=O)c1cc2n(C)c3ccc(NC(=O)c4ccccc4)cc3c(=O)n2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccccc1)c1ccc2c(c1)c(=O)n1nc(C(=O)O)cc1n2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
To a stirring suspension of sodium hydride (0.05 9, 1.25 mmol, 60% dispersion in mineral oil) in 20 mL of DMF was added dropwise a solution of 7-(benzoylamino)-4,9-dihydro-4-methyl-9-oxopyrazolo-[5,1-b]quinazoline-2-carboxylic acid, ethyl ester (0.40 g, 1.02 mmol, Example 2) in 30 mL of DMF. The mixture was stirred for 30 minutes at 0° C. followed by dropwise addition of iodomethane (0.07 mL, 1.12 mmol). The ice-bath was removed, the mixture was stirred at room temperature for 2 hours, then concentrated to a yellow solid. The solid was dissolved into water, acidified to a pH of about 7 with a saturated solution of potassium phosphate, monobasic, and extracted into chloroform (2×50 mL). The combined chloroform extract was dried (MgSO4), filtered, and concentrated. Medium pressure chromatography (silica gel, 2.5% methanol in chloroform) of the crude afforded 0.22 g (52%) of the title compound as its ethyl ester; yellow solid, mp 214°-217° C.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12](=[O:26])[CH2:13][CH:14](P(OCC)(OCC)=O)[C:15]([OH:17])=[O:16])([CH3:10])([CH3:9])[CH3:8].[CH:27]1([CH2:33][CH2:34][CH:35]=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[CH:50]1([NH2:56])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1>C1COCC1.C(OCC)(=O)C>[CH:50]1([NH2:56])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1.[C:7]([O:11][C:12](=[O:26])[CH2:13]/[C:14](=[CH:35]\[CH2:34][CH2:33][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)/[C:15]([OH:17])=[O:16])([CH3:8])([CH3:9])[CH3:10]
Reactant: CCOP(=O)(OCC)C(CC(=O)OC(C)(C)C)C(=O)O
Reactant: O=CCCC1CCCCC1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: NC1CCCCC1
Product: CC(C)(C)OC(=O)C/C(=C\CCC1CCCCC1)C(=O)O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 67 %

Procedure:
Potassium tert-butoxide (20.2 g, 0.18 mol) was added portionwise over 10 minutes to a solution of 3-(diethoxyphosphoryl)succinic acid 1-tert-butyl ester (25.4 g, 82 mmol) in THF (115 ml), at 0° C., under nitrogen. The mixture was stirred at 0° C. for 40 minutes and then cooled to −20° C. A solution of 3-cyclohexylpropan-1-al (11.5 g, 82 mmol in THF (60 ml) was added dropwise over 10 minutes between −20 and −10° C., under nitrogen. The mixture was stirred between −20 and −5° C. for 3 hours and then aqueous citric acid (10%, 250 ml) and ethyl acetate (200 ml) was added. The organic phase was separated and the aqueous fraction was washed with ethyl acetate (200 ml). The combined organic fractions were washed with saturated sodium bicarbonate solution (2×100 ml), aqueous citric acid solution (10%, 100 ml) and demineralised water (100 ml) and then concentrated in vacuo. The resulting solid was taken up in ethyl acetate (150 ml) and cyclohexylamine (9.4 ml, 82 mmol) was added dropwise over 5 minutes at 20-25° C. The mixture was stirred at 20-25° C. for 16 hours and then filtered. The residue was dried in vacuo at 40° C. for 4 hours to leave the title compound as a colourless solid (21.7 g, 67% yield, 95% pure by NMR).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH2:36]([O:54][CH2:55][C@H:56](O)[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46]/[CH:47]=[CH:48]\[CH2:49][CH2:50][CH2:51][CH2:52][CH3:53].C1(P([N:81]=[N+:82]=[N-:83])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[CH2:36]([O:54][CH2:55][C@@H:56]([N:81]=[N+:82]=[N-:83])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46]/[CH:47]=[CH:48]\[CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOC[C@H](O)CCCCCCCCC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\CCCCCCCCOC[C@H](CCCCCCCCC)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triphenyl phosphine (14.4 g, 55 mmol) was dissolved in THF and cooled to 0° C. under nitrogen. Di-tertbutyl azodicarboxylate (13.7 g, 59.5 mmol) was added slowly and the reaction was stirred for 30 mins. Then the alcohol (20 g, 45.8 mmol) was added dropwise and allowed to stir for 10 mins, then diphenyl phosphorylazide (15.1 g, 55 mmol) was added and allowed to stir overnight, warming to ambient temperature. The reaction was evaporated to dryness in vacuo and directly loaded onto a silica gel column and eluted with 0-10% ethyl acetate/hexane gradient to provide (2S)-2-azidoundecyl(9Z,12Z)-octadeca-9,12-dien-1-yl ether which was carried directly into the next reaction without characterization.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]3[CH2:9][N:8]([CH3:20])[C:7](=[O:21])[C:6]=2[CH:22]=1.[C-:23]#N.[K+]>C(O)C#C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][C:19]#[CH:23])=[O:16])=[C:10]3[CH2:9][N:8]([CH3:20])[C:7](=[O:21])[C:6]=2[CH:22]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Reactant: [C-]#N
Agent: C#CCO
Agent: [K+]
Product: C#CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Reaction time: 1 h

Procedure:
A mixture of 20.0 g (65.9 mmol) of ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate, 1.0 g (15.4 mmol) of potassium cyanide and 100 ml of propargyl alcohol is stirred at 125° for 20 hours and at 135° for 1 hour, evaporated to dryness in vacuo and the residue is taken up in chloroform. The chloroform solution is washed twice with water, dried over magnesium sulphate and evaporated. The residue is chromatographed on silica gel while eluting with ethyl acetate. By recrystallization of the resulting material from chloroform/toluene there is obtained 2-propynyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 220°-222°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([NH:12][CH:13]([C:17]2[CH:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[C:14]([OH:16])=[O:15])[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].[N:25]12[CH2:32][CH2:31][CH:28]([CH2:29][CH2:30]1)[C@@H:27](O)[CH2:26]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[CH3:24][O:23][C:20]1[N:19]=[CH:18][C:17]([CH:13]([NH:12][C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:14](=[O:16])[O:15][C@@H:27]2[CH:28]3[CH2:31][CH2:32][N:25]([CH2:30][CH2:29]3)[CH2:26]2)=[CH:22][CH:21]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CCOC(=O)c1cccc(NC(C(=O)O)c2ccc(OC)nc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccc(OC)nc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
A mixture of 2-(3-(ethoxycarbonyl)phenylamino)-2-(6-methoxypyridin-3-yl)acetic acid (I64) (951 mg, 2.51 mmol), (R)-quinuclidin-3-ol (694 mg, 5.47 mmol), HOBT (837 mg, 5.47 mmol), and DCC (1.13 g, 5.47 mmol) in dry THF (35 ml) was stirred at room temperature overnight. The solvent was evaporated, and the crude product was partitioned between DCM and 2M K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by flash chromatography (DMC/MeOH=97/3 to 95/5) to obtain ethyl 3-(1-(6-methoxypyridin-3-yl)-2-oxo-2-((R)-quinuclidin-3-yloxy)ethylamino)benzoate (348 mg, 27.5% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13]CC(=O)C[CH2:9]1)[C:2]1C=CC=C[CH:3]=1.[F:15][C:16]([F:48])([F:47])[C:17]1[CH:18]=[C:19]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:20]([N:22]1[CH2:39][CH2:38][C:25]2([N:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]([CH3:36])[NH:27][C:26]2=[O:37])[CH2:24][CH2:23]1)=[O:21].CN(C)CCCCl>>[F:48][C:16]([F:15])([F:47])[C:17]1[CH:18]=[C:19]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:20]([N:22]1[CH2:23][CH2:24][C:25]2([N:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:28]([CH3:36])[N:27]([CH2:3][CH2:2][CH2:1][N:8]([CH3:13])[CH3:9])[C:26]2=[O:37])[CH2:38][CH2:39]1)=[O:21]
Reactant: CC1NC(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N1c1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CN(C)CCCCl
Product: CC1N(CCCN(C)C)C(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N1c1ccccc1

Procedure:
The title compound, MS: m/e=571.1 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one 1-benzyl-piperidin-4-one and 3-dimethylamino1-propyl chloride.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(C(C)C)CC)(C)C.Cl[C:21]1[O:22][C:23]2[C:24](=[C:26]([C:38]#[N:39])[C:27]([CH3:37])=[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:29]=2[F:30])[N:25]=1>ClCCl>[C:38]([C:26]1[C:24]2[N:25]=[C:21]([NH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[O:22][C:23]=2[C:29]([F:30])=[C:28]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:27]=1[CH3:37])#[N:39]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CCOC(=O)CCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCNc1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.5 %

Procedure:
With cooling with ice, ethyl 4-aminobutanoate hydrochloride (149 mg, 0.892 mmol) and diisopropylethylamine (303 μl, 1.78 mmol) were added to a dichloromethane (7 ml) solution of 2-chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (213 mg, 0.743 mmol), followed by stirring at room temperature for 15 hours. The reaction liquid was concentrated under reduced pressure, ethyl acetate was added, followed by washing with saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1→1:1, v/v) to obtain the entitled compound (279 mg, 99%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([O:24][CH2:25][CH3:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[N:36]=[C:37]=[O:38].C(N(CC)C(C)C)(C)C.Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:27])[CH:4]([O:24][CH2:25][CH3:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:37]([NH:36][C:30]3[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=3[F:28])=[O:38])[CH2:13][CH2:14]2)=[CH:8][CH:7]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CCCCCCCNCC1(c2ccc(CC(OCC)C(=O)OC)cc2)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCN(CC1(c2ccc(CC(OCC)C(=O)OC)cc2)CC1)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-ethoxy-3-[4-(1-heptylaminomethyl-cyclopropyl)-phenyl]-propionic acid methyl ester (54 mg, 0.13 mmol), and 2,4-difluorophenylisocyanate (0.156 mmol, 0.0185 mL) in toluene (2.5 mL) was added N,N-diisopropylethylamine (0.29 mmol, 0.050 mL). The mixture was allowed to stir at room temperature for 18 hours, then was poured over 1 M HCl (5 mL). The aqueous layer was isolated and extracted with diethyl ether (2×). The organic layers were combined, washed with 2 M HCl (1×), brine (1×), dried over anhydrous sodium sulfate, and concentrated to give a clear film. The crude product was chromatographed on silica (Merck silica gel 60, art#9385-3) eluting with 20% ethyl acetate/hexanes to give 3-(4-{1-[3-(2,4-difluoro-phenyl)-1-heptyl-ureidomethyl]-cyclopropyl}-phenyl)-2-ethoxy-propionic acid methyl ester as a clear film (50 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:16](O)[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.P(Br)(Br)[Br:20].O.[C:24]1([P:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCOCC.CCCCCC>[Br-:20].[Cl:1][C:2]1[C:3]([CH2:16][CH2:17][P+:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(O)c1cc2c(cc1Cl)C(C)(C)CCC2(C)C
Reactant: BrP(Br)Br
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2cc(CC[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c(Cl)cc21
Product: [Br-]
Reaction time: 1.5 h

Procedure:
To a solution of 3.15 g (11.8 mmol) of (±)-1-(3-chloro-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)ethanol in ether and hexane stirring at 0° C. under argon, was added dropwise 31.9 g (11.2 mL, 118 mmol) of phosphorus tribromide and the mixture stirred 1.5 hours. Water was then carefully added and the mixture extracted with several portions of ether. The ether extracts were washed with water, sodium bicarbonate, brine, and dried (MgSO4). The solvent was removed in-vacuo and the residual oil taken up in 175 mL of benzene. To this was added 3.09 g (11.8 mmol) of triphenylphosphine and the solution stirred for 24 hours at room temperature. Purification was done using flash chromatography (SiO2, 0.5% ethyl acetate in hexanes, 5% MeOH in methylene chloride) to give the title compound as a white foam.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)#[N:28].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][N:24]1[CH:25]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]3[N:16]([C:12]([CH2:11][C:8]4[CH:9]=[CH:10][C:5]5[N:6]([C:2]([C:33]6[CH:34]=[C:29]([CH:30]=[CH:31][CH:32]=6)[C:27]#[N:28])=[CH:3][N:4]=5)[CH:7]=4)=[CH:13][N:14]=3)[N:17]=2)[CH:22]=[N:23]1
Reactant: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(Br)n5c4)n3n2)cn1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(-c6cccc(C#N)c6)n5c4)n3n2)cn1
Temperature: 150 °C

Procedure:
3-(3-Bromo-imidazo[1,2-a]pyridin-6-ylmethyl)-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 296, 80 mg, 0.196 mmol) was dissolved in DME (0.653 mL) with 3-cyanophenylboronic acid (28.2 mg, 0.196 mmol), 2 M Na2CO3 solution (0.353 mL, 0.705 mmol) and tetrakis(triphenylphosphine)palladium (11.3 mg, 0.010 mmol). The RM was heated at 150° C. 5 min under microwave irradiations. It was taken up with EtOAc and washed with 10% Na2CO3 solution and brine. The precipitate from the aqueous layer was filtered off and dried to afford the title compound as a grey solid (tR 0.8 min (conditions 2), MH+=431).
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:27])[C:17]3[CH:18]=[C:19]([C:23](=O)[CH2:24]Cl)[CH:20]=[CH:21][CH:22]=3)=[CH:12][CH:11]=2)=[C:6]([Cl:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[S-:32][C:33]#[N:34].[K+].C([OH:38])C>>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:27])[C:17]3[CH:18]=[C:19]([C:23]4[NH:34][C:33](=[O:38])[S:32][CH:24]=4)[CH:20]=[CH:21][CH:22]=3)=[CH:12][CH:11]=2)=[C:6]([Cl:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCc2ccc(C(O)c3cccc(C(=O)CCl)c3)cc2)c(Cl)c1O
Reactant: CCO
Reactant: N#C[S-]
Agent: [K+]
Product: CC(=O)c1ccc(OCc2ccc(C(O)c3cccc(-c4csc(=O)[nH]4)c3)cc2)c(Cl)c1O
Yield: 6.1 %

Procedure:
Heat a solution of 1-(3-{[4-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-phenyl]-hydroxy-methyl}-phenyl)-2-chloro-ethanone (0.075 mg, 0.163 mmol) and potassium thiocyanate (159 mg, 1.63 mmol) in ethanol (0.20M) overnight at 70° C. Evaporate solvents and chromatograph residue. Major fraction isolated was the title compound (0.005 g, 0.010 mmol, 6.1%): 1H NMR (400 MHz, DMSO-d6) δ 2.61 (s, 3H), 5.10 (s, 2H), 5.30 (s, 2H), 5.82 (s, 1H), 6.11 (s, 1H), 6.88 (d, J=9.8 Hz, 1H), 7.41 (m, 4H), 7.49 (m, 1H), 7.71 (d, J=7.4 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.92 (d, J=9.4 Hz, 1H), 8.04 (s, 1H), 13.12 (s, 1H). MS (m/z): 480 (M−H).
Reaction SMILES: [O:1]=[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7](O)=[O:8].S(Cl)([Cl:18])=O>C1C=CC=CC=1>[O:1]=[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([Cl:18])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCC(=O)c1ccccc1
Solvent: c1ccccc1
Product: O=C(Cl)CCCCC(=O)c1ccccc1

Procedure:
6-Oxo-6-phenyl hexanoic acid (10.3g; 50 mmole), thionyl chloride (25 ml) and dry benzene (150 ml) were heated under reflux for 3 hours. The reagent and solvent were removed on the rotary evaporator. A further 100 ml of benzene was added and the solution again evaporated under reduced pressure (to remove last traces of thionyl chloride). The quantitatively formed, analytically pure brown solid (mp 53°-6°) was used directly in the Friedel-Crafts acylation of step (b).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10](S)[NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.CN(C)C=O>[Ni].C(Cl)(Cl)Cl.CO>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(-c2c[nH]c(S)n2)ccn1
Agent: [Ni]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1cc(-c2c[nH]cn2)ccn1

Procedure:
To a solution of 2.3 g. (12 mmoles) of 4-(2-amino-4-pyridyl)imidazole-2-thiol in 60 ml. of dimethylformamide was added 8 g. of Raney nickel and the mixture heated at 115° C. for 3 hours. The mixture was filtered and the filtrate concentrated to a brown solid. After trituration with boiling chloroform, the solid was taken up in 50 ml. of absolute ethanol, treated with charcoal and the filtered solution concentrated to a small volume. The precipitate was filtered and dried, 1.12 g. (60%), m.p. 193°-196° C. The analytical sample was prepared by chromatographing on Florisil TM using chloroform-methanol (9:1, v:v) as the eluent, m.p. 196°-198° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:12](O)[CH2:13][OH:14].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]1[O:14][CH2:13][CH2:12][O:5]1
Reactant: OCCO
Reactant: COc1ccc(Br)c(C=O)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(Br)c(C2OCCO2)c1
Temperature: 25 °C
Yield: 103.2 %

Procedure:
To a solution of Compound 19 (50.0 g, 0.23 mol) in toluene (650 mL) were added ethylene glycol (14.2 mL, 0.26 mol) and camphorsulfonic acid (10.7 g, 46 mmol). The reaction solution was heated under reflux with a Dean-Stark trap for 6 h and then cooled to room temperature and diluted with ethyl acetate (300 mL). The resulting solution was washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo to give Compound 20 (61.5 g, quantitative) as a yellow oil: 1H NMR (CDCl3, 500 MHz) δ 7.44 (d, J=8.5 Hz, 1H), 7.15 (d, J=3.5 Hz, 1H), 6.79 (dd, J=8.5, 3.0 Hz, 1H), 6.04 (s, 1H), 4.18-4.06 (m, 4H), 3.81 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:12]2[C:13]([NH:15][C:16](=[O:17])[C:11]=12)=[O:14].N1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[CH2:27](OCC)C>>[N:24]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:20]=[CH:19][CH:18]=[C:12]3[C:13]([NH:15][C:16](=[O:17])[C:11]=23)=[O:14])[CH2:25][CH2:26][CH2:27][CH2:22][CH2:23]1
Reactant: CCOCC
Reactant: C1CNCCN1
Reactant: O=C1NC(=O)c2c(CCCCCCCCBr)cccc21
Product: O=C1NC(=O)c2c(CCCCCCCCN3CCCCC3)cccc21

Procedure:
8Bromooctylphthalimide (517 mg; 2.0 mmoles) and piperazine (0.40 ml; 4.0 mmoles) were dissolved in anhydrous ethyl ether (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1.CC1C=CC(S(O[CH2:29][CH2:30][CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:6]1[CH:7]=[C:2]([O:1][CH2:29][CH2:30][CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:3]=[C:4]([CH3:17])[C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=1
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(C=O)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 77.4 %

Procedure:
To a solution of 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (2.26 g, 10.0 mmol) and 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (3.51 g, 12.0 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.80 g, 13.0 mmol), and the mixture was stirred at 90° C. for 24 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=40:60-80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (2.68 g, yield 77%) as colorless crystals.