Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C@H:4]([OH:20])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:3].[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22].C(N(CC)CC)C>ClCCl>[CH3:3][C@H:2]1[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[O:20][C:21](=[O:22])[NH:1]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCCCCCCCCCCCCC[C@@H](O)[C@H](C)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCC[C@H]1OC(=O)N[C@H]1C
Reaction time: 5 h

Procedure:
(2S, 3R)-2-amino-3-octadecanol (155, 750 μg, 2.6 μmol) was dissolved in dichloromethane (100 μL) to which 1,1′-carbonyldiimidazole (0.85 mg, 5.3 μmol) and triethylamine (0.4 μL, 2.9 μmol) was added. The solution was stirred for 5 h and then the solvent removed by a stream of nitrogen. The crude product 158 was analyzed without purification: IR (NaCI) 36, 2919, 2851, 1742, 1713, 1551, 1470, 1395, 1321, 49, 1239, 1094, 1061, 1001, 768, 743, 664 cm−1; FABMS m/z 785, 623, 474, 406, 362, 328, 312, 286, 268.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([OH:20])=O)[CH:8]=1)=[O:5].C(OC(=O)[NH:38][CH2:39][CH2:40][NH2:41])(C)(C)C>>[NH2:38][CH2:39][CH2:40][NH:41][C:18]([C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:23]([Cl:25])=[CH:24][C:2]=2[Cl:1])[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)=[O:20]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Product: NCCNC(=O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1

Procedure:
The title compound was prepared according to the method described for Example 49 using 5-(2,4-dichloro-5-(pyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 111) and tert-butyl(2-aminoethyl)carbamate.
Reaction SMILES: [CH2:1]([C:4]([CH2:9][OH:10])([CH2:7][OH:8])[CH2:5][OH:6])[CH2:2][CH3:3].[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=O)=[CH:14][CH:13]=1>>[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]23[O:10][CH2:9][C:4]([CH2:1][CH2:2][CH3:3])([CH2:7][O:8]2)[CH2:5][O:6]3)=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CCCC(CO)(CO)CO
Product: CCCC12COC(c3ccc(I)cc3)(OC1)OC2

Procedure:
1-(4-Iodophenyl)-4-propyl-2,6,7-trioxabicyclo[2,2,2]octane was prepared from 2-n-propyl-2-hydroxymethyl-propan-1,3-diol and 4-iodobenzoyl chloride using the method described in Example 1 stages (i)-(iii)
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:50])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:50])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([C:46]([F:47])([F:48])[F:49])[CH:41]=2)[CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C(F)(F)F)c2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (262 mg, 0.70 mmol) and 3-oxo-3-[3-(2-trifluoromethyl-pyridin-4-yl)-phenyl]-propionic acid tert-butyl ester (Example K38) (256 mg, 0.70 mmol) according to the general procedure M. Obtained as a light brown foam (440 mg, 94%).
Reaction SMILES: [Br:1][C:2]1[C:6](Br)=[C:5]([Br:8])[NH:4][N:3]=1.[CH2:9]([O:11]CC)C.C([Li])CCC.CN(C)C=O>CCCCCC.O>[Br:8][C:5]1[C:6]([CH:9]=[O:11])=[C:2]([Br:1])[NH:3][N:4]=1
Reactant: CCOCC
Reactant: Brc1n[nH]c(Br)c1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1c(Br)n[nH]c1Br
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
81.7 g (0.268 mol) of 3,4,5-tribromopyrazole are introduced with stirring into 1500 mL of diethyl ether at a temperature in the region of 20° C. and under an argon atmosphere. The mixture is cooled to a temperature in the region of −78° C., followed by dropwise addition of 335 mL (0.536 mol) of a 1.6 M solution of n-butyllithium in hexane over 3 hours 15 minutes. The reaction mixture is stirred for 1.5 hours at a temperature in the region of −75° C., followed by dropwise addition of 100 mL (1.34 mol) of dimethylformamide, while keeping the temperature below −70° C. The mixture is stirred for a further 2 hours at a temperature in the region of −75° C., and then for 15 hours at a temperature in the region of 20° C. The reaction medium is then cooled in an ice-water bath and 1000 mL of water are added. After separation of the phases by settling, the aqueous phase is extracted with 500 mL of diethyl ether and with three times 500 mL of ethyl acetate. The aqueous phase is then acidified with citric acid solution to pH 3 (formation of a precipitate is observed) and extracted with twice 1000 mL of diethyl ether. The organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa), and the yellow solid obtained is taken up in 300 mL of water and stirred for 2 hours at a temperature in the region of 20° C. The mixture is then filtered and the solid is washed with twice 50 mL of water, dried in a fume cupboard and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 51.3 g of 3,5-dibromo-1H-pyrazole-4-carboxaldehyde are thus obtained in the form of a yellow powder melting at 173° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:49][C:50]1[CH:58]=[CH:57][CH:56]=[CH:55][C:51]=1[CH:52]([OH:54])[CH3:53]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:54][CH:52]([C:51]2[CH:55]=[CH:56][CH:57]=[CH:58][C:50]=2[Br:49])[CH3:53])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CC(O)c1ccccc1Br
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC(C)c4ccccc4Br)cc3)c2cc1OC
Temperature: 25 °C
Yield: 37.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (90 mg) was added to toluene/triethylamine=10/1 (9 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (151 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-bromo-α-methylbenzyl alcohol (90 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (60 mg, yield 35%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:27]([Cu])#[N:28]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:27]#[N:28])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2-c1ccc(OC)cc1
Reactant: N#C[Cu]
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2-c1ccc(OC)cc1

Procedure:
Prepared in analogy to that of Example 105(a) from 2,3,7-tribromo-4-hydroxy-1-(4-methoxy-phenyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and CuCN. The title compound, ESI MS (m/z): 494 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH:17]([CH3:19])[CH3:18])[C:6](=[O:7])[NH:5][C:4]2([CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]([CH3:16])([CH3:15])[CH2:8]2)[O:3]1.[CH2:20]1[O:22][CH:21]1[CH2:23][OH:24]>C(O)CCCCC.Cl>[CH3:1][C:2]1([CH:17]([CH3:19])[CH3:18])[C:6](=[O:7])[NH:5][C:4]2([CH2:8][C:9]([CH3:16])([CH3:15])[N:10]([CH2:20][CH:21]([OH:22])[CH2:23][OH:24])[C:11]([CH3:14])([CH3:13])[CH2:12]2)[O:3]1
Reactant: OCC1CO1
Reactant: CC(C)C1(C)OC2(CC(C)(C)NC(C)(C)C2)NC1=O
Agent: Cl
Solvent: CCCCCCO
Product: CC(C)C1(C)OC2(CC(C)(C)N(CC(O)CO)C(C)(C)C2)NC1=O

Procedure:
26.8 g (0.1 mole) of 2,7,7,9,9-pentamethyl-2-isopropyl-1-oxa-4,8-diaza-spiro[4.5]decan-3-one and 7.4 g (0.1 mole) of glycidol in 60 ml of hexanol were stirred for 65 hours at 140° C. in a stirring apparatus, using as catalyst 3 drops of concentrated HCl. The mixture was then evaporated on a rotary evaporator and the residue was recrystallized from xylene/methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:9]([C:11]1[N:16]=[C:15]([Cl:17])[N:14]=[C:13]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])[CH:12]=1)[CH3:10]>CN(C)C=O>[ClH:17].[CH2:9]([C:11]1[N:16]=[C:15]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH3:1])[N:14]=[C:13]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])[CH:12]=1)[CH3:10]
Reactant: CCc1cc(N2CCc3ccccc3C2C)nc(Cl)n1
Reactant: Cc1ccccc1N
Solvent: CN(C)C=O
Product: CCc1cc(N2CCc3ccccc3C2C)nc(Nc2ccccc2C)n1
Product: Cl
Yield: 62.1 %

Procedure:
After 2-methylaniline(0.46 ml, 4.31 mmol) was added to a mixture solution of 6-ethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(0.61 g, 2.12 mmol) and dimethylformamide(5 ml), 0.52 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:32])([CH2:12][CH2:13][C:14]1[N:15]([CH3:31])[C:16]([C:19](=[O:30])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][CH:18]=1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[C:1]([O:5][C:6]([NH:8][C@:9]([CH3:32])([CH2:12][CH2:13][C:14]1[N:15]([CH3:31])[C:16]([C:19](=[O:30])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:18]=1)[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(CC[C@](C)(CO)NC(=O)OC(C)(C)C)ccc1C(=O)CCCCc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1c(CC[C@](C)(C=O)NC(=O)OC(C)(C)C)ccc1C(=O)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.3 %

Procedure:
To a solution of (2R)-2-t-butoxycarbonylamino-2-methyl-4-[1-methyl-5-(5-phenylpentanoyl)pyrrol-2-yl]butan-1-ol (0.3520 g, 0.80 mmol) obtained in Example (43a) in dichloromethane (8 ml) were added successively molecular sieves 4A (0.2234 g) and pyridinium dichromate (0.4594 g, 1.22 mmol), and the resulting mixture was stirred at room temperature for 20 hours. After stirring, ether was added to the reaction mixture, and the resulting mixture was filtered. The filtrate was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (3:2) as the eluent to afford the title compound (0.2195 g, yield: 63%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5][N:4]=[CH:3]1.S(Cl)([Cl:13])=O.[CH3:15]O>>[ClH:13].[CH3:15][O:9][C:8]([CH:6]1[CH2:7][NH:2][CH:3]=[N:4][CH2:5]1)=[O:10]
Reactant: O=C(O)C1CN=CNC1
Reactant: O=S(Cl)Cl
Reactant: CO
Agent: Cl
Product: COC(=O)C1CN=CNC1
Yield: 60 %

Procedure:
1,4,5,6-Tetrahydropyrimidine-5-carboxylic acid hydrochloride (6.34 g, 38.5 mmol) was dissolved in anhydrous methanol (200 ml) with stirring, and thionyl chloride (2.74 ml, 38.5 mmol) was added dropwise. The resulting solution was refluxed with stirring for 18 hours, then evaporated in vacuo to white solids. The crude product was recrystallized from anhydrous methanol to yield 4.12 g (60%) white crystals, mp 160°-164° C. Calculated: C 40.34, H 6.21, N 15.69; found: C 40.17, H 6.41, N 15.73.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22](O)=[O:23])=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:29][CH2:28]1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([NH:26][C@H:27]3[CH2:28][CH2:29][C@H:30]([CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:32]3)=[O:23])=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc2oc(C(=O)O)cc2c1
Reactant: CC(C)(C)OC(=O)CC[C@H]1CC[C@H](N)CC1
Product: CC(C)(C)OC(=O)CC[C@H]1CC[C@H](NC(=O)c2cc3cc(C(=N)NC(=O)OCc4ccccc4)ccc3o2)CC1

Procedure:
In the same manner as in Example 15 (3), 5-(benzyloxycarbonylamidino)-2-benzofurancarboxylic acid (3.98 g, 11.8 mmol) and t-butyl trans-3-(4-aminocyclohexyl)propionate (2.70 g, 1 1.8 mmol) were condensed to give 5.04 g of t-butyl trans-3-[4-[[5-(benzyloxycarbonylamidino)-2-benzofuranyl]carbonylamino]cyclohexyl]propionate as a colorless solid (78%). In the same manner as in Example 85, this solid (4.90 g, 8.95 mmol) was subjected to hydrogen reduction to give 3.52 g of compound (161) as a colorless solid (95%), which was treated with methanesulfonic acid (0.82 g, 8.52 mmol) in tetrahydrofuran solvent to give 3.82 g of methanesulfonate of compound (161) as a colorless solid (88%).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C@H:16]([NH:26][CH3:27])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:32]([O:36][C:37](=[O:48])[NH:38][CH2:39]C1CCN(CCCl)C1)([CH3:35])([CH3:34])[CH3:33].[CH3:49][CH2:50][N:51]([CH2:54][CH3:55])[CH2:52][CH3:53]>CC#N>[C:32]([O:36][C:37]([N:38]([CH3:39])[CH:49]1[CH2:53][CH2:52][N:51]([CH2:54][CH2:55][N:26]([CH3:27])[C@@H:16]2[CH2:15][N:14]3[C:13]4[CH:12]=[C:11]([C:28]([O:30][CH3:31])=[O:29])[CH:10]=[CH:9][C:8]=4[C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[C:21]3[C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[O:18][CH2:17]2)[CH2:50]1)=[O:48])([CH3:35])([CH3:34])[CH3:33]
Reactant: CN[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCl)C1
Solvent: CC#N
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCN1CCC(N(C)C(=O)OC(C)(C)C)C1)COc1ccccc1-3
Temperature: 140 °C
Yield: 64 %

Procedure:
A solution of methyl (7R)-14-cyclohexyl-7-(methylamino)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (1 eq) in MeCN was treated with tert-butyl[1-(2-chloroethyl)pyrrolidin-3-yl]methylcarbamate (2.4 eq) and NEt3 (2 eq) and heated at 140° C. in a microwave oven. The solvent was removed in vacuo and the residue purified by FC (Biotage; DCM/MeOH) to get the title compound as a white powder (64%). (ES+) m/z 645 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:14](Cl)(=[O:16])[CH3:15].[Al+3].[Cl-].[Cl-].[Cl-]>>[C:14]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)Oc1ccc(-c2ccccc2)cc1
Yield: 94 %

Procedure:
When a mixture of 4-hydroxybiphenyl with acetyl chloride and AlCl3 in a molar ratio of 1:1:1 was reacted for 1 hr, only 4-acetoxybiphenyl ##STR66## was obtained in a yield of 94%.
Reaction SMILES: C(O[C:4]([C:6]1[S:7][C:8]([CH2:12][CH3:13])=[C:9]([OH:11])[N:10]=1)=[O:5])C.[C:14]1([CH3:23])[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21]O)[CH:15]=1.Cl.C[O:26][C:27]([C:29]1([NH2:38])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1)=[O:28]>>[CH2:12]([C:8]1[S:7][C:6]([C:4]([NH:38][C:29]2([C:27]([OH:28])=[O:26])[CH2:30][C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:37]2)=[O:5])=[N:10][C:9]=1[O:11][CH2:21][CH2:20][C:16]1[CH:15]=[C:14]([CH3:23])[CH:19]=[CH:18][CH:17]=1)[CH3:13]
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Reactant: Cc1cccc(CCO)c1
Reactant: CCOC(=O)c1nc(O)c(CC)s1
Agent: Cl
Product: CCc1sc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)nc1OCCc1cccc(C)c1

Procedure:
5-Ethyl-4-hydroxy-thiazole-2-carboxylic acid ethyl ester (F. A. J. Kerdesky et al., J. Med. Chem. 34 (1991), 2158-2165) (100 mg, 0.497 mmol) was reacted with 2-m-tolyl-ethanol in analogy to step 1 of example 1 and subsequently the ester moiety hydrolyzed in analogy to example 2. The obtained carboxylic acid was reacted with 2-amino-indane-2-carboxylic acid methyl ester hydrochloride in analogy to step 2 of example 13 and the obtained ester hydrolyzed in analogy to example 2.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:5][N:4]=1)[NH2:2].[C:17]([O-])([O-])(OCC)[CH3:18]>>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]3[N:4]([C:17]([CH3:18])=[N:2][N:1]=3)[CH:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(C)([O-])[O-]
Reactant: COc1cccc(-c2ccc(NN)nc2)c1
Product: COc1cccc(-c2ccc3nnc(C)n3c2)c1

Procedure:
In the manner described in Example 37, a mixture of 2-hydrazino-5-(3-methoxyphenyl)pyridine and ethyl orthoacetate provides the product of the Example.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14]C1C=CC=CC=1)=[O:12])C1C=CC=CC=1.[C:49]([C:52]1[CH:57]=[CH:56][C:55](B(O)O)=[CH:54][CH:53]=1)([OH:51])=[O:50]>>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([C:55]3[CH:56]=[CH:57][C:52]([C:49]([OH:51])=[O:50])=[CH:53][CH:54]=3)=[CH:46][CH:47]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:12])[C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(Br)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1

Procedure:
Aryl halide 9 was coupled to 4-carboxyphenylboronic acid to give 32 on a 0.1 mmol scale via General Procedure H. 32 was not purified at this stage and was deprotected without purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:20]([CH:30]2[CH2:32][CH2:31]2)CC2C=CC(OC)=CC=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[NH2:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36][CH2:35]1.[N:41]([C:44]1[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=1)=[C:42]=[O:43].C(O)(C(F)(F)F)=O>O.C(Cl)Cl>[CH:30]1([NH:20][C:4]2[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][N:15]=4)=[O:12])=[CH:9][N:10]=3)[N:7]=[C:2]([NH:33][C@H:34]3[CH2:39][CH2:38][C@H:37]([NH:40][C:42]([NH:41][C:44]4[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=4)=[O:43])[CH2:36][CH2:35]3)[CH:3]=2)[CH2:31][CH2:32]1
Reactant: O=C=Nc1cccnc1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C(=O)Nc4ccncn4)cnc23)C2CC2)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cccnc1)N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4ccncn4)n3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Chloro-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(pyrimidin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (70 mg, 0.156 mmol) and trans-1,4-diaminocyclohexane (533 mg, 4.67 mmol) were heated together at 160° C. for 1.5 hrs. The reaction mixture was suspended in water, filtered through a Buchner funnel, dried under high vacuum and taken to the next step without further purification. The crude product from the above reaction (40.0 mg, 0.076 mmol) was dissolved in DCM (1 mL) and treated with 3-isocyanatopyridine (9.11 mg, 0.076 mmol). The reaction mixture was stirred at room temperature for 30 minutes, concentrated, and treated with TFA (1.168 mL, 15.16 mmol). The reaction mixture was heated at 70° C. for 1 hr, concentrated and purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 30% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA)) to isolate the title compound, 8-(cyclopropylamino)-6-((trans)-4-(3-pyridin-3-ylureido)cyclohexylamino)-N-(pyrimidin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (18.4 mg, 46%), as a white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=1.59 (M+H=528.28). 1H NMR (400 MHz, MeOD) δ ppm 9.27 (1H, d, J=2.27 Hz), 9.03 (1H, s), 8.71 (1H, d, J=6.04 Hz), 8.36-8.49 (2H, m), 8.32 (1H, ddd, J=8.69, 2.52, 1.13 Hz), 8.12 (1H, s), 7.95 (1H, dd, J=8.81, 5.54 Hz), 6.11 (1H, s), 3.98 (1H, s), 3.66 (1H, s), 2.60 (1H, ddd, J=6.86, 3.34, 3.15 Hz), 2.22-2.38 (2H, m), 2.08 (2H, d, J=10.58 Hz), 1.73 (2H, dd, J=12.46, 2.64 Hz), 1.31-1.57 (2H, m), 0.80-0.99 (2H, m), 0.55-0.78 (2H, m).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[N:18]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[F:39])[C:19]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1O)=[O:20]>N1C=CC=CC=1>[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[N:18]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[F:39])[C:19]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[O:4][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:6])=[O:5])=[O:20]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: O=C(c1c(O)ccc2ccccc12)N(Cc1ccccc1F)C1Cc2ccccc2C1
Solvent: c1ccncc1
Product: O=C(c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12)N(Cc1ccccc1F)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoromethanesulfonic acid anhydrous (0.27 mL, 1.6 mmol) is added dropwise in 10 minutes to a solution of 2-hydroxy-naphthalene-1-carboxylic acid indan-2-yl-(2-fluoro-benzyl)-amide (17) (323 mg, 0.8 mmol) in anhydrous pyridine (5 mL) at 0° C. under nitrogen. The mixture is stirred at room temperature overnight and concentrated under reduced pressure. The residue (18) is dried in vacuo and used for the next step without further purification.