Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH2:4][OH:5].[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:10])[CH3:11])(=[O:14])[CH3:13]
Reactant: CC(C)=CCCC(C)CCO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCC(C)CCC=C(C)C

Procedure:
100 Grams of 3,7-dimethyloct-6-en-1-ol is dissolved in 150 ml. of pyridine and 100 ml. of acetic anhydride and left at room temperature for about 48 hours. Then the mixture is extracted with ether and the ethereal extracts washed with water, 10% aqueous HCl and brine to yield 1-acetoxy-3,7-dimethyloct-6-ene which is purified by distillation.
Reaction SMILES: [N:1]1([C:7]([C:9]2[N:10]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([OH:20])=O)=[CH:13][CH:12]=3)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:26]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([N:31]2[CH2:32][CH2:33][N:34]([C:18]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[N:10]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:9]([C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:8])=[CH:17]4)=[O:20])[CH2:35][CH2:36]2)[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: O=C(O)c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC(F)(F)F
Reactant: C1CCC(N2CCNCC2)C1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC(F)(F)F)N1CCN(C2CCCC2)CC1
Yield: 49 %

Procedure:
The title compound was synthesized in analogy to example 46, intermediate e), from 2-(morpholine-4-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indole-5-carboxylic acid and 1-cyclopentylpiperazine (commercially available), to give the desired product as a white solid (49%).
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O-:9])=O.[C:13]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20](=[O:32])[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH:30][CH3:31])[CH2:24][CH2:23]1>>[C:13]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20]([O:21][CH:22]1[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][N:30]([CH3:31])[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:11][CH3:12])=[O:10])[CH2:26][CH2:27]1)=[O:32]
Reactant: CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reactant: COC(=O)CCCCCC(=O)[O-]
Product: COC(=O)CCCCCC(=O)N(C)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Yield: 102.5 %

Procedure:
Monomethyl pimelate (79 mg, 0.450 mmol) and 1-[2-(methylamino)ethyl]piperidin-4-yl biphenyl-2-ylcarbamate (159 mg, 0.450 mmol) were used to give the title compound (235 mg; yield, 100%) as a colorless oily substance according to the method described in Example 12a.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1.[CH2:24]=[O:25]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:24][OH:25])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1
Reactant: C=O
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Solvent: Cc1ccccc1C
Product: OCCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, 8-chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in xylene is heated in an oil bath at 122°-124° C. with repeated addition of portions of paraformaldehyde to give 8-chloro-1-(2-hydroxyethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C(C(O)=O)(F)(F)F.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:15]2[C:19]([CH2:20][O:21][C:22](=[O:24])[CH3:23])=[CH:18][C:17]([CH2:25][O:26][C:27](=[O:29])[CH3:28])=[N:16]2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>O>[C:27]([O:26][CH2:25][C:17]1[CH:18]=[C:19]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[NH:15][N:16]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OCc1cc(COC(C)=O)n(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)OCc1cc(COC(C)=O)[nH]n1
Reaction time: 1 h

Procedure:
To a solution of 90 ml. of CF3CO2H and 15 ml. of H2O, cooled to -20° was added, in portions, 10 g. (0.022 mol) of the end product of Example 20. After the addition was complete, the solution was stirred at -15° to -20° for 1 hour, poured into excess saturated K2CO3 solution and extracted with EtOAc. The organic phase was dried (MgSO4), concentrated and the residue chromatographed on silica gel to give the end product as a pale yellow oil. The analytical sample was obtained as a colorless oil by bulb to bulb distillation: bp 175 (0.05 mm).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:14]1[N:15]=[CH:16][C:17]2[C:23](=[O:24])[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][N:20]([CH2:30][CH3:31])[C:18]=2[N:19]=1.Cl.C1(N2CCNCC2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:14]3[N:15]=[CH:16][C:17]4[C:23](=[O:24])[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][N:20]([CH2:30][CH3:31])[C:18]=4[N:19]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)ncc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(c4ccccc4)CC3)ncc2c1=O
Yield: 83 %

Procedure:
A solution of 3.2 g of (0.02 mol) of N-phenyl-piperazine in 30 cm3 of toluene is added to 2.8 g (0.01 mol) of 2-chloro-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine dissolved in 30 cm3 of toluene. Reaction takes place practically instantaneously with evolution of heat and the mixture sets solid due to formation of phenylpiperazine hydrochloride. The mixture is diluted with 100 cm3 of ethyl acetate, the solution is filtered, washed with water and dried (MgSO4) and the solvent is evaporated. The residue is recrystallised from 110 cm3 of isopropanol and yields 3.38 g (84%) of 2-(4'-phenyl-piperazino)-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine; melting point 186° C.
Reaction SMILES: Br[CH:2]([CH2:8][C:9]([OH:11])=[O:10])[C:3](=[O:7])[C:4]([OH:6])=[O:5].[C:12]([NH:15][CH2:16][CH2:17][SH:18])(=[O:14])[CH3:13].C(N(CC)CC)C>ClCCl>[C:12]([NH:15][CH2:16][CH2:17][S:18][CH:2]([CH2:8][C:9]([OH:11])=[O:10])[C:3](=[O:7])[C:4]([OH:6])=[O:5])(=[O:14])[CH3:13]
Reactant: O=C(O)CC(Br)C(=O)C(=O)O
Reactant: CC(=O)NCCS
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCSC(CC(=O)O)C(=O)C(=O)O
Yield: 60.7 %

Procedure:
In 20 ml of dichloromethane was suspended 1.0 g of 3-bromo-2-oxoglutaric acid. To the suspension was added, while stirring under ice-cooling, 0.5 g of 2-acetamidoethanethiol, followed by addition of 1.83 ml of triethylamine. The reaction solution was stirred at room temperature for one hour, then the solvent was evaporated off. To the residue were added ethyl acetate and water. The aqueous layer was taken, which was adjusted to pH 1~2 with 1N-HCl, followed by extraction with ethyl acetate. The extract solution was washed with water and dried (MgSO4), followed by evaporating off the solvent to give 0.67 g of 3-(2-acetamidoethylthio)-2-oxoglutaric acid as a pale yellow oily product. To this product were added, while stirring under ice-cooling, 0.32 ml of dicyclohexylamine and 0.34 g of 4-nitrobenzyl bromide. The reaction solution was stirred for 15 hours at room temperature, followed by dilution with ethyl acetate. The crystals which separated out were filtered off, and the filtrate was washed with water and dried (MgSO4), followed by evaporating off the solvent. The residue was subjected to a silica gel column chromatography, followed by elution with ethyl acetate then with ethyl acetate--acetic acid (100:3) to give 0.4 g of the subject Compound (70) as a pale yellow oily product.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[C:15]([O:19][C:20]([N:22]1[CH:27]2[CH2:28][CH2:29][CH2:30][CH:23]1[CH2:24][NH:25][CH2:26]2)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([N:22]1[CH:23]2[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:26][N:25]([C:2]1[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=3)[N:3]=1)[CH2:24]2)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1C2CCCC1CNC2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Product: CC(C)(C)OC(=O)N1C2CCCC1CN(c1ccc3cc([N+](=O)[O-])ccc3n1)C2

Procedure:
Is prepared according to method A from 2-chloro-6-nitroquinoline and 3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]3[CH:21]=[CH:20][N:19]=[C:10]3[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:4][CH2:3]1.[Cl:22]C1C=CC=C(C(OO)=[O:30])C=1.Cl>C(Cl)Cl.CCOCC>[ClH:22].[CH3:1][N+:2]1([O-:30])[CH2:7][CH2:6][N:5]([C:8]2[N:9]3[CH:21]=[CH:20][N:19]=[C:10]3[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:4][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN1CCN(C2=Nc3ccccc3Sc3nccn32)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C[N+]1([O-])CCN(C2=Nc3ccccc3Sc3nccn32)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To the solution of 88 mg of 5-(4-methylpiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine in 1 ml of methylene chloride, 74 mg of m-chloroperbenzoic acid are added at 0° C. The mixture is stirred at 0° C. overnight; this is diluted with 1 ml of ether, one equivalent of ethereal hydrochloric acid solution is added and the resulting precipitate is collected. Recrystallization from methanol-ethyl acetate yields 5-(4-methyl-4-oxidopiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine hydrochloride, melting at 155° with decomposition.
Reaction SMILES: [CH2:1]([N:8]([CH:35]([CH3:37])[CH3:36])[C:9](=[O:34])[CH2:10][N:11]1[C:20](=[O:21])[CH2:19][C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][CH:43]=[C:42]2[CH:48]=O>>[CH2:1]([N:8]([CH:35]([CH3:37])[CH3:36])[C:9](=[O:34])[CH2:10][N:11]1[C:20](=[O:21])[C:19](=[CH:48][C:42]2[C:41]3[C:45](=[CH:46][CH:47]=[C:39]([F:38])[CH:40]=3)[NH:44][CH:43]=2)[C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:12]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c[nH]c2ccc(F)cc12
Reactant: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Product: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)C(=Cc2c[nH]c3ccc(F)cc23)c2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Yield: 71.5 %

Procedure:
Following the procedure described for Example 1(A), Step A, N-benzyl-2-(8,9-difluoro-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-acetamide (Preparation 9) (100 mg, 0.198 mmol) was condensed with 5-fluoro-1H-indole-3-carbaldehyde (38.8 mg, 0.238 mmol). Purification by medium pressure chromatography eluting with 50% EtOAc in CH2Cl2 provided 91.5 mg of N-benzyl-2-[8,9-difluoro-4-(5-fluoro-1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide. 1H NMR (CDCl3) δ 7.92 (d, 1H), 7.10-7.67 (m, 13H), 6.84 (m, 1H), 6.64 (m, 1H), 4.37-4.97 (m, 5H), 4.20 (m, 1H), 1.20 (m, 6H); MS 647.4 (M+1), 645.3 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:25]([F:28])([F:27])[F:26])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.O.[NH2:30][NH2:31].O1CCCC1>O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:14][C:15]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:16]=3[C:17]([NH:30][NH2:31])=[O:19])=[O:18])=[CH:11][C:10]([C:25]([F:26])([F:27])[F:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: Cc1cccc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)NN)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.40 g of 2-[1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazine-4-one, 0.09 ml of hydrazine monohydrate and 20 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.26 g of 1-(3-chloro-2-pyridinyl)-N-[2-(hydrazinocarbonyl)-6-methylphenyl]-3-trifluoromethyl-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.5 %

Procedure:
To a solution of (R)-tert Butoxycarbonylamino-(4-hydroxy-phenyl)-acetic acid (2.54 g, 9.55 mmol) in DMF (5 mL) was added imidazole (1.43 g, 21 mmol) followed by t-butyldimethylsilyl chloride (1.58 g, 10.5 mmol). The resulting mixture was stirred at rt for overnight. Additional t-butyldimethylsilyl chloride (1.43 g, 9.55 mmol) was added and let the reaction continue for another hour. The reaction mixture was diluted with EtOAc and washed with H2O three times and concentrated. To the residue was added aqueous 1N NaOH and then acidified with concentrated HCl. The resulting mixture was extracted with EtOAc three times. The combined organic layer was dried (MgSO4) and concentrated to provide the titled compound (4.5 g).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=1>C(#N)C>[I:1][C:14]1[S:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[N:11][C:10]=1[CH3:9]
Reactant: CC(=O)Nc1nc(C)cs1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CC(=O)Nc1nc(C)c(I)s1

Procedure:
N-Iodosuccinimide (4.75 g) is added portion wise to a solution of N-(4-methyl-thiazol-2-yl)-acetamide (3 g) in acetonitrile (60 ml) at room temperature. After 5 minutes a precipitate forms which is collected by filtration and washed with cold acetonitrile to give the title compound as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:24])(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O>[C:5]([Cl:3])(=[O:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: O
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)Cl
Temperature: 40 °C
Reaction time: 0.83 h

Procedure:
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 9.35 ml (128 mmol) of thionyl chloride, and a water condenser, is placed 24.90 ml (80 mmol) of linoleic acid. Addition of the thionyl chloride is completed with heating to about 40° C. over the course of about 40 minutes. When addition of the thionyl chloride is complete the mixture is heated and stirred for an additional 50 minutes. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl chloride, (9Z,12Z)-octadeca-9,12-dienoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:14]([CH:43]=[CH:44][N:45]=3)[CH:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:40]=[CH:41][CH:42]=3)[C:21]([NH:23][C:24]3[CH:39]=[CH:38][C:27]([C:28]([O:30]CC4C=CC=CC=4)=[O:29])=[CH:26][CH:25]=3)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:14]([CH:43]=[CH:44][N:45]=3)[CH:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:40]=[CH:41][CH:42]=3)[C:21]([NH:23][C:24]3[CH:39]=[CH:38][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(-c3cccc(C(=O)Nc4ccc(C(=O)OCc5ccccc5)cc4)c3)cn3ccnc23)cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(Nc2nc(-c3cccc(C(=O)Nc4ccc(C(=O)O)cc4)c3)cn3ccnc23)cc1OC
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
A solution of benzyl 4-(3-(8-(3,4-dimethoxyphenylamino)imidazo[1,2-a]pyrazin-6-yl)benzamido)benzoate (1.75 g, 2.92 mmol) in ethyl acetate (500 mL) and ethanol (500 mL) at 60° C. was treated with 10% palladium on carbon (5.11 g, 50% water by weight) and sparged with hydrogen for 30 min at 60° C. then stirred under balloon pressure hydrogen at 60° C. for 30 min. After this time, the reaction was sparged with nitrogen for 10 min and filtered hot through diatomaceous earth. The filtrate was concentrated under reduced pressure and the residue obtained was exhaustively triturated: boiling acetonitrile (50 mL×2); then boiling methanol (50 mL); then boiling 1:1 methanol/acetonitrile (50 mL); then boiling acetonitrile (50 mL); then boiling 1:1 methanol/acetonitrile (50 mL) to afford 4-(3-(8-(3,4-dimethoxyphenylamino)imidazo[1,2-a]pyrazin-6-yl)benzamido)benzoic acid (458 mg, 31%) as an off-white solid: mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ 12.74 (br s, 1H), 10.67 (s, 1H), 9.57 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.25 (d, J=7.8 Hz, 1H), 8.80-7.89 (m, 7H), 7.69-7.53 (m, 3H), 6.93 (d, J=8.7 Hz, 1H), 3.78 (s, 3H), 3.71 (s, 3H); ESI MS m/z 510 [M+H]+; HPLC, 6.50 min, 95.6% (AUC).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:2].[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[N:8]([Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26])[C:7](=[O:9])[C@H:6]1[NH:10][C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@H](NC(=O)Cc2ccccc2)C(=O)N1[Si](C)(C)C(C)(C)C

Procedure:
Such a preferred procedure comprises treating the (3S,4S)-4-acetoxy-3-phenylacetamido-azetidin-2-one (II) with tert-butyldimethyl chlorosilane in the presence of 4-dimethylaminopyridine and, optionally, of pyridine in an organic solvent, isolating the (3S,4S)-4-acetoxy-3-phenylacetamido-1-tert-butyldimethylsilyl-azetidin-2-one (III) thus obtained and treating with an inorganic sulfide to obtain (3S,4S)-4-acetoxy-3-phenylethanethioylamino-1-tert-butyldime thylsilyl-azetidin-2-one (IV) and treating this compound with a base in an organic solvent at a temperature of 70°÷130° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][S:21]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O)(=[O:23])=[O:22]>>[CH3:20][S:21]([C:24]1[CH:25]=[C:26]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:29]=[CH:30][CH:31]=1)(=[O:22])=[O:23]
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CS(=O)(=O)c1cccc(C=O)c1
Product: CS(=O)(=O)c1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-methylsulfonylbenzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-methylsulfonylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH2:1]([P:3]([C:14]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[Cl:31])[CH:17]=[CH:16][C:15]=1[N+:32]([O-:34])=[O:33])(=O)[O:4][CH2:5][O:6][C:7](=[S:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:36]>>[CH2:1]([P:3]([C:14]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[Cl:31])[CH:17]=[CH:16][C:15]=1[N+:32]([O-:34])=[O:33])(=[S:36])[O:4][CH2:5][O:6][C:7](=[S:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:2]
Reactant: CCP(=O)(OCOC(=S)C(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: CCP(=S)(OCOC(=S)C(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
In the same way, 2,2-dimethyl(thiopropionyl)oxymethyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate is reacted with phosphorus pentasulfide to yield O-[2,2-dimethyl(thiopropionyl)oxymethyl] P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinothioate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:8]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)([O-:10])=[O:9].C(COC)OC.C(=O)([O-])[O-].[K+].[K+]>O>[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: Brc1ccccn1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ccccn2)cc1
Temperature: 95 °C

Procedure:
2-Bromopyridine (650 μL), 4-nitrophenylboronic acid (1.479 g) and palladium tetrakistriphenylphosphine (391.5 mg) were added to a mixture of 40 mL of dimethoxyethane and 10 mL of 2.0 M aqueous potassium carbonate under an atmosphere of dry N2. The reaction mixture was heated at 95° C. overnight. The reaction mixture was then cooled to room temperature and diluted with water (200 mL). The resulting precipitate was collected, washed with water and air-dried. The dried material was purified using silica gel chromatography to give 1.40 g of 2-(4-nitrophenyl)pyridine.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]3[CH:18]=[C:17]4[CH2:20][CH2:21][CH2:22][C:23](=[O:24])[C:16]4=[CH:15][C:14]=3[O:13][CH2:12][C:11]=2[CH:25]=1)(C)C.C(O)=[O:27]>>[C:6]([C:7]1[CH:8]=[CH:9][C:10]2[C:19]3[CH:18]=[C:17]4[CH2:20][CH2:21][CH2:22][C:23](=[O:24])[C:16]4=[CH:15][C:14]=3[O:13][CH2:12][C:11]=2[CH:25]=1)(=[O:27])[CH3:5]
Reactant: C[Si](C)(C)C#Cc1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Reactant: O=CO
Product: CC(=O)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Temperature: 65 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
A 20 mL vial with stirbar was charged with 3-((trimethylsilyl)ethynyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (850 mg, 2.44 mmol) and formic acid (9.8 mL). The solution was heated to 65° C. After 3 h, the reaction was judged complete. The mixture was concentrated under reduced pressure; the resulting residue was taken up in CH2Cl2 and loaded onto a prepacked 25 g silica gel cartridge. The product was purified by chromatography on a prepacked 80 g silica gel column eluting with a solvent gradient from 5% to 85% EtOAc/hexanes. The product containing fractions were combined and concentrated to provide 3-acetyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (616 mg, 86%): 400 MHz 1H NMR (CDCl3) δ 8.00-7.94 (m, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.77 (s, 1H), 7.64 (s, 2H), 5.16 (s, 2H), 2.98 (t, J=6.1 Hz, 2H), 2.69-2.64 (m, 2H), 2.63 (s, 3H), 2.21-2.09 (m, 2H).