Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:31])([F:30])[C:14]1[N:19]=[CH:18][C:17]([CH:20]([CH2:23][C:24]2([CH:27]([F:29])[F:28])[CH2:26][CH2:25]2)[CH2:21][NH2:22])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([C:17]1[CH:18]=[N:19][C:14]([C:13]([F:31])([F:12])[F:30])=[CH:15][CH:16]=1)[CH2:23][C:24]1([CH:27]([F:28])[F:29])[CH2:25][CH2:26]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(CC1(C(F)F)CC1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(CC1(C(F)F)CC1)c1ccc(C(F)(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(6-trifluoromethyl-pyridin-3-yl)-3-(1-difluoromethyl-cyclopropyl)-propylamine. LCMS (MH+): m/z=467.1, tR (minutes, Method G)=2.62
Reaction SMILES: Cl.[F:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH2:21][CH:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[O:19][N:18]=3)[N:14]=[C:13]([CH3:28])[N:12]=2)=[O:10])=[CH:5][C:4]=1[O:31][CH3:32].F[C:34](C1C(F)=C(F)C(F)=C(F)C=1F)([S:38]([C:41](F)(F)F)(=[O:40])=[O:39])[C:35]([O-])=[O:36]>C(Cl)Cl>[F:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH2:21][CH:20]([CH:22]4[CH2:23][CH2:24][N:25]([C:35](=[O:36])[CH2:34][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:26][CH2:27]4)[O:19][N:18]=3)[N:14]=[C:13]([CH3:28])[N:12]=2)=[O:10])=[CH:5][C:4]=1[O:31][CH3:32]
Reactant: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCNCC4)C3)nc(C)n2)ccc1F
Reactant: O=C([O-])C(F)(c1c(F)c(F)c(F)c(F)c1F)S(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCN(C(=O)CS(C)(=O)=O)CC4)C3)nc(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.6 %

Procedure:
To a stirred solution of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide hydrochloride (0.20 g, 0.43 mmol Preparation #K. 1) in DCM (10 mL) was added TEA (0.13 g, 1.29 mmol, Spectrochem) and perfluorophenyl-2-(methylsulfonyl)acetate (0.196 g, 0.645 mmol, See Ref: US 20090312338). The resulting solution was stirred at RT for about 16 h. The crude reaction mixture was purified by preparative HPLC (Table 2, Method f) to afford N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-(2-(methylsulfonyl)acetyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide 0.072 g (31.3%); LC/MS (Table 1, Method d) Rt=0.55 min; MS m/z: 548.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[N:27]=[C:26]([NH:28][C:29]4[C:34]([Cl:35])=[C:33]([F:36])[CH:32]=[C:31]([CH2:37][NH2:38])[C:30]=4[Cl:39])[NH:25][C:15]3=[N:16][C:17]=2[N:18]2[CH2:23][CH2:22][CH:21]([F:24])[CH2:20][CH2:19]2)=[O:11])[CH2:5][CH2:4]1.[C:42](Cl)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44].C1COCC1>CO>[F:41][C:2]([F:40])([F:1])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[N:27]=[C:26]([NH:28][C:29]4[C:34]([Cl:35])=[C:33]([F:36])[CH:32]=[C:31]([CH2:37][NH:38][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[C:30]=4[Cl:39])[NH:25][C:15]3=[N:16][C:17]=2[N:18]2[CH2:19][CH2:20][CH:21]([F:24])[CH2:22][CH2:23]2)=[O:11])[CH2:5][CH2:4]1
Reactant: NCc1cc(F)c(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(N4CCC(F)CC4)nc3[nH]2)c1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1cc(F)c(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(N4CCC(F)CC4)nc3[nH]2)c1Cl
Reaction time: 0.33 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-{2,6-dichloro-5-fluoro-3-(aminomethyl)-phenylamino}-5-[4-fluoro-piperidinyl]-3H-imidazo[4,5-b]pyridine-6-carboxamide (130 mg, 0.210 mmol), pivaloyl chloride (26 μL, 0.21 mmol), TEA (75 mg, 0.74 mmol) and 5 mL THF is stirred for 20 min and diluted with MeOH. The crude product is purified via prep. HPLC (C-18 stable bond, eluent gradient: water(+0.15% HCOOH)/MeOH 9:1->MeOH).
Reaction SMILES: [Cl-].[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[C:9]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:8]=2[CH:32]=1)#[N:3].[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH:42]=O)=[CH:37][CH:36]=1>O1CCCC1.C(O)C>[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]=[CH:42][CH2:12][C:9]2[C:8]3[CH:32]=[C:4]([C:2]#[N:3])[CH:5]=[CH:6][C:7]=3[O:11][CH:10]=2)=[CH:37][CH:36]=1
Reactant: COc1ccc(CC=O)cc1
Reactant: N#Cc1ccc2occ(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2c1
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C=CCc2coc3ccc(C#N)cc23)cc1
Reaction time: 24 h

Procedure:
2.14 g of (5-cyano-3-benzofuranyl)methyltriphenylphosphonium chloride and 0.7 g of 4-methoxyphenylacetaldehyde were dissolved in a solvent mixture of 100 ml of tetrahydrofuran and 100 ml of ethanol. The thus prepared solution was mixed with 0.71 g of 1,8-diaza-bicyclo[5.4.0]-7-undecene and stirred for 24 hours. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using toluene as an elution solvent, thereby obtaining 0.86 g of yellow and oily 3-[3-(4-methoxyphenyl)allyl]-5-benzofurancarbonitrile as a mixture of E and Z forms. The thus obtained E/Z mixture was dissolved in 100 ml of ethanol, and the solution was subjected to catalytic hydrogenation under normal pressure in the presence of 370 mg of 5% palladium carbon catalyst. Thereafter, the catalyst was removed by filtration, and the solvent was distilled off to obtain 0.6 g of 3-[3-(4-methoxyphenyl)propyl]-5-benzofurancarbonitrile. The thus obtained methoxy compound was dissolved in 20 ml of dichloromethane. With stirring at -40° C., to the resulting solution was added dropwise 10 ml of a dichloromethane solution containing 0.4 ml of boron tribromide. The resulting mixture was warmed up to room temperature and stirred for 2 hours. The resulting reaction solution was poured into cold dilute hydrochloric acid and extracted with chloroform. After drying the resulting organic layer and distilling off the solvent, the thus obtained residue was purified by subjecting it to silica gel column chromatography using toluene as an elution solvent. In this way, 280 mg of 3-[3-(4-hydroxyphenyl)propyl]-5-benzofurancarbonitrile.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]([CH3:30])[S:8]([N:11]1[C:15]2[CH:16]=[N:17][N:18]([CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19](=[O:20])[C:14]=2[N:13]=[CH:12]1)(=[O:10])=[O:9].[Cl:31]C(Cl)(Cl)C(Cl)(Cl)Cl.[Cl-].[NH4+]>O1CCCC1>[CH3:6][N:7]([CH3:30])[S:8]([N:11]1[C:15]2[CH:16]=[N:17][N:18]([CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19](=[O:20])[C:14]=2[N:13]=[C:12]1[Cl:31])(=[O:10])=[O:9]
Reactant: CN(C)S(=O)(=O)n1cnc2c(=O)n(COCc3ccccc3)ncc21
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1c(Cl)nc2c(=O)n(COCc3ccccc3)ncc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
5.3 ml of n-butyl lithium (2.0 M cyclohexane solution) was added to a 150-ml tetrahydrofuran solution of 3.34 g of 5-benzyloxymethyl-4-oxo-4,5-dihydroimidazo[4,5-d]pyridazine-1-sulfonic acid dimethylamide under a nitrogen atmosphere at −78° C., and the mixture was stirred at −78° C. for one hour. Then, 20 ml of a tetrahydrofuran solution of 3.26 g of hexachloroethane was added to this solution. The mixture was allowed to warm to room temperature. 25 ml of a 5% aqueous solution of ammonium chloride was added to the solution, and the mixture was extracted with 50 ml of ethyl acetate. The organic layer was washed successively with 25 ml of water and 25 ml of a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. The organic liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 2.31 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (2:3).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[C:10]([CH3:12])[O:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[O:13]=P(Cl)(Cl)Cl.C(Cl)(Cl)Cl.CCCCCC>C(OC(=O)C)(=O)C>[CH3:8][C:6]1[NH:7][C:2](=[O:13])[C:3]2[CH:11]=[C:10]([CH3:12])[O:9][C:4]=2[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(Cl)c2cc(C)oc2n1
Solvent: CCCCCC
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1nc2oc(C)cc2c(=O)[nH]1

Procedure:
4-Chloro-2,6-dimethylfuro[2,3-d]pyrimidine (M).To a 50 mL flask was added 1.64 g (1 mmol) L and 10 mL POCl3. The resulting mixture was refluxed for 2 h, and the solvent was removed under reduced pressure to afford a dark residue. To this was added 30 mL of CHCl3 and 3 g of silica gel. The solvent was evaporated to afford a plug. Column chromatography of the plug with hexane:acetyl acetate=20:1 as eluent afford 1.55 g (85%) M as a yellow solid; Rf 0.26 (Hexane/EtOAC 15:1); 1H NMR (DMSO-d6) δ 2.48 (s, 3 H), 2.63 (s, 3 H), 6.77 (s, 1 H).
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]([F:25])([F:24])[C:7]([N:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]2[C:15]3[CH:16]=[C:17]([O:22]C)[CH:18]=[CH:19][C:20]=3[CH2:21][C@H:10]12)=[O:8].C([O-])([O-])=O.[K+].[K+].Cl>ClCCl>[F:25][C:6]([F:5])([F:24])[C:7]([N:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]2[C:15]3[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:20]=3[CH2:21][C@H:10]12)=[O:8]
Reactant: COc1ccc2c(c1)[C@H]1CCCN(C(=O)C(F)(F)F)[C@H]1C2
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: O=C(N1CCC[C@@H]2c3cc(O)ccc3C[C@@H]21)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Boron tribromide (1 mol/L in heptane, 27 mL) is added to a solution of 2,2,2-trifluoro-1-(cis-6-methoxy-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl)-ethanone (8.1 g) in dichloromethane (120 mL) chilled in an ice bath. The resulting mixture is warmed in the cooling bath to room temperature overnight. The solution is cooled again in an ice bath, diluted with dichloromethane (50 mL), and then 25% aqueous K2CO3 (20 mL) is carefully added. The mixture is stirred for 30 min and then acidified by the addition of 4 M aqueous hydrochloric acid (60 mL). The organic phase is separated, washed with 1 M aqueous hydrochloric acid (40 mL), and dried (MgSO4). The solvent is evaporated to give the title compound as a solid. Yield: 7.3 g (95% of theory); LC (method 1): tR=3.43 min; Mass spectrum (ESI+): m/z=286 [M+H]+.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:24]=[CH:23][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH:51]2[CH2:53][O:52]2)=[CH:45][CH:44]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH2:21]([NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:53][C@H:51]([OH:52])[CH2:50][O:49][C:46]3[CH:47]=[CH:48][C:43]([OH:42])=[CH:44][CH:45]=3)=[CH:24][CH:23]=2)[CH2:13][CH2:14]1)=[O:19])[CH3:22]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Solvent: O=CO
Product: CCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 26.7 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-ethyl-1-piperidinecarboxamide formate (0.336 g, 1.0 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.364 g, 0.90 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.17 g, 0.24 mmol).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=O)=[CH:21][CH:20]=1)#[N:18]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:23]([C:22]2[CH:26]=[CH:27][C:19]([C:17]#[N:18])=[CH:20][CH:21]=2)=[N:16][N:15]=1
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(C#N)cc2)o1
Yield: 30 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (1.09 mg, 5.00 mmol) was converted using 4-cyanobenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate=100:0 to 50:50, 490 mg, 30%) which was obtained as a white solid. MS: m/e=329.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.[Cl:13][C:14]1[CH:19]=[C:18]([S:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([O:8][C:15]2[CH:16]=[CH:17][C:18]([S:20]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)(=[O:21])=[O:22])=[CH:19][C:14]=2[Cl:13])[CH:7]=1
Reactant: O=S(=O)(Cc1ccc(F)cc1)c1ccc(F)c(Cl)c1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Product: O=C(O)Cc1cc(Cl)cc(Oc2ccc(S(=O)(=O)Cc3ccc(F)cc3)cc2Cl)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 18 step (iv) and the product from step (i).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[CH3:31][S:32][C:33]1[N:38]=[CH:37][C:36]([Sn](CCCC)(CCCC)CCCC)=[CH:35][N:34]=1.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:36]3[CH:35]=[N:34][C:33]([S:32][CH3:31])=[N:38][CH:37]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(SC)nc1
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2cnc(SC)nc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 39.2 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (80 mg, 0.17 mmol), 2-methylsulfanyl-5-tributylstannanyl-pyrimidine (143 mg, 0.34 mmol) and PdCl2(PPh3)2 (24 mg, 0.034 mmol) in 4 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and brine, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified twice by silica gel chromatography (0-5% EtOAc/CH2Cl2, then 5-50% EtOAc/hexanes+1% AcOH) to give 34 mg of the title compound. MS: (+) m/z 511.33 (M+1).
Reaction SMILES: Cl[C:2]([F:7])([F:6])[C:3]([O-])=O.[Na+].C(COC)OC.COCCOCCOC.[CH:24]1[CH:29]=[C:28]2C=[CH:31][C:32]3[C:37]([C:38](=[O:39])[C:27]2=[CH:26][CH:25]=1)=[CH:36][CH:35]=[CH:34][CH:33]=3>O>[F:6][C:2]1([F:7])[CH:31]2[CH:3]1[C:28]1[CH:29]=[CH:24][CH:25]=[CH:26][C:27]=1[C:38](=[O:39])[C:37]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=12
Reactant: O=c1c2ccccc2ccc2ccccc12
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: COCCOCCOC
Product: O=C1c2ccccc2C2C(c3ccccc31)C2(F)F

Procedure:
A solution of an alkali halodifluoroacetate such as sodium chlorodifluoroacetate in a solvent (for example, glyme, diglyme) is added over a period of 4 to 8 hours (preferably 6 hours) to a solution of dibenzosuberenone (for example in diglyme) with stirring and under nitrogen, maintaining the reaction temperature at 160°-165° C. Other reaction temperatures may be employed depending upon the reactants used, as described in Ciganek et al., “Imine Analogues of Tricyclic Antidepressants,” J. Med. Chem., 1981, 24,336-41; or in Coyne and Cusic, “Aminoalkyldibenzo[a,e]cyclopropa[c]cycloheptene Derivatives. A Series of Potent Antidepressants,” J. Med. Chem., 1974, Vol. 17, No. 1, 72-75. The reaction mixture is brought to room temperature, then poured into water and extracted (e.g., with diethylether or pentane). The 1,1-difluoro-1a,10b-dihydrodibenzo[a,e]cyclopropa[c]cyclohepten-6(1H)-one is isolated and purified by conventional means, for example, the organic phase is washed with water, dried (e.g., over Na2SO4), evaporated, and the residue is recrystallized (e.g., from ethanol, and optionally recrystallized again, e.g., from acetone/hexane).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:11]=1[C:12]([N:14]=[C:15]=[O:16])=[O:13]>C(#N)C>[Cl:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:11]=1[C:12]([NH:14][C:15]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:16])=[O:13]
Reactant: Nc1ccc(Br)cn1
Reactant: O=C=NC(=O)c1c(F)cccc1Cl
Solvent: CC#N
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(Br)cn1

Procedure:
An 0.4 g. portion of 5-bromo-2-aminopyridine was dissolved in 20 ml. of acetonitrile, and was reacted with 0.5 g. of 2-chloro-6-fluorobenzoyl isocyanate as described in Example 1. The yield was 0.5 g. of the desired product, m.p. 207°-213° C. Elemental analysis gave the following results:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[CH:30]([CH3:34])[NH:29][CH2:28][CH2:27]3)=[CH:18][N:17]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:29]3[CH2:28][CH2:27][C:26]4[C:31](=[CH:32][CH:33]=[C:24]([C:19]5[C:20]([O:22][CH3:23])=[N:21][C:16]([O:15][CH3:14])=[N:17][CH:18]=5)[CH:25]=4)[CH:30]3[CH3:34])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: COc1ncc(-c2ccc3c(c2)CCNC3C)c(OC)n1
Product: COc1ncc(-c2ccc3c(c2)CCN(C(=O)c2cc4ncc(Br)cn4n2)C3C)c(OC)n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(2,4-Dimethoxy-pyrimidin-5-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[O:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:25]2([OH:28])[CH2:26][CH2:27][O:22][CH2:23][CH2:24]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCOCC1
Reactant: Fc1cc(Br)cc(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2cc(F)cc(OCc3ccccc3)c2)CCOCC1
Temperature: -75 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
A solution of 3-benzyloxy-1-bromo-5-fluorobenzene (29.1 g) in 250 ml of tetrahydrofuran was cooled to about -75° C. and n-butyl lithium (1.6M in hexane, 65 ml) was added dropwise.. The mixture was stirred at about -75° C. for about 1 hour and a solution of tetrahydropyran-4-one (10.4 g) was added dropwise. The mixture was stirred at about -75° C. for about 1 more hour then allowed to warm to about 0° C. A saturated aqueous solution of ammonium chloride was added and the tetrahydrofuran was evaporated in vacuo. The residue was partitioned between water and ethyl acetate. The organic phase was separated and dried over sodium sulfate. The residue was purified by column chromatography on silica gel eluting with methylene chloride/hexanes to give 9.2 g of the title compound as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([C@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3C(OC(C)(C)C)=O)[S:10][CH:11]=2)=[CH:3][CH:2]=1.[ClH:24]>C(Cl)Cl.O1CCOCC1>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]([C@H:12]3[CH2:16][CH2:15][CH2:14][NH:13]3)[S:10][CH:11]=2)=[CH:5][CH:6]=1.[ClH:24]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nc(-c2ccncc2)cs1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1cc(-c2csc([C@H]3CCCN3)n2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 31-mg aliquot of crude product from Step 2 was dissolved in CH2Cl2 (3 mL) and 4 M HCl in dioxane (1 mL) was added. The mixture was stirred at rt for 2 h and concentrated to leave (R)-4-(pyridin-4-yl)-2-(pyrrolidin-2-yl)thiazole as its HCl salt (35 mg). LC-MS Method 1 tR=0.40 min, m/z=232.
Reaction SMILES: [C:1]([S:5]([CH2:8][C@@H:9]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:10]([NH:12][C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][N:36](C(OC(C)(C)C)=O)[CH:37]=1)[C:14]([NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C@H:19]([CH:21]1[CH2:23][CH2:22]1)[F:20])=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CO>[C:1]([S:5]([CH2:8][C@@H:9]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:10]([NH:12][C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)[C:14]([NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C@H:19]([CH:21]1[CH2:22][CH2:23]1)[F:20])=[O:15])=[O:11])(=[O:6])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1cnc(C[C@H](NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)C(=O)N[C@@H](CC2CCCCC2)[C@@H](O)[C@@H](F)C2CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](F)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
A mixture of 610 mg (0.8 mmol) of crude (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-3-fluoro-2-hydroxypropyl]-1-Boc-imidazole-4-propionamide and 110 mg (0.8 mmol) of potassium carbonate in 10 ml of methanol is stirred at room temperature under argon for 1 hour. Subsequently, 100 mg (1.9 mmol) of ammonium chloride are added. The mixture is stirred at room temperature for a further 15 minutes and thereafter evaporated under reduced pressure. The residue is dissolved in 20 ml of ethyl acetate and washed in succession with 10 ml of water and 10 ml of saturated sodium chloride solution. The aqueous phases are back-extracted twice with 20 ml of ethyl acetate. The pooled organic phases are dried over sodium sulphate and evaporated under reduced pressure. For purification, the residue (300 mg of a foam) is purified on 50 g of silica gel using a 9:1:0.1 mixture of methylene chloride, isopropanol and ammonia as the eluent. After lyophilization from dioxan there are obtained 95 mg of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-3-fluoro-2-hydroxypropyl]imidazole-4-propionamide as a colourless powder; MS: 633 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:25])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.Br[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:29](=[O:30])[O:28]1.[I-].[Na+].C(OC(C)C)(C)C>CN(C)C=O.O.C(N(CC)CC)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:25])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O:22][CH:27]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[C:29](=[O:30])[O:28]4)=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: O=C1OC(Br)c2ccccc21
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(N)n3)[C@H]2SC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Solvent: O
Product: C=CC1=C(C(=O)OC2OC(=O)c3ccccc32)N2C(=O)C(NC(=O)C(=O)c3csc(N)n3)[C@H]2SC1
Yield: 74.2 %

Procedure:
To a solution of 7-[(2-aminothiazol-4-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylic acid (1.0 g) in N,N-dimethylformamide (10 ml) were added triethylamine (0.27 g), 3-bromophthalide (0.56 g) and sodium iodide (0.39 g) at 10° C. with stirring, and the stirring was continued at the same temperature for half an hour. After the reaction mixture was poured into water (50 ml), it was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1 by volume). The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate, followed by evaporation to give an oil, which was pulverized with diisopropyl ether to obtain phthalid-3-yl 7-[(2-aminothiazol-4-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylate (1.0 g).